Publications by authors named "Matthew Hall"

686 Publications

Impact of the AAP Guideline on Management of Brief Resolved Unexplained Events.

Hosp Pediatr 2022 Aug 15. Epub 2022 Aug 15.

University of Washington and Seattle Children's Hospital, Seattle Washington.

Objectives: In May 2016, the American Academy of Pediatrics published a clinical practice guideline (CPG) defining apparent life-threatening events (ALTEs) as brief resolved unexplained events (BRUEs) and recommending risk-based management. We analyzed the association of CPG publication on admission rate, diagnostic testing, treatment, cost, length of stay (LOS), and revisits in patients with BRUE.

Methods: Using the Pediatric Health Information Systems database, we studied patients discharged from the hospital with a diagnosis of ALTE/BRUE from January 2012 to December 2019. We grouped encounters into 2 time cohorts on the basis of discharge date: preguideline (January 2012-January 2016) and postguideline (July 2016-December 2019). We used interrupted time series to test if the CPG publication was associated with level change and change in slope for each metric.

Results: The study included 27 941 hospitalizations for ALTE/BRUE from 36 hospitals. There was an early decrease in 12 diagnostic tests that the CPG strongly recommended against. There was a positive change in the use of electrocardiogram (+3.5%, P < .001), which is recommended by CPG. There was a significant reduction in admissions (-13.7%, P < .001), utilization of medications (-8.3%, P < .001), cost (-$1146.8, P < .001), and LOS (-0.2 days, P < .001), without a change in the revisit rates. In the postguideline period, there were an estimated 2678 admissions avoided out of 12 508 encounters.

Conclusions: Publication of the American Academy of Pediatrics BRUE CPG was associated with substantial reductions in testing, utilization of medications, admission rates, cost, and LOS, without a change in the revisit rates.
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http://dx.doi.org/10.1542/hpeds.2021-006427DOI Listing
August 2022

A humanized nanobody phage display library yields potent binders of SARS CoV-2 spike.

PLoS One 2022 10;17(8):e0272364. Epub 2022 Aug 10.

National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America.

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) ex vivo model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0272364PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365158PMC
August 2022

Antibiotics and outcomes of CF pulmonary exacerbations in children infected with MRSA and Pseudomonas aeruginosa.

J Cyst Fibros 2022 Aug 6. Epub 2022 Aug 6.

Division of Infectious Diseases, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.

Background: Limited data exist to inform antibiotic selection among people with cystic fibrosis (CF) with airway infection by multiple CF-related microorganisms. This study aimed to determine among children with CF co-infected with methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (Pa) if the addition of anti-MRSA antibiotics to antipseudomonal antibiotic treatment for pulmonary exacerbations (PEx) would be associated with improved clinical outcomes compared with antipseudomonal antibiotics alone.

Methods: Retrospective cohort study using data from the CF Foundation Patient Registry-Pediatric Health Information System linked dataset. The odds of returning to baseline lung function and having a subsequent PEx requiring intravenous antibiotics were compared between PEx treated with anti-MRSA and antipseudomonal antibiotics and those treated with antipseudomonal antibiotics alone, adjusting for confounding by indication using inverse probability of treatment weighting.

Results: 943 children with CF co-infected with MRSA and Pa contributed 2,989 PEx for analysis. Of these, 2,331 (78%) PEx were treated with both anti-MRSA and antipseudomonal antibiotics and 658 (22%) PEx were treated with antipseudomonal antibiotics alone. Compared with PEx treated with antipseudomonal antibiotics alone, the addition of anti-MRSA antibiotics to antipseudomonal antibiotic therapy was not associated with a higher odds of returning to ≥90% or ≥100% of baseline lung function or a lower odds of future PEx requiring intravenous antibiotics.

Conclusions: Children with CF co-infected with MRSA and Pa may not benefit from the addition of anti-MRSA antibiotics for PEx treatment. Prospective studies evaluating optimal antibiotic selection strategies for PEx treatment are needed to optimize clinical outcomes following PEx treatment.
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http://dx.doi.org/10.1016/j.jcf.2022.08.001DOI Listing
August 2022

Incidence and Relative Burden of Surgical Site Infections in Children Undergoing Non-Emergent Surgery: Implications for Performance Benchmarking and Prioritization of Prevention Efforts.

Ann Surg 2022 Aug 9. Epub 2022 Aug 9.

Department of Surgery, Boston Children's Hospital, Boston, MA.

Objective: To establish surgical site infection (SSI) performance benchmarks in pediatric surgery and to develop a prioritization framework for SSI prevention based on procedure-level SSI burden.

Summary Background Data: Contemporary epidemiology of SSI rates and event burden in elective pediatric surgery remain poorly characterized.

Methods: Multicenter analysis using sampled SSI data from 90 hospitals participating in NSQIP-Pediatric and procedural volume data from the Pediatric Health Information System (PHIS) database. Procedure-level incisional and organ space SSI (OSI) rates for 17 elective procedure groups were calculated from NSQIP-Pediatric data and estimates of procedure-level SSI burden were extrapolated using procedural volume data. The relative contribution of each procedure to the cumulative sum of SSI events from all procedures was used as a prioritization framework.

Results: 11689 non-emergent procedures were included. The highest incisional SSI rates were associated with gastrostomy closure (4.1%), small bowel procedures (4.0%), and gastrostomy (3.7%), while the highest OSI rates were associated with esophageal atresia/tracheoesophageal fistula (EA/TEF) repair (8.1%), colorectal procedures (1.8%), and small bowel procedures (1.5%). 66.1% of the cumulative incisional SSI burden from all procedures were attributable to three procedure groups (gastrostomy: 27.5%, small bowel: 22.9%, colorectal: 15.7%), and 72.8% of all OSI events were similarly attributable to three procedure groups (small bowel: 28.5%, colorectal: 26.0%, EA/TEF repair: 18.4%).

