Publications by authors named "Ian Smith"

743 Publications

Letter to the Editor on "Effectiveness of a Web-Based Direct-to-User Transfer Training Program" -Response.

Arch Phys Med Rehabil 2022 May 21. Epub 2022 May 21.

Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA; Human Engineering Research Laboratories, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA; Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA; Department of Physical Therapy, University of Pittsburgh, Pittsburgh, PA. Electronic address:

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http://dx.doi.org/10.1016/j.apmr.2022.05.002DOI Listing
May 2022

Evaluation of statistical approaches for association testing in noisy drug screening data.

BMC Bioinformatics 2022 May 18;23(1):188. Epub 2022 May 18.

Department of Medical Biophysics, University of Toronto, Toronto, Canada.

Background: Identifying associations among biological variables is a major challenge in modern quantitative biological research, particularly given the systemic and statistical noise endemic to biological systems. Drug sensitivity data has proven to be a particularly challenging field for identifying associations to inform patient treatment.

Results: To address this, we introduce two semi-parametric variations on the commonly used concordance index: the robust concordance index and the kernelized concordance index (rCI, kCI), which incorporate measurements about the noise distribution from the data. We demonstrate that common statistical tests applied to the concordance index and its variations fail to control for false positives, and introduce efficient implementations to compute p-values using adaptive permutation testing. We then evaluate the statistical power of these coefficients under simulation and compare with Pearson and Spearman correlation coefficients. Finally, we evaluate the various statistics in matching drugs across pharmacogenomic datasets.

Conclusions: We observe that the rCI and kCI are better powered than the concordance index in simulation and show some improvement on real data. Surprisingly, we observe that the Pearson correlation was the most robust to measurement noise among the different metrics.
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http://dx.doi.org/10.1186/s12859-022-04693-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9118710PMC
May 2022

Spatial variability of microzooplankton grazing on phytoplankton in coastal southern Florida, USA.

PeerJ 2022 25;10:e13291. Epub 2022 Apr 25.

Department of Biological Sciences, University of New Hampshire, Durham, NH, United States.

Microzooplankton are considered the primary consumers of phytoplankton in marine environments. Microzooplankton grazing rates on phytoplankton have been studied across the globe, but there are still large regions of the ocean that are understudied, such as sub-tropical coastal oceans. One of these regions is the coastal area around south Florida, USA. We measured microzooplankton grazing rates in two distinct environments around south Florida; the oligotrophic Florida Keys and the mesotrophic outflow from the Everglades. For 2-years from January 2018 to January 2020, we set up 55 dilution and light-dark bottle experiments at five stations to estimate the microzooplankton community grazing rate, instantaneous phytoplankton growth rate, and primary production. Our results suggest that microzooplankton are consuming a higher proportion of the primary production near the Everglades outflow compared to the Florida Keys. We also found that changes in phytoplankton growth rates are disconnected from changes in the microzooplankton grazing rates in the Florida Keys. Overall, the data from the Everglades outflow is what would be expected based on global patterns, but factors other than microzooplankton grazing are more important in controlling phytoplankton biomass in the Florida Keys.
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http://dx.doi.org/10.7717/peerj.13291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048640PMC
April 2022

Ketamine sex- and dose-dependently mitigates behavioral sequelae induced by a predator-based psychosocial stress model of post-traumatic stress disorder.

Behav Brain Res 2022 06 16;428:113895. Epub 2022 Apr 16.

Psychology Program, The School of Health and Behavioral Sciences, Ohio Northern University, 525 S. Main St., Ada, OH 45810, USA.

Current pharmacotherapy for post-traumatic stress disorder (PTSD), a debilitating psychiatric condition that develops in a subset of traumatized individuals, is inadequate. Over the past two decades, numerous studies have shown that ketamine, a non-competitive NMDA receptor antagonist, exerts rapid antidepressant effects in both humans and rodents, but the anxiolytic profile of ketamine, as well as its ability to treat PTSD-related symptoms, is still unclear. Thus, we examined the ability of a single administration of ketamine to prevent the onset of PTSD-like sequelae in a chronic psychosocial stress model of PTSD. Adult male and female Sprague-Dawley rats were exposed to a cat on two occasions, in combination with chronic social instability. Immediately following the cat exposure on Day 1, rats were given intraperitoneal injections of 10 mg/kg or 15 mg/kg ketamine or vehicle; control rats were injected with vehicle. Three weeks after the second cat exposure, we assessed symptoms of hyperarousal and anxiety-like behavior in the rats. In males, chronic stress led to greater anxiety on the elevated plus maze and in the open field; in females, chronic stress resulted in an exaggerated startle response and greater anxiety in the open field. These effects were most effectively prevented by the administration of 10 mg/kg ketamine. These findings demonstrate that ketamine can prophylactically prevent the onset of PTSD-like behaviors in males and females. Their sex-dependent nature is consistent with previous preclinical research and highlights the need for future research to examine their neurobiological basis.
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http://dx.doi.org/10.1016/j.bbr.2022.113895DOI Listing
June 2022

Scoping the future for interventional radiology and interventional neuroradiology: a clinical physics perspective.

Phys Eng Sci Med 2022 Mar 7. Epub 2022 Mar 7.

