Publications by authors named "Ian Smith"

707 Publications

The experiences of therapists providing psychological treatment for adults with depression and intellectual disabilities as part of a randomised controlled trial.

J Appl Res Intellect Disabil 2021 Apr 7. Epub 2021 Apr 7.

Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK.

Background: Health professionals were trained to deliver adapted psychological interventions for depression to people with learning disabilities and depression alongside a supporter. Exploring the delivery of psychological interventions can help increase access to therapy.

Method: Twenty-seven participants took part in six focus groups, and the data were subject to a Framework Analysis.

Results: The structure and focus of the manualised therapies, and the use of specific techniques were perceived as key to service-user engagement. Supporters' involvement was valued by therapists if they had a good relationship and regular contact with the individual they supported. Regular clinical supervision was regarded as vital in understanding their role, assessing progress and delivering the interventions.

Conclusions: The findings highlight that health professionals can embrace a focussed therapeutic role and increase access to psychological therapies for people with intellectual disabilities.
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http://dx.doi.org/10.1111/jar.12886DOI Listing
April 2021

Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D).

Eur J Cancer 2021 Mar 22;148:287-296. Epub 2021 Mar 22.

Institute Jules Bordet and l' Université Libre de Bruxelles (U.L.B), Brussels, Belgium.

Aim: To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial.

Patients And Methods: 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac).

Results: At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74-1.00) for L+T versus T and 0.93 (95% CI, 0.81-1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T versus T and 0.88 (95% CI, 0.71-1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS% = 83% versus79%)] subgroups.

Conclusion: T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer.

Trial Registration: clinicaltrials.gov Identifier NCT00490139.
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http://dx.doi.org/10.1016/j.ejca.2021.01.053DOI Listing
March 2021

Methodological Priorities for Patient Preferences Research: Stakeholder Input to the PREFER Public-Private Project.

Patient 2021 Mar 15. Epub 2021 Mar 15.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Julius Centrum, STR 6.131, PO Box 85500, 3508 GA, Utrecht, The Netherlands.

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http://dx.doi.org/10.1007/s40271-021-00502-6DOI Listing
March 2021

Patient Preferences in Rare Diseases: A Qualitative Study in Neuromuscular Disorders to Inform a Quantitative Preference Study.

Patient 2021 Feb 27. Epub 2021 Feb 27.

Translational and Clinical Research Institute, Newcastle University, Newcastle-Upon-Tyne, UK.

Introduction: It has become increasingly important to include patient preference information in decision-making processes for drug development. As neuromuscular disorders represent multisystem, debilitating, and progressive rare diseases with few treatment options, this study aimed to explore unmet health care needs and patient treatment preferences for two neuromuscular disorders, myotonic dystrophy type 1 (DM1) and mitochondrial myopathies (MM) to inform early stages of drug development.

Methods: Fifteen semi-structured interviews and five focus group discussions (FGDs) were held with DM1 and MM adult patients and caregivers. Topics discussed included (1) reasons for study participation; (2) disease signs/symptoms and their impact on daily lives; (3) top desired benefits; and (4) acceptability of risks and tolerance levels for a hypothetical new treatment. Data were analyzed following a thematic 'code' approach.

Results: A total of 52 participants representing a wide range of disease severities participated. 'Muscle strength' and 'energy and endurance' were the disease-related unmet needs most often mentioned. Additionally, improved 'balance', 'cognition' and 'gut function' were the top desired treatment benefits, while 'damage to the liver, kidneys or eyes' was the most concerning risk. Factors influencing their tolerance to risks related to previously having experienced the risk and differentiation between permanent and temporary risks. A few differences were elicited between patients and caregivers.

Conclusions: This qualitative study provided an open forum to elicit treatment-desired benefits and acceptable risks to be established by patients themselves. These findings can inform decisions for developing new treatments and the design of clinical trials for DM1 and MM.
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http://dx.doi.org/10.1007/s40271-020-00482-zDOI Listing
February 2021

In vitro invasiveness and antimicrobial resistance of Salmonella enterica subspecies isolated from wild and captive reptiles.

Zoonoses Public Health 2021 Mar 2. Epub 2021 Mar 2.

Adelaide Zoo, Zoos South Australia, SA, Australia.

