Publications by authors named "Matthew Thompson"

545 Publications

Trends in the prescription of systemic anticancer therapy and mortality among patients with advanced non-small cell lung cancer: a real-world retrospective observational cohort study from the I-O optimise initiative.

BMJ Open 2021 May 3;11(5):e043442. Epub 2021 May 3.

Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Objectives: To assess how a decade of developments in systematic anticancer therapy (SACT) for advanced non-small cell lung cancer (NSCLC) affected overall survival (OS) in a large UK University Hospital.

Design: Real-world retrospective observational cohort study using existing data recorded in electronic medical records.

Setting: A large National Health Service (NHS) university teaching hospital serving 800 000 people living in a diverse metropolitan area of the UK.

Participants: 2119 adults diagnosed with advanced NSCLC (tumour, node, metastasis stage IIIB or IV) between 2007 and 2017 at Leeds Teaching Hospitals NHS Trust.

Main Outcomes And Measures: OS following diagnosis and the analysis of factors associated with receiving SACT.

Results: Median OS for all participants was 2.9 months, increasing for the SACT-treated subcohort from 8.4 months (2007-2012) to 9.1 months (2013-2017) (p=0.02); 1-year OS increased from 33% to 39% over the same period for the SACT-treated group. Median OS for the untreated subcohort was 1.6 months in both time periods. Overall, 30.6% (648/2119) patients received SACT; treatment rates increased from 28.6% (338/1181) in 2007-2012 to 33.0% (310/938) in 2013-2017 (p=0.03). Age and performance status were independent predictors for SACT treatment; advanced age and higher performance status were associated with lower SACT treatment rates.

Conclusion: Although developments in SACT during 2007-2017 correspond to some changes in survival for treated patients with advanced NSCLC, treatment rates remain low and the prognosis for all patients remains poor.
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http://dx.doi.org/10.1136/bmjopen-2020-043442DOI Listing
May 2021

Viral genomes reveal patterns of the SARS-CoV-2 outbreak in Washington State.

Sci Transl Med 2021 May 3. Epub 2021 May 3.

Seattle Children's Research Institute, 98101 Seattle, WA, USA.

The rapid spread of SARS-CoV-2 has gravely impacted societies around the world. Outbreaks in different parts of the globe have been shaped by repeated introductions of new viral lineages and subsequent local transmission of those lineages. Here, we sequenced 3940 SARS-CoV-2 viral genomes from Washington State to characterize how the spread of SARS-CoV-2 in Washington State (USA) in early 2020 was shaped by differences in timing of mitigation strategies across counties, as well as by repeated introductions of viral lineages into the state. Additionally, we show that the increase in frequency of a potentially more transmissible viral variant (614G) over time can potentially be explained by regional mobility differences and multiple introductions of 614G, but not the other variant (614D) into the state. At an individual level, we observed evidence of higher viral loads in patients infected with the 614G variant. However, using clinical records data, we did not find any evidence that the 614G variant impacts clinical severity or patient outcomes. Overall, this suggests that with regards to D614G, the behavior of individuals has been more important in shaping the course of the pandemic in Washington State than this variant of the virus.
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http://dx.doi.org/10.1126/scitranslmed.abf0202DOI Listing
May 2021

Anisotropic Synthetic Allomelanin Materials via Solid State Polymerization of Self-Assembled 1,8-Dihydroxynaphthalene Dimers.

Angew Chem Int Ed Engl 2021 Apr 28. Epub 2021 Apr 28.

Northwestern University, Chemistry, 2145 Sheridan Road, 6000, Evanston, UNITED STATES.

Melanosomes have diverse morphologies in nature, including spheres, rods, and platelets. By contrast, shapes of synthetic melanins have been almost entirely limited to spherical nanoparticles with few exceptions produced by complex templated synthetic methods. Here, we report a non-templated method to access synthetic melanins with a variety of architectures including spheres, sheets, and platelets. Three 1,8-dihydroxynaphthalene dimers (4-4', 2-4' and 2-2') were used as self-assembling synthons. These dimers pack to form well-defined structures of varying morphologies depending on the isomer. Specifically, distinctive ellipsoidal platelets can be obtained using 4-4' dimers. Solid-state polymerization of the preorganized dimers generates polymeric synthetic melanins while maintaining the initial particle morphologies. This work provides a new route to anisotropic synthetic melanins, where the building blocks are preorganized into specific shapes, followed by solid-state polymerization.
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http://dx.doi.org/10.1002/anie.202103447DOI Listing
April 2021

Experiences along the diagnostic pathway for patients with advanced lung cancer in the USA: a qualitative study.

BMJ Open 2021 Apr 22;11(4):e045056. Epub 2021 Apr 22.

Department of Family Medicine, University of Washington, Seattle, Washington, USA.

Background: Most patients with lung cancer are diagnosed at advanced stages. However, the advent of oral targeted therapies has improved the prognosis of many patients with lung cancer.

Purpose: We aimed to understand the diagnostic experiences of patients with advanced lung cancer with oncogenic mutations.

Methods: Qualitative interviews were conducted with patients with advanced or metastatic non-small cell lung cancer with oncogenic alterations. Patients were recruited from online support groups within the USA. Interviews were conducted remotely or in person. Analysis used an iterative inductive and deductive process. Themes were mapped to the Model for Pathways to Treatment.

Results: 40 patients (12 male and 28 female) with a median age of 48 were included. We identified nine distinct themes. During the 'patient interval', individuals became concerned about symptoms, but often attributed them to other causes. Prolonged or more severe symptoms prompted care-seeking. During the 'primary care interval', doctors initially treated for illnesses other than cancer. Discovery of an imaging abnormality was a turning point in diagnostic pathways. Occasionally, severity of symptoms prompted patients to seek emergency care. During the 'secondary care interval', obtaining tissue samples was pivotal in confirming diagnosis. Delays in accessing oncology care sometimes led to patient distress. Obtaining genetic testing was crucial in directing patients to receive targeted treatments.

Conclusions: Patients experienced multiple different routes to their diagnosis. Some patients perceived delays, inefficiencies and lack of coordination, which could be distressing. Shifting the stage of diagnosis of lung cancer to optimise the impact of targeted therapies will require concerted efforts in early detection.
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http://dx.doi.org/10.1136/bmjopen-2020-045056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070881PMC
April 2021

Development of continuous flow systems to access secondary amines through previously incompatible biocatalytic cascades.