The Wesley Hospital, Brisbane, Australia.

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http://dx.doi.org/10.1007/s13246-022-01115-5DOI Listing
March 2022

Methods for isolating and analyzing physiological hyaluronan: a review.

Am J Physiol Cell Physiol 2022 04 23;322(4):C674-C687. Epub 2022 Feb 23.

Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.

The carbohydrate hyaluronan (or hyaluronic acid, HA) is found in all human tissues and biofluids where it has wide-ranging functions in health and disease that are dictated by both its abundance and size. Consequently, hyaluronan evaluation in physiological samples has significant translational potential. Although the analytical tools and techniques for probing other biomolecules such as proteins and nucleic acids have become standard approaches in biochemistry, those available for investigating hyaluronan are less well established. In this review, we survey methods related to the assessment of native hyaluronan in biological specimens, including protocols for separating it from biological matrices and technologies for determining its concentration and molecular weight.
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http://dx.doi.org/10.1152/ajpcell.00019.2022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8977137PMC
April 2022

Positive role of continuous positive airway pressure for intensive care unit patients with severe hypoxaemic respiratory failure due to COVID-19 pneumonia: A single centre experience.

J Intensive Care Soc 2022 Feb;23(1):27-33

Respiratory Support and Sleep Centre, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK.

Objectives: Continuous positive airway pressure (CPAP) may be a useful treatment strategy for patients with severe COVID-19 pneumonia but its effectiveness in preventing mechanical ventilation is unknown. We aimed to evaluate the outcomes of COVID-19 patients treated with CPAP and determine predictors of CPAP response.

Design: This was a retrospective observational cohort study.

Setting: The study took place in the intensive care unit (ICU) at Royal Papworth Hospital (RPH) in Cambridge, UK.

Patients: We included all consecutive patients with confirmed COVID-19 pneumonia who were transferred from neighbouring hospitals between 14th March and 6th May, 2020 for consideration of ventilatory support.

Intervention: We instituted the use of CPAP for all patients who arrived in RPH not intubated and were not making satisfactory progress on supplemental oxygen alone.

Measurements And Main Results: Of 33 self-ventilating patients included in this study, 22 (66.7%) were male and the mean age was 54 ± 13.23 patients received CPAP. They were more hypoxaemic than those treated with oxygen alone (PaO/FiO ratio; 84.3 ± 19.0 vs 170.0 ± 46.0 mmHg, p = 0.001). There was a significant improvement in PaO/FiO ratio 1-2 hours after CPAP initiation (167.4 ± 49.0 from 84.3 ± 19.0 mmHg, p = 0.001). 14 (61%) patients responded to CPAP and 9 required intubation. There was no difference between these two groups in terms of the severity of baseline hypoxaemia (PaO/FiO ratio; 84.5 ± 16.0 vs 83.9 ± 23.0 mmHg, p = 0.94) but CPAP responders had significantly lower C-reactive protein (CRP) (176 ± 83 vs 274 ± 63 mg/L, p = 0.007), interleukin-6 (IL-6) (30 ± 47 vs 139 ± 148 pg/mL, p = 0.037), and D-dimer (321 ± 267 vs 941 + 1990 ng/mL, p = 0.003). CT pulmonary angiogram was performed in 6 out of 9 intubated patients and demonstrated pulmonary emboli in 5 of them. All patients were discharged from ICU and there were no fatalities.

Conclusions: In this cohort, CPAP was an effective treatment modality to improve hypoxaemia and prevent invasive ventilation in a substantial proportion of patients with severe respiratory failure. Accepting the small sample size, we also found raised biomarkers of inflammation (CRP and IL-6) and coagulopathy (D-Dimer) to be more useful predictors of CPAP responsiveness than the severity of hypoxaemia, and could help to guide intubation decisions in this clinical setting.
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http://dx.doi.org/10.1177/1751143720971543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855222PMC
February 2022

TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia.

Elife 2022 02 22;11. Epub 2022 Feb 22.

Department of Physiology and Biophysics, University of California, Irvine, Irvine, United States.

The membrane protein TREM2 (Triggering Receptor Expressed on Myeloid cells 2) regulates key microglial functions including phagocytosis and chemotaxis. Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD). Because abnormalities in Ca signaling have been observed in several AD models, we investigated TREM2 regulation of Ca signaling in human induced pluripotent stem cell-derived microglia (iPSC-microglia) with genetic deletion of TREM2. We found that iPSC-microglia lacking TREM2 (TREM2 KO) show exaggerated Ca signals in response to purinergic agonists, such as ADP, that shape microglial injury responses. This ADP hypersensitivity, driven by increased expression of P2Y and P2Y receptors, results in greater release of Ca from the endoplasmic reticulum stores, which triggers sustained Ca influx through Orai channels and alters cell motility in TREM2 KO microglia. Using iPSC-microglia expressing the genetically encoded Ca probe, Salsa6f, we found that cytosolic Ca tunes motility to a greater extent in TREM2 KO microglia. Despite showing greater overall displacement, TREM2 KO microglia exhibit reduced directional chemotaxis along ADP gradients. Accordingly, the chemotactic defect in TREM2 KO microglia was rescued by reducing cytosolic Ca using a P2Y receptor antagonist. Our results show that loss of TREM2 confers a defect in microglial Ca response to purinergic signals, suggesting a window of Ca signaling for optimal microglial motility.
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http://dx.doi.org/10.7554/eLife.73021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906810PMC
February 2022

Clinical outcomes in patients with triple negative or HER2 positive lobular breast cancer: a single institution experience.

