Publications by authors named "David Liu"

840 Publications

The Use of Head-Worn Displays for Vital Sign Monitoring in Critical and Acute Care: Systematic Review.

JMIR Mhealth Uhealth 2021 May 11;9(5):e27165. Epub 2021 May 11.

School of Psychology, The University of Queensland, St Lucia, QLD, Australia.

Background: Continuous monitoring of patient vital signs may improve patient outcomes. Head-worn displays (HWDs) can provide hands-free access to continuous vital sign information of patients in critical and acute care contexts and thus may reduce instances of unrecognized patient deterioration.

Objective: The purpose of the study is to conduct a systematic review of the literature to evaluate clinical, surrogate, and process outcomes when clinicians use HWDs for continuous patient vital sign monitoring.

Methods: The review was registered with PROSPERO (CRD42019119875) and followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. A literature search was conducted for articles published between January 1995 and June 2020 using the following databases: PubMed, Embase, CINAHL, PsycINFO, and Web of Science. Overall, 2 reviewers independently screened titles and abstracts and then assessed the full text of the articles. Original research articles that evaluated the clinical, surrogate, or process outcomes of head-mounted displays for continuous vital sign monitoring in critical care or acute care contexts were included.

Results: Of the 214 records obtained, 15 (7%) articles met the predefined criteria and were included in this review. Of the 15 studies, 7 (47%) took place in a clinical context, whereas the remainder took place in a simulation environment. In 100% (7/7) of the studies that evaluated gaze behavior, changes were found in gaze direction with HWDs. Change detection improvements were found in 67% (2/3) of the studies evaluating changes in the participants' ability to detect changes in vital signs. Of the 10 studies assessing the ease of use of the HWD, most participants of 7 (70%) studies reported that the HWD was easy to use. In all 6 studies in which participants were asked if they would consider using the HWD in their practice, most participants responded positively, but they often suggested improvements on the HWD hardware or display design. Of the 7 studies conducted in clinical contexts, none reported any clinical outcomes.

Conclusions: Although there is limited and sometimes conflicting evidence about the benefits of HWDs from certain surrogate and process outcomes, evidence for clinical outcomes is lacking. Recommendations are to employ user-centered design when developing HWDs, perform longitudinal studies, and seek clinical outcomes.

Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42019119875; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=119875.
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http://dx.doi.org/10.2196/27165DOI Listing
May 2021

First-in-Human Phase I Study of Envafolimab, a Novel Subcutaneous Single-Domain Anti-PD-L1 Antibody, in Patients with Advanced Solid Tumors.

Oncologist 2021 May 11. Epub 2021 May 11.

3D Medicines Co., Ltd., Sichuan, People's Republic of China.

Lessons Learned: Subcutaneous injection was an effective route of administration for envafolimab with a favorable pharmacokinetic profile in patients with previously treated advanced solid tumors Subcutaneous envafolimab was well tolerated and had durable antitumor activity at a wide range of doses and schedules Envafolimab has the potential to be a more convenient option than currently approved intravenous PD-1/PD-L1 inhibitors BACKGROUND: Envafolimab is a novel fusion of a humanized single-domain PD-L1 antibody and human IgG1 Fc fragment formulated for subcutaneous injection. This study explored the safety and feasibility of subcutaneous administration of envafolimab as an alternative to intravenous administration of PD-1/PD-L1 inhibitors in the treatment of advanced, refractory solid tumors.

Methods: This was a first-in-human, open-label phase I trial. In a dose-escalation phase, patients received subcutaneous envafolimab 0.01-10 mg/kg once weekly following a modified 3+3 design. In a dose-exploration phase, patients received subcutaneous envafolimab 300 mg once every 4 weeks.

Results: Twenty-eight patients were enrolled (dose escalation n = 18, dose exploration n = 10, median age 66 years; 71% male; ECOG performance score = 0 [21%] or 1 [79%]). No dose-limiting toxicities or injection-site reactions were reported. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve and maximum plasma concentration. Median time to maximum plasma concentration was 4-7 days. In the dose-exploration phase, terminal half-life was 14 days after dose 1 in cycle 1 and 23 days at steady state. Three patients experienced a confirmed partial response.

Conclusion: Subcutaneous envafolimab had a favorable safety and pharmacokinetic profile, with promising preliminary antitumor activity in patients with advanced solid tumors.
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http://dx.doi.org/10.1002/onco.13817DOI Listing
May 2021

The NIDA clinical trials network: evolving, expanding, and addressing the opioid epidemic.

Addict Sci Clin Pract 2021 May 8;16(1):28. Epub 2021 May 8.

Center for the Clinical Trials Network, National Institute On Drug Abuse, National Institutes of Health, 3WFN Room 09A48 MSC 6022, 301 North Stonestreet Avenue, Bethesda, MD, 20892, USA.

Over the past two decades, the National Drug Abuse Treatment Clinical Trials Network (CTN), a program of the National Institute on Drug Abuse (NIDA), has expanded from the initial six Nodes to 16 Nodes, as a nationwide consortium of research scientists and treatment providers working together to improve care for substance use in the nation's communities. Encompassing both specialty care programs and general medical settings, the Network has become a unique resource for expertise on clinically focused research, bridging the gap between research and treatment delivery. Over 22 years, the CTN has completed 101 studies, resulting in 650 publications. In response to the opioid epidemic, a CTN task force generated a comprehensive list of research priorities in the areas of prevention, treatment, knowledge dissemination, and workforce training, to form the basis of the Network's opioid portfolio. The Network's opioid portfolio currently includes five main categories of studies: (1) large multi-site studies; (2) studies aimed at closing the treatment gap; (3) expansion of ongoing studies to improve service delivery and implementation; (4) studies to explore the use of substance use data in electronic health record systems; (5) training and dissemination projects to expand the research/health care provider workforce. With funding from the Helping to End Addiction Long-Term Initiative (HEAL), the CTN established five new Nodes, which, along with the pre-existing Nodes, are distributed in every region of the nation and engage researchers and clinicians in areas that have been among the hardest hit by the opioid epidemic. Through this expanded network and its commitment to developing personalized, evidence-based treatments, the CTN is poised to address and provide solutions for the ongoing epidemic of opioid use and addiction.
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http://dx.doi.org/10.1186/s13722-021-00238-6DOI Listing
May 2021

Single- and Multiple-Dose Pharmacokinetics and Pharmacodynamics of PN-943, a Gastrointestinal-Restricted Oral Peptide Antagonist of α4β7, in Healthy Volunteers.