Angew Chem Int Ed Engl 2021 Apr 15. Epub 2021 Apr 15.

The University of Manchester, chemistry, UNITED KINGDOM.

A key aim of biocatalysis is to mimic the ability of eukaryotic cells to carry out multistep cascades in a controlled and selective way. As biocatalytic cascades get more complex, reactions become unattainable under typical batch conditions. Here a number of continuous flow systems were used to overcome batch incompatibility, thus allowing for successful biocatalytic cascades. As proof-of-principle, reactive carbonyl intermediates were generated in situ using alcohol oxidases, then passed directly to a series of packed-bed modules containing different aminating biocatalysts which accordingly produced a range of structurally distinct amines. The method was expanded to employ a batch incompatible sequential amination cascade via an oxidase/transaminase/imine reductase sequence, introducing different amine reagents at each step without cross reactivity. The combined approaches allowed for the biocatalytic synthesis of the natural product 4O-methylnorbelladine. The flow biocatalysis platform shown here significantly increases the scope of novel biocatalytic cascades, removing previous limitations due to reaction and reagent batch incompatibility.
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http://dx.doi.org/10.1002/anie.202103805DOI Listing
April 2021

Ensuring Informed Decision-Making for Cancer Screening.

J Am Board Fam Med 2021 Mar-Apr;34(2):435-438

From the Leeds Institute of Health Sciences, University of Leeds, UK (SHB); Department of Family Medicine, University of Washington, Seattle (MJT); Nuffield Department of Primary Care Health Sciences, University of Oxford, UK (BDN).

The history of cancer screening has demonstrated that the case for cancer screening is not straightforward. In contemporary practice, sharing decision-making with patients has become expected of family physicians. At the same time, increasing emphasis has been placed on encouraging patients to participate in screening programs to improve cancer outcomes. The success of cancer screening is often judged by the number of those who participate. Improving cancer outcomes should be a priority for family medicine, but the importance of this goal should not undermine doctors' commitment to helping patients make informed decisions that are consistent with their values and priorities. If we are serious about empowering patients, we need to be more open about the limitations of cancer screening, to help patients make up their minds.
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http://dx.doi.org/10.3122/jabfm.2021.02.200353DOI Listing
July 2020

Extracting COVID-19 diagnoses and symptoms from clinical text: A new annotated corpus and neural event extraction framework.

J Biomed Inform 2021 Mar 26;117:103761. Epub 2021 Mar 26.

Biomedical & Health Informatics, University of Washington, Box 358047, Seattle, WA 98109, USA.

Coronavirus disease 2019 (COVID-19) is a global pandemic. Although much has been learned about the novel coronavirus since its emergence, there are many open questions related to tracking its spread, describing symptomology, predicting the severity of infection, and forecasting healthcare utilization. Free-text clinical notes contain critical information for resolving these questions. Data-driven, automatic information extraction models are needed to use this text-encoded information in large-scale studies. This work presents a new clinical corpus, referred to as the COVID-19 Annotated Clinical Text (CACT) Corpus, which comprises 1,472 notes with detailed annotations characterizing COVID-19 diagnoses, testing, and clinical presentation. We introduce a span-based event extraction model that jointly extracts all annotated phenomena, achieving high performance in identifying COVID-19 and symptom events with associated assertion values (0.83-0.97 F1 for events and 0.73-0.79 F1 for assertions). Our span-based event extraction model outperforms an extractor built on MetaMapLite for the identification of symptoms with assertion values. In a secondary use application, we predicted COVID-19 test results using structured patient data (e.g. vital signs and laboratory results) and automatically extracted symptom information, to explore the clinical presentation of COVID-19. Automatically extracted symptoms improve COVID-19 prediction performance, beyond structured data alone.
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http://dx.doi.org/10.1016/j.jbi.2021.103761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997694PMC
March 2021

Building eConsult (Electronic Consults) Capability at an Academic Medical Center to Improve Efficiencies in Delivering Specialty Care.

J Prim Care Community Health 2021 Jan-Dec;12:21501327211005303

University of Colorado School of Medicine, Aurora, CO, USA.

As the COVID-19 health crisis continues to reshape healthcare, systems across the country face increasing pressure to adapt their models of care to expand access to care, while also improving efficiency and quality in the face of limited resources. Consequently, many have shown a growing interest and receptivity to the expansion of telehealth models to help meet these demands. Electronic consultations (eConsults) are a telehealth modality that allow for a non-face-to-face asynchronous consultation between a primary care provider (PCP) and a specialist aimed at facilitating specialist input without the need for a patient visit. The aim of this case study is to describe eConsults, how they differ from traditional in person models of care and other models of telemedicine and to review the evidence related to the effectiveness of eConsults by PCPs and clinicians from multiple specialties at the University of Colorado School of Medicine. We have worked to develop an infrastructure, delivery system integration, and care model adaptations that aim to improve delivery system performance by ensuring proper care in appropriate settings and lowering costs through reduced utilization. Lastly, we have increased care coordination, improved collaboration and better care transitions through strengthening of relationships between community-based PCPs and academic medical center-based specialists. This work has resulted in cost savings to patients and positive provider satisfaction.
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http://dx.doi.org/10.1177/21501327211005303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010812PMC
April 2021

Impact of Web-Based Self-Scheduling on Finalization of Well-Child Appointments in a Primary Care Setting: Retrospective Comparison Study.

JMIR Med Inform 2021 Mar 18;9(3):e23450. Epub 2021 Mar 18.

Department of Neurology, Mayo Clinic, Rochester, MN, United States.

Background: Web-booking of flights, hotels, and sports events has become commonplace in the travel and entertainment industry, but self-scheduling of health care appointments on the web is not yet widely used. An electronic health record that integrates appointment scheduling and patient web-based access to medical records creates an opportunity for patient self-scheduling. The Mayo Clinic developed and implemented a feature in its Patient Online Services (POS) web and mobile platform that allows software-managed self-scheduling of well-child visits.

Objective: This study aims to examine the use of a new self-scheduling appointment feature within POS in both web and mobile formats and determine the use characteristics, outcomes, and efficiency of self-scheduling compared with staff scheduling.

