Publications by authors named "John Campbell"

731 Publications

Genetic analysis of dietary intake identifies new loci and functional links with metabolic traits.

Nat Hum Behav 2021 Aug 23. Epub 2021 Aug 23.

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Dietary intake is a major contributor to the global obesity epidemic and represents a complex behavioural phenotype that is partially affected by innate biological differences. Here, we present a multivariate genome-wide association analysis of overall variation in dietary intake to account for the correlation between dietary carbohydrate, fat and protein in 282,271 participants of European ancestry from the UK Biobank (n = 191,157) and Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 91,114), and identify 26 distinct genome-wide significant loci. Dietary intake signals map exclusively to specific brain regions and are enriched for genes expressed in specialized subtypes of GABAergic, dopaminergic and glutamatergic neurons. We identified two main clusters of genetic variants for overall variation in dietary intake that were differently associated with obesity and coronary artery disease. These results enhance the biological understanding of interindividual differences in dietary intake by highlighting neural mechanisms, supporting functional follow-up experiments and possibly providing new avenues for the prevention and treatment of prevalent complex metabolic diseases.
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http://dx.doi.org/10.1038/s41562-021-01182-wDOI Listing
August 2021

Weightbearing CT Analysis of the Transverse Tarsal Joint During Eversion and Inversion.

Foot Ankle Int 2021 Aug 11:10711007211034821. Epub 2021 Aug 11.

Institute for Foot and Ankle Reconstruction, Mercy Medical Center, Baltimore, MD, USA.

Background: Understanding of the movement and function of the transverse tarsal joint (TTJt) continues to evolve. Most studies have been done in cadavers or under nonphysiologic conditions. Weightbearing computed tomographic (WBCT) scans may provide more accurate information about the position of the TTJt when the hindfoot is in valgus or varus.

Methods: Five volunteers underwent bilateral weightbearing CT scans while standing on a platform that positioned both hindfeet in 20 degrees of valgus and 20 degrees of varus. Each bone of the foot was segmented, and the joint surfaces of the talus, calcaneus, cuboid, and navicular were identified. The principal axes for each joint surface were determined and used to calculate the angles and distances between the bones with the foot in valgus or varus.

Results: In the coronal plane, the angle between the talus and calcaneus rotated 17.1 degrees as the hindfoot moved from valgus to varus. The distance between the centers of the talus and calcaneus decreased 7.1 mm. The cuboid translated 3.9 mm medially relative to the calcaneus. There was no change in angle or distance between the cuboid and navicular. The navicular rotated 25.4 degrees into varus relative to the talus.

Conclusion: The TTJt locking mechanism was previously thought to occur from the talonavicular and calcaneocuboid joint axes moving from parallel to divergent as the hindfoot inverts. The current data show a more complex interaction between the four bones that comprise the TTJt and suggests that the locking mechanism may occur because of tightening of the ligaments and joint capsules.

Clinical Relevance: This study uses weight bearing CT scans of healthy, asymptomatic volunteers standing on valgus and varus platforms to characterize the normal motion of the transverse tarsal joint of the foot. A better understanding of how the transverse tarsal joint functions may assist clinicians in both the conservative and surgical management of hindfoot pathology.
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http://dx.doi.org/10.1177/10711007211034821DOI Listing
August 2021

The uptake of foil from needle and syringe provision services and its role in smoking or snorting heroin among people who inject drugs in Scotland.

Int J Drug Policy 2021 Jul 30;98:103369. Epub 2021 Jul 30.

School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, Scotland; Public Health Scotland, NHS National Services Scotland, Glasgow, Scotland.

Background: In the UK, legislation was implemented in 2014 allowing needle and syringe provision (NSP) services to offer foil to people who inject drugs (PWID) to encourage smoking rather than injecting. This paper aims to examine the association between foil uptake and smoking or snorting heroin among PWID. This is the first large scale national study to examine foil uptake and smoking or snorting heroin among PWID post legislative change.

Method: Data from 1453 PWID interviewed via Scotland's Needle Exchange Surveillance Initiative in 2017-2018 were analysed using multivariate logistic regression.

Results: Overall, 36% of PWID had obtained foil from NSP services in the past six months. The odds of smoking or snorting heroin were higher among those who had obtained foil (Adjusted Odds Ratio (AOR) 3.79 (95% CI 2.98-4.82) p<0.001) compared to those who had not. Smoking or snorting heroin was associated with lower odds of injecting four or more times daily (AOR 0.60 (95% CI 0.40-0.90) p = 0.012) and injecting into the groin or neck (AOR 0.57 (95% CI 0.46-0.71) p<0.001) but increased odds of having had a skin and soft tissue infection (SSTI) (AOR 1.49 (95% CI 1.17-1.89) p = 0.001) and having experienced an overdose (AOR 1.58 (95% CI 1.18-2.10) p = 0.002) both in the past year.