Clin Pharmacol Drug Dev 2021 May 4. Epub 2021 May 4.

Protagonist Therapeutics, Inc, Newark, California, USA.

PN-943 is an orally stable, gastrointestinal-restricted peptide that binds specifically to α4ß7 integrin on leukocytes, blocking leukocyte trafficking to and activation in the gut, inhibiting colon inflammation and reducing signs and symptoms of active ulcerative colitis. Two pharmacokinetic/pharmacodynamic studies were conducted in healthy volunteers. Study 1 was a first-in-human study with 40 male subjects receiving PN-943, 100 to 1400 mg or placebo, as single doses and 57 male subjects receiving PN-943, 100 to 1000 mg or placebo, as multiple doses. Study 2 was a randomized, crossover study comparing multiple doses of 450-mg PN-943 twice daily as a liquid solution and as an immediate-release tablet in 10 subjects. No subjects discontinued due to treatment-emergent adverse events. Consistent with the gastrointestinal-restricted nature of the peptide, systemic exposure was minimal; there was an approximate dose-proportional increase in area under the plasma concentration-time curve. There was minimal accumulation with once-daily dosing and an absence of time-dependent changes in pharmacokinetics. Administration of PN-943 after a high-fat meal reduced peak plasma concentration and area under the plasma concentration-time curve. There was minimal (<0.1%) urinary excretion of intact drug, and there was a dose-related increase in fecal excretion of intact PN-943. Dose-dependent increases in blood receptor occupancy and reduction in blood receptor expression were observed, supporting target engagement. Twice-daily dosing resulted in sustained receptor occupancy with low plasma fluctuations (143%). PN-943 was generally well tolerated following single and multiple oral doses with low systemic exposure. Twice-daily dosing resulted in sustained pharmacokinetics and pharmacodynamics, supporting further investigation in efficacy studies.
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http://dx.doi.org/10.1002/cpdd.946DOI Listing
May 2021

Evolution of delayed resistance to immunotherapy in a melanoma responder.

Nat Med 2021 May 3. Epub 2021 May 3.

Department of Pathology, Harvard Medical School, Brigham and Woman's Hospital, Boston, MA, USA.

Despite initial responses, most melanoma patients develop resistance to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor-immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course.
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http://dx.doi.org/10.1038/s41591-021-01331-8DOI Listing
May 2021

A transpedicular approach to complex ventrally situated thoracic intradural extramedullary tumors: technique, indications, and multiinstitutional case series.

Neurosurg Focus 2021 May;50(5):E19

1Department of Neurosurgery, State University of New York, Upstate Medical University, Syracuse, New York; and.

Objective: Ventrally situated thoracic intradural extramedullary tumors are surgically challenging and difficult to access, and they may be complicated by extensive adhesions and calcifications. Selecting an approach for adequate ventral access is key to complete resection and optimization of outcomes. The authors present a case series of patients who underwent resection of ventral thoracic intradural extramedullary tumors and discuss indications and considerations for this technique. Additionally, they describe the use of a posterolateral transpedicular approach for resection of ventral thoracic intradural extramedullary tumors compared with other techniques, and they summarize the literature supporting its application.

Methods: From May 2017 to August 2020, 5 patients with ventral thoracic intradural extramedullary tumors underwent resection at one of the two academic institutions.

Results: Patient ages ranged from 47 to 75 (mean 63.4) years. All tumors were diagnosed as meningiomas or schwannomas by histological examination. Three of the 5 patients had evidence of partial or extensive tumor calcification. Four of the 5 patients underwent an initial posterolateral transpedicular approach for resection, with positive radiographic and clinical outcomes from surgery. One patient initially underwent an unsuccessful traditional direct posterior approach and required additional resection 2 years later after interval disease progression. There were no postoperative wound infections, CSF leaks, or other complications related to the transpedicular approach.

Conclusions: Posterolateral transpedicular tumor resection is a safe technique for the treatment of complex ventrally situated thoracic intradural extramedullary tumors compared with the direct posterior approach. Anecdotally, this approach appears to be particularly beneficial in patients with calcified tumors.
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http://dx.doi.org/10.3171/2021.2.FOCUS20968DOI Listing
May 2021

PRKCA Overexpression Is Frequent in Young Oral Tongue Squamous Cell Carcinoma Patients and Is Associated with Poor Prognosis.

Cancers (Basel) 2021 Apr 25;13(9). Epub 2021 Apr 25.

Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, 1090 Vienna, Austria.

