Publications by authors named "Jessica Lee"

498 Publications

Biological Sex Modifies Aldosterone's Secretion at a Cellular Level.

J Endocrinol 2021 Oct 1. Epub 2021 Oct 1.

G Williams, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, United States.

Inconsistencies have been reported on the effect of sex on aldosterone levels leading to clinical confusion. The reasons for these inconsistencies, are uncertain but include: estrogen and/or its receptor modulating target gene responses to mineralocorticoid receptor activation and aldosterone secretagogues' levels. This study's goal was to determine whether aldosterone's biosynthesis also differed by sex. Two approaches were used. First, plasma renin activity (PRA) and aldosterone were measured in rats. Both were significantly higher in males. Secondly, using rat zona glomerulosa (ZG) cells, we assessed three ex-vivo areas:1) activity/levels of early steps in aldosterone's biosynthesis (StAR and CYP11A1); 2) activity/levels of a late step (CYP11B2); and 3) the status of the MR mediated, ultrashort-feedback-loop. Females had higher expression of CYP11A1 and StAR; and increased CYP11A1 activity (increased pregnenolone/ corticosterone levels) but did not differ in CYP11B2 expression or activity (aldosterone/ levels). Activating the ZG's MR (thereby activating the ultrashort-feedback-loop) reduced CYP11B2's activity similarly in both sexes. Ex-vivo, these molecular effects were accompanied, in females, by lower aldosterone basally but higher aldosterone with angiotensin II stimulation. In conclusion, we documented that not only was there a sex-mediated difference in the activity of aldosterone's biosynthesis, but also these differences at the molecular level, help explain the variable reports on aldosterone's circulating levels. Basally, both in-vivo and ex-vivo, males had higher aldosterone levels, likely secondary to higher aldosterone secretagogue levels. However, in response to acute stimulation, aldosterone levels are higher in females because of the greater levels and/or activity of their StAR/CYP11A1.
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http://dx.doi.org/10.1530/JOE-21-0126DOI Listing
October 2021

Enhanced recovery Pathways in gynecologic surgery: Are they safe and effective in the elderly?

Gynecol Oncol Rep 2021 Nov 20;38:100862. Epub 2021 Sep 20.

New York University School of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, New York, NY, United States.

Objective: To compare perioperative outcomes of the elderly versus non-elderly patients on ERPs undergoing laparotomy for gynecologic surgery.

Methods: From January 2016 to June 2017, patients undergoing elective laparotomies for gynecologic surgery were enrolled in a perioperative ERP protocol. Outcomes were compared between the elderly (age ≥ 70 years) and the non-elderly (age ≤ 69 years). Primary outcomes were length of stay and perioperative complication rates. Comparisons were performed using chi-squared tests or Fisher's exact tests for categorical data and Student's -test or Wilcoxon rank-sum tests for continuous variables, with p < 0.05 for significance.

Results: One hundred eighty-nine patients were enrolled in the study, including 16 patients ≥ 70 years old. The median age was 75 years for the elderly and 45 years for the non-elderly. Elderly patients were more likely to have more complex surgery and longer operative times (absolute median difference of 39 min). Despite the increasing complexity of surgical procedures for elderly patients, there were no statistically significant differences in serious inpatient complications (Clavien-Dindo score 3A or greater), pain and nausea scores, 30-day complications and readmission rates. Elderly patients had a longer median length of stay compared to non-elderly patients by one day (p < 0.001), however, this was not statistically significant on multivariate analysis.

Conclusion: In our series, elderly patients on the ERP had similar rates of complications and readmission when compared to non-elderly patients, despite undergoing more complex surgeries. This suggests that ERP may be feasible and safe in the elderly population undergoing elective gynecologic laparotomy.
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http://dx.doi.org/10.1016/j.gore.2021.100862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479239PMC
November 2021

Catastrophic congenital hemangioma with severe coagulopathy leading to fatal cardiac failure: Case report and review.

Pediatr Dermatol 2021 Sep 30. Epub 2021 Sep 30.

Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

We present a complex case of a neonate, delivered urgently for hydrops fetalis, with a large vascular mass of the extremity, diagnosed postnatally as a congenital hemangioma. The patient suffered immediate cardiac compromise and severe coagulopathy atypical for the diagnosis and subsequently died from these complications. Treatment was imperative but challenging due to a lack of a standardized treatment approach and few historical reports of equally critically ill patients. In this report, we review potential medical and surgical interventions and discuss treatment considerations in similar, life-threatening cases of congenital hemangiomas.
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http://dx.doi.org/10.1111/pde.14825DOI Listing
September 2021

Timing of Nerve Recovery After Nerve Grafting in Obstetrical Brachial Plexus Palsy Patients With Isolated Upper Trunk Neuromas.

Ann Plast Surg 2021 10;87(4):446-450

Division of Pediatric Plastic Surgery, Children's Hospital of Pittsburgh, Pittsburgh, PA.

Background: The timing of nerve recovery after nerve grafting in obstetrical brachial plexus palsy patients has not been well reported. One prior study reported a return to baseline function at 3 to 6 months postoperatively. However, there is a paucity of studies to corroborate this timing, and there have been no studies delineating the timeline to obtain clinically meaningful function.