Reptiles are carriers of Salmonella and can intermittently shed bacteria in their faeces. Contact with snakes and lizards is a source of human salmonellosis. Here, two populations of reptiles, wild and captive were surveyed for Salmonella. One hundred thirty wild-caught reptiles were sampled for Salmonella including 2 turtle, 9 snake and 31 lizard species. Fifty-two of 130 (40%) animals were Salmonella positive: one of 5 (20%) turtles, 7 of 14 (50%) snakes and 44 of 111 (39.6%) lizards. One hundred twenty-two reptiles were sampled from a zoo collection including 1 turtle, 6 tortoise, 9 lizard, 14 snake and 1 crocodile species. Forty-two of 122 (34.4%) captive reptiles sampled were Salmonella positive. Salmonella was most commonly isolated from lizards and snakes. Fifteen serotypes were identified from zoo and 19 from wild-caught reptiles and most were members of subspecies enterica (I), salamae (II), arizonae (IIIa) or diarizonae (IIIb). Antimicrobial susceptibility testing was conducted on all Salmonella isolates; only two exhibited resistance, a Salmonella subsp. (II) ser. 21:z :z (Wandsbek) isolate cultured from a wild-caught reptile and a Salmonella Typhimurium DT120 isolated from a captive snake. The invasive capacity of reptile-associated Salmonella strains into cultured human intestinal epithelial (Caco2) and mouse macrophages cell lines (J774A.1) was also investigated. All isolates were invasive into both cell lines. Significant (P 0.001) variability in invasiveness into polarized Caco2 cells was observed. Salmonella Eastbourne exhibited the highest invasiveness into Caco2 cells and Salmonella Chester the lowest, with mean per cent recoveries of 19.99 0.32 and 1.23 0.30, respectively. Invasion into J774A.1 macrophages was also variable but was not significant. Salmonella subsp. II ser. 17:g,t:- (Bleadon) exhibited the highest invasiveness into J774A.1 with a mean per cent recovery of 10.19 0.19. Thus, reptile-associated Salmonellae are likely to have different capacities to cause disease in humans.
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http://dx.doi.org/10.1111/zph.12820DOI Listing
March 2021

Patient Preferences for Lung Cancer Treatment: A Qualitative Study Protocol Among Advanced Lung Cancer Patients.

Front Public Health 2021 5;9:622154. Epub 2021 Feb 5.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.

Lung cancer is the deadliest and most prevalent cancer worldwide. Lung cancer treatments have different characteristics and are associated with a range of benefits and side effects for patients. Such differences may raise uncertainty among drug developers, regulators, payers, and clinicians regarding the value of these treatment effects to patients. The value of conducting patient preference studies (using qualitative and/or quantitative methods) for benefits and side effects of different treatment options has been recognized by healthcare stakeholders, such as drug developers, regulators, health technology assessment bodies, and clinicians. However, evidence-based guidelines on how and when to conduct and use these studies in drug decision-making are lacking. As part of the Innovative Medicines Initiative PREFER project, we developed a protocol for a qualitative study that aims to understand which treatment characteristics are most important to lung cancer patients and to develop attributes and levels for inclusion in a subsequent quantitative preference survey. The study protocol specifies a four-phased approach: (i) a scoping literature review of published literature, (ii) four focus group discussions with stage III and IV Non-Small Cell Lung Cancer patients, (iii) two nominal group discussions with stage III and IV Non-Small Cell Lung Cancer patients, and (iv) multi-stakeholder discussions involving clinicians and preference experts. This protocol outlines methodological and practical steps as to how qualitative research can be applied to identify and develop attributes and levels for inclusion in patient preference studies aiming to inform decisions across the drug life cycle. The results of this study are intended to inform a subsequent quantitative preference survey that assesses patient trade-offs regarding lung cancer treatment options. This protocol may assist researchers, drug developers, and decision-makers in designing qualitative studies to understand which treatment aspects are most valued by patients in drug development, regulation, and reimbursement.
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http://dx.doi.org/10.3389/fpubh.2021.622154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900128PMC
February 2021

Can a chloride channel blocker mitigate muscle fatigue?

J Physiol 2021 Feb 19. Epub 2021 Feb 19.

Human Performance Lab, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada.

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http://dx.doi.org/10.1113/JP281424DOI Listing
February 2021

Structure of Blood Coagulation Factor VIII in Complex with an Anti-C1 Domain Pathogenic Antibody Inhibitor.

Blood 2021 Feb 2. Epub 2021 Feb 2.

Western Washington University, Bellingham, Washington, United States.

Antibody inhibitor development in hemophilia A represents the most significant complication resulting from factor VIII (fVIII) replacement therapy. Recent studies have demonstrated that epitopes present in the C1 domain contribute to a pathogenic inhibitor response. In this study, we report the structure of a Group A anti-C1 domain inhibitor, termed 2A9, in complex with a B domain-deleted, bioengineered fVIII construct (ET3i). The 2A9 epitope forms direct contacts to the C1 domain at three different surface loops consisting of Lys2065-Trp2070, Arg2150-Tyr2156 and Lys2110-Trp2112. Additional contacts are observed between 2A9 and the A3 domain, including the Phe1743-Tyr1748 loop and the N-linked glycosylation at Asn1810. Most of the C1 domain loops in the 2A9 epitope also represent a putative interface between fVIII and von Willebrand factor (vWF). Lastly, the C2 domain in the ET3i:2A9 complex adopts a large, novel conformational change, translocating outward from the structure of fVIII by 20 Å. This study reports the first structure of an anti-C1 domain antibody inhibitor and the first fVIII:inhibitor complex with a therapeutically active fVIII construct. Further structural understanding of fVIII immunogenicity may result in the development of more effective and safe fVIII replacement therapies.
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http://dx.doi.org/10.1182/blood.2020008940DOI Listing
February 2021

Host reproductive cycle influences the pouch microbiota of wild southern hairy-nosed wombats (Lasiorhinus latifrons).