Conclusions: A small number of procedures account for a disproportionate burden of SSIs in pediatric surgery. The results of this analysis can be used as a prioritization framework for refocusing SSI prevention efforts where they are needed most.
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http://dx.doi.org/10.1097/SLA.0000000000005673DOI Listing
August 2022

Selective cellular probes for mammalian thioredoxin reductase TrxR1: rational design of RX1, a modular 1,2-thiaselenane redox probe.

Chem 2022 May 14;8(5):1493-1517. Epub 2022 Apr 14.

Department of Pharmacy, Ludwig-Maximilians University of Munich, Butenandtstr. 5-13, 81377 Munich, DE.

Quantifying the activity of key cellular redox players is crucial for understanding physiological homeostasis, and for targeting their perturbed states in pathologies including cancer and inflammatory diseases. However, cellularly-selective probes for oxidoreductase turnover are sorely lacking. We rationally developed the first probes that selectively target the mammalian selenoprotein thioredoxin reductase (TrxR), using a cyclic selenenylsulfide oriented to harness TrxR's unique selenolthiol chemistry while resisting the cellular monothiol background. Lead probe had excellent TrxR1-selective performance in cells, cross-validated by knockout, selenium starvation, knock-in, and chemical inhibitors. Its background-free fluorogenicity enabled us to perform the first quantitative high-throughput live cell screen for TrxR1 inhibitors, which indicated that tempered SAr electrophiles may be more selective TrxR drugs than the classical electrophiles used hitherto. The design thus sets the stage for imaging of the activity of this key oxidoreductase in health and disease, and can also drive TrxR1-inhibitor drug design.
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http://dx.doi.org/10.1016/j.chempr.2022.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9351623PMC
May 2022

Zero Setup Margin Mask versus Frame Immobilization during Gamma Knife Icon™ Stereotactic Radiosurgery for Brain Metastases.

Cancers (Basel) 2022 Jul 13;14(14). Epub 2022 Jul 13.

Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA.

We compared the clinical outcomes of BM treated with mask immobilization with zero-SM (i.e., zero-PTV) to standard zero-SM frame immobilization SRS. Consecutive patients with BM, 0.5-2.0 cm in maximal diameter, treated with single-fraction SRS (22-24 Gy) during March 2019-February 2021 were included. Univariable and multivariable analysis were performed using the Kaplan-Meier method and Cox proportional hazards regression. A total of 150 patients with 453 BM met inclusion criteria. A total of 129 (28.5%) lesions were treated with a zero-SM mask immobilization and 324 (71.5%) with zero-SM frame immobilization. Frame immobilization treatments were associated with a higher proportion of gastrointestinal and fewer breast-cancer metastases ( = 0.024), and a higher number of treated lesions per SRS course (median 7 vs. 3; < 0.001). With a median follow up of 15 months, there was no difference in FFLF between the mask and frame immobilization groups on univariable ( = 0.29) or multivariable analysis ( = 0.518). Actuarial FFLF at 1 year was 90.5% for mask and 92% for frame immobilization ( = 0.272). Radiation necrosis rates at 1 year were 12.5% for mask and 4.1% for frame immobilization ( = 0.502). For BM 0.5-2.0 cm in maximal diameter treated with single-fraction SRS using 22-24 Gy, mask immobilization with zero SM produces comparable clinical outcomes to frame immobilization. The initial findings support omitting a SM when using mask immobilization with this treatment approach on a Gamma Knife Icon™.
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http://dx.doi.org/10.3390/cancers14143392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320023PMC
July 2022

Induction Chemotherapy and Ablative Stereotactic Magnetic Resonance Image-Guided Adaptive Radiation Therapy for Inoperable Pancreas Cancer.

Front Oncol 2022 23;12:888462. Epub 2022 Jun 23.

Department of Radiation Oncology, Miami Cancer Institute, Miami, FL, United States.

Background: Radiation therapy (RT) dose for inoperable pancreatic ductal adenocarcinoma (PDAC) has historically been non-ablative to avoid injuring gastrointestinal (GI) organs at risk (OARs). Accruing data suggest that dose escalation, in select patients, may significantly improve clinical outcomes. Early results of ablative stereotactic magnetic resonance image-guided adaptive radiation therapy (A-SMART) have been encouraging, although long-term outcomes are not well understood.

Methods: A single institution retrospective analysis was performed of inoperable non-metastatic PDAC patients who received induction chemotherapy then 5-fraction A-SMART on a 0.35T-MR Linac from 2018-2021.

Results: Sixty-two patients were evaluated with a median age of 66 years (range 35-91) and nearly all achieved Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (96.8%). Locally advanced disease was common (72.6%), otherwise borderline resectable (22.6%), or medically inoperable (4.8%). All received induction chemotherapy for a median 4.2 months (range, 0.2-13.3) most commonly FOLFIRINOX (n=43; 69.4%). Median prescribed dose was 50 Gy (range 40-50); median biologically effective dose (BED) was 100 Gy. The median local control (LC), progression-free survival (PFS), and overall survival (OS) from diagnosis were not reached, 20 months, and 23 months, respectively. Also, 2-year LC, PFS, and OS were 68.8%, 40.0%, and 45.5%, respectively. Acute and late grade 3+ toxicity rates were 4.8% and 4.8%, respectively.

Conclusions: To our knowledge, this is the largest series of induction chemotherapy followed by ablative 5-fraction SMART delivered on an MR Linac for inoperable PDAC. The potential for this novel treatment strategy is to achieve long-term LC and OS, compared to chemotherapy alone, and warrants prospective evaluation.
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http://dx.doi.org/10.3389/fonc.2022.888462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9259801PMC
June 2022

Teaching principles of translational science to a broad scientific audience using a case study approach: A pilot course from the National Center for Advancing Translational Sciences.

J Clin Transl Sci 2022 21;6(1):e66. Epub 2022 Mar 21.

National Institutes of Health, National Center for Advancing Translational Sciences, Bethesda, MD, USA.