Oral tongue squamous cell carcinomas (OTSCCs) have an increasing incidence in young patients, and many have an aggressive course of disease. The objective of this study was to identify candidate prognostic protein markers associated with early-onset OTSCC. We performed an exploratory screening for differential protein expression in younger (≤45 years) versus older (>45 years) OTSCC patients in The Cancer Genome Atlas (TCGA) cohort ( = 97). Expression of candidate markers was then validated in an independent Austrian OTSCC patient group ( = 34) by immunohistochemistry. Kaplan-Meier survival estimates were computed, and genomic and mRNA enrichment in silico analyses were performed. Overexpression of protein kinase C alpha (PRKCA) was significantly more frequent among young patients of both the TCGA ( = 0.0001) and the Austrian cohort ( = 0.02), associated with a negative anamnesis for alcohol consumption ( = 0.009) and tobacco smoking ( = 0.02) and poorer overall survival (univariate = 0.02, multivariate < 0.01). Within the young subgroup, both overall and disease-free survival were significantly decreased in patients with PRKCA overexpression (both < 0.001). TCGA mRNA enrichment analysis revealed 332 mRNAs with significant differential expression in PRKCA-upregulated versus PRKCA-downregulated OTSCC (all FDR ≤ 0.01). Our findings suggest that PRKCA overexpression may be a hallmark of a novel molecular subtype of early-onset alcohol- and tobacco-negative high-risk OTSCC. Further analysis of the molecular PRKCA interactome may decipher the underlying mechanisms of carcinogenesis and clinicopathological behavior of PRKCA-overexpressing OTSCC.
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http://dx.doi.org/10.3390/cancers13092082DOI Listing
April 2021

Treatment response assessment following transarterial radioembolization for hepatocellular carcinoma.

Abdom Radiol (NY) 2021 Apr 28. Epub 2021 Apr 28.

Department of Radiology, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.

Transarterial radioembolization with yttrium-90 microspheres is an established therapy for hepatocellular carcinoma. Post-procedural imaging is important for the assessment of both treatment response and procedural complications. A variety of challenging treatment-specific imaging phenomena complicate imaging assessment, such as changes in tumoral size, tumoral and peritumoral enhancement, and extrahepatic complications. A review of the procedural steps, emerging variations, and timelines for post-treatment tumoral and extra-tumoral imaging changes are presented, which may aid the reporting radiologist in the interpretation of post-procedural imaging. Furthermore, a description of post-procedural complications and their significance is provided.
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http://dx.doi.org/10.1007/s00261-021-03095-8DOI Listing
April 2021

Annual trends in Google searches provides insights related to rhinosinusitis exacerbations.

Eur Arch Otorhinolaryngol 2021 Apr 20. Epub 2021 Apr 20.

Department of Otorhinolaryngology, Head and Neck Surgery, Vienna General Hospital (AKH), Medical University of Vienna, Vienna, Austria.

Purpose: Temporal trends of disease-specific internet searches may provide novel insights into seasonal dynamics of disease burden and, by extension, disease pathophysiology. The aim of this study was to define the temporal trends in rhinosinusitis-specific internet searches.

Methods: This was a cross sectional analysis of search volume for predefined search terms. Google trends was used to explore the volume of searches for five specific search terms related to rhinosinusitis: nose, mucus, sinus, sinusitis, chronic sinusitis, which were entered into Google web search between 2004 and 2019. Results were analyzed within search "context" which included temporally associated related searches. Relative search volume (RSV) was analyzed for English and non-English speaking countries from the Northern and Southern hemispheres. Analysis of seasonality was performed using the cosinor model.

Results: The five specific search terms were most related to rhinosinusitis-related search contexts, indicating that they were appropriately reflective of internet queries by patients for rhinosinusitis. The RSV for rhinosinusitis-related terms and more general search terms increased with each passing year indicating constant interest in rhinosinusitis. Cosinor time series analysis revealed inquiry peaks in winter months for all five specific rhinosinusitis-related search terms independent from the hemisphere.

Conclusion: Over a 15-year period, Google searches with rhinosinusitis-specific search terms consistently peaked during the winter around the world. These findings indirectly support the model of viral infection or exposure as the predominant cause of acute rhinosinusitis and acute exacerbations of chronic rhinosinusitis.
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http://dx.doi.org/10.1007/s00405-021-06806-5DOI Listing
April 2021

Sutured Versus Mesh-Augmented Hiatus Hernia Repair: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Ann Surg 2021 Apr 7. Epub 2021 Apr 7.

College of Medicine and Public Health, Flinders University, South Australia, Australia Department of Surgery, Flinders Medical Centre, South Australia, Australia Department of Surgery, Austin Hospital, Victoria, Australia.

Objective: This meta-analysis systematically reviewed published randomized control trials (RCTs) comparing sutured versus mesh-augmented hiatus hernia (HH) repair. Our primary endpoint was HH recurrence at short- and long-term follow-up. Secondary endpoints were: surgical complications, operative times, dysphagia and quality of life.

Summary Background Data: Repair of large hiatus hernias is increasingly being performed. However, there is no consensus for the optimal technique for hiatal closure between sutured versus mesh-augmented (absorbable or non-absorbable) repair.

Methods: A systematic review of Medline, Scopus (which encompassed Embase), Cochrane Central Register of Controlled Trials, Web of Science and PubMed was performed to identify relevant studies comparing mesh-augmented versus sutured HH repair. Data were extracted and compared by meta-analysis, using odds ratio and mean differences with 95% confidence intervals.

Results: Seven RCTs were found which compared mesh-augmented (non-absorbable mesh: n = 296; absorbable mesh: n = 92) with sutured repair (n = 347). There were no significant differences for short-term hernia recurrence (defined as 6-12 months, 10.1% mesh versus 15.5% sutured, P = 0.22), long-term hernia recurrence (defined as 3-5 years, 30.7% mesh vs 31.3% sutured, P = 0.69), functional outcomes and patient satisfaction. The only statistically significant difference was that the mesh repair required a longer operation time (P = 0.05, OR 2.33, 95% CI 0.03-24.69).

Conclusions: Mesh repair for hiatus hernia does not offer any advantage over sutured hiatal closure. As both techniques deliver good and comparable clinical outcomes, a suture only technique is still an appropriate approach.
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http://dx.doi.org/10.1097/SLA.0000000000004902DOI Listing
April 2021

The NIH Somatic Cell Genome Editing program.

Nature 2021 Apr 7;592(7853):195-204. Epub 2021 Apr 7.

McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium's plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled-along with validated datasets-into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit-and the knowledge generated by its applications-as a means to accelerate the clinical development of new therapies for a wide range of conditions.
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http://dx.doi.org/10.1038/s41586-021-03191-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026397PMC
April 2021

Implementation facilitation to introduce and support emergency department-initiated buprenorphine for opioid use disorder in high need, low resource settings: protocol for multi-site implementation-feasibility study.