Breast Cancer Res Treat 2022 Apr 4;192(3):563-571. Epub 2022 Feb 4.

The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK.

Purpose: Invasive lobular carcinomas (ILC) are characterised by loss of the cell adhesion molecule E-cadherin. Approximately 15% of ILC are ER negative at the time of breast cancer diagnosis, or at relapse due to loss of ER expression. Less than 5% of classical ILC but up to 35% of pleomorphic ILC are HER2 positive (HER2+).

Methods: Retrospective analysis of clinic-pathological data from patients with Triple negative (TN) or HER2+ ILC diagnosed 2004-2014 at the Royal Marsden Hospital. The primary endpoint was median overall survival (OS) in patients with metastatic disease. Secondary endpoints included response rate to neo-adjuvant chemotherapy (NAC), median disease-free interval (DFI) and OS for patients with early disease.

Results: Three of 16 patients with early TN ILC and 7/33 with early HER2+ ILC received NAC with pCR rates of 0/3 and 3/5 patients who underwent surgery, respectively. Median DFI was 28.5 months [95% Confidence interval (95%CI) 15-78.8] for TN ILC and not reached (NR) (111.2-NR) for HER2+ early ILC. Five-year OS was 52% (95%CI 23-74%) and 77% (95%CI 58-88%), respectively. Twenty-three patients with advanced TN ILC and 14 patients with advanced HER2+ ILC were identified. Median OS was 18.3 months (95%CI 13.0-32.8 months) and 30.4 months (95%CI 8.8-NR), respectively.

Conclusions: In our institution we report a high relapse rate after treatment for early TN ILC, but median OS from metastatic disease is similar to that expected from TN IDC. Outcomes for patients with advanced HER2+ ILC were less favourable than those expected for IDC, possibly reflecting incomplete exposure to anti-HER2 therapies.

Clinical Trial Registration: ROLo (ClinicalTrials.gov Identifier: NCT03620643), ROSALINE (ClinicalTrials.gov Identifier: NCT04551495).
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http://dx.doi.org/10.1007/s10549-021-06432-zDOI Listing
April 2022

The Impact of a Mobile App on Participation in Cardiac Rehabilitation and Understanding Barriers to Success: Comparative Cohort Study.

JMIR Cardio 2022 Jan 17;6(1):e24174. Epub 2022 Jan 17.

Queensland Cardiovascular Group, St Andrew's Specialist Centre, Brisbane, Australia.

Background: Poor patient uptake of cardiac rehabilitation (CR) remains a challenge for multiple reasons including geographic, time, cultural, cost, and psychological constraints.

Objective: We evaluated the impact on CR participation rates associated with the addition of the option of mobile app-based CR (Cardihab) for patients declining conventional CR.

Methods: A total of 204 consecutive patients were offered CR following angioplasty; of these, 99 were in cohort 1 (offered conventional CR only) and 105 were in cohort 2 (app-based CR offered to those declining conventional CR). Patients in each cohort were followed throughout a 6-week CR program and participation rates were compared for both groups. Patients in cohort 2 declining both forms of CR were interviewed to assess reasons for nonparticipation.

Results: CR participation improved from 21% (95% CI 14%-30%) to 63% (95% CI 53%-71%) with the addition of the app (P<.001). Approximately 25% (9/39) of the group declining the app-based program identified technology issues as the reason for nonparticipation. The remainder declined both CR programs or were ineligible due to frailty or comorbidities.

Conclusions: Providing patients with the additional option of an app-based CR program substantially improved CR participation. Technology and psychological barriers can limit CR participation. Further innovation in CR delivery systems is required to improve uptake.
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http://dx.doi.org/10.2196/24174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804955PMC
January 2022

Proton pump inhibitors associated with rapid eye movement sleep behaviour disorder.

BMJ Case Rep 2021 Dec 31;14(12). Epub 2021 Dec 31.

Respiratory Support and Sleep Centre (RSSC), Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK.

We present the case of a 65-year-old woman diagnosed with rapid eye movement sleep behaviour disorder (REMBD) based on typical symptoms and confirmed with an inpatient polysomnogram. She was prescribed clonazepam and later temazepam but continued to have intrusive symptoms. She subsequently recalled that the onset of dream enactment coincided with starting high-dose omeprazole for acid reflux. With this insight, she stopped the omeprazole. Within days, the dream enactment and nocturnal movements subsided. She stopped taking the temazepam and was symptom free for a few months. However, she was started on lansoprazole for recurrent dyspepsia. Once again she experienced violent movements in sleep. This is the first time an association between proton pump inhibitors (PPIs) and REMBD has been reported. PPIs have many effects on the central nervous system and should be considered as a possible provoking factor in people presenting with REMBD.
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http://dx.doi.org/10.1136/bcr-2021-246469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720946PMC
December 2021

Impact of Duration of Neoadjuvant Aromatase Inhibitors on Molecular Expression Profiles in Estrogen Receptor-positive Breast Cancers.