Methods: OBPP patients with upper trunk neuromas-in-continuity who were treated with resection and sural nerve grafting at a single institution were studied. Time to return to baseline function was assessed by Active Movement Scale (AMS) scores preoperatively and postoperatively. Time to clinically meaningful function, defined as an AMS score of ≥6, was also assessed.

Results: Eleven patients with isolated upper trunk neuromas-in-continuity underwent excision and reversed sural nerve grafting. Three of 11 patients also underwent spinal accessory to suprascapular nerve transfers. Average age at surgery was 9.8 ± 1.9 months. One patient did not have follow-up data and was excluded. Average follow-up was 37.1 ± 16.8 months. Average return to baseline AMS score was approximately 4 to 8 months for shoulder abduction, shoulder flexion, shoulder external rotation, elbow flexion, and forearm supination. Clinically meaningful function was obtained in most patients between 9 and 15 months. The remaining patients who did not achieve clinically meaningful function had all obtained scores of 5, which reflects less than one half normal range of motion against gravity.

Conclusions: Nerve recovery after surgical intervention in OBPP patients who undergo resection of an upper trunk neuroma-in-continuity and nerve grafting is more rapid than in adults but longer than previously reported in OBPP literature. This study provides an important data point in delineating the timeline of nerve recovery.
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http://dx.doi.org/10.1097/SAP.0000000000002939DOI Listing
October 2021

Speak Like You Sing: Integrating Classical Techniques From Theatre and Music in Spoken Dialogue for Opera.

J Voice 2021 Sep 14. Epub 2021 Sep 14.

Advanced Certificate in Vocal Pedagogy, New York University, #111-906 HanShin Apt. 52, Seongbuk-ro 4-gil, Seongbuk-gu, Seoul, South Korea 02831.

Objective: In order to maintain characterization throughout a production, opera singers frequently need skills in more than one vocal task. This exploratory study investigated spoken dialogue before and after two hours of training (one-hour class, one-hour tutorial) in the use of language as an actor, with breath management, pitch range, and resonance strategies of a singer. Comparative recordings of sung and spoken material were analyzed for acoustic qualities.

Design: At the National Opera Center, New York, six professional singers from different voice categories recorded one minute of spoken dialogue before training. Approximately a week later, they recorded one minute of an aria, unaccompanied, followed by the spoken dialogue post-training, then improvised a one - two-minute performance moving between singing and speaking. Data were analyzed for fundamental frequency (F0), sound pressure level (SPL), and long-term average spectrum (LTAS).

Results: Comparing for all singers pre- to post-training, mean F0 of spoken dialogue increased and SPL mean and range increased. Comparing aria to spoken dialogue post-training, SPL range increased. F0 ranges were closer to each other in improvisation than in separate performances of aria and dialogue. Energy peaks between 2 and 4 kHz on LTAS appeared in more than one performing condition.

Conclusions: In spoken dialogue post-training, some F0 and SPL data gravitated toward those of the aria and away from the initial recording, suggesting that participants were beginning to transfer production skills from singing to speaking. A perceptual study is needed to assess characterization and the use of language pre- and post-training.
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http://dx.doi.org/10.1016/j.jvoice.2021.08.008DOI Listing
September 2021

The case of a 19-year-old woman with headache, papilledema, and diplopia.

Ann Clin Transl Neurol 2021 Oct 17;8(10):2038-2039. Epub 2021 Sep 17.

Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

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http://dx.doi.org/10.1002/acn3.51452DOI Listing
October 2021

How Our Technology Use Changed in 2020: Perspectives From Three Youths.

JMIR Ment Health 2021 Sep 15;8(9):e26154. Epub 2021 Sep 15.

Department of Pediatrics, University of Wisconsin - Madison, Madison, WI, United States.

The Technology and Adolescent Mental Wellness program (TAM) is a research program with the primary goals of promoting research on the topic of adolescent technology use and mental wellness, creatively disseminating that research, and fostering community among stakeholders. Our foundational question is this: How can technology support adolescent mental wellness? Youth are key stakeholders in pursuit of this foundational question. In this commentary, we invited 3 members of TAM's youth advisory board to respond to the following question: "How did your technology use change in 2020?" Jessica, Jared, and Babayosimi describe their technology use during COVID-19 as dynamic, and neither uniformly positive nor negative. Further, these 3 youths differ in their perceptions of the same technologies-social media and online school, for example-as well as their perceived ability to self-regulate use of those technologies. We invite you to weigh these perspectives just as we do at TAM-not as empirical findings in themselves, but as examples of youth ideas for future empirical investigation.
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http://dx.doi.org/10.2196/26154DOI Listing
September 2021

Head-Down-Tilt Bed Rest With Elevated CO: Effects of a Pilot Spaceflight Analog on Neural Function and Performance During a Cognitive-Motor Dual Task.

Front Physiol 2021 25;12:654906. Epub 2021 Aug 25.

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, United States.