Addict Sci Clin Pract 2021 03 9;16(1):16. Epub 2021 Mar 9.

Department of Emergency Medicine, Yale School of Medicine, New Haven, CT, USA.

Background: For many reasons, the emergency department (ED) is a critical venue to initiate OUD interventions. The prevailing culture of the ED has been that substance use disorders are non-emergent conditions better addressed outside the ED where resources are less constrained. This study, its rapid funding mechanism, and accelerated timeline originated out of the urgent need to learn whether ED-initiated buprenorphine (BUP) with referral for treatment of OUD is generalizable, as well as to develop strategies to facilitate its adoption across a variety of ED settings and under real-world conditions. It both complements and uses methods adapted from Project ED Health (CTN-0069), a Hybrid Type 3 implementation-effectiveness study of using Implementation Facilitation (IF) to integrate ED-initiated BUP and referral programs.

Methods: ED-CONNECT (CTN 0079) was a three-site implementation study exploring the feasibility, acceptability, and impact of introducing ED-initiated BUP in rural and urban settings with high-need, limited resources, and different staffing structures. We used a multi-faceted approach to develop, introduce and iteratively refine site-specific ED clinical protocols and implementation plans for opioid use disorder (OUD) screening, ED-initiated BUP, and referral for treatment. We employed a participatory action research approach and use mixed methods incorporating data derived from abstraction of medical records and administrative data, assessments of recruited ED patient-participants, and both qualitative and quantitative inquiry involving staff from the ED and community, patients, and other stakeholders.

Discussion: This study was designed to provide the necessary, time-sensitive understanding of how to identify OUD and initiate treatment with BUP in the EDs previously not providing ED-initiated BUP, in communities in which this intervention is most needed: high need, low resource settings.

Trial Registration: The study was prospectively registered on ClinicalTrials.gov (NCT03544112) on June 01, 2018: https://clinicaltrials.gov/ct2/show/NCT03544112 .
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http://dx.doi.org/10.1186/s13722-021-00224-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941881PMC
March 2021

Prime editing in mice reveals the essentiality of a single base in driving tissue-specific gene expression.

Genome Biol 2021 Mar 16;22(1):83. Epub 2021 Mar 16.

Department of Medicine, Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA.

Background: Most single nucleotide variants (SNVs) occur in noncoding sequence where millions of transcription factor binding sites (TFBS) reside. Here, a comparative analysis of CRISPR-mediated homology-directed repair (HDR) versus the recently reported prime editing 2 (PE2) system was carried out in mice over a TFBS called a CArG box in the Tspan2 promoter.

Results: Quantitative RT-PCR showed loss of Tspan2 mRNA in aorta and bladder, but not heart or brain, of mice homozygous for an HDR-mediated three base pair substitution in the Tspan2 CArG box. Using the same protospacer, mice homozygous for a PE2-mediated single-base substitution in the Tspan2 CArG box displayed similar cell-specific loss of Tspan2 mRNA; expression of an overlapping long noncoding RNA was also nearly abolished in aorta and bladder. Immuno-RNA fluorescence in situ hybridization validated loss of Tspan2 in vascular smooth muscle cells of HDR and PE2 CArG box mutant mice. Targeted sequencing demonstrated variable frequencies of on-target editing in all PE2 and HDR founders. However, whereas no on-target indels were detected in any of the PE2 founders, all HDR founders showed varying levels of on-target indels. Off-target analysis by targeted sequencing revealed mutations in many HDR founders, but none in PE2 founders.

Conclusions: PE2 directs high-fidelity editing of a single base in a TFBS leading to cell-specific loss in expression of an mRNA/long noncoding RNA gene pair. The PE2 platform expands the genome editing toolbox for modeling and correcting relevant noncoding SNVs in the mouse.
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http://dx.doi.org/10.1186/s13059-021-02304-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962346PMC
March 2021

High Prevalence of MYO6 Variants in an Austrian Patient Cohort With Autosomal Dominant Hereditary Hearing Loss.

Otol Neurotol 2021 Mar 8. Epub 2021 Mar 8.

Department of Otorhinolaryngology, Head and Neck Surgery Department for Cell and Developmental Biology, Center for Anatomy and Cell Biology Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.

Introduction: Genetic hearing loss (HL) is often monogenic. Whereas more than half of autosomal recessive (AR) cases in Austria are caused by mutations in a single gene, no disproportionately frequent contributing genetic factor has been identified in cases of autosomal dominant (AD) HL. The genetic characterization of HL continues to improve diagnosis, genetic counseling, and lays a foundation for the development of personalized medicine approaches.

Methods: Diagnostic HL panel screening was performed in an Austrian multiplex family with AD HL, and segregation was tested with polymerase chain reaction and Sanger sequencing. In an independent approach, 18 unrelated patients with AD HL were screened for causative variants in all known HL genes to date and segregation was tested if additional family members were available. The pathogenicity of novel variants was assessed based on previous literature and bioinformatic tools such as prediction software and protein modeling.

Results: In six of the 19 families under study, candidate pathogenic variants were identified in MYO6, including three novel variants (p.Gln441Pro, p.Ser612Tyr, and p.Gln650ValfsTer7). Some patients carried more than one likely pathogenic variant in known deafness genes.

Conclusion: These results suggest a potential high prevalence of MYO6 variants in Austrian cases of AD HL. The presence of multiple rare HL variants in some patients highlights the relevance of considering multiple-hit diagnoses for genetic counseling and targeted therapy design.
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http://dx.doi.org/10.1097/MAO.0000000000003076DOI Listing
March 2021

Transcriptional mediators of treatment resistance in lethal prostate cancer.

Nat Med 2021 03 4;27(3):426-433. Epub 2021 Mar 4.

Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. ). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8 T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.
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http://dx.doi.org/10.1038/s41591-021-01244-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960507PMC
March 2021

Routine Esophagograms Following Hiatus Hernia Repair Minimizes Reoperative Morbidity: A Multicenter Comparative Cohort Study.

Ann Surg 2021 Feb 12. Epub 2021 Feb 12.

*Oesophagogastric Surgery Unit, Flinders Medical Centre, Bedford Park, South Australia, 5042, Australia †Department of Surgery, Austin Hospital, Heidelberg, Victoria, 3084, Australia ‡Discipline of Surgery, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, 5042, Australia §Upper Gastrointestinal Surgical Unit, Lyell McEwin Hospital, Elizabeth Vale, South Australia, 5112, Australia.

Objective: Determine the utility of routine esophagograms following hiatus hernia repair and its impact on patient outcomes.

Background: Hiatus hernia repairs are common. Early complications such as re-herniation, esophageal obstruction and perforation, although infrequent, incur significant morbidity. Whether routine postoperative esophagograms enable early recognition of these complications, expedite surgical management, reduce reoperative morbidity, and improve functional outcomes are unclear.

Methods: Analysis of a prospectively-maintained database of hiatus hernia repairs in 14 hospitals, and review of esophagograms in this cohort.

Results: 1829 hiatus hernias were repaired. Of these, 1571 (85.9%) patients underwent a postoperative esophagogram. Overall, 1 in 48 esophagograms resulted in an early (<14 days) reoperation, which was undertaken in 44 (2.4%) patients. Compared to those without an esophagogram, patients who received this test prior to reoperation (n = 37) had a shorter time to diagnosis (2.4 vs. 3.9 days, p = 0.041) and treatment (2.4 vs. 4.3 days, p = 0.037) of their complications. This was associated with lower rates of open surgery (10.8% vs. 42.9%, p = 0.034), gastric resection (0.0% vs. 28.6%, p = 0.022), postoperative morbidity (13.5% vs. 85.7%, p < 0.001), unplanned intensive care admission (16.2% vs. 85.7%, p < 0.001), and decreased length-of-stay (7.3 vs. 18.3 days, p = 0.009). Furthermore, we identified less intraoperative and postoperative complications, as well as superior functional outcomes at one-year follow-up in patients who underwent early reoperations for an esophagogram-detected asymptomatic re-herniation than those who needed surgery for late symptomatic recurrences.

Conclusions: Postoperative esophagograms decrease the morbidity associated with early and late reoperations, and should be considered for routine use following hiatus hernia surgery.
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http://dx.doi.org/10.1097/SLA.0000000000004812DOI Listing
February 2021

Pharyngeal Pouch Surgery in Octo- and Nonagenarians is Safe and Effective: A Multicentre Comparative Cohort Study.

World J Surg 2021 Jun 19;45(6):1819-1827. Epub 2021 Feb 19.

Oesophagogastric Surgery Unit, Flinders Medical Centre, Flinders Drive, Bedford Park, SA, 5042, Australia.

Background: Surgery is the only effective treatment strategy for a symptomatic pharyngeal pouch. However, octo- and nonagenarians are often denied referral to a surgeon because of perceived increased risks. Here, we compare the outcomes of pharyngeal pouch surgery in octo- and nonagenarians with patients under 80 years-of-age and determine the factors which predict post-operative complications and improvement in swallowing.

Methods: Analysis of a prospectively maintained database of patients who underwent pharyngeal pouch surgery across seven hospitals over 15 years.

Results: In total, 113 patients (≥80 years-of-age: 27, <80 years-of-age: 86) underwent endoscopic or open pharyngeal pouch surgery. Despite more comorbidities and a longer hospital stay (median: one extra day), patients ≥80 years-of-age had comparable operative time, complication profile, intensive care admission, emergency reoperation, and revisional pouch surgery as their younger counterparts. Furthermore, the severity of complications was not significantly different between the two age cohorts. No surgical mortality was recorded. Multivariate analysis demonstrated that diverticulectomy combined with cricopharyngeal myotomy independently predicted higher rates of complications (OR: 4.53, 95% CI: 1.43-14.33, p = 0.010), but also greater symptomatic improvement (OR: 4.36, 95% CI: 1.50-12.67, p = 0.007). Importantly, a greater proportion of octo- and nonagenarians experienced improved swallowing than patients <80 years-of-age (96.3% vs. 74.4%, p = 0.013). Moreover, advanced age was not predictive of post-operative complications on multivariate analysis.

Conclusions: Pharyngeal pouch surgery in octo- and nonagenarians is safe and effective. Surgical correction in this age group alleviates symptoms and improves quality-of-life for most patients. These patients should not be denied surgery on the basis of advanced age alone.
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http://dx.doi.org/10.1007/s00268-021-05999-4DOI Listing
June 2021

Massively parallel assessment of human variants with base editor screens.

Cell 2021 Feb;184(4):1064-1080.e20

Genetic Perturbation Platform, Broad Institute, Cambridge, MA 02142, USA. Electronic address:

Understanding the functional consequences of single-nucleotide variants is critical to uncovering the genetic underpinnings of diseases, but technologies to characterize variants are limiting. Here, we leverage CRISPR-Cas9 cytosine base editors in pooled screens to scalably assay variants at endogenous loci in mammalian cells. We benchmark the performance of base editors in positive and negative selection screens, identifying known loss-of-function mutations in BRCA1 and BRCA2 with high precision. To demonstrate the utility of base editor screens to probe small molecule-protein interactions, we screen against BH3 mimetics and PARP inhibitors, identifying point mutations that confer drug sensitivity or resistance. We also create a library of single guide RNAs (sgRNAs) predicted to generate 52,034 ClinVar variants in 3,584 genes and conduct screens in the presence of cellular stressors, identifying loss-of-function variants in numerous DNA damage repair genes. We anticipate that this screening approach will be broadly useful to readily and scalably functionalize genetic variants.
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http://dx.doi.org/10.1016/j.cell.2021.01.012DOI Listing
February 2021

Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity.