There are numerous examples of translational science innovations addressing challenges in the translational process, accelerating progress along the translational spectrum, and generating solutions relevant to a wide range of human health needs. Examining these successes through an education lens can identify core principles and effective practices that lead to successful translational outcomes. The National Center for Advancing Translational Sciences (NCATS) is identifying and teaching these core principles and practices to a broad audience via online courses in translational science which teach from case studies of NCATS-led or supported research initiatives. In this paper, we share our approach to the design of these courses and offer a detailed description of our initial course, which focused on a preclinical drug discovery and development project spanning academic and government settings. Course participants were from a variety of career stages and institutions. Participants rated the course high in overall value to them and in providing a unique window into the translational science process. We share our model for course development as well as initial findings from the course evaluation with the goal of continuing to stimulate development of novel education activities teaching foundational principles in translational science to a broad audience.
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http://dx.doi.org/10.1017/cts.2022.374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201875PMC
March 2022

Preferential Gs protein coupling of the galanin Gal receptor in the µ-opioid-Gal receptor heterotetramer.

Pharmacol Res 2022 Aug 22;182:106322. Epub 2022 Jun 22.

Integrative Neurobiology Section, USA. Electronic address:

Recent studies have proposed that heteromers of µ-opioid receptors (MORs) and galanin Gal receptors (GalRs) localized in the mesencephalon mediate the dopaminergic effects of opioids. The present study reports converging evidence, using a peptide-interfering approach combined with biophysical and biochemical techniques, including total internal reflection fluorescence microscopy, for a predominant homodimeric structure of MOR and GalR when expressed individually, and for their preference to form functional heterotetramers when co-expressed. Results show that a heteromerization-dependent change in the GalR homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-GalR heterotetramer, which is thus bound to Gs via the GalR homodimer and Gi via the MOR homodimer, provides the framework for a canonical Gs-Gi antagonist interaction at the adenylyl cyclase level. These novel results shed light on the intense debate about the oligomeric quaternary structure of G protein-coupled receptors, their predilection for heteromer formation, and the resulting functional significance.
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http://dx.doi.org/10.1016/j.phrs.2022.106322DOI Listing
August 2022

Respiratory virus testing and clinical outcomes among children hospitalized with pneumonia.

J Hosp Med 2022 Jun 23. Epub 2022 Jun 23.

Division of Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.

Background: Despite the increased availability of diagnostic tests for respiratory viruses, their clinical utility for children with community-acquired pneumonia (CAP) remains uncertain.

Objective: To identify patterns of respiratory virus testing across children's hospitals prior to the COVID-19 pandemic and to determine whether hospital-level rates of viral testing were associated with clinical outcomes.

Design, Setting, And Participants: Multicenter retrospective cohort study of children hospitalized for CAP at 19 children's hospitals in the United States from 2010-2019.

Main Outcomes And Measures: Using a novel method to identify the performance of viral testing, we assessed time trends in the use of viral tests, both overall and stratified by testing method. Adjusted proportions of encounters with viral testing were compared across hospitals and were correlated with length of stay, antibiotic and oseltamivir use, and performance of ancillary laboratory testing.

Results: There were 46,038 hospitalizations for non-severe CAP among children without complex chronic conditions. The proportion with viral testing increased from 38.8% to 44.2% during the study period (P < .001). Molecular testing increased (27.2% to 40.0%, P < .001) and antigen testing decreased (33.2% to 7.8%, P < .001). Hospital-specific adjusted proportions of testing ranged from 10.0% to 83.5% and were not associated with length of stay, antibiotic use, or antiviral use. Hospitals that performed more viral testing did not have lower rates of ancillary laboratory testing.

Conclusions: Viral testing practices varied widely across children's hospitals and were not associated with clinically important process or outcome measures. Viral testing may not influence clinical management for many children hospitalized with CAP.
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http://dx.doi.org/10.1002/jhm.12902DOI Listing
June 2022

Pulsed-Reduced Dose Rate (PRDR) Radiotherapy for Recurrent Primary Central Nervous System Malignancies: Dosimetric and Clinical Results.

Cancers (Basel) 2022 Jun 15;14(12). Epub 2022 Jun 15.

Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA.

Purpose: The objective was to describe PRDR outcomes and report EQD2 OAR toxicity thresholds.

Methods: Eighteen patients with recurrent primary CNS tumors treated with PRDR at a single institution between April 2017 and September 2021 were evaluated. The radiotherapy details, cumulative OAR doses, progression-free survival (PFS), overall survival (OS), and toxicities were collected.

Results: The median PRDR dose was 45 Gy (range: 36-59.4 Gy); the median cumulative EQD2 prescription dose was 102.7 Gy (range: 93.8-120.4 Gy). The median cumulative EQD2 D for the brain was 111.4 Gy (range: 82.4-175.2 Gy). Symptomatic radiation necrosis occurred in three patients, for which the median EQD2 brain D was 115.9 Gy (110.4-156.7 Gy). The median PFS and OS after PRDR were 6.3 months (95%CI: 0.9-11.6 months) and 8.6 months (95%CI: 4.9-12.3 months), respectively. The systematic review identified five peer-reviewed studies with a median cumulative EQD2 prescription dose of 110.3 Gy. At a median follow-up of 8.7 months, the median PFS and OS were 5.7 months (95%CI: 2.1-15.4 months) and 6.7 months (95%CI: 3.2-14.2 months), respectively.

Conclusion: PRDR re-irradiation is a relatively safe and feasible treatment for recurrent primary CNS tumors. Despite high cumulative dose to OARs, the risk of high-grade, treatment-related toxicity within the first year of follow-up remains acceptable.
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http://dx.doi.org/10.3390/cancers14122946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221236PMC
June 2022

Dedicated isotropic 3-D T1 SPACE sequence imaging for radiosurgery planning improves brain metastases detection and reduces the risk of intracranial relapse.

Radiother Oncol 2022 Aug 2;173:84-92. Epub 2022 Jun 2.

Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA; Department of Radiation Oncology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA; Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA. Electronic address:

Background: Stereotactic radiosurgery (SRS) is increasingly used for brain metastases (BM) patients, but distant intracranial failure (DIF) remains the principal disadvantage of this focal therapeutic approach. The objective of this study was to determine if dedicated SRS imaging would improve lesion detection and reduce DIF.