Conclusion: The promotion of smoking drugs via foil provision from NSP services may contribute to the package of harm reduction measures for PWID alongside the provision of injecting equipment. We found that those in receipt of foil were more likely to smoke or snort heroin, and that smoking or snorting heroin was associated with a lower likelihood of some risky injecting behaviours, namely frequent injecting and injecting into the groin or neck. But it remains uncertain if the provision of foil can lead to a reduction in health harms, such as SSTI and overdose. Future research is needed to understand PWID motivations for smoking drugs, obtaining foil from NSP services, and its uses particularly among polydrug users.
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http://dx.doi.org/10.1016/j.drugpo.2021.103369DOI Listing
July 2021

Association Between Graft Choice and 6-Year Outcomes of Revision Anterior Cruciate Ligament Reconstruction in the MARS Cohort.

Am J Sports Med 2021 08 14;49(10):2589-2598. Epub 2021 Jul 14.

University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Although graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome.

Hypothesis: In the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up.

Study Design: Cohort study; Level of evidence, 2.

Methods: Patients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery.

Results: A total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores ( = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized ( = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts ( = .87) or between BTB autografts and soft tissue allografts ( = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft ( = .010; OR, 0.56; 95% CI, 0.36-0.87).

Conclusion: BTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.
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http://dx.doi.org/10.1177/03635465211027170DOI Listing
August 2021

Biosecurity practices in western Canadian cow-calf herds and their association with animal health.

Can Vet J 2021 07;62(7):712-718

Department of Large Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan S7N 5B4 (Wennekamp, Waldner, Parker, Campbell); Department of Production Animal Health, University of Calgary Faculty of Veterinary Medicine, 11877 85th Street NW, Calgary, Alberta (Windeyer); Department of Agricultural and Resource Economics, College of Agriculture and Bioresources, University of Saskatchewan, 51 Campus Drive, Saskatoon, Saskatchewan S7N 5A8, Canada (Larson).

Biosecurity practices of beef cow-calf herds in western Canada have not been studied extensively nor is there a good understanding of their association with herd health. A survey was sent to 103 cow-calf producers of the Western Canadian Cow-Calf Surveillance Network. Eighty completed questionnaires were returned. Bulls were purchased for all herds during the 2014 to 2017 study period; 54% of herds purchased heifers and 42% purchased cows. The use of standard biosecurity practices was generally low with 30% of producers keeping purchased animals separate and 30% vaccinating new additions. None of the evaluated biosecurity practices were associated with reporting Johne's disease. The purchase of > 10 bulls, the purchase of cows, not vaccinating animals bought into the herd, and use of community pasture were associated with a bovine respiratory disease outbreak. Outbreaks of calf diarrhea were associated with the purchase of 10 or more bulls, the use of a community pasture, and leasing or sharing bulls.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218943PMC
July 2021

The Hallux Metatarsophalangeal Capsule: An Anatomic Study With Respect to Percutaneous Hallux Valgus Correction.

Foot Ankle Int 2021 Jun 30:10711007211027262. Epub 2021 Jun 30.

Mercy Medical Center, Institute of Foot and Ankle Reconstruction, Baltimore, MD, USA.

Background: Minimally invasive surgery for the treatment of hallux valgus deformities has become increasingly popular. Knowledge of the location of the hallux metatarsophalangeal (MTP) proximal capsular origin on the metatarsal neck is essential for surgeons in planning and executing extracapsular corrective osteotomies. A cadaveric study was undertaken to further study this anatomic relationship.

Methods: Ten nonpaired fresh-frozen frozen cadaveric specimens were used for this study. Careful dissection was performed, and the capsular origin of the hallux MTP joint was measured from the central portion of the metatarsal head in the medial, lateral, dorsal, plantarmedial, and plantarlateral dimensions.

Results: The ten specimens had a mean age of 77 years, with 5 female and 5 male. The mean distances from the central hallux metatarsal head to the MTP capsular origin were 15.2 mm dorsally, 8.4 mm medially, 9.6 mm laterally, 19.3 mm plantarmedially, and 21.0 mm plantarlaterally.

Conclusion: The MTP capsular origin at the hallux metatarsal varies at different anatomic positions. Knowledge of this capsular anatomy is critical for orthopedic surgeons when planning and performing minimally invasive distal metatarsal osteotomies for the correction of hallux valgus.

Type Of Study: Cadaveric Study.
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http://dx.doi.org/10.1177/10711007211027262DOI Listing
June 2021

Cytometric analysis of T cell phenotype using cytokine profiling for improved manufacturing of an EBV-specific T cell therapy.

Clin Exp Immunol 2021 Oct 14;206(1):68-81. Epub 2021 Jul 14.

Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Jack Copland Centre, Edinburgh, UK.