Spaceflight has widespread effects on human performance, including on the ability to dual task. Here, we examine how a spaceflight analog comprising 30 days of head-down-tilt bed rest (HDBR) combined with 0.5% ambient CO (HDBR + CO) influences performance and functional activity of the brain during single and dual tasking of a cognitive and a motor task. The addition of CO to HDBR is thought to better mimic the conditions aboard the International Space Station. Participants completed three tasks: (1) COUNT: counting the number of times an oddball stimulus was presented among distractors; (2) TAP: tapping one of two buttons in response to a visual cue; and (3) DUAL: performing both tasks concurrently. Eleven participants (six males) underwent functional MRI (fMRI) while performing these tasks at six time points: twice before HDBR + CO, twice during HDBR + CO, and twice after HDBR + CO. Behavioral measures included reaction time, standard error of reaction time, and tapping accuracy during the TAP and DUAL tasks, and the dual task cost (DTCost) of each of these measures. We also quantified DTCost of fMRI brain activation. In our previous HDBR study of 13 participants (with atmospheric CO), subjects experienced TAP accuracy improvements during bed rest, whereas TAP accuracy declined while in the current study of HDBR + CO. In the HDBR + CO subjects, we identified a region in the superior frontal gyrus that showed decreased DTCost of brain activation while in HDBR + CO, and recovered back to baseline levels before the completion of bed rest. Compared to HDBR alone, we found different patterns of brain activation change with HDBR + CO. HDBR + CO subjects had increased DTCost in the middle temporal gyrus whereas HDBR subjects had decreased DTCost in the same area. Five of the HDBR + CO subjects developed signs of spaceflight-associated neuro-ocular syndrome (SANS). These subjects exhibited lower baseline dual task activation and higher slopes of change during HDBR + CO than subjects with no signs of SANS. Collectively, this pilot study provides insight into the additional and/or interactive effects of CO levels during HDBR, and information regarding the impacts of this spaceflight analog environment on the neural correlates of dual tasking.
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http://dx.doi.org/10.3389/fphys.2021.654906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424013PMC
August 2021

From inventories to inquiry: The use of leadership inventories in the context of an undergraduate research living-learning program.

New Dir Stud Leadersh 2021 06;2021(170):69-76

University of Maryland.

Team research that is designed to maximize social impact first requires an in-depth understanding of self, values, personal characteristics, and collaboration. This article explores how leadership assessments and inventories can be utilized to enhance the development of the research process in the context of an intentionally scaffolded first-year course and the complementary curricula and team experience that follows. True Colors, Character Values Scale, Myers-Briggs Type Indicator, CliftonStrengths, and the Thomas-Kilmann Conflict Mode Instrument will be discussed in this article.
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http://dx.doi.org/10.1002/yd.20443DOI Listing
June 2021

Characterization of Non-Small-Cell Lung Cancers With MET Exon 14 Skipping Alterations Detected in Tissue or Liquid: Clinicogenomics and Real-World Treatment Patterns.

JCO Precis Oncol 2021 25;5. Epub 2021 Aug 25.

Foundation Medicine Inc, Cambridge, MA.

Purpose: exon 14 (ex14) skipping alterations are oncogenic drivers in non-small-cell lung cancer (NSCLC). We present a comprehensive overview of ex14 samples from 1,592 patients with NSCLC, associated clinicogenomic characteristics, potential mechanisms of acquired resistance, treatment patterns, and outcomes to MET inhibitors.

Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on samples from 69,219 patients with NSCLC. For treatment patterns and outcomes analysis, patients with advanced ex14-altered NSCLC were selected from the Flatiron Health-Foundation Medicine clinicogenomic database, a nationwide deidentified electronic health record-derived database linked to Foundation Medicine CGP for patients treated between January 2011 and March 2020.

Results: A total of 1,592 patients with NSCLC (2.3%) were identified with 1,599 ex14 alterations spanning multiple functional sites (1,458 of 60,244 tissue samples and 134 of 8,975 liquid samples). Low tumor mutational burden and high programmed death ligand 1 expression were enriched in ex14-altered samples. , , and coamplifications and mutations were present in 34%, 19%, 11%, and 42% of tissue samples, respectively. Comparing tissue and liquid cohorts, coalteration frequency and acquired resistance mechanisms, including multiple mutations, , , , and PI3K pathway alterations, were generally similar. Positive percent agreement with the tissue was 100% for ex14 pairs collected within 1 year (n = 7). Treatment patterns showed increasing adoption of MET inhibitors in ex14-altered NSCLC after receipt of CGP results; the real-world response rate to MET inhibitors was 45%, and time to treatment discontinuation was 4.4 months.

Conclusion: Diverse ex14 alterations were present in 2%-3% of NSCLC cases. Tissue and liquid comparisons showed high concordance and similar coalteration profiles. Characterizing common co-occurring alterations and immunotherapy biomarkers, including those present before or acquired after treatment, may be critical for predicting responses to MET inhibitors and informing rational combination strategies.
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http://dx.doi.org/10.1200/PO.21.00122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407654PMC
August 2021

Mapping the dynamic transfer functions of eukaryotic gene regulation.

Cell Syst 2021 Aug 24. Epub 2021 Aug 24.

Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27606, USA. Electronic address:

Biological information can be encoded within the dynamics of signaling components, which has been implicated in a broad range of physiological processes including stress response, oncogenesis, and stem cell differentiation. To study the complexity of information transfer across the eukaryotic promoter, we screened 119 dynamic conditions-modulating the pulse frequency, amplitude, and pulse width of light-regulating the binding of an epigenome editor to a fluorescent reporter. This system revealed tunable gene expression and filtering behaviors and provided a quantification of the limit to the amount of information that can be reliably transferred across a single promoter as ∼1.7 bits. Using a library of over 100 orthogonal chromatin regulators, we further determined that chromatin state could be used to tune mutual information and expression levels, as well as completely alter the input-output transfer function of the promoter. This system unlocks the information-rich content of eukaryotic gene regulation.
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http://dx.doi.org/10.1016/j.cels.2021.08.003DOI Listing
August 2021

Lifestyle Counseling for Medication Adherence in Glaucoma.

Clin Ophthalmol 2021 17;15:3521-3529. Epub 2021 Aug 17.

Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: Medication adherence in glaucoma patients remains sub-par despite proven benefits of regular administration. The objective was to analyze medication adherence before and after lifestyle counseling in patients with ocular hypertension (OHT) or primary open-angle glaucoma (POAG) (mild, moderate, severe).

Methods: Prospective cohort study from May to July 2018 at a single academic center. From 391 consecutive records, 247 were excluded based on exclusion criteria with 28 patients not meeting inclusion criteria resulting in the final sample of 116 patients (33 had OHT, 83 had POAG - 28 mild, 39 moderate, 16 severe). Scripted lifestyle counseling focusing on diet, exercise, vitamin intake, stress management, and medication adherence was administered by a team of trained medical students. Primary outcome measure was self-reported medication adherence, defined as not missing an eye drop administration in the past month. A 2-3 week follow-up with scripted telephone survey assessing medication adherence, diet, and exercise was collected.

Results: At baseline, in 116 patients, 59.5% were adherent to their medication with a breakdown of 42.4% OHT, 64.3% mild, 66.7% moderate, and 68.7% severe and an increasing trend in medication adherence was found across increasing disease severity (p=0.055). Of the 76 (65.5%) patients reached for follow-up, 17 (22.4%) became adherent following lifestyle counseling (p=0.02) increasing overall adherence to 78.9% from 62.5%.

Conclusion: In our study, comprehensive lifestyle counseling succeeded in increasing medication adherence in patients with OHT and POAG.
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http://dx.doi.org/10.2147/OPTH.S321351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380305PMC
August 2021

A Framework for Commitment to Social Justice and Antiracism in Academic Medicine.

ATS Sch 2021 Jun 12;2(2):159-162. Epub 2021 Mar 12.

Division of Pulmonary, Allergy, and Critical Care, Department of Medicine.

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http://dx.doi.org/10.34197/ats-scholar.2020-0149CMDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357068PMC
June 2021

Effects of long-term immobilisation on endomysium of the soleus muscle in humans.

Exp Physiol 2021 Oct 24;106(10):2038-2045. Epub 2021 Aug 24.

Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.

New Findings: What is the central question of this study? While muscle fibre atrophy in response to immobilisation has been extensively examined, intramuscular connective tissue, particularly endomysium, has been largely neglected: does endomysium content of the soleus muscle increase during bed rest? What is the main finding and its importance? Absolute endomysium content did not change, and previous studies reporting an increase are explicable by muscle fibre atrophy. It must be expected that even a relative connective tissue accumulation will lead to an increase in muscle stiffness.

Abstract: Muscle fibres atrophy during conditions of disuse. Whilst animal data suggest an increase in endomysium content with disuse, that information is not available for humans. We hypothesised that endomysium content increases during immobilisation. To test this hypothesis, biopsy samples of the soleus muscle obtained from 21 volunteers who underwent 60 days of bed rest were analysed using immunofluorescence-labelled laminin γ-1 to delineate individual muscle fibres as well as the endomysium space. The endomysium-to-fibre-area ratio (EFAr, as a percentage) was assessed as a measure related to stiffness, and the endomysium-to-fibre-number ratio (EFNr) was calculated to determine whether any increase in EFAr was absolute, or could be attributed to muscle fibre shrinkage. As expected, we found muscle fibre atrophy (P = 0.0031) that amounted to shrinkage by 16.6% (SD 28.2%) on day 55 of bed rest. ENAr increased on day 55 of bed rest (P < 0.001). However, when analysing EFNr, no effect of bed rest was found (P = 0.62). These results demonstrate that an increase in EFAr is likely to be a direct effect of muscle fibre atrophy. Based on the assumption that the total number of muscle fibres remains unchanged during 55 days of bed rest, this implies that the absolute amount of connective tissue in the soleus muscle remained unchanged. The increased relative endomysium content, however, could be functionally related to an increase in muscle stiffness.
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http://dx.doi.org/10.1113/EP089734DOI Listing
October 2021

Hospital readmissions after stroke in patients with and without dementia and undergone gastrostomy tube placement.

Arch Gerontol Geriatr 2021 Nov-Dec;97:104498. Epub 2021 Jul 29.

Department of Internal Medicine, Division of Geriatrics and Palliative Medicine, McGovern Medical School, University of Texas, Houston, TX, USA.