Methods: Between 02/2020 and 01/2021, SRS patients at a tertiary care institution underwent dedicated treatment planning MRIs of the brain including MPRAGE and SPACE post-contrast sequences. DIF was calculated using the Kaplan-Meier method; comparisons were made to a historical consecutive cohort treated using MPRAGE alone (02/2019-01/2020).

Results: 134 patients underwent 171 SRS courses for 821 BM imaged with both MPRAGE and SPACE (primary cohort). MPRAGE sequence evaluation alone detected 679 lesions. With neuroradiologists evaluating SPACE and MPRAGE, an additional 108 lesions were identified (p < 0.001). Upon multidisciplinary review, 34 additional lesions were identified. Compared to the historical cohort (103 patients, 135 SRS courses, 479 BM), the primary cohort had improved median time to DIF (13.5 vs. 5.1 months, p = 0.004). The benefit was even more pronounced for patients treated for their first SRS course (18.4 vs. 6.3 months, p = 0.001). SRS using MPRAGE and SPACE was associated with a 60% reduction in risk of DIF compared to the historical cohort (HR: 0.40; 95% CI: 0.28-0.57, p < 0.001).

Conclusions: Among BM patients treated with SRS, a treatment planning SPACE sequence in addition to MPRAGE substantially improved lesion detection and was associated with a statistically significant and clinically meaningful prolongation in time to DIF, especially for patients undergoing their first SRS course.
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http://dx.doi.org/10.1016/j.radonc.2022.05.029DOI Listing
August 2022

Suite of TMPRSS2 Assays for Screening Drug Repurposing Candidates as Potential Treatments of COVID-19.

ACS Infect Dis 2022 Jun 1;8(6):1191-1203. Epub 2022 Jun 1.

National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States.

SARS-CoV-2 is the causative viral pathogen driving the COVID-19 pandemic that prompted an immediate global response to the development of vaccines and antiviral therapeutics. For antiviral therapeutics, drug repurposing allows for rapid movement of the existing clinical candidates and therapies into human clinical trials to be tested as COVID-19 therapies. One effective antiviral treatment strategy used early in symptom onset is to prevent viral entry. SARS-CoV-2 enters ACE2-expressing cells when the receptor-binding domain of the spike protein on the surface of SARS-CoV-2 binds to ACE2 followed by cleavage at two cut sites by TMPRSS2. Therefore, a molecule capable of inhibiting the protease activity of TMPRSS2 could be a valuable antiviral therapy. Initially, we used a fluorogenic high-throughput screening assay for the biochemical screening of 6030 compounds in NCATS annotated libraries. Then, we developed an orthogonal biochemical assay that uses mass spectrometry detection of product formation to ensure that hits from the primary screen are not assay artifacts from the fluorescent detection of product formation. Finally, we assessed the hits from the biochemical screening in a cell-based SARS-CoV-2 pseudotyped particle entry assay. Of the six molecules advanced for further studies, two are approved drugs in Japan (camostat and nafamostat), two have entered clinical trials (PCI-27483 and otamixaban), while the other two molecules are peptidomimetic inhibitors of TMPRSS2 taken from the literature that have not advanced into clinical trials (compounds 92 and 114). This work demonstrates a suite of assays for the discovery and development of new inhibitors of TMPRSS2.
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http://dx.doi.org/10.1021/acsinfecdis.2c00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9172053PMC
June 2022

Multi-Institutional Outcomes of Stereotactic Magnetic Resonance Image Guided Adaptive Radiation Therapy With a Median Biologically Effective Dose of 100 Gy for Non-bone Oligometastases.

Adv Radiat Oncol 2022 Nov-Dec;7(6):100978. Epub 2022 Apr 25.

Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, Florida.

Purpose: Randomized data show a survival benefit of stereotactic ablative body radiation therapy in selected patients with oligometastases (OM). Stereotactic magnetic resonance guided adaptive radiation therapy (SMART) may facilitate the delivery of ablative dose for OM lesions, especially those adjacent to historically dose-limiting organs at risk, where conventional approaches preclude ablative dosing.

Methods And Materials: The RSSearch Registry was queried for OM patients (1-5 metastatic lesions) treated with SMART. Freedom from local progression (FFLP), freedom from distant progression (FFDP), progression-free survival (PFS), and overall survival (LS) were estimated using the Kaplan-Meier method. FFLP was evaluated using RECIST 1.1 criteria. Toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4 criteria.

Results: Ninety-six patients with 108 OM lesions were treated on a 0.35 T MR Linac at 2 institutions between 2018 and 2020. SMART was delivered to mostly abdominal or pelvic lymph nodes (48.1%), lung (18.5%), liver and intrahepatic bile ducts (16.7%), and adrenal gland (11.1%). The median prescribed radiation therapy dose was 48.5 Gy (range, 30-60 Gy) in 5 fractions (range, 3-15). The median biologically effective dose corrected using an alpha/beta value of 10 was 100 Gy (range, 48-180). No acute or late grade 3+ toxicities were observed with median 10 months (range, 3-25) follow-up. Estimated 1-year FFLP, FFDP, PFS, and OS were 92.3%, 41.1%, 39.3%, and 89.6%, respectively. Median FFDP and PFS were 8.9 months (95% confidence interval, 5.2-12.6 months) and 7.6 months (95% confidence interval, 4.5-10.6 months), respectively.

Conclusions: To our knowledge, this represents the largest analysis of SMART using ablative dosing for non-bone OM. A median prescribed biologically effective dose of 100 Gy resulted in excellent early FFLP and no significant toxicity, likely facilitated by continuous intrafraction MR visualization, breath hold delivery, and online adaptive replanning. Additional prospective evaluation of dose-escalated SMART for OM is warranted.
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http://dx.doi.org/10.1016/j.adro.2022.100978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9130084PMC
April 2022

Clinical Characteristics of Patients Returning to Emergency Department With Initial False-Negative Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)-Based COVID-19 Test.

J Acute Med 2022 Mar;12(1):29-33

Baylor University Medical Center Department of Emergency Medicine Dallas, TX USA.