Methods: Within a primary care setting, we collected 13 months of all appointment activity for the well-child visit for children aged 2-12 years. As these specific appointment types are for minors, self-scheduling is performed by parents or other proxies. We compared the appointment actions of scheduling and cancelling for both self-scheduled and staff-scheduled appointments. The frequency in which patients were using self-scheduling outside of normal business hours was quantified, and we compared no-show outcomes of finalized appointments.

Results: Of the 1099 patients who performed any self-scheduling actions, 73.1% (803/1099) exclusively used self-scheduling and self-cancelling software. For those with access to self-scheduling (patients registered with the Mayo Clinic POS), 4.92% (1201/24,417) of all well-child appointment-scheduling actions were self-scheduled. Staff scheduling required more than a single appointment step (eg, schedule, cancel, reschedule) in 28.32% (3729/13,168) compared with only 6.93% (53/765) of self-scheduled appointments (P<.001). Self-scheduling appointment actions took place outside of regular business hours 29.5% (354/1201) of the time. No-shows accounted for 3.07% (28/912) of the self-scheduled finalized appointments compared with 4.12% (693/16,828) of staff-scheduled appointments, which is a nonsignificant difference (P=.12). Staff-scheduled finalized appointments (that allowed for scheduling appointments for more than 12 weeks in the future) revealed a potential demand of 11.15% (1876/16,828) for appointments with longer lead times.

Conclusions: Self-scheduling can generate a significant number of finalized appointments, decreasing the need for staff scheduler time. We found that 29.5% (354/1201) of the self-scheduling activity took place outside of the usual staff scheduler hours, adding convenience value to the scheduling process. For exclusive self-schedulers, 93.1% (712/765) finalized the appointment in a single step. The no-show rates were not adversely affected by the self-scheduling.
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http://dx.doi.org/10.2196/23450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077742PMC
March 2021

Outcomes of Patients with Sarcoma and COVID-19 Infection: A Single Institution Cohort Analysis.

Cancer Invest 2021 Apr 26;39(4):315-320. Epub 2021 Mar 26.

Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington, USA.

Outcomes for patients (pts) with sarcoma and COVID-19 are unknown. This is a single institution retrospective study of adults with sarcoma and COVID-19. Ten pts [median age 60 (range 24-69)] were identified. Five were hospitalized; two died from COVID-19 complications; another died from sarcoma. Time between last systemic treatment dose and COVID-19 diagnosis was 6-41 days in pts who died. 5 underwent prior radiation (RT); time between RT and COVID-19 diagnosis was 20-62 days for pts who died. All three pts with WBC differential data (two died) were lymphopenic. Efforts to capture outcomes for a larger cohort are urgently needed.
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http://dx.doi.org/10.1080/07357907.2021.1903914DOI Listing
April 2021

Range of Motion to Impingement Curves Create a New Patient-Specific Impingement-Free Zone for Acetabular Cup Placement.

Surg Technol Int 2021 02 10;38. Epub 2021 Feb 10.

Northwell Health, Lenox Hill Hospital, New York, New York.

Introduction: The acetabular "safe zone" has recently been questioned as a reliable reference for predicting total hip arthroplasty impingement and instability as many dislocations occur within the described parameters. Recently, an improved understanding of spino-pelvic mechanics has provided surgeons useful information to both identify those at a higher risk of dislocation and, in some cases, allows altering component positioning to accommodate the patient's individual "functional" range of motion. The purpose of this study was to create a new patient-specific impingement-free zone by considering range of motion (ROM) to prosthetic impingement for both high flexion and extension poses, thus demarcating a zone that avoids both anterior and posterior impingement, thereby creating an objective approach to identifying a patient's ideal functional safe zone.

Materials And Methods: A validated hip ROM three-dimensional simulator was utilized to create ROM-to-impingement curves for both high flexion as well as pivot and turn poses. The user imported a computerized tomography (CT) with a supine pelvic tilt (PT) value of zero and implant models (tapered wedge stem, 132° neck angle, 15° stem version, 36mm femoral head). Femur-to-pelvis relative motions were determined for three upright seated poses (femur flexed at 90° and 40° internal rotation, with 0°, 10°, and 20° posterior PT), one chair rise pose (femur flexed at 90° and 0° internal rotation, with the pelvis flexed anteriorly until the pelvis made contact with the femur), and three standing pivot and turn poses (femur set at 5° extension, and 35° external rotation, with 5° posterior PT, 0°, and 5° anterior PT). ROM-to-impingement curves for cup inclination versus anteversion were graphed and compared against the Lewinnek safe zone.

Results: The ROM-to-impingement curves provide an objective assessment of potential impingement sites as they relate to femoral rotation and pelvic tilt. The area between the stand and sit curves is the impingement-free area. A sitting erect pose with a simulated stiff spine (0° PT) yielded less impingement-free combinations of cup inclination and version than poses with greater than 0° posterior pelvic tilt.

Conclusion: The results demonstrate that the acetabular target zone has a relatively small margin for error between the sitting and standing ROM curves to impingement. Importantly, anterior and posterior pelvic tilt can markedly increase the risk of impingement, potentially leading to posterior or anterior dislocations, respectively. This study highlights the importance of correctly identifying the patient-specific functional range of motion to execute optimal component positioning.
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February 2021

Evaluating Specimen Quality and Results from a Community-Wide, Home-Based Respiratory Surveillance Study.

J Clin Microbiol 2021 Apr 20;59(5). Epub 2021 Apr 20.

Department of Medicine, University of Washington, Seattle, Washington, USA

While influenza and other respiratory pathogens cause significant morbidity and mortality, the community-based burden of these infections remains incompletely understood. The development of novel methods to detect respiratory infections is essential for mitigating epidemics and developing pandemic-preparedness infrastructure. From October 2019 to March 2020, we conducted a home-based cross-sectional study in the greater Seattle, WA, area, utilizing electronic consent and data collection instruments. Participants received nasal swab collection kits via rapid delivery within 24 hours of self-reporting respiratory symptoms. Samples were returned to the laboratory and were screened for 26 respiratory pathogens and a housekeeping gene. Participant data were recorded via online survey at the time of sample collection and 1 week later. Of the 4,572 consented participants, 4,359 (95.3%) received a home swab kit and 3,648 (83.7%) returned a nasal specimen for respiratory pathogen screening. The 3,638 testable samples had a mean RNase P relative cycle threshold ( ) value of 19.0 (SD, 3.4), and 1,232 (33.9%) samples had positive results for one or more pathogens, including 645 (17.7%) influenza-positive specimens. Among the testable samples, the median time between shipment of the home swab kit and completion of laboratory testing was 8.0 days (interquartile range [IQR], 7.0 to 14.0). A single adverse event occurred and did not cause long-term effects or require medical attention. Home-based surveillance using online participant enrollment and specimen self-collection is a safe and feasible method for community-level monitoring of influenza and other respiratory pathogens, which can readily be adapted for use during pandemics.
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http://dx.doi.org/10.1128/JCM.02934-20DOI Listing
April 2021

Measuring patient experience of diagnostic care and acceptability of testing.