Introduction: Percutaneous endoscopic gastrostomy (PEG) in stroke patients is associated with high hospital readmission rates. The impact of dementia on hospital readmission rates in stroke patients who underwent PEG is unknown. We aimed to assess if stroke patients with dementia who undergo PEG are at risk for readmission.

Methods: We conducted a retrospective, observational study using the National Readmission Database from Healthcare Cost and Utilization Project (HCUP) from 2013 to 2014. Patients 65 years or older admitted with stroke and who had gastrostomy in the same hospital admission were included. We compared readmission rates at 30 and 60 days between patients with and without dementia and assessed the five most common readmission diagnosis. The association of dementia and hospital readmission was analyzed.

Results: Out of 492,727 patients over 65 who had stroke/PEG, 45,477 (9 %) had dementia. Patients with dementia underwent PEG placement more frequently than those without dementia (4.3% vs. 3.3%, respectively). There was no significant difference in the 30 and 60 days readmission rates between those with dementia and those without. Septicemia, aspiration pneumonitis and complications from the procedure were among top five readmission diagnosis. Dementia was not significantly associated with 30-day (odds ratio (OR) 0.99, 95% CI 0.87-1.13) or 60-day (OR 1, 95% CI 0.89-1.12) readmissions.

Conclusions: Risks and benefits of gastrostomy in older adults with stroke and dementia should be honestly discussed with patients and their families since it exposes them to a higher risk of hospital readmission due to aspiration pneumonitis and complications from PEG.
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http://dx.doi.org/10.1016/j.archger.2021.104498DOI Listing
July 2021

Second-Order Conditioning in Humans.

Authors:
Jessica C Lee

Front Behav Neurosci 2021 8;15:672628. Epub 2021 Jul 8.

School of Psychology, University of New South Wales, Sydney, NSW, Australia.

In contrast to the large body of work demonstrating second-order conditioning (SOC) in non-human animals, the evidence for SOC in humans is scant. In this review, I examine the existing literature and suggest theoretical and procedural explanations for why SOC has been so elusive in humans. In particular, I discuss potential interactions with conditioned inhibition, whether SOC is rational, and propose critical parameters needed to obtain the effect. I conclude that SOC is a real but difficult phenomenon to obtain in humans, and suggest directions for future research.
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http://dx.doi.org/10.3389/fnbeh.2021.672628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295922PMC
July 2021

Effects of Spaceflight Stressors on Brain Volume, Microstructure, and Intracranial Fluid Distribution.

Cereb Cortex Commun 2021 30;2(2):tgab022. Epub 2021 Mar 30.

Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL 32611, USA.

Astronauts are exposed to elevated CO levels onboard the International Space Station. Here, we investigated structural brain changes in 11 participants following 30-days of head-down tilt bed rest (HDBR) combined with 0.5% ambient CO (HDBR + CO) as a spaceflight analog. We contrasted brain changes observed in the HDBR + CO group with those of a previous HDBR sample not exposed to elevated CO. Both groups exhibited a global upward shift of the brain and concomitant intracranial free water (FW) redistribution. Greater gray matter changes were seen in the HDBR + CO group in some regions. The HDBR + CO group showed significantly greater FW decrements in the posterior cerebellum and the cerebrum than the HDBR group. In comparison to the HDBR group, the HDBR + CO group exhibited greater diffusivity increases. In half of the participants, the HDBR + CO intervention resulted in signs of Spaceflight Associated Neuro-ocular Syndrome (SANS), a constellation of ocular structural and functional changes seen in astronauts. We therefore conducted an exploratory comparison compared between subjects that did and did not develop SANS and found asymmetric lateral ventricle enlargement in the SANS group. These results enhance our understanding of the underlying mechanisms of spaceflight-induced brain changes, which is critical for promoting astronaut health and performance.
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http://dx.doi.org/10.1093/texcom/tgab022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152913PMC
March 2021

Developing Drugs for Prevention of Chemotherapy-Induced Nausea and Vomiting: Draft Guidance from the FDA.

Clin Cancer Res 2021 Jul 15. Epub 2021 Jul 15.

Division of Gastroenterology, Office of New Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, Maryland.

The administration of preventative therapy for chemotherapy-induced nausea and vomiting (CINV) is an essential component of the treatment plan for many patients with cancer. In May 2021, the FDA issued a draft guidance for industry to facilitate the clinical development of drugs for the prevention of CINV in adults. FDA guidance has a vital role in the regulatory dialogue between the Agency and external stakeholders. Sharing the FDA's current recommended approach can expedite drug development and ultimately the availability of safe and effective therapies to patients in need. In addition, guidance documents may be leveraged to facilitate communication between regulatory agencies, the academic community, patient advocacy groups, and the pharmaceutical industry. The draft guidance for industry (May 2021) outlines the FDA's current recommendations regarding clinical development programs for drugs for the prevention of CINV and the required attributes of patients for enrollment, aspects of trial design, and efficacy assessments. This article provides an overview of the recommendations contained in the draft guidance.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1941DOI Listing
July 2021

Morphometry of the Lateral Orbitofrontal Cortex is Associated With Eating Dispositions in Early Adolescence: Findings From a Large Population-Based Study.

Soc Cogn Affect Neurosci 2021 Jul 3. Epub 2021 Jul 3.

Department of Psychology, University of Waterloo, Waterloo, Canada.