Science 2021 02;371(6531):803-810

Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

Although bespoke, sequence-specific proteases have the potential to advance biotechnology and medicine, generation of proteases with tailor-made cleavage specificities remains a major challenge. We developed a phage-assisted protease evolution system with simultaneous positive and negative selection and applied it to three botulinum neurotoxin (BoNT) light-chain proteases. We evolved BoNT/X protease into separate variants that preferentially cleave vesicle-associated membrane protein 4 (VAMP4) and Ykt6, evolved BoNT/F protease to selectively cleave the non-native substrate VAMP7, and evolved BoNT/E protease to cleave phosphatase and tensin homolog (PTEN) but not any natural BoNT protease substrate in neurons. The evolved proteases display large changes in specificity (218- to >11,000,000-fold) and can retain their ability to form holotoxins that self-deliver into primary neurons. These findings establish a versatile platform for reprogramming proteases to selectively cleave new targets of therapeutic interest.
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http://dx.doi.org/10.1126/science.abf5972DOI Listing
February 2021

PrimeDesign software for rapid and simplified design of prime editing guide RNAs.

Nat Commun 2021 02 15;12(1):1034. Epub 2021 Feb 15.

Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA, USA.

Prime editing (PE) is a versatile genome editing technology, but design of the required guide RNAs is more complex than for standard CRISPR-based nucleases or base editors. Here we describe PrimeDesign, a user-friendly, end-to-end web application and command-line tool for the design of PE experiments. PrimeDesign can be used for single and combination editing applications, as well as genome-wide and saturation mutagenesis screens. Using PrimeDesign, we construct PrimeVar, a comprehensive and searchable database that includes candidate prime editing guide RNA (pegRNA) and nicking sgRNA (ngRNA) combinations for installing or correcting >68,500 pathogenic human genetic variants from the ClinVar database. Finally, we use PrimeDesign to design pegRNAs/ngRNAs to install a variety of human pathogenic variants in human cells.
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http://dx.doi.org/10.1038/s41467-021-21337-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884779PMC
February 2021

PRimary Care Opioid Use Disorders treatment (PROUD) trial protocol: a pragmatic, cluster-randomized implementation trial in primary care for opioid use disorder treatment.

Addict Sci Clin Pract 2021 01 31;16(1). Epub 2021 Jan 31.

Kaiser Permanente Northwest, Center for Health Research, 3800 N. Interstate Avenue, Portland, OR, 97227-1098, USA.

Background: Most people with opioid use disorder (OUD) never receive treatment. Medication treatment of OUD in primary care is recommended as an approach to increase access to care. The PRimary Care Opioid Use Disorders treatment (PROUD) trial tests whether implementation of a collaborative care model (Massachusetts Model) using a nurse care manager (NCM) to support medication treatment of OUD in primary care increases OUD treatment and improves outcomes. Specifically, it tests whether implementation of collaborative care, compared to usual primary care, increases the number of days of medication for OUD (implementation objective) and reduces acute health care utilization (effectiveness objective). The protocol for the PROUD trial is presented here.

Methods: PROUD is a hybrid type III cluster-randomized implementation trial in six health care systems. The intervention consists of three implementation strategies: salary for a full-time NCM, training and technical assistance for the NCM, and requiring that three primary care providers have DEA waivers to prescribe buprenorphine. Within each health system, two primary care clinics are randomized: one to the intervention and one to Usual Primary Care. The sample includes all patients age 16-90 who visited the randomized primary care clinics from 3 years before to 2 years after randomization (anticipated to be > 170,000). Quantitative data are derived from existing health system administrative data, electronic medical records, and/or health insurance claims ("electronic health records," [EHRs]). Anonymous staff surveys, stakeholder debriefs, and observations from site visits, trainings and technical assistance provide qualitative data to assess barriers and facilitators to implementation. The outcome for the implementation objective (primary outcome) is a clinic-level measure of the number of patient days of medication treatment of OUD over the 2 years post-randomization. The patient-level outcome for the effectiveness objective (secondary outcome) is days of acute care utilization [e.g. urgent care, emergency department (ED) and/or hospitalizations] over 2 years post-randomization among patients with documented OUD prior to randomization.

Discussion: The PROUD trial provides information for clinical leaders and policy makers regarding potential benefits for patients and health systems of a collaborative care model for management of OUD in primary care, tested in real-world diverse primary care settings. Trial registration # NCT03407638 (February 28, 2018); CTN-0074 https://clinicaltrials.gov/ct2/show/NCT03407638?term=CTN-0074&draw=2&rank=1.
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http://dx.doi.org/10.1186/s13722-021-00218-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849121PMC
January 2021

A novel irinotecan-lipiodol nanoemulsion for intravascular administration: pharmacokinetics and biodistribution in the normal and tumor bearing rat liver.

Drug Deliv 2021 Dec;28(1):240-251

Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Colorectal cancer is one of the most common cancers in the United States and treatment options are limited for patients who develop liver metastases. Several chemotherapeutic regimens have been used for transvascular liver-directed therapy in the treatment of colorectal liver metastases without clear evidence of superiority of one therapy over another. We describe the development of a novel nanoemulsion through combining irinotecan (IRI), a first line systemic agent used for the treatment of colon cancer, with lipiodol, an oily contrast medium derived from poppy seed oil, and evaluated its pharmacokinetic and biodistribution profile as a function of portal venous chemoembolization (PVCE) versus transarterial chemoembolization (TACE) delivery. The Tessari technique was used to create a stable emulsion (20 mg IRI mixed with 2 mL lipiodol) with resultant particle size ranging from 28.9 nm to 56.4 nm. Pharmacokinetic profile established through venous sampling in Buffalo rats demonstrate that the area under the curve (AUC) of IRI was significantly less after PVCE with IRI-lipiodol as compared to IRI alone (131 vs. 316 µg*min/mL, -value = .023), suggesting significantly higher amounts of IRI retention in the liver with the IRI-lipiodol nanoemulsion via first-pass extraction. Subseqent biodistribution studies in tumor-bearing WAG/Rjj rats revealed more IRI present in the tumor following TACE versus PVCE (29.19 ± 12.33 µg/g versus 3.42 ± 1.62; -value = .0033) or IV (29.19 ± 12.33 µg/g versus 1.05 ± 0.47; -value = .0035). The IRI-lipiodol nanoemulsion demonstrated an acceptable hepatotoxicity profile in all routes of administration. In conclusion, the IRI-lipiodol nanoemulsion via TACE showed promise and warrants further investigation as an option for the treatment of metastatic colorectal cancer.
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http://dx.doi.org/10.1080/10717544.2020.1869863DOI Listing
December 2021