Diagnosis (Berl) 2021 Jan 28. Epub 2021 Jan 28.

Department of Behavioural Science and Health, UCL, London, UK.

A positive patient experience has been long recognised as a key feature of a high-quality health service, however, often assessment of patient experience excludes diagnostic care. Experience of diagnostic services and the acceptability of diagnostic tests are often conflated, with lack of clarity about when and how either should be measured. These problems contrast with the growth in the development and marketing of new tests and investigation strategies. Building on the appraisal of current practice, we propose that the experience of diagnostic services and the acceptability of tests should be assessed separately, and describe distinct components of each. Such evaluations will enhance the delivery of patient-centred care, and facilitate patient choice.
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http://dx.doi.org/10.1515/dx-2020-0112DOI Listing
January 2021

Diagnostic accuracy of an app-guided, self-administered test for influenza among individuals presenting to general practice with influenza-like illness: study protocol.

BMJ Open 2020 11 19;10(11):e036298. Epub 2020 Nov 19.

Family Medicine, University of Washington, Seattle, Washington, USA.

Introduction: Diagnostic tests for influenza in Australia are currently only authorised for use in clinical settings. At-home diagnostic testing for influenza could reduce the need for patient contact with healthcare services, which potentially could contribute to symptomatic improvement and reduced spread of influenza. We aim to determine the accuracy of an app-guided nasal self-swab combined with a lateral flow immunoassay for influenza conducted by individuals with influenza-like illness (ILI).

Methods And Analysis: Adults (≥18 years) presenting with ILI will be recruited by general practitioners (GP) participating in Australian Sentinel Practices Research Network. Eligible participants will have a nasal swab obtained by their GP for verification of influenza A/B status using reverse transcription polymerase chain reaction (RT-PCR) test at an accredited laboratory. Participants will receive an influenza test kit and will download an app that collects self-reported symptoms and influenza risk factors, then instructs them in obtaining a low-nasal self-swab, running a QuickVue influenza A+B lateral flow immunoassay (Quidel Corporation) and interpreting the results. Participants will also interpret an enhanced image of the test strip in the app. The primary outcome will be the accuracy of participants' test interpretation compared with the laboratory RT-PCR reference standard. Secondary analyses will include accuracy of the enhanced test strip image, accuracy of an automatic test strip reader algorithm and validation of prediction rules for influenza based on self-reported symptoms. A post-test survey will be used to obtain participant feedback on self-test procedures.

Ethics And Dissemination: The study was approved by the Human Research and Ethic Committee (HREC) at the University of Adelaide (H-2019-116). Protocol details and any amendments will be reported to https://www.tga.gov.au/. Results will be published in the peer-reviewed literature, and shared with stakeholders in the primary care and diagnostics communities.

Trial Registration Number: Australia New Zealand Clinical Trial Registry (U1111-1237-0688).
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http://dx.doi.org/10.1136/bmjopen-2019-036298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678361PMC
November 2020

Extracting COVID-19 Diagnoses and Symptoms From Clinical Text: A New Annotated Corpus and Neural Event Extraction Framework.

ArXiv 2020 Dec 2. Epub 2020 Dec 2.

Coronavirus disease 2019 (COVID-19) is a global pandemic. Although much has been learned about the novel coronavirus since its emergence, there are many open questions related to tracking its spread, describing symptomology, predicting the severity of infection, and forecasting healthcare utilization. Free-text clinical notes contain critical information for resolving these questions. Data-driven, automatic information extraction models are needed to use this text-encoded information in large-scale studies. This work presents a new clinical corpus, referred to as the COVID-19 Annotated Clinical Text (CACT) Corpus, which comprises 1,472 notes with detailed annotations characterizing COVID-19 diagnoses, testing, and clinical presentation. We introduce a span-based event extraction model that jointly extracts all annotated phenomena, achieving high performance in identifying COVID-19 and symptom events with associated assertion values (0.83-0.97 F1 for events and 0.73-0.79 F1 for assertions). In a secondary use application, we explored the prediction of COVID-19 test results using structured patient data (e.g. vital signs and laboratory results) and automatically extracted symptom information. The automatically extracted symptoms improve prediction performance, beyond structured data alone.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724670PMC
December 2020

Low-intensity vibration restores nuclear YAP levels and acute YAP nuclear shuttling in mesenchymal stem cells subjected to simulated microgravity.

NPJ Microgravity 2020 Dec 1;6(1):35. Epub 2020 Dec 1.

Mechanical and Biomedical Engineering, Boise State University, Boise, ID, USA.

Reducing the musculoskeletal deterioration that astronauts experience in microgravity requires countermeasures that can improve the effectiveness of otherwise rigorous and time-expensive exercise regimens in space. The ability of low-intensity vibrations (LIV) to activate force-responsive signaling pathways in cells suggests LIV as a potential countermeasure to improve cell responsiveness to subsequent mechanical challenge. Mechanoresponse of mesenchymal stem cells (MSC), which maintain bone-making osteoblasts, is in part controlled by the "mechanotransducer" protein YAP (Yes-associated protein), which is shuttled into the nucleus in response to cyto-mechanical forces. Here, using YAP nuclear shuttling as a measurement outcome, we tested the effect of 72 h of clinostat-induced simulated microgravity (SMG) and daily LIV application (LIV) on the YAP nuclear entry driven by either acute LIV (LIV) or Lysophosphohaditic acid (LPA), applied after the 72 h period. We hypothesized that SMG-induced impairment of acute YAP nuclear entry would be alleviated by the daily application of LIV. Results showed that while both acute LIV and LPA treatments increased nuclear YAP entry by 50 and 87% over the basal levels in SMG-treated MSCs, nuclear YAP levels of all SMG groups were significantly lower than non-SMG controls. LIV, applied in parallel to SMG, restored the SMG-driven decrease in basal nuclear YAP to control levels as well as increased the LPA-induced but not LIV-induced YAP nuclear entry over SMG only, counterparts. These cell-level observations suggest that daily LIV treatments are a feasible countermeasure for restoring basal nuclear YAP levels and increasing the YAP nuclear shuttling in MSCs under SMG.
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http://dx.doi.org/10.1038/s41526-020-00125-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708987PMC
December 2020

Viral-induced alternative splicing of host genes promotes influenza replication.