Early adolescence is a critical period for eating behavior as children gain autonomy around food choice and peer influences increase in potency. From a neurodevelopmental perspective, significant structural changes take place in the prefrontal cortex during this time, including the orbitofrontal cortex (OFC), which is involved in socially contextualized decision making. We examined morphological features of the OFC in relation to food choice in a sample of 10,309 early adolescent children from the ABCD study. Structural parameters of the OFC and insula were examined for relationships with two important aspects of food choice: limiting consumption of fast/fried food and maximizing consumption of nutritious foods. Raw, partially and fully adjusted models were evaluated. Findings revealed that larger surface area of the lateral OFC was associated with higher odds of limiting fast/fried food consumption in raw (OR=1.07, CI:1.02,1.12, p=.002, pFDR=.012), partially adjusted (OR=1.11, CI:1.03,1.19, p=.004, pFDR=.024), and fully adjusted models (OR=1.11, CI:1.03,1.19, p=.006, pFDR=.036). In contrast, larger insula volume was associated with lower odds of maximizing healthy foods in raw (OR=0.94, CI:.91,0.97, p <.001, pFDR=.003) and partially adjusted (OR=0.93, CI: 0.88-0.98, p=.008, pFDR=.048) models. These findings refine understanding of the OFC as a network node implicated in socially mediated eating behavior.
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http://dx.doi.org/10.1093/scan/nsab084DOI Listing
July 2021

Secondary biogenic amine deficiencies: genetic etiology, therapeutic interventions, and clinical effects.

Neurogenetics 2021 10 2;22(4):251-262. Epub 2021 Jul 2.

Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.

Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that lead to secondary defects in the synthesis, catabolism, transport, and metabolism of biogenic amines can lead to neurotransmitter abnormalities, which can present with similar features. Eleven patients with secondary neurotransmitter abnormalities were enrolled between 2011 and 2015. All patients underwent research-based whole exome and/or whole genome sequencing (WES/WGS). A trial of treatment with levodopa/carbidopa and 5-hydroxytryptophan was initiated. In six families with abnormal neurotransmitter profiles and neurological phenotypes, variants in known disease-causing genes (KCNJ6, SCN2A, CSTB in 2 siblings, NRNX1, KIF1A and PAK3) were identified, while one patient had a variant of uncertain significance in a candidate gene (DLG4) that may explain her phenotype. In 3 patients, no compelling candidate genes were identified. A trial of neurotransmitter replacement therapy led to improvement in motor and behavioral symptoms in all but two patients. The patient with KCNJ6 variant did not respond to L-dopa therapy, but rather experienced increased dyskinetic movements even at low dose of medication. The patient's symptoms harboring the NRNX1 deletion remained unaltered. This study demonstrates the utility of genome-wide sequencing in further understanding the etiology and pathophysiology of neurometabolic conditions, and the potential of secondary neurotransmitter deficiencies to serve as novel therapeutic targets. As there was a largely favorable response to therapy in our case series, a careful trial of neurotransmitter replacement therapy should be considered in patients with cerebrospinal fluid (CSF) monoamines below reference range.
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http://dx.doi.org/10.1007/s10048-021-00652-7DOI Listing
October 2021

The transcription factors SIX3 and VAX1 are required for suprachiasmatic nucleus circadian output and fertility in female mice.

J Neurosci Res 2021 Jul 2. Epub 2021 Jul 2.

Department of Obstetrics, Gynecology, and Reproductive Sciences and Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA, USA.

The homeodomain transcription factors sine oculis homeobox 3 (Six3) and ventral anterior homeobox 1 (Vax1) are required for brain development. Their expression in specific brain areas is maintained in adulthood, where their functions are poorly understood. To identify the roles of Six3 and Vax1 in neurons, we conditionally deleted each gene using Synapsin , a promoter targeting maturing neurons, and generated Six3 and Vax1 mice. Six3 and Vax1 females, but not males, had reduced fertility, due to impairment of the luteinizing hormone (LH) surge driving ovulation. In nocturnal rodents, the LH surge requires a precise timing signal from the brain's circadian pacemaker, the suprachiasmatic nucleus (SCN), near the time of activity onset. Indeed, both Six3 and Vax1 females had impaired rhythmic SCN output, which was associated with weakened Period 2 molecular clock function in both Six3 and Vax1 mice. These impairments were associated with a reduction of the SCN neuropeptide vasoactive intestinal peptide in Vax1 mice and a modest weakening of SCN timekeeping function in both Six3 and Vax1 mice. Changes in SCN function were associated with mistimed peak PER2::LUC expression in the SCN and pituitary in both Six3 and Vax1 females. Interestingly, Six3 ovaries presented reduced sensitivity to LH, causing reduced ovulation during superovulation. In conclusion, we have identified novel roles of the homeodomain transcription factors SIX3 and VAX1 in neurons, where they are required for proper molecular circadian clock function, SCN rhythmic output, and female fertility.
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http://dx.doi.org/10.1002/jnr.24864DOI Listing
July 2021

Applying the Noninferiority Paradigm to Assess Exposure-Response Similarity and Dose Between Pediatric and Adult Patients.