Anim Microbiome 2021 Jan 25;3(1):13. Epub 2021 Jan 25.

School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.

Background: Marsupials are born much earlier than placental mammals, with most crawling from the birth canal to the protective marsupium (pouch) to further their development. However, little is known about the microbiology of the pouch and how it changes throughout a marsupial's reproductive cycle. Here, using stringent controls, we characterized the microbial composition of multiple body sites from 26 wild Southern Hairy-nosed Wombats (SHNWs), including pouch samples from animals at different reproductive stages.

Results: Using qPCR of the 16S rRNA gene we detected a microbial community in the SHNW pouch. We observed significant differences in microbial composition and diversity between the body sites tested, as well as between pouch samples from different reproductive stages. The pouches of reproductively active females had drastically lower microbial diversity (mean ASV richness 19 ± 8) compared to reproductively inactive females (mean ASV richness 941 ± 393) and were dominated by gram positive bacteria from the Actinobacteriota phylum (81.7-90.6%), with the dominant families classified as Brevibacteriaceae, Corynebacteriaceae, Microbacteriaceae, and Dietziaceae. Three of the five most abundant sequences identified in reproductively active pouches had closest matches to microbes previously isolated from tammar wallaby pouches.

Conclusions: This study represents the first contamination-controlled investigation into the marsupial pouch microbiota, and sets a rigorous framework for future pouch microbiota studies. Our results indicate that SHNW pouches contain communities of microorganisms that are substantially altered by the host reproductive cycle. We recommend further investigation into the roles that pouch microorganisms may play in marsupial reproductive health and joey survival.
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http://dx.doi.org/10.1186/s42523-021-00074-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836174PMC
January 2021

Alginate Affects Bioactivity of Chimeric Collagen-Binding LL37 Antimicrobial Peptides Adsorbed to Collagen-Alginate Wound Dressings.

ACS Biomater Sci Eng 2020 06 21;6(6):3398-3410. Epub 2020 May 21.

Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, Massachusetts 01609, United States.

Chronic infected wounds cause more than 23,000 deaths annually. Antibiotics and antiseptics are conventionally used to treat infected wounds; however, they can be toxic to mammalian cells, and their use can contribute to antimicrobial resistance. Antimicrobial peptides (AMPs) have been utilized to address the limitations of antiseptics and antibiotics. In previous work, we modified the human AMP LL37 with collagen-binding domains from collagenase (CBD) or fibronectin (CBD) to facilitate peptide tethering and delivery from collagen-based wound dressings. We found that CBD-LL37 and CBD-LL37 were retained and active when bound to 100% collagen scaffolds. Collagen wound dressings are commonly made as composites with other materials, such as alginate. The goal of this study was to investigate how the presence of alginate affects the tethering, release, and antimicrobial activity of LL37 and CBD-LL37 peptides adsorbed to commercially available collagen-alginate wound dressings (FIBRACOL Plus-a 90% collagen and 10% alginate wound dressing). We found that over 85% of the LL37, CBD-LL37, and CBD-LL37 was retained on FIBRACOL Plus over a 14-day release study (90.3, 85.8, and 98.6%, respectively). Additionally, FIBRACOL Plus samples loaded with peptides were bactericidal toward , even after 14 days in release buffer but demonstrated no antimicrobial activity against , and . The presence of alginate in solution induced conformational changes in the CBD-LL37 and LL37 peptides, resulting in increased peptide helicity, and reduced antimicrobial activity against . Peptide-loaded FIBRACOL Plus scaffolds were not cytotoxic to human dermal fibroblasts. This study demonstrates that CBD-mediated LL37 tethering is a viable strategy to reduce LL37 toxicity, and how substrate composition plays a crucial role in modulating the antimicrobial activity of tethered AMPs.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00227DOI Listing
June 2020

Influence of landscape management practices on urban greenhouse gas budgets.

Carbon Balance Manag 2021 Jan 7;16(1). Epub 2021 Jan 7.

Department of Earth and Environment, Boston University, Boston, MA, 02215, USA.

Background: With a lack of United States federal policy to address climate change, cities, the private sector, and universities have shouldered much of the work to reduce carbon dioxide (CO) and other greenhouse gas emissions. This study aims to determine how landcover characteristics influence the amount of carbon (C) sequestered and respired via biological processes, evaluating the role of land management on the overall C budget of an urban university. Boston University published a comprehensive Climate Action Plan in 2017 with the goal of achieving C neutrality by 2040. In this study, we digitized and discretized each of Boston University's three urban campuses into landcover types, with C sequestration and respiration rates measured and scaled to provide a University-wide estimate of biogenic C fluxes within the broader context of total University emissions.

Results: Each of Boston University's three highly urban campuses were net sources of biogenic C to the atmosphere. While trees were estimated to sequester 0.6 ± 0.2 kg C m canopy cover year, mulch and lawn areas in 2018 emitted C at rates of 1.7 ± 0.4 kg C m year and 1.4 ± 0.4 kg C m year, respectively. C uptake by tree canopy cover, which can spatially overlap lawn and mulched landcovers, was not large enough to offset biogenic emissions. The proportion of biogenic emissions to Scope 1 anthropogenic emissions on each campus varied from 0.5% to 2%, and depended primarily on the total anthropogenic emissions on each campus.