Elife 2020 12 3;9. Epub 2020 Dec 3.

Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, United States.

Viral infection induces the expression of numerous host genes that impact the outcome of infection. Here, we show that infection of human lung epithelial cells with influenza A virus (IAV) also induces a broad program of alternative splicing of host genes. Although these splicing-regulated genes are not enriched for canonical regulators of viral infection, we find that many of these genes do impact replication of IAV. Moreover, in several cases, specific inhibition of the IAV-induced splicing pattern also attenuates viral infection. We further show that approximately a quarter of the IAV-induced splicing events are regulated by hnRNP K, a host protein required for efficient splicing of the IAV M transcript in nuclear speckles. Finally, we find an increase in hnRNP K in nuclear speckles upon IAV infection, which may alter accessibility of hnRNP K for host transcripts thereby leading to a program of host splicing changes that promote IAV replication.
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http://dx.doi.org/10.7554/eLife.55500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735754PMC
December 2020

End-user perspectives of two mHealth decision support tools: Electronic Community Case Management in Northern Malawi.

Int J Med Inform 2021 01 10;145:104323. Epub 2020 Nov 10.

Global eHealth Unit, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK; Assert Research Centre, University College Cork, Ireland; Malawi eHealth Research Centre, University College Cork, Ireland.

Background: The introduction of a paper-based Community Case Management (CCM) in Malawi has contributed to a reduction of child morbidity and mortality rates. In addition, the introduction of electronic Community Case Management (eCCM) (smartphones with built in CCM apps) may help to reduce the under-five mortality rates even further.

Purpose: It is not uncommon for Apps with a similar area of interest to develop different features to assist the end users. Such differences between Apps may have a significant role to play in its overall adoption and integration. The purpose of this research was to explore end users perspectives of two eCCM decision support tools developed and implemented by the Supporting LIFE project (SL eCCM App) and D-Tree International's (Mangologic eCCM App)in Northern Malawi.

Methods: A mixed methods approach was applied, involving a survey of 109 users (106 Health Surveillance Assistants (HSAs), and 3 Integrated Management of Childhood Il6lnesses (IMCI) coordinators). This was followed up with semi-structured interviews with 34 respondents (31 HSAs, and 3 IMCI coordinators). Quantitative data was analyzed using SPSS version 20 where descriptive statistics and Chi-Squared tests were generated. Qualitative data were analyzed based on thematic analysis.

Results: Participants reported that both Apps could assist the HSAs in the management of childhood illnesses. However, usability differed between the two apps where the Supporting LIFE eCCM App was found to be easier to use (61%) compared to the Mangologic eCCM App (4%). Both Apps were perceived to provide credible and accurate information.

Conclusion: It is essential that the quality of the data within Mobile Health (mHealth) Apps is high, however even Apps with excellent levels of data quality may not succeed if the overall usability of the App is low. Therefore it is essential that the Apps has high levels of data quality, usability and credibility. The results of this study will help inform mobile Health (mHealth) App designers in developing future eCCM Apps as well as researchers and policy makers when considering the adoption of mHealth solutions in the future in Malawi and other LMICs.
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http://dx.doi.org/10.1016/j.ijmedinf.2020.104323DOI Listing
January 2021

Towards Molecular Simulations that are Transparent, Reproducible, Usable By Others, and Extensible (TRUE).

Mol Phys 2020 8;118(9-10). Epub 2020 Apr 8.

Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.

Systems composed of soft matter (e.g., liquids, polymers, foams, gels, colloids, and most biological materials) are ubiquitous in science and engineering, but molecular simulations of such systems pose particular computational challenges, requiring time and/or ensemble-averaged data to be collected over long simulation trajectories for property evaluation. Performing a molecular simulation of a soft matter system involves multiple steps, which have traditionally been performed by researchers in a "bespoke" fashion, resulting in many published soft matter simulations not being reproducible based on the information provided in the publications. To address the issue of reproducibility and to provide tools for computational screening, we have been developing the open-source Molecular Simulation and Design Framework (MoSDeF) software suite. In this paper, we propose a set of principles to create Transparent, Reproducible, Usable by others, and Extensible (TRUE) molecular simulations. MoSDeF facilitates the publication and dissemination of TRUE simulations by automating many of the critical steps in molecular simulation, thus enhancing their reproducibility. We provide several examples of TRUE molecular simulations: All of the steps involved in creating, running and extracting properties from the simulations are distributed on open-source platforms (within MoSDeF and on GitHub), thus meeting the definition of TRUE simulations.
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http://dx.doi.org/10.1080/00268976.2020.1742938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576934PMC
April 2020

Viral genomes reveal patterns of the SARS-CoV-2 outbreak in Washington State.

medRxiv 2020 Sep 30. Epub 2020 Sep 30.

University of Washington, Seattle, WA, USA.

The rapid spread of SARS-CoV-2 has gravely impacted societies around the world. Outbreaks in different parts of the globe are shaped by repeated introductions of new lineages and subsequent local transmission of those lineages. Here, we sequenced 3940 SARS-CoV-2 viral genomes from Washington State to characterize how the spread of SARS-CoV-2 in Washington State (USA) was shaped by differences in timing of mitigation strategies across counties, as well as by repeated introductions of viral lineages into the state. Additionally, we show that the increase in frequency of a potentially more transmissible viral variant (614G) over time can potentially be explained by regional mobility differences and multiple introductions of 614G, but not the other variant (614D) into the state. At an individual level, we see evidence of higher viral loads in patients infected with the 614G variant. However, using clinical records data, we do not find any evidence that the 614G variant impacts clinical severity or patient outcomes. Overall, this suggests that at least to date, the behavior of individuals has been more important in shaping the course of the pandemic than changes in the virus.
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http://dx.doi.org/10.1101/2020.09.30.20204230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536883PMC
September 2020

The TAT Protein Transduction Domain as an Intra-Articular Drug Delivery Technology.