Precision genome editing using cytosine and adenine base editors in mammalian cells.

Nat Protoc 2021 02 18;16(2):1089-1128. Epub 2021 Jan 18.

Merkin Institute of Transformative Technologies in Healthcare, The Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Genome editing has transformed the life sciences and has exciting prospects for use in treating genetic diseases. Our laboratory developed base editing to enable precise and efficient genome editing while minimizing undesired byproducts and toxicity associated with double-stranded DNA breaks. Adenine and cytosine base editors mediate targeted A•T-to-G•C or C•G-to-T•A base pair changes, respectively, which can theoretically address most human disease-associated single-nucleotide polymorphisms. Current base editors can achieve high editing efficiencies-for example, approaching 100% in cultured mammalian cells or 70% in adult mouse neurons in vivo. Since their initial description, a large set of base editor variants have been developed with different on-target and off-target editing characteristics. Here, we describe a protocol for using base editing in cultured mammalian cells. We provide guidelines for choosing target sites, appropriate base editor variants and delivery strategies to best suit a desired application. We further describe standard base-editing experiments in HEK293T cells, along with computational analysis of base-editing outcomes using CRISPResso2. Beginning with target DNA site selection, base-editing experiments in mammalian cells can typically be completed within 1-3 weeks and require only standard molecular biology techniques and readily available plasmid constructs.
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http://dx.doi.org/10.1038/s41596-020-00450-9DOI Listing
February 2021

Asynchronous Telepsychiatry Interviewer Training Recommendations: A Model for Interdisciplinary, Integrated Behavioral Health Care.

Telemed J E Health 2021 Jan 12. Epub 2021 Jan 12.

Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, California, USA.

Asynchronous telepsychiatry (ATP) is an integrative model of behavioral health service delivery that is applicable in a variety of settings and populations, particularly consultation in primary care. This article outlines the development of a training model for ATP clinician skills. Clinical and procedural training for ATP clinicians (n = 5) was provided by master's-level, clinical mental health providers developed by three experienced telepsychiatrists (P.Y. D.H., and J.S) and supervised by a tele-psychiatrist (PY, GX, DL) through seminar, case supervision, and case discussions. A training manual and one-on-one sessions were employed for initial training. Unstructured expert discussion and feedback sessions were conducted in the training phase of the study in year 1 and annually thereafter over the remaining 4 years of the study. The notes gathered during those sessions were synthesized into themes to gain a summary of the study telepsychiatrist training recommendations for ATP interviewers. Expert feedback and discussion revealed three overarching themes of recommended skill sets for ATP interviewers: (1) comprehensive skills in brief psychiatric interviewing, (2) adequate knowledge base of behavioral health conditions and therapeutic techniques, and (3) clinical documentation, integrated care/consultation practices, and e-competency skill sets. The model of training and skill requirements from expert feedback sessions included these three skill sets. Technology training recommendations were also identified and included: (1) awareness of privacy/confidentiality for electronic data gathering, storage, management, and sharing; (2) technology troubleshooting; and (3) video filming/retrieval. We describe and provide a suggested training model for the use of ATP integrated behavioral health. The training needs for ATP clinicians were assessed on a limited convenience sample of experts and clinicians, and more rigorous studies of training for ATP and other technology-focused, behavioral health services are needed. Clinical Trials number: NCT03538860.
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http://dx.doi.org/10.1089/tmj.2020.0076DOI Listing
January 2021

International recommendations for personalised selective internal radiation therapy of primary and metastatic liver diseases with yttrium-90 resin microspheres.

Eur J Nucl Med Mol Imaging 2021 May 12;48(5):1570-1584. Epub 2021 Jan 12.

Department of Nuclear Medicine, Jules Bordet Institute, Université Libre de Bruxelles, Rue Héger-Bordet 1, B-1000, Brussels, Belgium.

Purpose: A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90 (Y)-resin microspheres.

Methods: A steering committee of 23 international experts representing all participating specialties formulated recommendations for SIRT with Y-resin microspheres activity prescription and post-treatment dosimetry, based on literature searches and the responses to a 61-question survey that was completed by 43 leading experts (including the steering committee members). The survey was validated by the steering committee and completed anonymously. In a face-to-face meeting, the results of the survey were presented and discussed. Recommendations were derived and level of agreement defined (strong agreement ≥ 80%, moderate agreement 50%-79%, no agreement ≤ 49%).

Results: Forty-seven recommendations were established, including guidance such as a multidisciplinary team should define treatment strategy and therapeutic intent (strong agreement); 3D imaging with CT and an angiography with cone-beam-CT, if available, and Tc-MAA SPECT/CT are recommended for extrahepatic/intrahepatic deposition assessment, treatment field definition and calculation of the Y-resin microspheres activity needed (moderate/strong agreement). A personalised approach, using dosimetry (partition model and/or voxel-based) is recommended for activity prescription, when either whole liver or selective, non-ablative or ablative SIRT is planned (strong agreement). A mean absorbed dose to non-tumoural liver of 40 Gy or less is considered safe (strong agreement). A minimum mean target-absorbed dose to tumour of 100-120 Gy is recommended for hepatocellular carcinoma, liver metastatic colorectal cancer and cholangiocarcinoma (moderate/strong agreement). Post-SIRT imaging for treatment verification with Y-PET/CT is recommended (strong agreement). Post-SIRT dosimetry is also recommended (strong agreement).