Clin Cancer Res 2022 03;28(6):1217-1228

Clinical Trials and Statistics Unit (ICR-CTSU)- Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom.

Purpose: Aromatase inhibitor (AI) treatment is the standard of care for postmenopausal women with primary estrogen receptor-positive breast cancer. The impact of duration of neoadjuvant endocrine therapy (NET) on molecular characteristics is still unknown. We evaluated and compared changes of gene expression profiles under short-term (2-week) versus longer-term neoadjuvant AIs.

Experimental Design: Global gene expression profiles from the PeriOperative Endocrine Therapy for Individualised Care (POETIC) trial (137 received 2 weeks of AIs and 47 received no treatment) and targeted gene expression from 80 patients with breast cancer treated with NET for more than 1 month (NeoAI) were assessed. Intrinsic subtyping, module scores covering different cancer pathways and immune-related genes were calculated for pretreated and posttreated tumors.

Results: The differences in intrinsic subtypes after NET were comparable between the two cohorts, with most Luminal B (90.0% in the POETIC trial and 76.3% in NeoAI) and 50.0% of HER2 enriched at baseline reclassified as Luminal A or normal-like after NET. Downregulation of proliferative-related pathways was observed after 2 weeks of AIs. However, more changes in genes from cancer-signaling pathways such as MAPK and PI3K/AKT/mTOR and immune response/immune-checkpoint components that were associated with AI-resistant tumors and differential outcome were observed in the NeoAI study.

Conclusions: Tumor transcriptional profiles undergo bigger changes in response to longer NET. Changes in HER2-enriched and Luminal B subtypes are similar between the two cohorts, thus AI-sensitive intrinsic subtype tumors associated with good survival might be identified after 2 weeks of AI. The changes of immune-checkpoint component expression in early AI resistance and its impact on survival outcome warrants careful investigation in clinical trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612503PMC
March 2022

The baseline neutrophil lymphocyte ratio predicts survival in soft-tissue sarcoma: A 17-year cohort study.

J Plast Reconstr Aesthet Surg 2022 Apr 27;75(4):1372-1379. Epub 2021 Nov 27.

Faculty of Medicine and Health Sciences, University of Leeds, Leeds, UK; Academic Plastic Surgery Office, Department of Plastic and Reconstructive Surgery, Leeds Teaching Hospitals Trust, Leeds LS1 3EX, UK. Electronic address:

Background: Abnormal ratios of peripheral blood cells, e.g. neutrophil-lymphocyte ratio (NLR), are strongly associated with poor outcomes in numerous cancers. In soft-tissue sarcoma (STS), the NLR has been studied in populations outside the UK although many have major methodological flaws, which represents the rationale for this study.

Methods: Over 17 years old (2002-2019) adults with extremity STS were included. The baseline NLR (at the time of diagnosis) was calculated. The association between NLR, disease recurrence and survival was explored using cubic splines and a threshold of 3 selected, which is in keeping with the literature. Multivariable Cox regression was used to estimate overall survival, disease-free survival and recurrence with Hazard Ratios (HR) and 95% confidence intervals (CI).

Results: Overall, 401 patients were included. The median follow-up was 3 years 8 months (interquartile range 1 years 7 months to 5 years 2 months). During surveillance 148 died (37%), of which 123 (76%) were attributable to sarcoma. At the time of diagnosis, an NLR≥3 was independently associated with worse overall survival (adjusted HR 1.44 [95% 1.01, 2.03]). However, the baseline NLR was not associated with the risk of recurrence (adjusted HR 0.98 [95% CI 0.62, 1.57]) or disease-free survival (adjusted HR 1.11 [95% CI 0.79, 1.56]).

Conclusions: At the time of diagnosis of STS, the NLR is strongly associated with survival and may serve as a cheap and readily available biomarker to personalise treatment plans for patients.
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http://dx.doi.org/10.1016/j.bjps.2021.11.063DOI Listing
April 2022

Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes.

Front Behav Neurosci 2021 2;15:786234. Epub 2021 Dec 2.

Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, United States.

Early-life adversity (ELA), often clinically referred to as "adverse childhood experiences (ACE)," is the exposure to stress-inducing events in childhood that can result in poor health outcomes. ELA negatively affects neurodevelopment in children and adolescents resulting in several behavioral deficits and increasing the risk of developing a myriad of neuropsychiatric disorders later in life. The neurobiological mechanisms by which ELA alters neurodevelopment in childhood have been the focus of numerous reviews. However, a comprehensive review of the mechanisms affecting adolescent neurodevelopment (i.e., synaptic pruning and myelination) is lacking. Synaptic pruning and myelination are glia-driven processes that are imperative for brain circuit refinement during the transition from adolescence to adulthood. Failure to optimize brain circuitry between key brain structures involved in learning and memory, such as the hippocampus and prefrontal cortex, leads to the emergence of maladaptive behaviors including increased anxiety or reduced executive function. As such, we review preclinical and clinical literature to explore the immediate and lasting effects of ELA on brain circuit development and refinement. Finally, we describe a number of therapeutic interventions best-suited to support adolescent neurodevelopment in children with a history of ELA.
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http://dx.doi.org/10.3389/fnbeh.2021.786234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678604PMC
December 2021

Opportunities and Challenges of Web-Based and Remotely Administered Surveys for Patient Preference Studies in a Vulnerable Population.