Background: The coronavirus disease 2019 (COVID-19) outbreak is an international public health emergency. Early identification of COVID-19 patients with false-negative RT-PCR tests is paramount in the ED to prevent both nosocomial and community transmission. This study aimed to compare clinical characteristics of repeat emergency department (ED) visits among coronavirus disease 2019 (COVID-19) patients with initial false-negative reverse transcriptase-polymerase chain reaction (RT-PCR)-based COVID-19 test.

Methods: This is a retrospective, multi-center, cohort study conducted at 12 hospitals affiliated with Baylor Scott & White Health system. Patients visiting the EDs of these hospitals between June and August 2020 were screened. Patients tested negative for viral RNA by quantitative RT-PCR in the first ED visit and positive in the second ED visit were included. The primary outcome was the comparison of clinical characteristics between two consecutive ED visits including the clinical symptoms, triage vital signs, laboratory, and chest X-ray (CXR) results.

Results: A total of 88 confirmed COVID-19 patients with initial false-negative RT-PCR COVID-19 test in the ED were included in the final analyses. The mean duration of symptoms in the second ED visit was significantly higher (3.6 ± 0.4 vs. 2.6 ± 0.3 days, = 0.020). In the first ED visit, lymphocytopenia (35.2%), fever (32.6%), nausea (29.5%), and dyspnea (27.9%) are the most common signs of COVID-19 infection during the window period. There were significant increases in the rate of hypoxia (13.6% vs. 4.6%, = 0.005), abnormal infiltrate on CXR (59.7% vs. 25.9%, < 0.001), and aspartate aminotransferase (AST) elevation (26.1% vs. 9.1%, < 0.001) in the second ED visit.

Conclusions: Early COVID-19 testing (less than 3 days of symptom duration) could be associated with a false-negative result. In this window period, lymphocytopenia, fever, nausea, and dyspnea are the most common early signs that can potentially be clinical hints for COVID-19 diagnosis.
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http://dx.doi.org/10.6705/j.jacme.202203_12(1).0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9096506PMC
March 2022

Methodological progress note: A clinician's guide to propensity scores.

J Hosp Med 2022 04 14;17(4):283-286. Epub 2022 Feb 14.

Children's Hospital Association, Lenexa, Kansas, USA.

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http://dx.doi.org/10.1002/jhm.12791DOI Listing
April 2022

Racial and ethnic differences in pediatric unintentional injuries requiring hospitalization.

J Hosp Med 2022 01 19;17(1):19-27. Epub 2022 Jan 19.

Department of Pediatrics, Division of Emergency Medicine, Children's Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.

Background/objective: This study aims to comprehensively examine racial and ethnic differences in pediatric unintentional injuries requiring hospitalization by age across injury mechanisms.

Study Design: This was a retrospective, nationally representative cross-sectional analysis of discharge data within the 2016 Kids' Inpatient Database for 98,611 children ≤19 years with unintentional injuries resulting in hospitalization. Injury categories included passengers and pedestrians injured in a motor vehicle crash, falls, drownings, burns, firearms, drug and nondrug poisonings, suffocations, and other injuries. Relative risk (RR) for injuries requiring hospitalization were calculated for children of Black, Hispanic, and Other races and ethnicities compared with White children, and then RR were further stratified by age. Excessive hospitalizations were calculated as the absolute number of hospitalizations for each race and ethnicity group that would have been avoided if each group had the same rate as White children.

Results: Black children were significantly more likely to be hospitalized compared with White children for all injury mechanisms except falls, and in nearly all age groups with the greatest RR for firearm injuries (RR 9.8 [95% confidence interval: 9.5-10.2]). Differences were associated with 6263 excessive hospitalizations among all racial and ethnic minority children compared with White children.

Conclusions: Racial and ethnic minority children represent populations at persistent disproportionate risk for injuries resulting in hospitalization; risk that varies in important ways by injury mechanism and children's age. These findings suggest the importance of the environmental and societal exposures that may drive these differences, but other factors, such as provider bias, may also contribute.
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http://dx.doi.org/10.1002/jhm.2735DOI Listing
January 2022

Host Sex Modulates the Energetics of Pathogen Proliferation and Its Dependence on Environmental Resources.

Am Nat 2022 05 4;199(5):E186-E196. Epub 2022 Apr 4.

AbstractSex differences in immunity are predicted to underlie much of the frequently observed sex differences in the prevalence or severity of infection. We propose the additional hypothesis that differences in the ability of males and females to acquire and use resources will also affect how readily a pathogen can convert host energy into transmission stages, thereby contributing to sex differences in infection dynamics. To test this we manipulated the resource environment of male and female by altering the availability of food and then exposed hosts to a bacterial pathogen. We measured the production of transmission spores and virulence via the reduction in life span, together with feeding rates and changes in mass-independent metabolic rate, as a measure of the intake and expenditure of energy during infection. When raised in the presence of high resource levels, females more readily allowed for resources in the environment to be translated to pathogen exploitation, as represented by increased spore production, greater virulence, and higher energy use. In contrast, the traits of infected males were robust to changes in resource availability. High food availability thus exaggerated the degree of sexual dimorphism observed between the sexes. It also modified the relationship between host energy use, virulence, and pathogen spore production for each sex. These results suggest that a host's resource environment can affect how a male or female is exploited by a pathogen and may thus be an additional factor driving sex-specific patterns of disease susceptibility or severity.
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http://dx.doi.org/10.1086/718717DOI Listing
May 2022

Expression of Staphylococcal Virulence Genes In Situ in Human Skin and Soft Tissue Infections.

Antibiotics (Basel) 2022 Apr 14;11(4). Epub 2022 Apr 14.

Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA.

Background: , the most common pathogen in skin and soft tissue infections (SSTI), harbors many well-characterized virulence genes. However, the expression of many of them in SSTIs is unknown. In this study, virulence genes expressed in SSTI were investigated.

Methods: Fifty-three subjects presenting to the outpatient's care and emergency departments with a purulent SSTI at two medical centers in Wisconsin, USA, were enrolled in the study. Total mRNA was extracted from the purulent or swab materials, made into cDNA and sequenced on MiSeq platform. The relative cDNA counts to and identifications of the transcripts were carried out with respect to USA300 reference genome and using SAMTOOLS v.1.3 and BWA, respectively.