Adoptive immunotherapy using Epstein-Barr Virus (EBV)-specific T cells is a potentially curative treatment for patients with EBV-related malignancies where other clinical options have proved ineffective. We describe improved good manufacturing practice (GMP)-compliant culture and analysis processes for conventional lymphoblastoid cell line (LCL)-driven EBV-specific T cell manufacture, and describe an improved phenotyping approach for analysing T cell products. We optimized the current LCL-mediated clinical manufacture of EBV-specific T cells to establish an improved process using xenoprotein-free GMP-compliant reagents throughout, and compared resulting products with our previous banked T cell clinical therapy. We assessed effects of changes to LCL:T cell ratio in T cell expansion, and developed a robust flow cytometric marker panel covering T cell memory, activation, differentiation and intracellular cytokine release to characterize T cells more effectively. These data were analysed using a t-stochastic neighbour embedding (t-SNE) algorithm. The optimized GMP-compliant process resulted in reduced cell processing time and improved retention and expansion of central memory T cells. Multi-parameter flow cytometry determined the optimal protocol for LCL stimulation and expansion of T cells and demonstrated that cytokine profiling using interleukin (IL)-2, tumour necrosis factor (TNF)-α and interferon (IFN)-γ was able to determine the differentiation status of T cells throughout culture and in the final product. We show that fully GMP-compliant closed-process culture of LCL-mediated EBV-specific T cells is feasible, and profiling of T cells through cytokine expression gives improved characterization of start material, in-process culture conditions and final product. Visualization of the complex multi-parameter flow cytometric data can be simplified using t-SNE analysis.
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http://dx.doi.org/10.1111/cei.13640DOI Listing
October 2021

Assessing the Relevance of Solution Phase Stress Testing of Solid Dosage Form Drug Products: A Cross-Industry Benchmarking Study.

J Pharm Sci 2021 Jun 7. Epub 2021 Jun 7.

Baertschi Consulting LLC, Carmel, IN 46033, USA.

Stress testing (also known as forced degradation) of pharmaceutical products has long been recognized as a critical part of the drug development process, providing foundational information related to intrinsic stability characteristics and to the development of stability-indicating analytical methods. A benchmarking study was undertaken by nine pharmaceutical companies and the Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária, or ANVISA) with a goal of understanding the utility of various stress testing conditions for producing pharmaceutically-relevant chemical degradation of drugs. Special consideration was given to determining whether solution phase stress testing of solid drug products produced degradation products that were both unique when compared to other stress conditions and relevant to the formal drug product stability data. The results from studies of 62 solid dosage form drug products were compiled.  A total of 387 degradation products were reported as being observed in stress testing studies, along with 173 degradation products observed in accelerated and/or long-term stability studies for the 62 drug products.  Among these, 25 of the stress testing degradation products were unique to the solution phase stress testing of the drug products; however, none of these unique degradation products were relevant to the formal stability data. The relevant degradation products were sufficiently accounted for by stress testing studies that included only drug substance stressing (in solution and in the solid state) and drug product stressing (in the solid state). Based on these results, it is the opinion of the authors that for solid dosage form drug products, well-designed stress testing studies need not include solution phase stress testing of the drug product in order to be comprehensive.
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http://dx.doi.org/10.1016/j.xphs.2021.06.012DOI Listing
June 2021

Highly selective brain-to-gut communication via genetically defined vagus neurons.

Neuron 2021 07 1;109(13):2106-2115.e4. Epub 2021 Jun 1.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

The vagus nerve innervates many organs, and most, if not all, of its motor fibers are cholinergic. However, no one knows its organizing principles-whether or not there are dedicated neurons with restricted targets that act as "labeled lines" to perform certain functions, including two opposing ones (gastric contraction versus relaxation). By performing unbiased transcriptional profiling of DMV cholinergic neurons, we discovered seven molecularly distinct subtypes of motor neurons. Then, by using subtype-specific Cre driver mice, we show that two of these subtypes exclusively innervate the glandular domain of the stomach where, remarkably, they contact different enteric neurons releasing functionally opposing neurotransmitters (acetylcholine versus nitric oxide). Thus, the vagus motor nerve communicates via genetically defined labeled lines to control functionally unique enteric neurons within discrete subregions of the gastrointestinal tract. This discovery reveals that the parasympathetic nervous system utilizes a striking division of labor to control autonomic function.
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http://dx.doi.org/10.1016/j.neuron.2021.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273126PMC
July 2021

Reply.

Ophthalmology 2021 Aug 10;128(8):e41. Epub 2021 May 10.

National Eye Institute| National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.ophtha.2021.04.011DOI Listing
August 2021

Histologic, immunohistochemical, and scanning electron microscopic comparison of pre-iridal monocellular and fibrovascular membranes in normal and glaucomatous canine globes.

Vet Ophthalmol 2021 Apr 27. Epub 2021 Apr 27.

Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada.

Objectives: (i) To evaluate immunohistochemical labeling of pre-iridal monocellular and fibrovascular membranes and (ii) describe the light and scanning electron microscopic (SEM) characteristics of these membranes in glaucomatous and normal/control canine globes.

Materials And Methods: All globes were evaluated with light microscopy. Immunohistochemical labeling for CD18, Smooth muscle actin (SMA), and CD117 was completed on 40 canine globes with congenital/anterior segment dysgenesis-associated glaucoma (n = 10), primary/goniodysgenesis-associated glaucoma (n = 10), secondary glaucoma (n = 10), and normal/control globes (n = 10). SEM was completed on 10 globes: 5 with monocellular membranes, 3 with fibrovascular membranes, and 2 without a histologically detectable membrane.