Patient Prefer Adherence 2021 15;15:2509-2517. Epub 2021 Nov 15.

Applied Research Division for Cognitive and Psychological Science, IEO, European Institute of Oncology IRCCS, Milan, Italy.

The application of web-based and remotely administered surveys is becoming increasingly popular due to the fact that it offers numerous advantages over traditional paper-based or computer-based surveys completed in the presence of the researcher. However, it is unclear whether complex preference elicitation tasks administered online in highly vulnerable patient populations are also feasible. This commentary discusses opportunities and challenges of conducting quantitative patient preference studies in lung cancer patients using web-based modes of data collection. We refer to our recent experience in the context of the Patient Preference in Benefit-Risk Assessments during the Drug Life Cycle (PREFER) project. Among the main advantages were the possibility of reaching a wider and geographically distant population in a shorter timeframe while reducing the financial costs of testing, the greater flexibility offered and the reduced burden on the patients. Some limitations were also identified and should be the object of further research, including the potential lack of inclusiveness of the research, the lack of control over who is completing the survey, a poor comprehension of the study material, and ultimately a lower level of engagement with the study. Despite these limitations, experience from the PREFER project suggests that online quantitative methods for data collection may provide a valuable method to explore preferences in vulnerable patient populations beyond the COVID-19 pandemic.
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http://dx.doi.org/10.2147/PPA.S327006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613941PMC
November 2021

An Analysis of Demographic and Triage Assessment Findings in Bushfire-Affected Koalas () on Kangaroo Island, South Australia, 2019-2020.

Animals (Basel) 2021 Nov 12;11(11). Epub 2021 Nov 12.

School of Animal and Veterinary Sciences, Faculty of Sciences, Roseworthy Campus, University of Adelaide, Adelaide, SA 5371, Australia.

In the 2019-2020 Australian bushfires, Kangaroo Island, South Australia, experienced catastrophic bushfires that burnt approximately half the island, with an estimated 80% of the koala population lost. During and after the event, rescued koalas were triaged at a designated facility and a range of initial data were recorded including rescue location and date, sex, estimation of age, body condition and hydration, and assessment of burn severity ( = 304 records available). Koalas were presented to the triage facility over a span of 10 weeks, with 50.2% during the first 14 days of the bushfire response, the majority of which were rescued from regions of lower fire severity. Burns were observed in 67.4% of koalas, with the majority (60.9%) classified as superficial burns, primarily affecting the limbs and face. Poor body condition was recorded in 74.6% of burnt koalas and dehydration in 77.1%. Negative final outcomes (death or euthanasia, at triage or at a later date) occurred in 45.6% of koalas and were significantly associated with higher mean burn score, maximum burn severity, number of body regions burnt, poor body condition score, and dehydration severity. The findings of this retrospective study may assist clinicians in the field with decision making when triaging koalas in future fire rescue efforts.
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http://dx.doi.org/10.3390/ani11113237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614434PMC
November 2021

Impact of Peer-Assisted Learning on Ultrasound.

J Physician Assist Educ 2021 Dec;32(4):253-256

Sarah Garvick, MS, MPAS, PA-C, is an assistant professor, the associate program director, and director of preclinical education for the PA program at the Wake Forest School of Medicine, Winston-Salem, North Carolina.

Purpose: The aim of this study was to understand how peer-assisted learning (PAL) could be utilized by physician assistant (PA) students in an ultrasound student interest group (USIG) as a means of developing cognitive confidence and practical competence with the imaging modality.

Methods: An observational study that included 3 USIG workshops was designed. Pre- and postworkshop surveys were administered. All first-year PA students, regardless of participation in the USIG workshops, were asked to complete the voluntary and anonymous surveys.

Results: A statistically significant difference between those who attended at least one workshop and those who did not attend any workshops on their postworkshop scores (p = 0.02) was seen. There was a statistically significant association between the number of workshops attended and the postworkshop difference (p = 0.03).

Conclusion: Results show that, in the context of social cognitive theory, PAL is an efficacious learning modality that enhances learner and tutor performance in ultrasound.
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http://dx.doi.org/10.1097/JPA.0000000000000392DOI Listing
December 2021

Fibroblast to myofibroblast transition is enhanced by increased cell density.

Mol Biol Cell 2021 12 3;32(22):ar41. Epub 2021 Nov 3.