Conclusions: Our study quantifies the role of urban landcover in local C budgets, offering insights on how landscaping management strategies-such as decreasing mulch application rates and expanding tree canopy extent-can assist universities in minimizing biogenic C emissions and even potentially creating a small biogenic C sink. Although biogenic C fluxes represent a small fraction of overall anthropogenic emissions on urban university campuses, these biogenic fluxes are under active management by the university and should be included in climate action plans.
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http://dx.doi.org/10.1186/s13021-020-00160-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792215PMC
January 2021

A Comment on "A New Taxonomy for Postactivation Potentiation in Sport".

Int J Sports Physiol Perform 2021 01 5;16(2):163. Epub 2021 Jan 5.

University of Calgary, Calgary, AB, Canada.

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http://dx.doi.org/10.1123/ijspp.2020-0586DOI Listing
January 2021

Assessment of Ki67 in Breast Cancer: Updated Recommendations from the International Ki67 in Breast Cancer Working Group.

J Natl Cancer Inst 2020 Dec 28. Epub 2020 Dec 28.

University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.

Ki67 immunohistochemistry, commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 immunohistochemistry analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, pre-analytical handling considerations are critical. 2) A standardized visual scoring method has been established and is recommended for adoption. 3) Participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity. 4) The IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable ER-positive and HER2-negative patients, to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 ≤ 5% or ≥ 30% can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to pre-analytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I/II breast cancer. Further development of automated scoring might help to overcome some current limitations.
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http://dx.doi.org/10.1093/jnci/djaa201DOI Listing
December 2020

Contractile history affects sag and boost properties of unfused tetanic contractions in human quadriceps muscles.

Eur J Appl Physiol 2021 Feb 22;121(2):645-658. Epub 2020 Nov 22.

Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, 2500 University Drive NW Calgary, Alberta, T2N 1N4, Canada.

Purpose: A period of extra-efficient force production ("boost") followed by a decline in force ("sag") is often observed at the onset of unfused tetanic contractions. We tested the hypothesis that in human muscle boost and sag are diminished in repeated contractions separated by short rest periods and are re-established or enhanced following long rest periods.

Methods: Two sets of 3 unfused tetanic contractions were evoked in the right quadriceps muscle group of 29 participants via percutaneous stimulation of the femoral nerve. Contractions consisted of 20 pulses evoked at inter-pulse intervals of 1.25 × twitch time to peak torque. Contractions were evoked 5 s apart and sets were evoked 5 min apart.

Results: The ratio of the angular impulse of pulses 1-10 to the angular impulse of pulses 11-20 was used as the boost indicator. By this metric, boost was higher (P < 0.05) in the first relative to the second and third contractions within a set, but did not differ between sets (Set 1: 1.31 ± 0.15, 1.18 ± 0.12, 1.14 ± 0.12 vs Set 2: 1.34 ± 0.17, 1.17 ± 0.13, 1.14 ± 0.13). Sag (the percent decline in torque within each contraction) was also higher (P < 0.05) in the first relative to the second and third contractions within a set, but did not differ between sets (Set 1: 40.8 ± 7.5%, 35.4 ± 6.8%, 33.2 ± 7.8% vs Set 2: 42.1 ± 8.0%, 35.5 ± 6.8%, 33.9 ± 7.2%). Participants' sex and resistance training background did not influence boost or sag.

Conclusion: Boost and sag are sensitive to contractile history in whole human quadriceps. Optimizing boost may have application in strength and power sports.
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http://dx.doi.org/10.1007/s00421-020-04561-9DOI Listing
February 2021

Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial.

Lancet Oncol 2020 11;21(11):1443-1454

The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.

Background: Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki67) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67). The POETIC trial aimed to test these two hypotheses.

Methods: POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0-1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing.

Findings: Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1-74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75-1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9-92·0) for patients in the POAI group and 90·4% (88·7-91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67 and Ki67 (low-low) was 4·3% (95% CI 2·9-6·3), 8·4% (6·8-10·5) with high Ki67 and low Ki67 (high-low) and 21·5% (17·1-27·0) with high Ki67 and Ki67 (high-high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low-low group was 10·1% (95% CI 3·2-31·3), 7·7% (3·4-17·5) in the high-low group, and 15·7% (10·1-24·4) in the high-high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported.

Interpretation: POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67 or low POAI-induced Ki67 do well with adjuvant standard endocrine therapy (giving consideration to clinical-pathological factors), whereas those whose POAI-induced Ki67 remains high might benefit from further adjuvant treatment or trials of new therapies.

Funding: Cancer Research UK.
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http://dx.doi.org/10.1016/S1470-2045(20)30458-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606901PMC
November 2020

Serological evidence of exposure to a coronavirus antigenically related to severe acute respiratory syndrome virus (SARS-CoV-1) in the Grey-headed flying fox (Pteropus poliocephalus).