Conclusion: Practitioners are encouraged to work towards adoption of these recommendations.
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http://dx.doi.org/10.1007/s00259-020-05163-5DOI Listing
May 2021

Laboratory evolution of a sortase enzyme that modifies amyloid-β protein.

Nat Chem Biol 2021 03 11;17(3):317-325. Epub 2021 Jan 11.

Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Epitope-specific enzymes are powerful tools for site-specific protein modification but generally require genetic manipulation of the target protein. Here, we describe the laboratory evolution of the bacterial transpeptidase sortase A to recognize the LMVGG sequence in endogenous amyloid-β (Aβ) protein. Using a yeast display selection for covalent bond formation, we evolved a sortase variant that prefers LMVGG substrates from a starting enzyme that prefers LPESG substrates, resulting in a >1,400-fold change in substrate preference. We used this evolved sortase to label endogenous Aβ in human cerebrospinal fluid, enabling the detection of Aβ with sensitivities rivaling those of commercial assays. The evolved sortase can conjugate a hydrophilic peptide to Aβ, greatly impeding the ability of the resulting protein to aggregate into higher-order structures. These results demonstrate laboratory evolution of epitope-specific enzymes toward endogenous targets as a strategy for site-specific protein modification without target gene manipulation and enable potential future applications of sortase-mediated labeling of Aβ peptides.
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http://dx.doi.org/10.1038/s41589-020-00706-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904614PMC
March 2021

In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice.

Nature 2021 01 6;589(7843):608-614. Epub 2021 Jan 6.

Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20-60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.
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http://dx.doi.org/10.1038/s41586-020-03086-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872200PMC
January 2021

Perioperative thromboprophylaxis is highly variable in general surgery: results from a multicentre survey.

ANZ J Surg 2020 12;90(12):2401-2403

Department of Surgery, Austin Health, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/ans.16223DOI Listing
December 2020

Two-Level Separation Surgery for Thoracic Epidural Metastatic Disease: An Operative Video Demonstration.

World Neurosurg 2021 Mar 13;147:160. Epub 2020 Dec 13.

Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, New York, USA.

The spinal column is one of the most common regions of cancer metastasis. Spinal metastases typically occur in the vertebral body, and due to direct posterior extension or retropulsed pathological fractures, they often present with signs and symptoms of epidural spinal cord compression. This scenario requires surgical management to relieve compression and stabilize the spine. Separation surgery establishes a corridor to the ventral epidural space via pediculectomy, which allows for circumferential decompression and creation of a tumor-free margin around the thecal sac. Separation surgery is an increasingly popular method for the management of spinal metastases, particularly due to potentially reduced morbidity versus en bloc tumor resection, and its proven effectiveness when combined with spinal radiosurgery. Thus, separation surgery should be considered in patients with high-grade metastatic ventral epidural spinal cord compression. In this video, we present the case of a 61-year-old woman with metastatic hepatocellular carcinoma found to have severe spinal cord compression due to pathological vertebral body fractures at T10-T12, and ventral epidural disease at T10 and T12. The patient received T8-L2 posterior instrumented fusion and T10 and T12 separation surgery, with intraoperative cement embolization. We demonstrate the operative steps required to complete this procedure (Video 1).
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http://dx.doi.org/10.1016/j.wneu.2020.12.022DOI Listing
March 2021

Efficacy and Prognostic Factors for Y-90 Radioembolization (Y-90) in Metastatic Neuroendocrine Tumors with Liver Metastases.

Can J Gastroenterol Hepatol 2020 23;2020:5104082. Epub 2020 Nov 23.

Floyd and Delores Jones Cancer Institute, Virginia Mason Cancer Institute, Seattle, WA, USA.

Background: Yttrium-90 (Y-90) can be an effective liver-directed therapy for patients with metastatic neuroendocrine tumors (NETs), but population-based data are limited. We characterized the use of Y-90 in NET patients and identified factors associated with response.

Methods: We identified 49 patients with metastatic liver-dominant NETs across BC Cancer's six regional centres who received Y-90 between June 2011 and January 2017 in British Columbia, Canada. Baseline characteristics, radiographic responses, and outcomes were summarized.

Results: Of the 49 patients who received Y-90, the median age was 56 years (range 21-78), 49% were male, and 94% had an ECOG performance status of 0-1. The primary location of the NET included pancreas (31%), small bowel (41%), large bowel (6%), unknown (14%), and others (12%). 69% of these patients had liver metastases alone, and tumors were graded as 1 (61%), 2 (25%), 3 (2%), and unknown (12%). Prior therapies included surgery (63%), local ablative therapy (25%), somatostatin analogue (69%), and systemic therapy (35%). The median Y-90 dose was 2.2 GBq (range 0.8-3.6), as SIR-spheres (69%) or TheraSpheres (29%). Median time to Y-90 from diagnosis of metastases measured 1.54 years. 88% received segmental Y-90, with 1 (69%), 2 (29%), and 3 (2%) treatments. Y-90 resulted in partial response (53%), stable disease (33%), and progressive disease (12%). Y-90 was well-tolerated, with infrequent grade 3-4 biochemical toxicities (2%) and grade 3 abdominal pain (6%). Longer overall survival (OS) was associated with resection of primary tumor, well-differentiated histology, and low Ki-67. Median OS was 27.2 months (95% CI 8.0-46.5).

Conclusions: In our population-based cohort, Y-90 was well-tolerated in patients with metastatic liver-dominant NETs. Prior surgical resection was an important predictor of OS.
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http://dx.doi.org/10.1155/2020/5104082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704205PMC
November 2020