J Clin Pharmacol 2021 06;61 Suppl 1:S165-S174

Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

The use of extrapolation of efficacy in pediatric drug development programs is possible when disease progression and treatment response are similar in adult and pediatric populations. Historically, the exposure-response (E-R) similarity was assessed by visual inspection of 2 E-R curves to support pediatric extrapolation. The aim of this study was to develop a quantitative framework to describe the E-R relationship and the difference in E-R between pediatric and adult patients based on accumulated experience in pediatric drug development programs. Using clinical data for 8 drugs with either a linear or nonlinear E-R relationship, we adapted the methodology used in noninferiority testing to assess the E-R similarity between adult and pediatric patients at the targeted drug exposure. We implemented bootstrap-based and Bayesian-based methodologies to estimate the probability of concluding noninferiority of the E-R relationship. This approach provides objective criteria that can be applied to an assessment of E-R noninferiority in 2 populations to support extrapolation of efficacy in drug development programs from adults to pediatric populations.
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http://dx.doi.org/10.1002/jcph.1885DOI Listing
June 2021

Frailty and pre-frailty in cardiac surgery: a systematic review and meta-analysis of 66,448 patients.

J Cardiothorac Surg 2021 Jun 25;16(1):184. Epub 2021 Jun 25.

Critical Care, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Background: The burden of frailty on cardiac surgical outcomes is incompletely understood. Here we perform a systematic review and meta-analysis of studies comparing frail versus pre-frail versus non-frail patients following cardiac surgery.

Methods: We searched MEDLINE and EMBASE databases until July 2018 for studies comparing cardiac surgery outcomes in "frail", "pre-frail" and "non-frail" patients. Data was extracted in duplicate. Primary outcome was operative mortality.

Results: There were 19 observational studies with 66,448 patients. Frail patients were more likely female (risk ratio [RR]1.7; 95%CI:1.5-1.9), older (mean difference: 2.4; 95%CI:1.3-3.5 years older) with greater comorbidities and higher STS-PROM. Frailty (RR2.35; 95%CI:1.57-3.51; p < 0.0001) and pre-frailty (RR2.03; 95%CI:1.52-2.70; p < 0.00001) were associated with increased operative mortality compared with non-frail patients. Frailty was also associated with greater risk of prolonged hospital stay (RR1.83; 95%CI:1.61-2.08; p < 0.0001) and intermediate care facility discharge (RR2.71; 95%CI:1.45-5.05; p = 0.002). Frail (Hazard Ratio [HR]3.27; 95%CI:1.93-5.55; p < 0.0001) and pre-frail patients (HR2.30; 95%CI:1.29-4.09; p = 0.005) had worse mid-term mortality (median follow-up 1 years [range 0.5-4 years]). After adjustment for baseline imbalances, frailty was still associated with greater operative mortality (odds ratio [OR]1.97; 95%CI:1.51-2.57; p < 0.00001), intermediate care facility discharge (OR4.61; 95%CI:2.78-7.66; p < 0.00001) and midterm mortality (HR1.37; 95%CI:1.03-1.83; p = 0.03).

Conclusion: In patients undergoing cardiac surgery, frailty and pre-frailty were associated with 2-fold and 1.5-fold greater adjusted operative mortality, respectively, greater adjusted perioperative complications and frailty was associated with almost 5-fold risk of non-home discharge. Burden of frailty and pre-frailty on cardiac surgical outcomes.
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http://dx.doi.org/10.1186/s13019-021-01541-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229742PMC
June 2021

A single point mutation converts a proton-pumping rhodopsin into a red-shifted, turn-on fluorescent sensor for chloride.

Chem Sci 2021 Mar 17;12(15):5655-5663. Epub 2021 Mar 17.

Department of Chemistry and Biochemistry, The University of Texas at Dallas Richardson TX 75080 USA

The visualization of chloride in living cells with fluorescent sensors is linked to our ability to design hosts that can overcome the energetic penalty of desolvation to bind chloride in water. Fluorescent proteins can be used as biological supramolecular hosts to address this fundamental challenge. Here, we showcase the power of protein engineering to convert the fluorescent proton-pumping rhodopsin GR from into GR1, a red-shifted, turn-on fluorescent sensor for chloride in detergent micelles and in live . This non-natural function was unlocked by mutating D121, which serves as the counterion to the protonated retinylidene Schiff base chromophore. Substitution from aspartate to valine at this position (D121V) creates a binding site for chloride. The binding of chloride tunes the p of the chromophore towards the protonated, fluorescent state to generate a pH-dependent response. Moreover, ion pumping assays combined with bulk fluorescence and single-cell fluorescence microscopy experiments with , expressing a GR1 fusion with a cyan fluorescent protein, show that GR1 does not pump ions nor sense membrane potential but instead provides a reversible, ratiometric readout of changes in extracellular chloride at the membrane. This discovery sets the stage to use natural and laboratory-guided evolution to build a family of rhodopsin-based fluorescent chloride sensors with improved properties for cellular applications and learn how proteins can evolve and adapt to bind anions in water.
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http://dx.doi.org/10.1039/d0sc06061eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179538PMC
March 2021

Visuomotor Adaptation Brain Changes During a Spaceflight Analog With Elevated Carbon Dioxide (CO): A Pilot Study.