Results: Monocellular membranes were detected in all normal/control globes with light microscopy and appeared to be morphologically very similar to those in diseased globes. CD18 labeling was detected in 9/10 monocellular membranes in normal/control globes, 15/23 monocellular, and 7/8 fibrovascular membranes in globes with glaucoma. SMA and CD117 labeling was not detected in monocellular membranes of normal/control globes. SMA was expressed in 10/23 monocellular and 7/8 fibrovascular membranes of glaucomatous globes. CD117 was expressed in 7/23 monocellular and 5/8 fibrovascular membranes of glaucomatous globes. SEM of monocellular membranes revealed a continuous sheet of mostly spindle cells and few individual round cells that extended over the anterior iris face in normal/control and all glaucomatous globes.

Conclusion: Pre-iridal monocellular membranes are a normal component of the anterior iris surface, and CD18 immunoreactivity suggests some cells within these are of leukocytic origin. SMA and CD117 labeling of monocellular membranes in glaucomatous, but not normal/control globes, suggest metaplastic cellular change secondary to intraocular pathology related to glaucoma.
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http://dx.doi.org/10.1111/vop.12894DOI Listing
April 2021

Educational Case: Giant Cell Tumor of the Bone in Both the Axial and Appendicular Skeleton.

Acad Pathol 2021 Jan-Dec;8:23742895211008657. Epub 2021 Apr 9.

Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA, USA.

http://journals.sagepub.com/doi/10.1177/2374289517715040..
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http://dx.doi.org/10.1177/23742895211008657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040597PMC
April 2021

CpG-adjuvanted stable prefusion SARS-CoV-2 spike protein protected hamsters from SARS-CoV-2 challenge.

Sci Rep 2021 04 22;11(1):8761. Epub 2021 Apr 22.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

The COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 µg or 5 µg of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 μg or 5 μg of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.
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http://dx.doi.org/10.1038/s41598-021-88283-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062487PMC
April 2021

Chemokines and their receptors: predictors of the therapeutic potential of mesenchymal stromal cells.

J Transl Med 2021 04 17;19(1):156. Epub 2021 Apr 17.

Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.

Multipotent mesenchymal stromal cells (MSCs) are promising cellular therapeutics for the treatment of inflammatory and degenerative disorders due to their anti-inflammatory, immunomodulatory and regenerative potentials. MSCs can be sourced from a variety of tissues within the body, but bone marrow is the most frequently used starting material for clinical use. The chemokine family contains many regulators of inflammation, cellular function and cellular migration-all critical factors in understanding the potential potency of a novel cellular therapeutic. In this review, we focus on expression of chemokine receptors and chemokine ligands by MSCs isolated from different tissues. We discuss the differential migratory, angiogenetic and immunomodulatory potential to understand the role that tissue source of MSC may play within a clinical context. Furthermore, this is strongly associated with leukocyte recruitment, immunomodulatory potential and T cell inhibition potential and we hypothesize that chemokine profiling can be used to predict the in vivo therapeutic potential of MSCs isolated from new sources and compare them to BM MSCs.
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http://dx.doi.org/10.1186/s12967-021-02822-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052819PMC
April 2021

Perceptions of Peer Support for Victim-Survivors of Sexual Violence and Abuse: An Exploratory Study With Key Stakeholders.

J Interpers Violence 2021 Apr 15:8862605211007931. Epub 2021 Apr 15.

University of Bristol, UK.

Experiences of sexual violence, childhood sexual abuse, and sexual assault are common across all societies. These experiences damage physical and mental health, coping ability, and relationships with others. Given the breadth and magnitude of impacts, it is imperative that there are effective, accessible services to support victim-survivors, ease suffering, and empower people to cope, recover and thrive. Service provision for this population in the United Kingdom is complex and has been hit substantially by austerity. Since positive social support can buffer against negative impacts, peer support may be an effective approach. The aim of this exploratory study was to capture the views and perspectives of professional stakeholders concerning service provision for victim-survivors, particularly perceptions of peer support.In-depth semistructured interviews were conducted in the UK during 2018 with six professional stakeholders, highly experienced in the field of service provision for victim-survivors of sexual violence and abuse. An abductive approach to analysis was used, applying principles from thematic analysis. Our sample comprised four females and two males, and their roles included psychiatrist, general practitioner, service improvement facilitator, and senior positions within victim-survivor organizations.Interviews highlighted models of peer support for this population, good practice and safety considerations, and a lack of uniformity regarding quality and governance standards across the sector. Findings indicated that current funding models impact negatively on victim-survivor services, and that provision is fragmented and insufficient across statutory and not-for-profit sectors. The influence of the medical model upon service provision was evident, which resulted in apprehension around support delivered in less-usual forms-including peer support. Further research is needed to explore the potential of peer support for victim-survivors of sexual violence and abuse.
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http://dx.doi.org/10.1177/08862605211007931DOI Listing
April 2021

Does exercise attenuate age- and disease-associated dysfunction in unconventional T cells? Shining a light on overlooked cells in exercise immunology.

Eur J Appl Physiol 2021 Jul 6;121(7):1815-1834. Epub 2021 Apr 6.

Department for Health, University of Bath, Bath, UK.