Transbound Emerg Dis 2020 Nov 3. Epub 2020 Nov 3.

The University of Adelaide, Adelaide, SA, Australia.

Many infectious pathogens can be transmitted by highly mobile species, like bats that can act as reservoir hosts for viruses such as henipaviruses, lyssaviruses and coronaviruses. In this study, we investigated the seroepidemiology of protein antigens to Severe acute respiratory syndrome virus (SARS-CoV-1) and Middle eastern respiratory syndrome virus (MERS-CoV) in Grey-headed flying foxes (Pteropus poliocephalus) in Adelaide, Australia sampled between September 2015 and February 2018. A total of 301 serum samples were collected and evaluated using a multiplex Luminex binding assay, and median fluorescence intensity thresholds were determined using finite-mixture modelling. We found evidence of antibodies reactive to SARS-CoV-1 or a related antigen with 42.5% (CI: 34.3%-51.2%) seroprevalence but insufficient evidence of reactivity to MERS-CoV antigen. This study provides evidence that the Grey-headed flying foxes sampled in Adelaide have been exposed to a SARS-like coronavirus.
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http://dx.doi.org/10.1111/tbed.13908DOI Listing
November 2020

Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer's disease.

Nat Commun 2020 10 23;11(1):5370. Epub 2020 Oct 23.

Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.

The discovery of TREM2 as a myeloid-specific Alzheimer's disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD.
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http://dx.doi.org/10.1038/s41467-020-19227-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584603PMC
October 2020

A multidisciplinary approach to online support for device research translation: regulatory change and clinical engagement.

Health Policy Technol 2020 Oct 15. Epub 2020 Oct 15.

Clinical Research Development Ireland, Mount St., Dublin 2, Ireland.

Objectives: To promote medical device EU regulatory understanding in the biomedical research community and encourage greater levels of clinical engagement to further medical device research innovation, translation and effective clinical trials.

Methods: An interdisciplinary, iterative, needs-based design approach was used to develop medical device regulatory training, information and clinical expertise resources.

Results: A multimedia based self-paced e-Learning course focusing on the 'Fundamentals of Medical Device Design and Regulation' was produced in tandem with an interactive online web portal: Medtech Translate.

Conclusions: Health research translation relies on both clinical input and regulation to drive progress and to ensure quality and safety standards from concept development to clinical investigation. A lack of regulatory awareness and access to clinical expertise has the potential to significantly impact on health research translation and ambition for market. Our interdisciplinary academic-regulator-clinical-industry led approach meets the need for a coordinated stakeholder response to support innovation and promote growth in the medical technology sector.
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http://dx.doi.org/10.1016/j.hlpt.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560120PMC
October 2020

Comparison of Feedback Approaches to Improve Training in Partial Weight-Bearing.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:3264-3268

Assistive devices, including canes or crutches, are used in partial weight-bearing (PWB) to offload weight from limbs weakened by disease or injury, promote recovery, and prevent reinjury. While weight must be offloaded accurately to target loads prescribed by healthcare providers for maximum benefit, current training methods result in poor adherence. It is, however, currently unknown how best to provide feedback during training so that users can build an accurate internal model for PWB. In this work, we investigate seven feedback schemes using an instrumented cane, which vary the modality, timing, and the level of detail provided. We find that auditory schemes and a retrospective visual scheme outperform current clinical practices for PWB training. These findings provide results that can be applied directly to improve current clinical practices and provide valuable new insight into the design of feedback for training internal models in force-based motor control tasks. Clinically, this work presents a simple modification to clinical PWB training practices that can improve compliance by up to 75%, positively influencing rehabilitation outcomes and reducing the risk of complications.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176207DOI Listing
July 2020

The effects of inorganic phosphate on contractile function of slow skeletal muscle fibres are length-dependent.

Biochem Biophys Res Commun 2020 12 28;533(4):818-823. Epub 2020 Sep 28.

Human Performance Lab, Faculty of Kinesiology, University of Calgary 2500 University Drive NW, Calgary, AB, Canada; Biomechanics Laboratory, School of Sports, Federal University of Santa Catarina, Florianopolis, SC, Brazil.

Muscle operates across a wide range of sarcomere lengths. Inorganic phosphate (P) diminishes force output of striated muscle, with greater influence at short relative to long sarcomere lengths in fast skeletal and cardiac muscle fibres. The purpose of this study was to fill a gap in the literature regarding the length-dependent effects of P on contractile function of slow skeletal muscle fibres. Permeabilized slow skeletal muscle fibres from rabbit soleus were assessed at average sarcomere lengths of 2.0, 2.4, or 2.8 μm, with and without 20 mM P added to activating solutions (22±1 °C). The magnitude of P-induced reductions in peak force (43 ± 7% at 2.0 μm, 38 ± 7% at 2.4 μm, and 31 ± 8% at 2.8 μm) and peak stiffness (41 ± 9% at 2.0 μm, 36 ± 8% at 2.4 μm, and 26 ± 9% at 2.8 μm) were length dependent. Peak stiffness was less affected by P than peak force. P diminished the Ca-sensitivity of the force-pCa and stiffness-pCa relationships to a greater extent at 2.8 μm than 2.0 μm. Comparable results were obtained from a cooperative model of Ca and myosin binding to regulated actin. In conclusion, P is more detrimental to the peak force output of slow skeletal muscle fibres held at short relative to long sarcomere lengths, whereas P has a greater effect on the Ca-sensitivity of force production at long relative to short sarcomere lengths. Stiffness data suggest that P-induced reductions in force are primarily due to fewer bound cross-bridges, with a lesser contribution attributable to lower average force per cross-bridge.
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http://dx.doi.org/10.1016/j.bbrc.2020.09.092DOI Listing
December 2020

Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE).