Cartilage 2020 Sep 19:1947603520959392. Epub 2020 Sep 19.

Montana State University System, Bozeman, MT, USA.

Objective: Intra-articular drug delivery holds great promise for the treatment of joint diseases such as osteoarthritis. The objective of this study was to evaluate the TAT peptide transduction domain (TAT-PTD) as a potential intra-articular drug delivery technology for synovial joints.

Design: Experiments examined the ability of TAT conjugates to associate with primary chondrocytes and alter cellular function both and . Further experiments examined the ability of the TAT-PTD to bind to human osteoarthritic cartilage.

Results: The results show that the TAT-PTD associates with chondrocytes, is capable of delivering siRNA for chondrocyte gene knockdown, and that the recombinant enzyme TAT-Cre is capable of inducing genetic recombination within the knee joint in a reporter mouse model. Last, binding studies show that osteoarthritic cartilage preferentially uptakes the TAT-PTD from solution.

Conclusions: The results suggest that the TAT-PTD is a promising delivery strategy for intra-articular therapeutics.
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http://dx.doi.org/10.1177/1947603520959392DOI Listing
September 2020

Characterization of the genomically encoded fosfomycin resistance enzyme from .

Medchemcomm 2019 Nov 27;10(11):1948-1957. Epub 2019 Sep 27.

Department of Chemistry & Biochemistry , The University of Alabama , 250 Hackberry Lane , Box 870336 , Tuscaloosa , AL 35487 , USA . Email: ; Tel: +(205) 348 7020.

belongs to a group of rapidly growing mycobacteria (RGM) and accounts for approximately 65-80% of lung disease caused by RGM. It is highly pathogenic and is considered the prominent Mycobacterium involved in pulmonary infection in patients with cystic fibrosis and chronic pulmonary disease (CPD). FosM is a putative 134 amino acid fosfomycin resistance enzyme from subsp. bolletii that shares approximately 30-55% sequence identity with other vicinal oxygen chelate (VOC) fosfomycin resistance enzymes and represents the first of its type found in any Mycobacterium species. Genes encoding VOC fosfomycin resistance enzymes have been found in both Gram-positive and Gram-negative pathogens. Given that FosA enzymes from Gram-negative bacteria have evolved optimum activity towards glutathione (GSH) and FosB enzymes from Gram-positive bacteria have evolved optimum activity towards bacillithiol (BSH), it was originally suggested that FosM might represent a fourth class of enzyme that has evolved to utilize mycothiol (MSH). However, a sequence similarity network (SSN) analysis identifies FosM as a member of the FosX subfamily, indicating that it may utilize water as a substrate. Here we have synthesized MSH and characterized FosM with respect to divalent metal ion activation and nucleophile selectivity. Our results indicate that FosM is a Mn-dependent FosX-type hydrase with no selectivity toward MSH or other thiols as analyzed by NMR and mass spectroscopy.
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http://dx.doi.org/10.1039/c9md00372jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478155PMC
November 2019

Radiologic Evaluation of the Child with a Limp.

Pediatr Ann 2020 Sep;49(9):e395-e402

A child presenting with a limp can present a diagnostic challenge to pediatricians. Clinical presentation, age, and history all contribute to the initial differential diagnosis; however, imaging plays a key role in the ultimate diagnosis, and the correct imaging study is essential to save time and health care expenses. This article will present a few of the more common causes of a limp and the recently updated imaging recommendations from the American College of Radiology to aid in final diagnosis. [Pediatr Ann. 2020;49(9):e395-e402.].
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http://dx.doi.org/10.3928/19382359-20200821-01DOI Listing
September 2020

Extra-Articular Hip Resection and Reconstruction with Custom Acetabular Resection Guide and Implants in a Case of High-Grade Spindle Cell Sarcoma of the Proximal Femur: A Case Report.

JBJS Case Connect 2020 Jul-Sep;10(3):e1900529

1Orthopaedic Surgery & Rheumatology Center, Cleveland Clinic Florida, Weston, Florida 2Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington 3Orthopaedic Oncology, University of Washington Medical Center, Seattle, Washington 4University of Washington School of Medicine, Seattle, Washington.

Case: A 29-year-old man was admitted with acute atraumatic left hip pain and inability to bear weight. Subsequent workup revealed an intracapsular pathologic fracture of the femoral neck secondary to a high-grade spindle cell sarcoma. A unique method of extra-articular resection and reconstruction using a 3-dimensional (3D)-printed custom cutting jig and a custom acetabular component was pursued. Wide margins were achieved without violating the joint capsule but preserving pelvic integrity, allowing a return to an active lifestyle.

Conclusion: Three-dimensional-printed custom resection guides and implants can help achieve adequate resection margins while preserving pelvic integrity and function.
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http://dx.doi.org/10.2106/JBJS.CC.19.00529DOI Listing
April 2021

Long-term Outcomes for Extraskeletal Myxoid Chondrosarcoma: A SEER Database Analysis.

Cancer Epidemiol Biomarkers Prev 2020 Nov 20;29(11):2351-2357. Epub 2020 Aug 20.

Division of Medical Oncology, University of Washington, Seattle, Washington.

Background: Extraskeletal myxoid chondrosarcoma (EMCS) is a rare tumor that typically has an indolent course but high rate of recurrence. We queried the Surveillance, Epidemiology, and End Results (SEER) database to assess factors associated with metastasis, treatment, and survival.

Methods: We queried the SEER 1973-2016 database for patients with myxoid chondrosarcoma (ICD-O-3: 9231/3). Kaplan-Meier analyses and Cox proportional hazard models assessed effects on overall survival (OS) of demographics and clinical characteristics. Logistic regression assessed associations between tumor location and distant disease. Primary analysis was a complete case analysis; multiple imputation (MI) was used in a sensitivity analysis.

Results: Locoregional disease (LRD) was found in 373 (85%) of patients. In univariate analysis with LRD, surgery correlated with superior OS [HR = 0.27; 95% confidence interval (CI), 0.16-0.47]; chemotherapy and radiotherapy associated with inferior OS (HR = 1.90; 95% CI, 1.11-3.27 and HR = 1.45; 95% CI, 1.03-2.06, respectively). No treatment modality associated with OS in the adjusted, complete case model. In the adjusted sensitivity analysis, surgery associated with superior outcomes (HR = 0.36; 95% CI, 0.19-0.69). There was no OS difference by primary tumor site. 10-year OS with distant disease was 10% (95% CI, 2%-25%).