Unconventional T Cells (UTCs) are a unique population of immune cells that links innate and adaptive immunity. Following activation, UTCs contribute to a host of immunological activities, rapidly responding to microbial and viral infections and playing key roles in tumor suppression. Aging and chronic disease both have been shown to adversely affect UTC numbers and function, with increased inflammation, change in body composition, and physical inactivity potentially contributing to the decline. One possibility to augment circulating UTCs is through increased physical activity. Acute exercise is a potent stimulus leading to the mobilization of immune cells while the benefits of exercise training may include anti-inflammatory effects, reductions in fat mass, and improved fitness. We provide an overview of age-related changes in UTCs, along with chronic diseases that are associated with altered UTC number and function. We summarize how UTCs respond to acute exercise and exercise training and discuss potential mechanisms that may lead to improved frequency and function.
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http://dx.doi.org/10.1007/s00421-021-04679-4DOI Listing
July 2021

A Personal View of Microstructure and Properties of Al Alloys.

Authors:
John Campbell

Materials (Basel) 2021 Mar 8;14(5). Epub 2021 Mar 8.

School of Metallurgy and Materials, Engineering Faculty, University of Birmingham, Birmingham B15 2TT, UK.

This paper presents a personal view by the author of the role of bifilms in Al alloys. The mantra 'microstructure determines properties' is widely accepted as a truism, but is here critically assessed and found wanting. The case is made that bifilms from the casting process, while often invisible in the microstructure, are usually at least as important, if not of far greater importance, because they are often present as a dense population of cracks throughout the metal. The bifilm population controls the morphology of many features of cast and wrought structures. For cast alloys, bifilm control of pore morphology and Si morphology in Al-Si alloys is discussed, as is dendrite arm spacing (DAS). The tensile property benefits of grain refinement are seen to be mainly bifilm controlled. The properties ductility and fatigue appear to be especially dominated by bifilm content, as are invasive corrosion processes such as pitting, intergranular corrosion, hydrogen blistering and cracking. Bifilm control is proposed as a new concept permitting the improvement and control of metallurgical properties.
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http://dx.doi.org/10.3390/ma14051297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962965PMC
March 2021

Endovascular therapy for large iatrogenic inferior epigastric pseudoaneurysm.

J Vasc Surg 2021 Apr;73(4):1436-1437

Charleston Division, Department of Vascular and Endovascular Surgery, West Virginia University and CAMC Health Education and Research Institute, Charleston, WV. Electronic address:

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http://dx.doi.org/10.1016/j.jvs.2020.08.123DOI Listing
April 2021

Neurodevelopmental outcomes in preterm infants with retinopathy of prematurity.

Surv Ophthalmol 2021 Sep-Oct;66(5):877-891. Epub 2021 Mar 2.

Casey Eye Institute, Department of Ophthalmology, Oregon Health and Science University, Portland, OR, USA. Electronic address:

Over the past decade there has been a paradigm shift in the treatment of retinopathy of prematurity (ROP) with the introduction of antivascular endothelial growth factor (anti-VEGF) treatments. Anti-VEGF agents have the advantages of being easier to administer, requiring less anesthesia, having the potential for improved peripheral vision, and producing less refractive error than laser treatment. On the other hand, it is known that intravitreal administration of anti-VEGF agents lowers VEGF levels in the blood and raises the theoretical concern of intraocular anti-VEGF causing deleterious effects in other organ systems, including the brain. As a result, there has been increased attention recently on neurodevelopmental outcomes in infants treated with anti-VEGF agents. These studies should be put into context with what is known about systemic comorbidities, socioeconomic influences, and the effects of extreme prematurity itself on neurodevelopmental outcomes. We summarize what is known about neurodevelopmental outcomes in extremely preterm infants with ROP, discuss the implications for determining the neurodevelopmental status using neurodevelopmental testing as well as other indicators, and review the existing literature relating to neurodevelopmental outcomes in babies treated for ROP.
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http://dx.doi.org/10.1016/j.survophthal.2021.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351023PMC
March 2021

Simulation of the effects of forest harvesting under changing climate to inform long-term sustainable forest management using a biogeochemical model.

Sci Total Environ 2021 May 28;767:144881. Epub 2021 Jan 28.

Department of Civil and Environmental Engineering, Syracuse University, 151 Link Hall, Syracuse, NY 13244, USA.