J Clin Oncol 2020 12 20;38(34):3987-3998. Epub 2020 Sep 20.

University of Pittsburgh, NSABP Foundation, Pittsburgh, PA.

Purpose: Many patients with HR+, HER2- early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor approved for HR+, HER2- advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported evaluation in the adjuvant setting.

Methods: This open-label, phase III study included patients with HR+, HER2-, high-risk EBC, who had surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes, or one to three nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%, were eligible and randomly assigned (1:1) to standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years). The primary end point was invasive disease-free survival (IDFS), and secondary end points included distant relapse-free survival, overall survival, and safety.

Results: At a preplanned efficacy interim analysis, among 5,637 randomly assigned patients, 323 IDFS events were observed in the intent-to-treat population. Abemaciclib plus ET demonstrated superior IDFS versus ET alone ( = .01; hazard ratio, 0.75; 95% CI, 0.60 to 0.93), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. Safety data were consistent with the known safety profile of abemaciclib.

Conclusion: Abemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2- node-positive EBC at high risk of early recurrence.
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http://dx.doi.org/10.1200/JCO.20.02514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768339PMC
December 2020

Maximal Exercise Testing Using the Incremental Shuttle Walking Test Can Be Used to Risk-Stratify Patients with Pulmonary Arterial Hypertension.

Ann Am Thorac Soc 2021 01;18(1):34-43

Sheffield Pulmonary Vascular Disease Unit, Sheffield Teaching Hospitals National Health Service Foundation Trust, Royal Hallamshire Hospital, Sheffield, United Kingdom.

Exercise capacity predicts mortality in pulmonary arterial hypertension (PAH), but limited data exist on the routine use of maximal exercise testing. This study evaluates a simple-to-perform maximal test (the incremental shuttle walking test) and its use in risk stratification in PAH. Consecutive patients with pulmonary hypertension were identified from the ASPIRE (Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre) registry (2001-2018). Thresholds for levels of risk were identified at baseline and tested at follow-up, and their incorporation into current risk stratification approaches was assessed. Of 4,524 treatment-naive patients with pulmonary hypertension who underwent maximal exercise testing, 1,847 patients had PAH. A stepwise reduction in 1-year mortality was seen between levels 1 (≤30 m; 32% mortality) and 7 (340-420 m; 1% mortality) with no mortality for levels 8-12 (≥430 m) in idiopathic and connective tissue disease-related PAH. Thresholds derived at baseline of ≤180 m (>10%; high risk), 190-330 m (5-10%; intermediate risk), and ≥340 m (<5%; low risk of 1-yr mortality) were applied at follow-up and also accurately identified levels of risk. Thresholds were incorporated into the REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) 2.0 risk score calculator and French low-risk approach to risk stratification, and distinct categories of risk remained.: We have demonstrated that maximal exercise testing in PAH stratifies mortality risk at baseline and follow-up. This study highlights the potential value of the incremental shuttle walking test as an alternative to the 6-minute walking test, combining some of the advantages of maximal exercise testing and maintaining the simplicity of a simple-to-perform field test.
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http://dx.doi.org/10.1513/AnnalsATS.202005-423OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780966PMC
January 2021

Giant cell tumour of soft tissue-a rare presentation of a common pathology.

BJR Case Rep 2020 Sep 27;6(3):20200012. Epub 2020 May 27.

Plastic Surgeon St.James's University Hospital, Leeds, LS9 7TF, UK.

We present the case of a giant cell tumour of soft tissue (GCT-ST) presenting as a slow-growing paraspinal mass. Imaging investigations revealed a well-circumscribed subcutaneous lesion containing fluid-fluid levels and an internal solid nodule. The imaging findings resulted in only a tentative differential which included haematoma or complex epidermoid cyst but failed to provide a definitive diagnosis. The patient underwent an image-guided biopsy from which a histopathological diagnosis of a GCT-ST was made. GCT-ST is a primary soft tissue neoplasm that is clinically and histologically similar to giant cell tumour of bone. Given its rare occurrence, there is very little published literature on the characteristic imaging findings of GCT-ST to help with its diagnosis which is usually only made histologically. The aim of this case report is to highlight our specific imaging findings and add to the limited pre-existing imaging data on GCT-ST.
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http://dx.doi.org/10.1259/bjrcr.20200012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465752PMC
September 2020

COVID-19 and pneumothorax: a multicentre retrospective case series.