Conclusions: Surgery in LRD associated with improved OS in univariate analysis and adjusted models correcting for missing data. There was no OS benefit with chemotherapy or radiotherapy.

Impact: This represents the largest report of EMCS with long-term follow-up. Despite the reputedly indolent nature of EMCS, outcomes with metastatic disease are poor. We provide OS benchmarks and guidance for stratification in future prospective trials.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0447DOI Listing
November 2020

Cognitive function and adaptive skills after a one-year trial of cannabidiol (CBD) in a pediatric sample with treatment-resistant epilepsy.

Epilepsy Behav 2020 10 29;111:107299. Epub 2020 Jul 29.

University of Alabama at Birmingham, Department of Neurology, 1720 7th Avenue South, Birmingham, AL 35233, USA.

Objective: Cannabidiol (CBD) is a nonpsychoactive derivative of cannabis. Studies indicate that it is safe and effective in treating certain types of epilepsy. The present study examined the presence of adverse or beneficial cognitive or functional adaptive effects associated with CBD in the treatment of children, adolescents, and teenagers with treatment-resistant epilepsy (TRE) as part of an ongoing prospective, open-label safety study.

Methods: Participants (N = 38) between the age of 3 and 19 years with TRE were enrolled in an open-label study of a pharmaceutical formulation of CBD (Epidiolex®; GW Research Ltd.) as an add-on treatment. In addition to baseline physical, neurological, and laboratory testing, cognitive assessment was completed prior to initiating CBD and after one year, both using the NIH Toolbox Cognition Battery (NIHTB-CB). Many participants were unable to complete the NIHTB-CB because of the magnitude of their cognitive impairment (n = 24), and in these cases, the participant's caregiver was asked to complete the Adaptive Behavior Assessment System - Second Edition (ABAS-II) as a measure of functional adaptive skills.

Results: There were no statistically significant changes in cognitive function, as measured by the NIHTB-CB, in those participants who were able to complete such testing, but there was a nonsignificant trend toward improvement in some cognitive domains. For participants who were unable to complete formal standardized cognitive testing because of the magnitude of their cognitive impairment, their functional adaptive skills, as measured by the ABAS-II, were unchanged after a one-year trial of CBD.

Significance: Our findings suggest that CBD, as an add-on drug for TRE in a pediatric sample, does not appear to cause adverse effects (AEs) involving cognition or adaptive function over one year of treatment.
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http://dx.doi.org/10.1016/j.yebeh.2020.107299DOI Listing
October 2020

Enzyme-Directed Functionalization of Designed, Two-Dimensional Protein Lattices.

Biochemistry 2021 Apr 3;60(13):1050-1062. Epub 2020 Aug 3.

Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.

The design and construction of crystalline protein arrays to selectively assemble ordered nanoscale materials have potential applications in sensing, catalysis, and medicine. Whereas numerous designs have been implemented for the bottom-up construction of protein assemblies, the generation of artificial functional materials has been relatively unexplored. Enzyme-directed post-translational modifications are responsible for the functional diversity of the proteome and, thus, could be harnessed to selectively modify artificial protein assemblies. In this study, we describe the use of phosphopantetheinyl transferases (PPTases), a class of enzymes that covalently modify proteins using coenzyme A (CoA), to site-selectively tailor the surface of designed, two-dimensional (2D) protein crystals. We demonstrate that a short peptide (ybbR) or a molecular tag (CoA) can be covalently tethered to 2D arrays to enable enzymatic functionalization using Sfp PPTase. The site-specific modification of two different protein array platforms is facilitated by PPTases to afford both small molecule- and protein-functionalized surfaces with no loss of crystalline order. This work highlights the potential for chemoenzymatic modification of large protein surfaces toward the generation of sophisticated protein platforms reminiscent of the complex landscape of cell surfaces.
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http://dx.doi.org/10.1021/acs.biochem.0c00363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855359PMC
April 2021

Qualitative study to explore radiologist and radiologic technologist perceptions of outcomes patients experience during imaging in the USA.

BMJ Open 2020 07 20;10(7):e033961. Epub 2020 Jul 20.

Department of Family Medicine, University of Washington, Seattle, Washington, USA.

Objective: We aimed to explore the patient-centred outcomes (PCOs) radiologists and radiologic technologists perceive to be important to patients undergoing imaging procedures.

Design: We conducted a qualitative study of individual semi-structured interviews.

Participants: We recruited multiple types of radiologists including general, musculoskeletal neuroradiology, body and breast imagers as well as X-ray, ultrasound, CT or MRI radiologic technologists from Washington and Idaho.

Outcome: Thematic analysis was conducted to identify themes and subthemes related to PCOs of imaging procedures.

Results: Ten radiologists and six radiology technologists participated. Four main domains of PCOs were identified: emotions, physical factors, knowledge and patient burden. In addition to these outcomes, we also identified patient and provider factors that can potentially moderate these outcomes.

Conclusions: Radiologists and technologists perceived outcomes related to the effect of imaging procedures on patients' emotions, physical well-being, knowledge and burden from financial and opportunity costs to be important to patients undergoing imaging procedures. There are opportunities for the radiology community to measure and use these PCOs in comparisons of imaging procedures and potentially identify areas where these outcomes can be leveraged to drive a more patient-centred approach to radiology.
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http://dx.doi.org/10.1136/bmjopen-2019-033961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375501PMC
July 2020

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery.

Cochrane Database Syst Rev 2020 07 17;7:CD001298. Epub 2020 Jul 17.

Department of Obstetrics and Gynaecology, Tameside & Glossop Acute Services NHS Trust, Ashton-Under-Lyne, UK.

Background: Adhesions are fibrin bands that are a common consequence of gynaecological surgery. They are caused by conditions that include pelvic inflammatory disease and endometriosis. Adhesions are associated with comorbidities, including pelvic pain, subfertility, and small bowel obstruction. Adhesions also increase the likelihood of further surgery, causing distress and unnecessary expenses. Strategies to prevent adhesion formation include the use of fluid (also called hydroflotation) and gel agents, which aim to prevent healing tissues from touching one another, or drugs, aimed to change an aspect of the healing process, to make adhesions less likely to form.