Process ecosystem models are useful tools to provide insight on complex, dynamic ecological systems, and their response to disturbances. The biogeochemical model PnET-BGC was modified and tested using field observations from an experimentally whole-tree harvested northern hardwood watershed (W5) at the Hubbard Brook Experimental Forest (HBEF), New Hampshire, USA. In this study, the confirmed model was used as a heuristic tool to investigate long-term changes in hydrology, biomass accumulation, and soil solution and stream water chemistry for three different watershed cutting intensities (40%, 60%, 80%) and three rotation lengths (30, 60, 90 years) under both constant (current climate) and changing (MIROC5-RCP4.5) future climate scenarios and atmospheric CO through the year 2200. For the no future cutting scenario, total ecosystem stored carbon (i.e., sum of aboveground biomass, woody debris and soil) reached a maximum value of 207 t C ha under constant climate but increased to 452 t C ha under changing climate in 2200 due to a CO fertilization effect. Harvesting of trees decreased total ecosystem stored carbon between 7 and 36% for constant climate and 7-60% under changing climate, respectively, with greater reductions for shorter logging rotation lengths and greater watershed cutting intensities. Harvesting under climate change resulted in noticeable losses of soil organic matter (12-56%) coinciding with loss of soil nutrients primarily due to higher rates of soil mineralization associated with increases in temperature, compared with constant climate conditions (3-22%). Cumulative stream leaching of nitrate under climate change (181-513 kg N ha) exceeded constant climate values (139-391 kg N ha) for the various cutting regimes. Under both climate conditions the model projected greater sensitivity to varying the length of cutting period than cutting intensities. Hypothetical model simulations highlight future challenges in maintaining long-term productivity of managed forests under changing climate due to a potential for a deterioration of soil fertility.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144881DOI Listing
May 2021

Can effective supervised pelvic floor muscle training be provided by primary care nurses? A randomized controlled trial.

Int Urogynecol J 2021 Oct 23;32(10):2717-2725. Epub 2021 Feb 23.

Urogynaecology Unit, University Hospitals Plymouth NHS Trust, Plymouth, PL6 8DH, UK.

Introduction And Hypothesis: To determine whether primary care nurses with no prior experience can, after training, provide effective supervised pelvic floor muscle training (PFMT) by a three-group parallel randomized controlled trial (RCT): primary care nurse, urogynaecology nurse specialist and controls undertaken in 11 primary care/general practices, covering urban and rural settings in SW England. The sample consisted of 337 women with weak pelvic floor muscles (Modified Oxford Score 2 or less) in a randomly sampled survey.

Methods: Following detailed instruction and training, primary care nurses recruited patients who were randomized to PFMT provided by them, a urogynaecology nurse specialist or a 'no training' control group. The primary outcome measure to assess the effectiveness of training was pelvic floor muscle strength as measured by perineometry.

Results: Two hundred forty women aged 19 to 76 (median 49) years were recruited. After 3 months there was an increase in strength in both intervention groups compared with controls: median differences (95% CI) were 3.0 (0.3, 6.0) cmHO higher for the primary care nurse group (n = 50) compared to the control group (n = 56; p = 0.02) and 4.3 (1.0, 7.3) cmHO for the urogynaecology nurse specialist group (n = 53) compared to control (p < 0.01); there was no difference between the primary care nurse and urogynaecology nurse specialist groups [1.3 (-2.0,4.7; p = 0.70].

Conclusions: PFMT provided by trained primary care nurses achieved improvements in pelvic floor muscle strength compared with controls (and comparable to that of a urogynaecology nurse specialist). This could have implications for the provision of PFMT for all women and potentially help in the prevention of pelvic floor dysfunction.

Trial Registration: Registered with ClinicalTrials.gov; Identifier NCT01635894. This was done retrospectively to conform to current registration requirements. When the trial commenced (2003), there was no requirement to register; this was introduced in 2005. The International Committee of Medical Journal Editors (ICMJE) decided that from July 1, 2005, no trials would be considered for publication unless they are included on a clinical trials registry, hence the retrospective registration.
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http://dx.doi.org/10.1007/s00192-021-04692-3DOI Listing
October 2021

A Phenomic Perspective on Factors Influencing Breast Cancer Treatment: Integrating Aging and Lifestyle in Blood and Tissue Biomarker Profiling.

Front Immunol 2020 1;11:616188. Epub 2021 Feb 1.

Department for Health, University of Bath, Bath, United Kingdom.

Breast cancer is the most common malignancy among women worldwide. Over the last four decades, diagnostic and therapeutic procedures have improved substantially, giving patients with localized disease a better chance of cure, and those with more advanced cancer, longer periods of disease control and survival. However, understanding and managing heterogeneity in the clinical response exhibited by patients remains a challenge. For some treatments, biomarkers are available to inform therapeutic options, assess pathological response and predict clinical outcomes. Nevertheless, some measurements are not employed universally and lack sensitivity and specificity, which might be influenced by tissue-specific alterations associated with aging and lifestyle. The first part of this article summarizes available and emerging biomarkers for clinical use, such as measurements that can be made in tumor biopsies or blood samples, including so-called liquid biopsies. The second part of this article outlines underappreciated factors that could influence the interpretation of these clinical measurements and affect treatment outcomes. For example, it has been shown that both adiposity and physical activity can modify the characteristics of tumors and surrounding tissues. In addition, evidence shows that inflammaging and immunosenescence interact with treatment and clinical outcomes and could be considered prognostic and predictive factors independently. In summary, changes to blood and tissues that reflect aging and patient characteristics, including lifestyle, are not commonly considered clinically or in research, either for practical reasons or because the supporting evidence base is developing. Thus, an aim of this article is to encourage an integrative phenomic approach in oncology research and clinical management.
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http://dx.doi.org/10.3389/fimmu.2020.616188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882710PMC
June 2021

Do Independent Living Services Protect Youth Aging Out Foster Care From Adverse Outcomes? An Evaluation Using National Data.