Eur Respir J 2020 Nov 19;56(5). Epub 2020 Nov 19.

Addenbrooke's Hospital, Cambridge, UK

Introduction: Pneumothorax and pneumomediastinum have both been noted to complicate cases of coronavirus disease 2019 (COVID-19) requiring hospital admission. We report the largest case series yet described of patients with both these pathologies (including nonventilated patients).

Methods: Cases were collected retrospectively from UK hospitals with inclusion criteria limited to a diagnosis of COVID-19 and the presence of either pneumothorax or pneumomediastinum. Patients included in the study presented between March and June 2020. Details obtained from the medical record included demographics, radiology, laboratory investigations, clinical management and survival.

Results: 71 patients from 16 centres were included in the study, of whom 60 had pneumothoraces (six with pneumomediastinum in addition) and 11 had pneumomediastinum alone. Two of these patients had two distinct episodes of pneumothorax, occurring bilaterally in sequential fashion, bringing the total number of pneumothoraces included to 62. Clinical scenarios included patients who had presented to hospital with pneumothorax, patients who had developed pneumothorax or pneumomediastinum during their inpatient admission with COVID-19 and patients who developed their complication while intubated and ventilated, either with or without concurrent extracorporeal membrane oxygenation. Survival at 28 days was not significantly different following pneumothorax (63.1±6.5%) or isolated pneumomediastinum (53.0±18.7%; p=0.854). The incidence of pneumothorax was higher in males. 28-day survival was not different between the sexes (males 62.5±7.7% females 68.4±10.7%; p=0.619). Patients aged ≥70 years had a significantly lower 28-day survival than younger individuals (≥70 years 41.7±13.5% survival <70 years 70.9±6.8% survival; p=0.018 log-rank).

Conclusion: These cases suggest that pneumothorax is a complication of COVID-19. Pneumothorax does not seem to be an independent marker of poor prognosis and we encourage continuation of active treatment where clinically possible.
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http://dx.doi.org/10.1183/13993003.02697-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487269PMC
November 2020

A Deep Learning-Based Method for Identification of Bacteriophage-Host Interaction.

IEEE/ACM Trans Comput Biol Bioinform 2020 Aug 19;PP. Epub 2020 Aug 19.

Multi-drug resistance (MDR) has become one of the greatest threats to human health worldwide, and novel treatment methods of infections caused by MDR bacteria are urgently needed. Phage therapy is a promising alternative to solve this problem, to which the key is correctly matching target pathogenic bacteria with the corresponding therapeutic phage. Deep learning is powerful for mining complex patterns to generate accurate predictions. In this study, we develop PredPHI (Predicting Phage-Host Interactions), a deep learning-based tool capable of predicting the host of phages from sequence data. We collect >3000 phage-host pairs along with their protein sequences from PhagesDB and GenBank databases and extract a set of features. Then we select high-quality negative samples based on the K-Means clustering method and construct a balanced training set. Finally, we employ a deep convolutional neural network to build the predictive model. The results indicate that PredPHI can achieve a predictive performance of 81% in terms of the area under the receiver operating characteristic curve on the test set, and the clustering-based method is significantly more robust than that based on randomly selecting negative samples. These results highlight that PredPHI is a useful and accurate tool for identifying phage-host interactions from sequence data.
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http://dx.doi.org/10.1109/TCBB.2020.3017386DOI Listing
August 2020

Evidence-based guidelines for managing patients with primary ER+ HER2- breast cancer deferred from surgery due to the COVID-19 pandemic.

NPJ Breast Cancer 2020 8;6:21. Epub 2020 Jun 8.

West German Study Group, Mönchengladbach, Germany.

Many patients with ER+ HER2- primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER <6 or ER 6 and PgR <6) (ii) a biopsy for Ki67 analysis (on-treatment Ki67) could be considered after 2-4 weeks of NeoET (a: ER 7 or 8 and PgR <6 or b: ER 6 or 7 and PgR ≥6) or (iii) NeoET is an acceptable course of action (ER 8 and PgR ≥6). Cut-offs for percentage of cells positive are also given. For group (ii), a high early on-treatment level of Ki67 (>10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2- breast cancer during and in the aftermath of the COVID-19 crisis.
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http://dx.doi.org/10.1038/s41523-020-0168-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280290PMC
June 2020

Initial force production before sag is enhanced by prior contraction followed by a 3-minute rest period in fast motor units of the rat medial gastrocnemius.

J Electromyogr Kinesiol 2020 Aug 26;53:102429. Epub 2020 May 26.

Department of Neurobiology, Poznan University of Physical Education, Poland.