Result: A significantly higher cDNA count was observed for many of the virulence and regulatory gene transcripts in the pus samples compared to the swab samples relative to the cDNA counts for , a housekeeping gene. They were for S- (18.6 vs. 14.2), A (13.4 vs. 8.5), A (4.8 vs. 3.1), C (1.4 vs. 1.33), (17.7 vs. 8.33), (3.9 vs. 0.83), (6.04 vs. 3.16), (5.93 vs. 0.33), (6.3 vs. 1.33), (5.4 vs. 3.33) and (5.6 vs. 1.5).

Conclusions: A relative increase in the transcripts of several toxins, adhesion and regulatory genes with respect to a in purulent materials suggests their role in situ during SSTIs, perhaps in an orchestrated manner.
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http://dx.doi.org/10.3390/antibiotics11040527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032627PMC
April 2022

Phylogenetic estimation of the viral fitness landscape of HIV-1 set-point viral load.

Virus Evol 2022 16;8(1):veac022. Epub 2022 Mar 16.

Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Headington, Oxford OX3 7LF, UK.

Set-point viral load (SPVL), a common measure of human immunodeficiency virus (HIV)-1 virulence, is partially determined by viral genotype. Epidemiological evidence suggests that this viral property has been under stabilising selection, with a typical optimum for the virus between 10 and 10 copies of viral RNA per ml. Here we aimed to detect transmission fitness differences between viruses from individuals with different SPVLs directly from phylogenetic trees inferred from whole-genome sequences. We used the local branching index (LBI) as a proxy for transmission fitness. We found that LBI is more sensitive to differences in infectiousness than to differences in the duration of the infectious state. By analysing subtype-B samples from the Bridging the Evolution and Epidemiology of HIV in Europe project, we inferred a significant positive relationship between SPVL and LBI up to approximately 10 copies/ml, with some evidence for a peak around this value of SPVL. This is evidence of selection against low values of SPVL in HIV-1 subtype-B strains, likely related to lower infectiousness, and perhaps a peak in the transmission fitness in the expected range of SPVL. The less prominent signatures of selection against higher SPVL could be explained by an inherent limit of the method or the deployment of antiretroviral therapy.
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http://dx.doi.org/10.1093/ve/veac022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986633PMC
March 2022

Neutrophil and natural killer cell imbalances prevent muscle stem cell-mediated regeneration following murine volumetric muscle loss.

Proc Natl Acad Sci U S A 2022 04 4;119(15):e2111445119. Epub 2022 Apr 4.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109.

Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell– and progenitor-mediated myogenic repair. However, how immune cell infiltration and intercellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in the fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observed the heightened infiltration of natural killer (NK) cells as well as the persistence of neutrophils beyond 2 wk postinjury. Functional validation of NK cells revealed an antagonistic role in neutrophil accumulation in part via inducing apoptosis and CCR1-mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGFβ1). Blocking TGFβ signaling reduced neutrophil accumulation and fibrosis and improved muscle-specific force. Collectively, these results enhance our understanding of immune cell–stem cell cross talk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration.
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http://dx.doi.org/10.1073/pnas.2111445119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169656PMC
April 2022

Photon versus proton whole ventricular radiotherapy for non-germinomatous germ cell tumors: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2022 09 4;69(9):e29697. Epub 2022 Apr 4.

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

Purpose: To determine if proton therapy reduces doses to cranial organs at risk (OARs) as compared to photon therapy in children with non-germinomatous germ cell tumors (NGGCT) receiving whole ventricular radiotherapy (WVRT).

Methods And Materials: Dosimetric data for patients with NGGCT prospectively enrolled in stratum 1 of the Children's Oncology Group study ACNS1123 who received 30.6 Gy WVRT were compared. Target segmentation was standardized using a contouring atlas. Doses to cranial OARs were compared between proton and photon treatments. Clinically relevant dose-volume parameters that were analyzed included mean dose and dose to 40% of the OAR volume (D40).

Results: Mean and D40 doses to the supratentorial brain, cerebellum, and bilateral temporal, parietal, and frontal lobes were statistically significantly lower amongst proton-treated patients, as compared to photon-treated patients. In a subgroup analysis of patients uniformly treated with a 3-mm planning target volume, patients who received proton therapy continued to have statistically significantly lower doses to brain OARs.

Conclusions: Children treated with proton therapy for WVRT had lower doses to normal brain structures, when compared to those treated with photon therapy. Proton therapy should be considered for patients receiving WVRT for NGGCT.
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http://dx.doi.org/10.1002/pbc.29697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329212PMC
September 2022

Virtual Screening for the Discovery of Microbiome β-Glucuronidase Inhibitors to Alleviate Cancer Drug Toxicity.

J Chem Inf Model 2022 04 31;62(7):1783-1793. Epub 2022 Mar 31.

National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States.

Despite the potency of most first-line anti-cancer drugs, nonadherence to these drug regimens remains high and is attributable to the prevalence of "off-target" drug effects that result in serious adverse events (SAEs) like hair loss, nausea, vomiting, and diarrhea. Some anti-cancer drugs are converted by liver uridine 5'-diphospho-glucuronosyltransferases through homeostatic host metabolism to form drug-glucuronide conjugates. These sugar-conjugated metabolites are generally inactive and can be safely excreted the biliary system into the gastrointestinal tract. However, β-glucuronidase (βGUS) enzymes expressed by commensal gut bacteria can remove the glucuronic acid moiety, producing the reactivated drug and triggering dose-limiting side effects. Small-molecule βGUS inhibitors may reduce this drug-induced gut toxicity, allowing patients to complete their full course of treatment. Herein, we report the discovery of novel chemical series of βGUS inhibitors by structure-based virtual high-throughput screening (vHTS). We developed homology models for βGUS and applied them to large-scale vHTS against nearly 400,000 compounds within the chemical libraries of the National Center for Advancing Translational Sciences at the National Institutes of Health. From the vHTS results, we cherry-picked 291 compounds a multifactor prioritization procedure, providing 69 diverse compounds that exhibited positive inhibitory activity in a follow-up βGUS biochemical assay . Our findings correspond to a hit rate of 24% and could inform the successful downstream development of a therapeutic adjunct that targets the human microbiome to prevent SAEs associated with first-line, standard-of-care anti-cancer drugs.
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http://dx.doi.org/10.1021/acs.jcim.1c01414DOI Listing
April 2022

Comparison of catheters or new arteriovenous fistulas for commencement of haemodialysis in pregnant women with chronic kidney disease: an international observational study.