Child Maltreat 2021 Feb 10:1077559521992119. Epub 2021 Feb 10.

School of Social Work, Robert Stempel College of Public Health and Social Work, 5450Florida International University, Miami, FL, USA.

Objective: Youth aging out foster care are at high risk of experiencing adverse outcomes. Federal funded programs have provided independent living services (ILSs) to these youth. This study evaluated the effectiveness of the continuity of ILSs at ages 17-19 in protecting youth aging out foster care from homelessness and incarceration at ages 19-21.

Method: This study used data on 4,853 foster youth from the National Youth in Transition Database and the Adoption and Foster Care Analysis and Reporting System. Logistic regression was used to regress two binary outcomes on seven ILS variables and covariates.

Results: The results suggest that remaining in foster care, continuous receipts of academic support, and financial assistance services at ages 17-19 protected foster youth from experiencing homelessness. Remaining in foster care and continuous receipt of financial assistance services at ages 17-19 protected foster youth from incarceration at ages 19-21. But, surprisingly, continuous receipt of housing education and home management training, and health education and risk prevention training at ages 17-19 were each associated with increased risk of homelessness at ages 19-21. The results also showed statistically significant effects of several covariates.

Conclusion: Implications are provided based on the importance of financial assistance and academic support services.
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http://dx.doi.org/10.1177/1077559521992119DOI Listing
February 2021

Effect of comorbid migraine on propranolol efficacy for painful TMD in a randomized controlled trial.

Cephalalgia 2021 06 9;41(7):839-850. Epub 2021 Feb 9.

Center for Pain Research and Innovation, Adams School of Dentistry, 2331University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Introduction: The migraine-preventive drug propranolol is efficacious in reducing pain from temporomandibular disorder, suggesting potential modifying or mediating effects of comorbid migraine.

Methods: In this randomized controlled trial, myofascial temporomandibular disorder patients were treated with propranolol or placebo for 9 weeks. The primary endpoint was change in a facial pain index derived from daily symptom diaries. Linear and logistic regression models tested for a migraine × treatment-group interaction in reducing facial pain index. Counterfactual models explored changes in headache impact and heart rate as mediators of propranolol's efficacy.

Results: Propranolol's efficacy in reducing facial pain index was greater among the 104 migraineurs than the 95 non-migraineurs: For example, for the binary ≥ 30% reduction in facial pain index, odds ratios were 3.3 (95% confidence limits: 1.4, 8.1) versus 1.3 (0.5, 3.2), respectively, although the interaction was statistically non-significant ( = 0.139). Cumulative response curves confirmed greater efficacy for migraineurs than non-migraineurs (differences in area under the curve 26% and 6%, respectively;  = 0.081). While 9% of the treatment effect was mediated by reduced headache impact, 46% was mediated by reduced heart rate.

Conclusions: Propranolol was more efficacious in reducing temporomandibular disorder pain among migraineurs than non-migraineurs, with more of the effect mediated by reduced heart rate than by reduced headache impact.

Study Identification And Registration: SOPPRANO; NCT02437383; https://clinicaltrials.gov/ct2/show/NCT02437383.
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http://dx.doi.org/10.1177/0333102421989268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166404PMC
June 2021

Rapid GMP-Compliant Expansion of SARS-CoV-2-Specific T Cells From Convalescent Donors for Use as an Allogeneic Cell Therapy for COVID-19.

Front Immunol 2020 8;11:598402. Epub 2021 Jan 8.

Tissues, Cells and Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh, United Kingdom.

COVID-19 disease caused by the SARS-CoV-2 virus is characterized by dysregulation of effector T cells and accumulation of exhausted T cells. T cell responses to viruses can be corrected by adoptive cellular therapy using donor-derived virus-specific T cells. One approach is the establishment of banks of HLA-typed virus-specific T cells for rapid deployment to patients. Here we show that SARS-CoV-2-exposed blood donations contain CD4 and CD8 memory T cells which recognize SARS-CoV-2 spike, nucleocapsid and membrane antigens. Peptides of these antigens can be used to isolate virus-specific T cells in a GMP-compliant process. The isolated T cells can be rapidly expanded using GMP-compliant reagents for use as an allogeneic therapy. Memory and effector phenotypes are present in the selected virus-specific T cells, but our method rapidly expands the desirable central memory phenotype. A manufacturing yield ranging from 10 to 10 T cells can be obtained within 21 days culture. Thus, multiple therapeutic doses of virus-specific T cells can be rapidly generated from convalescent donors for potential treatment of COVID-19 patients.
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http://dx.doi.org/10.3389/fimmu.2020.598402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819874PMC
February 2021

ACL Study Group survey reveals the evolution of anterior cruciate ligament reconstruction graft choice over the past three decades.

Knee Surg Sports Traumatol Arthrosc 2021 Jan 24. Epub 2021 Jan 24.

Department of Orthopaedic Surgery, Stanford University Medical Center, Palo Alto, CA, USA.