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

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of the lung caused by a rampant inflammatory response that results in the deposition of excessive extracellular matrix (ECM). IPF patient lungs also develop fibroblastic foci that consist of activated fibroblasts and myofibroblasts. In concert with ECM deposition, the increased cell density within fibroblastic foci imposes confining forces on lung fibroblasts. In this work, we observed that increased cell density increases the incidence of the fibroblast-to-myofibroblast transition (FMT), but mechanical confinement imposed by micropillars has no effect on FMT incidence. We found that human lung fibroblasts (HLFs) express more α-SMA and deposit more collagen matrix, which are both characteristics of myofibroblasts, in response to TGF-β1 when cells are seeded at a high density compared with a medium or a low density. These results support the hypothesis that HLFs undergo FMT more readily in response to TGF-β1 when cells are densely packed, and this effect could be dependent on increased OB-cadherin expression. This work demonstrates that cell density is an important factor to consider when modelling IPF in vitro, and it may suggest decreasing cell density within fibroblastic foci as a strategy to reduce IPF burden.
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http://dx.doi.org/10.1091/mbc.E20-08-0536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8694087PMC
December 2021

Orchestrating and sharing large multimodal data for transparent and reproducible research.

Nat Commun 2021 10 4;12(1):5797. Epub 2021 Oct 4.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Reproducibility is essential to open science, as there is limited relevance for findings that can not be reproduced by independent research groups, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, scrutinized, challenged, and built upon. However, the intrinsic complexity and continuous growth of biomedical data makes it increasingly difficult to process, analyze, and share with the community in a FAIR (findable, accessible, interoperable, and reusable) manner. To overcome these issues, we created a cloud-based platform called ORCESTRA ( orcestra.ca ), which provides a flexible framework for the reproducible processing of multimodal biomedical data. It enables processing of clinical, genomic and perturbation profiles of cancer samples through automated processing pipelines that are user-customizable. ORCESTRA creates integrated and fully documented data objects with persistent identifiers (DOI) and manages multiple dataset versions, which can be shared for future studies.
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http://dx.doi.org/10.1038/s41467-021-25974-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490371PMC
October 2021

An examination of gender imbalance in Scottish adolescents' vocational interests.

PLoS One 2021 24;16(9):e0257723. Epub 2021 Sep 24.

Department of Experimental Psychology, Ghent University, Ghent, Belgium.

This paper documents Scottish adolescents' vocational interest types. Our research is based on the responses of 1,306 pupils from 18 secondary schools to an empirically verified online interest inventory test. Our results are threefold. First, the structural validity of the test with the Scottish sample is confirmed by evaluating the underlying circumplex structure of Holland's RIASEC vocational interests. Second, gender distribution along the six primary vocational interest dimensions is consistent with the research literature: young men scoring higher on the Realistic vocational interest and young women scoring higher on the Social dimension. Finally, we observe that across dimensions, vocational interests of young women are less diverse than those of young men. We discuss how these dissimilarities could lead to differences in education choice and career decision-making.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257723PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462744PMC
November 2021

Impact of the menstrual cycle on commercial prognostic gene signatures in oestrogen receptor-positive primary breast cancer.

Breast Cancer Res Treat 2021 Nov 15;190(2):295-305. Epub 2021 Sep 15.

Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK.

Purpose: Changes occur in the expression of oestrogen-regulated and proliferation-associated genes in oestrogen receptor (ER)-positive breast tumours during the menstrual cycle. We investigated if Oncotype® DX recurrence score (RS), Prosigna® (ROR) and EndoPredict® (EP/EPclin) prognostic tests, which include some of these genes, vary according to the time in the menstrual cycle when they are measured.

Methods: Pairs of test scores were derived from 30 ER-positive/human epidermal growth factor receptor-2-negative tumours sampled at two different points of the menstrual cycle. Menstrual cycle windows were prospectively defined as either W1 (days 1-6 and 27-35; low oestrogen and low progesterone) or W2 (days 7-26; high oestrogen and high or low progesterone).

Results: The invasion module score of RS was lower (- 10.9%; p = 0.098), whereas the ER (+ 16.6%; p = 0.046) and proliferation (+ 7.3%; p = 0.13) module scores were higher in W2. PGR expression was significantly increased in W2 (+ 81.4%; p = 0.0029). Despite this, mean scores were not significantly different between W1 and W2 for any of the tests and the two measurements showed high correlation (r = 0.72-0.93). However, variability between the two measurements led to tumours being assigned to different risk categories in the following proportion of cases: RS 22.7%, ROR 27.3%, EP 13.6% and EPclin 13.6%.

Conclusion: There are significant changes during the menstrual cycle in the expression of some of the genes and gene module scores comprising the RS, ROR and EP/EPclin scores. These did not affect any of the prognostic scores in a systematic fashion, but there was substantial variability in paired measurements.
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http://dx.doi.org/10.1007/s10549-021-06377-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558287PMC
November 2021

Effect of Active Lengthening and Shortening on Small-Angle X-ray Reflections in Skinned Skeletal Muscle Fibres.

Int J Mol Sci 2021 Aug 8;22(16). Epub 2021 Aug 8.

Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, Calgary, AB T2N1N4, Canada.