Unfused tetanic contractions evoked in fast motor units exhibit extra-efficient force production at the onset of contraction, an effect called "boost". Boost is diminished in subsequent contractions if there is a short rest period between contractions, but can be re-established with a longer period of rest. We tested the hypothesis that contractile activity and rest could enhance boost-related metrics. Two sets of 3 unfused tetani were evoked 3 min apart in fast fatigable (FF) and fast fatigue-resistant (FR) motor units of the rat medial gastrocnemius. The greatest changes occurred in the first unfused tetanic contractions. Relative to the first contraction in the first set, the first contraction in the second set exhibited higher peak force during boost in a subset of motor units (76% of FF and 48% of FR). Enhanced force during boost was influenced by interaction of slowing of twitch contraction time (up to 20% and 25%, for FF and FR motor units, respectively), half-relaxation time (up to 37% and 49% for FF and FR motor units, respectively), and potentiation of the first twitch (up to 13% and 5% for FF and FR motor units, respectively). Examination of twitches evoked between sets suggested opportunity for greater enhancement of boost with shorter intervening rest periods. The phenomenon of enhanced boost following motor unit activity may interest sports scientists.
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http://dx.doi.org/10.1016/j.jelekin.2020.102429DOI Listing
August 2020

Role of lipopolysaccharides and lipoteichoic acids on C-Chrysophsin-1 interactions with model Gram-positive and Gram-negative bacterial membranes.

Biointerphases 2020 05 26;15(3):031007. Epub 2020 May 26.

Department of Chemical Engineering, Worcester Polytechnic Institute, 100 Institute Road, Worcester, Massachusetts 01609.

Antimicrobial peptides (AMPs) are attractive as biomaterial coatings because they have broad spectrum activity against different microbes, with a low likelihood of incurring antimicrobial resistance. Direct action against the bacterial membrane is the most common mechanism of action (MOA) of AMPs, with specific MOAs dependent on membrane composition, peptide concentration, and environmental factors that include temperature. Chrysophsin-1 (CHY1) is a broad spectrum salt-tolerant AMP that is derived from a marine fish. A cysteine modification was made to the peptide to facilitate attachment to a surface, such as a biomedical device. The authors used quartz crystal microbalance with dissipation monitoring to study how temperature (23 and 37 °C) and lipid composition influence the MOA of cysteine-modified peptide (C-CHY1) with model membranes comprised of supported lipid bilayers (SLBs). These two temperatures were used so that the authors could better understand the differences in behavior between typical lab temperatures and physiologic conditions. The authors created model membranes that mimicked properties of Gram-negative and Gram-positive bacteria in order to understand how the mechanisms might differ for different types of bacterial systems. SLB models of Gram-positive bacterial membranes were formed using combinations of phosphatidylcholine, phosphatidylglycerol (PG), and S. aureus-derived lipoteichoic acid (LTA). SLB models of Gram-negative bacterial membranes were formed using combinations of phosphatidylethanolamine (PE), PG, and E. coli-derived lipopolysaccharides (LPS). The molecules that distinguish Gram-positive and Gram-negative membranes (LTA and LPS) have the potential to alter the MOA of C-CHY1 with the SLBs. The authors' results showed that the MOA for the Gram-positive SLBs was not sensitive to temperature, but the LTA addition did have an effect. Specifically, similar trends in frequency and dissipation changes across all overtones were observed, and the same mechanistic trends were observed in the polar plots at 23 and 37 °C. However, when LTA was added, polar plots showed an association between C-CHY1 and LTA, leading to SLB saturation. This was demonstrated by significant changes in dissipation, while the frequency (mass) was not increasing after the saturation point. For the Gram-negative SLBs, the composition did not have a significant effect on MOA, but the authors saw more differences between the two temperatures studied. The authors believe this is due to the fact that the gel-liquid crystal transition temperature of PE is 25 °C, which means that the bilayer is more rigid at 23 °C, compared to temperatures above the transition point. At 23 °C, a significant energetic shift would be required to allow for additional AMP insertion. This could be seen in the polar plots, where there was a steep slope but there was very little mass addition. At 37 °C, the membrane is more fluid and there is less of an energetic requirement for insertion. Therefore, the authors observed greater mass addition and fewer changes in dissipation. A better understanding of C-CHY1 MOA using different SLB models will allow for the more rational design of future therapeutic solutions that make use of antimicrobial peptides, including those involving biomaterial coatings.
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http://dx.doi.org/10.1116/1.5130774DOI Listing
May 2020

Specimen Requirements for Preeclampsia Markers.

J Appl Lab Med 2020 05;5(3):605-607

Department of Clinical Biochemistry, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

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http://dx.doi.org/10.1093/jalm/jfaa010DOI Listing
May 2020

T integrins CD103 and CD49a differentially support adherence and motility after resolution of influenza virus infection.

Proc Natl Acad Sci U S A 2020 06 21;117(22):12306-12314. Epub 2020 May 21.

Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, NY 14642;

Tissue-resident memory CD8 T (T) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon reexposure to that pathogen. In the pulmonary system, T are identified through S1P antagonist CD69 and expression of integrins CD103/β7 and CD49a/CD29(β1). Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the T cell surface phenotype develops by 2 wk postinfection, with the majority of the population expressing CD49a and a subset that is also positive for CD103. Despite a previously established role in retaining T in peripheral tissues, CD49a facilitates locomotion of virus-specific CD8 T cells, both in vitro and in vivo. These results demonstrate that CD49a may contribute to local surveillance mechanisms of the T population.
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http://dx.doi.org/10.1073/pnas.1915681117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275699PMC
June 2020