Purpose: Anterior cruciate ligament reconstruction (ACLR) aims to restore knee function and stability, allowing patients to return to the activities they enjoy and minimize further injury to the meniscus and cartilage and their ultimate progression to osteoarthritis. This study aims to present the evolution of graft choice over the last three decades according to members of the ACL Study Group (SG).

Methods: Prior to the January 2020 ACL SG biannual meeting, a survey was administered consisting of 87 questions and 16 categories, including ACLR graft choice. A similar questionnaire has been administered prior to each meeting and survey results from the past 14 meetings (1992 through 2020, excluding 1994) are included in this work. Survey responses are reported as frequencies in percentages to quantify changes in practice over the surgery period.

Results: In 1992, the most frequent graft choice for primary ACLR was bone-patellar tendon-bone (BTB) autograft, at nearly 90%. Hamstring tendon (HT) autografts have increased in popularity, currently over 50%, followed by just under 40% BTB autograft. Recently, quadriceps tendon (QT) autograft has increased in popularity since 2014.

Conclusion: Autograft (HT, BTB, QT) is an overwhelming favorite for primary ACLR over allograft. The preference for HT autograft increased over the study period relative to BTB autograft, with QT autograft gaining in popularity in recent years. Graft selection should be individualized for each patient and understanding the global trends in graft choice can help orthopaedic surgeons discuss graft options with their patients and determine the appropriate graft for each case.

Level Of Evidence: Level V, Expert Opinion.
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http://dx.doi.org/10.1007/s00167-021-06443-9DOI Listing
January 2021

Evaluation of bovine respiratory syncytial virus (BRSV) and bovine herpesvirus (BHV) specific antibody responses between heterologous and homologous prime-boost vaccinated western Canadian beef calves.

Can Vet J 2021 01;62(1):37-44

Department of Large Animal Clinical Sciences (Erickson, Berenik, Campbell, Gow, Waldner), Department of Microbiology (Lacoste, Ellis), Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan S7N 5B4; Department of Animal and Poultry Science, College of Agriculture and Bioresources, University of Saskatchewan, 51 Campus Drive, Saskatoon, Saskatchewan S7N 5A8 (Lardner).

Bovine respiratory disease (BRD) is an economically important cause of morbidity and mortality in beef calves. Control of BRD is most often addressed through "homologous" vaccination utilizing the same injectable modified-live viral (MLV) vaccine for both priming and boosting. Heterologous prime-boosting uses different routes and antigenic forms for priming and boosting. Three vaccine protocols were compared: an injectable (IJ) MLV (IJ-MLV) group (IJ-MLV priming at ~48 days and boosted with IJ-MLV at weaning), intranasal (IN) MLV (IN-MLV) group (intranasal priming with MLV at ~24 hours, boosted twice with an IJ-MLV), and intranasal killed viral (IN-KV) group (primed with an IN-MLV at ~24 hours, boosted twice with an IJ-KV). Serum antibody concentrations determined by enzyme-linked immunosorbent assays (ELISAs) were compared and the IN-KV group had significantly higher BRSV-specific antibody concentrations after boosting compared with the 2 homologous groups. No differences in BHV-specific antibody concentrations were observed between any of the groups.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739395PMC
January 2021

LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action.

Am J Physiol Endocrinol Metab 2020 Dec 28. Epub 2020 Dec 28.

Endocrinology, Beth Israel Deaconess Medical Center, United States.

Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. LRP1 also regulates energy balance in the hypothalamus by mediating leptin's anorexigenic action, although the underlying neurocircuitry involved is still unclear. Because GABAergic neurons are a major mediator of hypothalamic leptin action, we studied the role of GABAergic LRP1 in energy balance and leptin action using mice lacking LRP1 in Vgat- or AgRP-expressing neurons (Vgat-Cre; LRP1 or AgRP-Cre; LRP1). Here we show that LRP1 deficiency in GABAergic neurons results in severe obesity in male and female mice fed a normal chow diet. This effect is most likely due to increased food intake and decreased energy expenditure and locomotor activity. Increased adiposity in GABAergic neuron-specific LRP1-deficient mice is accompanied by hyperleptinemia and hyperinsulinemia. Insulin resistance and glucose intolerance in these mice are occurred without change in body weight. Importantly, LRP1 in GABAergic neurons is not required for leptin action, as evidenced by normal leptin's anorexigenic action and leptin-induced hypothalamic Stat3 phosphorylation. In contrast, LRP1 deficiency in AgRP neurons has no effect on adiposity and caloric intake. In conclusion, our data identify GABAergic neurons as a key neurocircuitry that underpins LRP1-dependent regulation of systemic energy balance and body-weight homeostasis. We further find that the GABAergic LRP1 signaling pathway modulates food intake and energy expenditure independently of leptin signaling and AgRP neurons.
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http://dx.doi.org/10.1152/ajpendo.00399.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260358PMC
December 2020

Vitamin D and COVID-19 in older age: evidence versus expectations.

Br J Gen Pract 2021 01 28;71(702):10-11. Epub 2020 Dec 28.

Primary Care Research Group, Institute of Health Services Research, University of Exeter Medical School, Exeter.

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http://dx.doi.org/10.3399/bjgp21X714377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759342PMC
January 2021
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