Objectives: To evaluate the effectiveness and safety of fluid and pharmacological agents on rates of pain, live births, and adhesion prevention in women undergoing gynaecological surgery.

Search Methods: We searched: the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and Epistemonikos to 22 August 2019. We also checked the reference lists of relevant papers and contacted experts in the field.

Selection Criteria: Randomised controlled trials investigating the use of fluid (including gel) and pharmacological agents to prevent adhesions after gynaecological surgery.

Data Collection And Analysis: We used standard methodological procedures recommended by Cochrane. We assessed the overall quality of the evidence using GRADE methods. Outcomes of interest were pelvic pain; live birth rates; incidence of, mean, and changes in adhesion scores at second look-laparoscopy (SLL); clinical pregnancy, miscarriage, and ectopic pregnancy rates; quality of life at SLL; and adverse events.

Main Results: We included 32 trials (3492 women), and excluded 11. We were unable to include data from nine studies in the statistical analyses, but the findings of these studies were broadly in keeping with the findings of the meta-analyses. Hydroflotation agents versus no hydroflotation agents (10 RCTs) We are uncertain whether hydroflotation agents affected pelvic pain (odds ratio (OR) 1.05, 95% confidence interval (CI) 0.52 to 2.09; one study, 226 women; very low-quality evidence). It is unclear whether hydroflotation agents affected live birth rates (OR 0.67, 95% CI 0.29 to 1.58; two studies, 208 women; low-quality evidence) compared with no treatment. Hydroflotation agents reduced the incidence of adhesions at SLL when compared with no treatment (OR 0.34, 95% CI 0.22 to 0.55, four studies, 566 women; high-quality evidence). The evidence suggests that in women with an 84% chance of having adhesions at SLL with no treatment, using hydroflotation agents would result in 54% to 75% having adhesions. Hydroflotation agents probably made little or no difference to mean adhesion score at SLL (standardised mean difference (SMD) -0.06, 95% CI -0.20 to 0.09; four studies, 722 women; moderate-quality evidence). It is unclear whether hydroflotation agents affected clinical pregnancy rate (OR 0.64, 95% CI 0.36 to 1.14; three studies, 310 women; moderate-quality evidence) compared with no treatment. This suggests that in women with a 26% chance of clinical pregnancy with no treatment, using hydroflotation agents would result in a clinical pregnancy rate of 11% to 28%. No studies reported any adverse events attributable to the intervention. Gel agents versus no treatment (12 RCTs) No studies in this comparison reported pelvic pain or live birth rate. Gel agents reduced the incidence of adhesions at SLL compared with no treatment (OR 0.26, 95% CI 0.12 to 0.57; five studies, 147 women; high-quality evidence). This suggests that in women with an 84% chance of having adhesions at SLL with no treatment, the use of gel agents would result in 39% to 75% having adhesions. It is unclear whether gel agents affected mean adhesion scores at SLL (SMD -0.50, 95% CI -1.09 to 0.09; four studies, 159 women; moderate-quality evidence), or clinical pregnancy rate (OR 0.20, 95% CI 0.02 to 2.02; one study, 30 women; low-quality evidence). No studies in this comparison reported on adverse events attributable to the intervention. Gel agents versus hydroflotation agents when used as an instillant (3 RCTs) No studies in this comparison reported pelvic pain, live birth rate or clinical pregnancy rate. Gel agents probably reduce the incidence of adhesions at SLL when compared with hydroflotation agents (OR 0.50, 95% CI 0.31 to 0.83; three studies, 538 women; moderate-quality evidence). This suggests that in women with a 46% chance of having adhesions at SLL with a hydroflotation agent, the use of gel agents would result in 21% to 41% having adhesions. We are uncertain whether gel agents improved mean adhesion scores at SLL when compared with hydroflotation agents (MD -0.79, 95% CI -0.82 to -0.76; one study, 77 women; very low-quality evidence). No studies in this comparison reported on adverse events attributable to the intervention. Steroids (any route) versus no steroids (4 RCTs) No studies in this comparison reported pelvic pain, incidence of adhesions at SLL or mean adhesion score at SLL. It is unclear whether steroids affected live birth rates compared with no steroids (OR 0.65, 95% CI 0.26 to 1.62; two studies, 223 women; low-quality evidence), or clinical pregnancy rates (OR 1.01, 95% CI 0.66 to 1.55; three studies, 410 women; low-quality evidence). No studies in this comparison reported on adverse events attributable to the intervention.

Authors' Conclusions: Gels and hydroflotation agents appear to be effective adhesion prevention agents for use during gynaecological surgery, but we found no evidence indicating that they improve fertility outcomes or pelvic pain, and further research is required in this area. It is also worth noting that for some comparisons, wide confidence intervals crossing the line of no effect meant that clinical harm as a result of interventions could not be excluded. Future studies should measure outcomes in a uniform manner, using the modified American Fertility Society score. Statistical findings should be reported in full. No studies reported any adverse events attributable to intervention.
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http://dx.doi.org/10.1002/14651858.CD001298.pub5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388178PMC
July 2020

Proapoptotic Peptide Brush Polymer Nanoparticles via Photoinitiated Polymerization-Induced Self-Assembly.

Angew Chem Int Ed Engl 2020 10 26;59(43):19136-19142. Epub 2020 Aug 26.

Department of Chemistry, Department of Materials Science & Engineering, Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60208, USA.

Herein, we report the photoinitiated polymerization-induced self-assembly (photo-PISA) of spherical micelles consisting of proapoptotic peptide-polymer amphiphiles. The one-pot synthetic approach yielded micellar nanoparticles at high concentrations and at scale (150 mg mL ) with tunable peptide loadings up to 48 wt. %. The size of the micellar nanoparticles was tuned by varying the lengths of hydrophobic and hydrophilic building blocks. Critically, the peptide-functionalized nanoparticles imbued the proapoptotic "KLA" peptides (amino acid sequence: KLAKLAKKLAKLAK) with two key properties otherwise not inherent to the sequence: 1) proteolytic resistance compared to the oligopeptide alone; 2) significantly enhanced cell uptake by multivalent display of KLA peptide brushes. The result was demonstrated improved apoptosis efficiency in HeLa cells. These results highlight the potential of photo-PISA in the large-scale synthesis of functional, proteolytically resistant peptide-polymer conjugates for intracellular delivery.
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http://dx.doi.org/10.1002/anie.202006385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722202PMC
October 2020