J Nephrol 2022 Jul 28;35(6):1689-1698. Epub 2022 Mar 28.

Divisions of Obstetric Medicine and Nephrology, Department of Medicine Sunnybrook Health Sciences Centre, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Background: Evidence surrounding vascular access options for commencing dialysis in pregnancy complicated by chronic kidney disease (CKD) is limited. Creation of new arteriovenous fistulas (AVFs) in pregnant women is rare.

Methods: Retrospective cohort study of approaches to vascular access in pregnancy in centres in Australia, the United Kingdom (UK) and Canada (2002-2018).

Results: Twenty-three women with advanced CKD commenced dialysis in pregnancy (n = 20) or planned to commence (n = 3). Access at dialysis start was a tunnelled catheter (n = 13), temporary catheter (n = 1), AVF created pre-conception but used in pregnancy (n = 3) and AVF created during pregnancy (n = 3). No women commencing dialysis with an AVF required a catheter. No differences in perinatal outcomes were observed comparing AVFs and catheters at dialysis commencement. No AVFs were created in pregnancy in Canadian women. From Australia and the UK, 10 women had a new AVF created in pregnancy, at median gestation 14.5 weeks (IQR 12.5, 20.75). Four women still needed a catheter for dialysis initiation and 3 eventually used the new AVF. Six AVFs were successfully used in pregnancy at median gestation 24 weeks (IQR 22.5, 28.5), 2 were successfully created but not used and 2 had primary failure. No catheter-associated complications were identified except one episode of catheter-related sepsis.

Conclusions: Catheter-related complications were minimal. In selected women, with sufficient pre-planning, an AVF can be created and successfully used during pregnancy to minimise catheter use if preferred. Pre-conception counselling in advanced CKD should include discussing vascular access options reflecting local expertise and patient preferences.
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http://dx.doi.org/10.1007/s40620-022-01288-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300570PMC
July 2022

GPC1-Targeted Immunotoxins Inhibit Pancreatic Tumor Growth in Mice via Depletion of Short-lived GPC1 and Downregulation of Wnt Signaling.

Mol Cancer Ther 2022 06;21(6):960-973

Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Glypican-1 (GPC1) is a cell surface proteoglycan that is upregulated in multiple types of human cancers including pancreatic cancer. Here, we investigated whether GPC1 could be a target of antibody-toxin fusion proteins (i.e., immunotoxins) for treating pancreatic cancer. We constructed a panel of GPC1-targeted immunotoxins derived from a functional domain of Pseudomonas exotoxin A. An albumin-binding domain was also introduced into the anti-GPC1 immunotoxin to improve serum half-life. Small-molecule screening was performed to identify irinotecan that shows synergistic efficacy with the immunotoxin. We showed that GPC1 was internalized upon antibody binding. Anti-GPC1 immunotoxins alone inhibited tumor growth in a pancreatic cancer xenograft model. The immunotoxin treatment reduced active β-catenin expression in tumor cells. Furthermore, immunotoxins containing an albumin-binding domain in combination with irinotecan caused pancreatic tumor regression. GPC1 expression was reduced by the immunotoxin treatment due to the degradation of the internalized GPC1 and its short cellular turnover rate. Our data indicate that the GPC1-targeted immunotoxin inhibits pancreatic tumor growth via degradation of internalized GPC1, downregulation of Wnt signaling, and inhibition of protein synthesis. The anti-GPC1 immunotoxin in combination with irinotecan thus provides a potential new treatment strategy for patients with pancreatic tumors.
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http://dx.doi.org/10.1158/1535-7163.MCT-21-0778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167738PMC
June 2022

Evaluation of the impact of pre-operative stereotactic radiotherapy on the acute changes in histopathologic and immune marker profiles of brain metastases.

Sci Rep 2022 03 16;12(1):4567. Epub 2022 Mar 16.

Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.

The unique acute effects of the large fractional doses that characterize stereotactic radiosurgery (SRS) or radiotherapy (SRT), specifically in terms of antitumor immune cellular processes, vascular damage, tumor necrosis, and apoptosis on brain metastasis have yet to be empirically demonstrated. The objective of this study is to provide the first in-human evaluation of the acute biological effects of SRS/SRT in resected brain metastasis. Tumor samples from patients who underwent dose-escalated preoperative SRT followed by resection with available non-irradiated primary tumor tissues were retrieved from our institutional biorepository. All primary tumors and irradiated metastases were evaluated for the following parameters: tumor necrosis, T-cells, natural killer cells, vessel density, vascular endothelial growth factor, and apoptotic factors. Twenty-two patients with irradiated and resected brain metastases and paired non-irradiated primary tumor samples met inclusion criteria. Patients underwent a median preoperative SRT dose of 18 Gy (Range: 15-20 Gy) in 1 fraction, with 3 patients receiving 27-30 Gy in 3-5 fractions, followed by resection within median interval of 67.8 h (R: 18.25-160.61 h). The rate of necrosis was significantly higher in irradiated brain metastases than non-irradiated primary tumors (p < 0.001). Decreases in all immunomodulatory cell populations were found in irradiated metastases compared to primary tumors: CD3 + (p = 0.003), CD4 + (p = 0.01), and CD8 + (p = 0.01). Pre-operative SRT is associated with acute effects such as increased tumor necrosis and differences in expression of immunomodulatory factors, an effect that does not appear to be time dependent, within the limited intervals explored within the context of this analysis.
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http://dx.doi.org/10.1038/s41598-022-08507-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8927473PMC
March 2022

Hospitalization rates from radiotherapy complications in the United States.