Our purpose was to use small-angle X-ray diffraction to investigate the structural changes within sarcomeres at steady-state isometric contraction following active lengthening and shortening, compared to purely isometric contractions performed at the same final lengths. We examined force, stiffness, and the 1,0 and 1,1 equatorial and M3 and M6 meridional reflections in skinned rabbit psoas bundles, at steady-state isometric contraction following active lengthening to a sarcomere length of 3.0 µm (15.4% initial bundle length at 7.7% bundle length/s), and active shortening to a sarcomere length of 2.6 µm (15.4% bundle length at 7.7% bundle length/s), and during purely isometric reference contractions at the corresponding sarcomere lengths. Compared to the reference contraction, the isometric contraction after active lengthening was associated with an increase in force (i.e., residual force enhancement) and M3 spacing, no change in stiffness and the intensity ratio I/I, and decreased lattice spacing and M3 intensity. Compared to the reference contraction, the isometric contraction after active shortening resulted in decreased force, stiffness, I/I, M3 and M6 spacings, and M3 intensity. This suggests that residual force enhancement is achieved without an increase in the proportion of attached cross-bridges, and that force depression is accompanied by a decrease in the proportion of attached cross-bridges. Furthermore, the steady-state isometric contraction following active lengthening and shortening is accompanied by an increase in cross-bridge dispersion and/or a change in the cross-bridge conformation compared to the reference contractions.
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http://dx.doi.org/10.3390/ijms22168526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395229PMC
August 2021

Optimization of a Series of RIPK2 PROTACs.

J Med Chem 2021 09 25;64(17):12978-13003. Epub 2021 Aug 25.

Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.
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http://dx.doi.org/10.1021/acs.jmedchem.1c01118DOI Listing
September 2021

Patient Preferences for Lung Cancer Treatments: A Study Protocol for a Preference Survey Using Discrete Choice Experiment and Swing Weighting.

Front Med (Lausanne) 2021 2;8:689114. Epub 2021 Aug 2.

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

Advanced treatment options for non-small cell lung cancer (NSCLC) consist of immunotherapy, chemotherapy, or a combination of both. Decisions surrounding NSCLC can be considered as preference-sensitive because multiple treatments exist that vary in terms of mode of administration, treatment schedules, and benefit-risk profiles. As part of the IMI PREFER project, we developed a protocol for an online preference survey for NSCLC patients exploring differences in preferences according to patient characteristics (preference heterogeneity). Moreover, this study will evaluate and compare the use of two different preference elicitation methods, the discrete choice experiment (DCE) and the swing weighting (SW) task. Finally, the study explores how demographic (i.e., age, gender, and educational level) and clinical (i.e., cancer stage and line of treatment) information, health literacy, health locus of control, and quality of life may influence or explain patient preferences and the usefulness of a digital interactive tool in providing information on preference elicitation tasks according to patients. An online survey will be implemented with the aim to recruit 510 NSCLC patients in Belgium and Italy. Participants will be randomized 50:50 to first receive either the DCE or the SW. The survey will also collect information on participants' disease-related status, health locus of control, health literacy, quality of life, and perception of the educational tool. This protocol outlines methodological and practical steps to quantitatively elicit and study patient preferences for NSCLC treatment alternatives. Results from this study will increase the understanding of which treatment aspects are most valued by NSCLC patients to inform decision-making in drug development, regulatory approval, and reimbursement. Methodologically, the comparison between the DCE and the SW task will be valuable to gain information on how these preference methods perform against each other in eliciting patient preferences. Overall, this protocol may assist researchers, drug developers, and decision-makers in designing quantitative patient preferences into decision-making along the medical product life cycle.
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http://dx.doi.org/10.3389/fmed.2021.689114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365300PMC
August 2021

A study protocol for quantifying patient preferences in neuromuscular disorders: a case study of the IMI PREFER Project.

Wellcome Open Res 2020 23;5:253. Epub 2020 Oct 23.

Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, UK.

Patient preference studies are increasingly used to inform decision-making during the medical product lifecycle but are rarely used to inform early stages of drug development.  The primary aim of this study is to quantify treatment preferences of patients with neuromuscular disorders, which represent serious and debilitating conditions with limited or no treatment options available. This quantitative patient preferences study was designed as an online survey, with a cross-over design.  This study will target two different diseases from the neuromuscular disorders disease group, myotonic dystrophy type 1 (DM1) and mitochondrial myopathies (MM). Despite having different physio-pathological pathways both DM1 and MM manifest in a clinically similar manner and may benefit from similar treatment options.  The sample will be stratified into three subgroups: two patient groups differentiated by age of symptom onset and one caregivers group.   Each subgroup will be randomly assigned to complete two of three different preference elicitation methods at two different time points: Q-methodology survey, discrete choice experiment, and best-worst scaling type 2, allowing cross-comparisons of the results across each study time within participants and within elicitation methods. Additional variables such as sociodemographic, clinical and health literacy will be collected to enable analysis of potential heterogeneity. This study protocol has undergone ethical review and approval by the Newcastle University R&D Ethics Committee (Ref: 15169/2018). All participants will be invited to give electronic informed consent to take part in the study prior accessing the online survey. All electronic data will be anonymised prior analysis. This study is part of the Patient Preferences in Benefit-Risk Assessments during the Drug Life Cycle (IMI-PREFER) project, a public-private collaborative research project aiming to develop expert and evidence-based recommendations on how and when patient preferences can be assessed and used to inform medical product decision making.
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http://dx.doi.org/10.12688/wellcomeopenres.16116.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356266PMC
October 2020

Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update.

J Clin Oncol 2021 12 29;39(35):3938-3958. Epub 2021 Jul 29.

UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC.

Purpose: This guideline updates recommendations of the ASCO guideline on chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) that is either endocrine-pretreated or hormone receptor (HR)-negative.

Methods: An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations.

Results: The Expert Panel reviewed abstracts from the literature review and retained 14 articles.

Recommendations: Patients with triple-negative, programmed cell death ligand-1-positive MBC may be offered the addition of immune checkpoint inhibitor to chemotherapy as first-line therapy. Patients with triple-negative, programmed cell death ligand-1-negative MBC should be offered single-agent chemotherapy rather than combination chemotherapy as first-line treatment, although combination regimens may be offered for life-threatening disease. Patients with triple-negative MBC who have received at least two prior therapies for MBC should be offered treatment with sacituzumab govitecan. Patients with triple-negative MBC with germline mutations previously treated with chemotherapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. Patients with HR-positive human epidermal growth factor receptor 2-negative MBC for whom chemotherapy is being considered should be offered single-agent chemotherapy rather than combination chemotherapy, although combination regimens may be offered for highly symptomatic or life-threatening disease. Patients with HR-positive MBC with disease progression on an endocrine agent may be offered treatment with either endocrine therapy with or without targeted therapy or single-agent chemotherapy. Patients with HR-positive MBC with germline mutations no longer benefiting from endocrine therapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. No recommendation regarding when a patient's care should be transitioned to hospice or best supportive care alone is possible.Additional information is available at www.asco.org/breast-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.21.01374DOI Listing
December 2021

Short midline catheters: High success rates for antibiotic therapy in children with cystic fibrosis.

J Vasc Access 2021 Jul 23:11297298211035310. Epub 2021 Jul 23.

Anaesthesia and Pain Management, The Royal Children's Hospital, Parkville, VIC, Australia.

Objective: Short midline catheter use in paediatric populations appears to be increasing, however data on success rates and efficacy are sparse. This study aims to describe the success rate when midline venous catheters are employed as a single device for intravenous antibiotic therapy in paediatric patients with cystic fibrosis.

Methods: A retrospective cohort study was performed in a single institution, retrieving electronic medical record data from July 2017 through March 2020. The primary outcome was device success, defined as a catheter that remained functional until the end of antibiotic therapy. Reasons for device failure were categorized in a standard fashion.

Results: Primary outcome data were available for 116 catheter insertions, involving 49 patients and 55 proceduralists. The success rate was 84% ( = 98). Median age at insertion was 15 years (range 4-19) and median weight 52 kg (13-81). Soft, polyether block amide, Arrow Seldinger Arterial Catheters were employed. Only 16 patients (14%) required general anaesthesia. Median time to failure was 6 days, and median time to successful completion of treatment was 13 days. Six of 18 failures occurred within 48 h and were likely insertion complications. The most common reasons for device failure were occlusion, extravasation, phlebitis and dislodgement. More than half of patients (56%) received antibiotic therapy at home.

Conclusion: There is a high single device success rate when inserting short midlines for 13-day intravenous pulmonary antibiotic therapy in children with cystic fibrosis. These results should be confirmed with a prospective study.
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http://dx.doi.org/10.1177/11297298211035310DOI Listing
July 2021

Glucocorticoid Abnormalities in Female Rats Exposed to a Predator-Based Psychosocial Stress Model of PTSD.

Front Behav Neurosci 2021 18;15:675206. Epub 2021 Jun 18.

Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV, United States.

People with post-traumatic stress disorder (PTSD) exhibit heightened anxiety and enhanced negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis. We previously reported that male rats exposed to a predator-based psychosocial stress model of PTSD exhibited comparable changes in anxiety-like behavior and HPA axis activity, including lower baseline levels of corticosterone and a greater suppression of corticosterone after dexamethasone administration. Here, we assessed whether we would observe similar effects in female rats exposed to this model. Adult female Sprague-Dawley rats were exposed to a cat on two occasions (separated by 10 days), in combination with chronic social instability. Three weeks after the second cat exposure, we assessed anxiety-like behavior on an elevated plus maze (EPM) and collected blood samples from rats in the absence or presence of dexamethasone to quantify serum corticosterone levels. Although stressed females did not display heightened anxiety on the EPM, they exhibited significantly lower overall corticosterone levels and a greater suppression of corticosterone after dexamethasone administration. The observation of significantly lower overall corticosterone levels in stressed females was replicated in a separate, independent experiment. These findings suggest that the predator-based psychosocial stress model of PTSD may be useful for studying mechanisms that underlie changes in HPA axis function in females exposed to trauma.
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http://dx.doi.org/10.3389/fnbeh.2021.675206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249699PMC
June 2021

Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom.

Clin Trials 2021 10 22;18(5):615-621. Epub 2021 Jun 22.

NIHR Cambridge Clinical Research Facility, Cambridge Clinical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency.
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http://dx.doi.org/10.1177/17407745211024764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479147PMC
October 2021

Identification of phosphosites that alter protein thermal stability.

Nat Methods 2021 07 17;18(7):760-762. Epub 2021 Jun 17.

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

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http://dx.doi.org/10.1038/s41592-021-01178-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783534PMC
July 2021
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