Sci Rep 2022 03 14;12(1):4371. Epub 2022 Mar 14.

Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Office 1R203, Miami, FL, 33176, USA.

Hospitalizations due to radiotherapy (RT) complications result in significant healthcare expenditures and adversely affect the quality of life of cancer patients. Using a nationally representative dataset, the objective of this study is to identify trends in the incidence of these hospitalizations, their causes, and the resulting financial burden. Data from the National Inpatient Sample was retrospectively analyzed from 2005 to 2016. RT complications were identified using ICD-9 and ICD-10 external cause-of-injury codes. The hospitalization rate was the primary endpoint, with cost and in-hospital death as secondary outcomes. 443,222,223 weighted hospitalizations occurred during the study period, of which 482,525 (0.11%) were attributed to RT. The 3 most common reasons for RT-related hospitalization were cystitis (4.8%, standard error [SE] = 0.09), gastroenteritis/colitis (3.7%, SE = 0.07), and esophagitis (3.5%, SE = 0.07). Aspiration pneumonitis (1.4-fold) and mucositis (1.3-fold) had the highest relative increases among these hospitalizations from 2005 to 2016, while esophagitis (0.58-fold) and disorders of the rectum and anus were the lowest (0.67-fold). The median length of stay of patient for hospitalization for RT complications was 4.1 (IQR, 2.2-7.5) days and the median charge per patient was $10,097 (IQR, 5755-18,891) and the total cost during the study period was $4.9 billion. Hospitalization for RT-related complications is relatively rare, but those that are admitted incur a substantial cost. Use of advanced RT techniques should be employed whenever possible to mitigate the risk of severe toxicity and therefore reduce the need to admit patients.
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http://dx.doi.org/10.1038/s41598-022-08491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921251PMC
March 2022

Risk Factors for Implant Removal After Surgical Fixation of Midshaft Clavicle Fractures.

Orthopedics 2022 Jul-Aug;45(4):e201-e206. Epub 2022 Mar 4.

Midshaft clavicle fractures are common injuries that traditionally have been managed nonoperatively. However, recent literature has shown lower rates of nonunion and improved patient-reported outcomes with surgical management. The rate of implant removal after surgical fixation varies across the literature from 5% to 82%, depending on the method of fixation. We performed a retrospective review of all patients who underwent open reduction and internal fixation (ORIF) with plate-and-screw constructs for midshaft fractures of the clavicle at 2 level I trauma centers to determine the rate of implant removal and identify variables associated with implant removal. We collected all patient-, injury-, and treatment-specific factors as well as information on reoperation for removal of implants. Bivariate analysis and multivariable logistic regression analysis were used to assess whether explanatory factors were associated with removal of implants after ORIF for midshaft clavicle fractures. Of the 146 patients who were treated with ORIF for midshaft clavicle fractures with plate-and-screw constructs, 41 (28%) underwent removal of the implant. The median follow-up was 836 days (interquartile range, 457-1567 days). Variables associated with increased risk of implant removal included anterior plate position (odds ratio, 5.32; 95% CI, 2.01-14.1) and number of holes in the plate (odds ratio, 1.28; 95% CI, 1.00-1.63). These results question whether anterior plating results in less implant prominence and less subsequent removal of implants. [. 2022;45(4):e201-e206.].
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http://dx.doi.org/10.3928/01477447-20220225-10DOI Listing
July 2022

Target 2035 - update on the quest for a probe for every protein.

RSC Med Chem 2022 Jan 3;13(1):13-21. Epub 2021 Dec 3.

Takeda California 9625 Towne Centre Drive San Diego California 92121 USA.

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.
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http://dx.doi.org/10.1039/d1md00228gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792830PMC
January 2022

Systematic review and meta-analysis of lung cancer brain metastasis and primary tumor receptor expression discordance.

Discov Oncol 2021 Nov 8;12(1):48. Epub 2021 Nov 8.

Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Office 1R203, Miami, FL, 33176, USA.

Background: Treatment paradigms for metastatic non-small cell lung cancer are increasingly based on biomarker-driven therapies, with the most common alteration being mutation in the epidermal growth factor receptor (EGFR). Change in expression of such biomarkers could have a profound impact on the choice and efficacy of a selected targeted therapeutic, and hence the objective of this study was to analyze discordance in EGFR status in patients with lung cancer brain metastasis (LCBM).

Methods: Using PRISMA guidelines, a systematic review was performed of series in the Medline database of biopsied or resected LCBM published before May, 2020. Key words included "lung cancer" and "brain metastasis" combined with "epidermal growth factor receptor/EGFR," and "receptor conversion/discordance or concordance." Weighted random effects models were used to calculate pooled estimates.

Results: We identified 501 patients from 19 full-text articles for inclusion in this study. All patients underwent biopsy or resection of at least one intracranial lesion to compare to the primary tumor. On primary/LCBM comparison, the weighted pooled estimate for overall EGFR receptor discordance was 10% (95% CI 5-17%). The weighted effects model estimated a gain of an EGFR mutation in a brain metastases in patients with negative primary tumors was 7% (95% CI 4-12%). Alternatively, the weighted effects model estimate of loss of an EGFR mutation in patients with detected mutations in the primary tumor was also 7% (95% CI 4-10%). KRAS testing was also performed on both primary tumors and LCBM in a subset of 148 patients. The weighted effects estimate of KRAS-mutation discordance among LCBM compared to primary tumors was 13% (95% CI 5-27%). The weighted effects estimated of KRAS gain and loss in LCBM was 10% (95% CI 6-18%) and 8% (95% CI 4-15%), respectively. Meta-regression analysis did not find any association with any factors that could be associated with discordances.

Conclusions: EGFR and KRAS mutation status discordance between primary tumor and LCBM occurs in approximately 10% and 13% of patients, respectively. Evaluation of LCBM receptor status is key to biomarker-driven targeted therapy for intracranial disease and awareness of subtype switching is critical for those patients treated with systemic therapy alone for intracranial disease.
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http://dx.doi.org/10.1007/s12672-021-00445-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8777541PMC
November 2021
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