Front Neural Circuits 2021 7;15:659557. Epub 2021 Jun 7.

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, United States.

Astronauts on board the International Space Station (ISS) must adapt to several environmental challenges including microgravity, elevated carbon dioxide (CO), and isolation while performing highly controlled movements with complex equipment. Head down tilt bed rest (HDBR) is an analog used to study spaceflight factors including body unloading and headward fluid shifts. We recently reported how HDBR with elevated CO (HDBR+CO) affects visuomotor adaptation. Here we expand upon this work and examine the effects of HDBR+CO on brain activity during visuomotor adaptation. Eleven participants (34 ± 8 years) completed six functional MRI (fMRI) sessions pre-, during, and post-HDBR+CO. During fMRI, participants completed a visuomotor adaptation task, divided into baseline, early, late and de-adaptation. Additionally, we compare brain activity between this NASA campaign (30-day HDBR+CO) and a different campaign with a separate set of participants (60-day HDBR with normal atmospheric CO levels, = 8; 34.25 ± 7.9 years) to characterize the specific effects of CO. Participants were included by convenience. During early adaptation across the HDBR+CO intervention, participants showed decreasing activation in temporal and subcortical brain regions, followed by post- HDBR+CO recovery. During late adaptation, participants showed increasing activation in the right fusiform gyrus and right caudate nucleus during HDBR+CO; this activation normalized to baseline levels after bed rest. There were no correlations between brain changes and adaptation performance changes from pre- to post HDBR+CO. Also, there were no statistically significant differences between the HDBR+CO group and the HDBR controls, suggesting that changes in brain activity were due primarily to bed rest rather than elevated CO. Five HDBR+CO participants presented with optic disc edema, a sign of Spaceflight Associated Neuro-ocular Syndrome (SANS). An exploratory analysis of HDBR+CO participants with and without signs of SANS revealed no group differences in brain activity during any phase of the adaptation task. Overall, these findings have implications for spaceflight missions and training, as ISS missions require individuals to adapt to altered sensory inputs over long periods in space. Further, this is the first study to verify the HDBR and elevated CO effects on the neural correlates of visuomotor adaptation.
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http://dx.doi.org/10.3389/fncir.2021.659557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215599PMC
June 2021

Acquired Resistance to KRAS Inhibition in Cancer.

N Engl J Med 2021 06;384(25):2382-2393

From Dana-Farber Cancer Institute (M.M.A., S.L., J.D., J.O.J., K.E.L., H.F., K.M.H., B.M.W., P.A.J., A.J.A.), Massachusetts General Hospital (R.S.H., Y.P.H.), and Brigham and Women's Hospital (L.M.S., A.J.A.), Boston, and Broad Institute of MIT and Harvard (S.L., X.Y., N.S.P., D.E.R., K.M.H., A.J.A.) and Foundation Medicine (J.L., A.B.S.), Cambridge - all in Massachusetts; Henry Ford Cancer Institute, Detroit (I.I.R.); Memorial Sloan Kettering Cancer Center, New York (K.C.A., G.J.R., P.L.); Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange (V.W.Z., S.S.Z., S.-H.I.O.), Boundless Bio, La Jolla (J.W., J.C.), and Mirati Therapeutics, San Diego (L.D.E., L.W., J.D.L., P.O., J.G.C.) - all in California; Sarah Cannon Research Institute, Tennessee Oncology/OneOncology, Nashville (M.L.J.); the University of Colorado, Aurora (T.P.); and Resolution Bioscience, Kirkland, WA (L.P.L., K.G., M.L.).

Background: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS). The mechanisms of acquired resistance to these therapies are currently unknown.

Methods: Among patients with -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS inhibitors.

Results: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the allele. Acquired bypass mechanisms of resistance included amplification; activating mutations in , , , and ; oncogenic fusions involving , , , , and ; and loss-of-function mutations in and . In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of mutations that confer resistance to KRAS inhibitors.

Conclusions: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).
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http://dx.doi.org/10.1056/NEJMoa2105281DOI Listing
June 2021

Optimizing Robotic Hysterectomy for the Patient Who Is Morbidly Obese with a Surgical Safety Pathway.

J Minim Invasive Gynecol 2021 Jun 15. Epub 2021 Jun 15.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, NYU Langone Health (Dr. Pothuri). Electronic address:

Study Objective: Obesity is a growing worldwide epidemic, and patients classified as obese undergoing gynecologic robotic surgery are at increased risk for surgical complications. This study aimed to evaluate the feasibility and outcomes of a surgical safety protocol known as the High BMI [Body Mass Index] Pathway (HBP) for patients with BMI ≥40 kg/m undergoing planned robotic hysterectomy. Our primary outcome was the rate of all-cause perioperative complications in patients undergoing surgery with the use of the HBP.

Design: A retrospective cohort study.

Setting: An academic teaching hospital.

Patients: A total of 138 patients classified as morbidly obese (BMI ≥40 kg/m) undergoing robotic hysterectomy.

Interventions: The HBP was developed by a multidisciplinary team and was instituted on January 1, 2016, as a quality improvement project. Patients classified as morbidly obese undergoing robotic hysterectomy after this date were compared with consecutive historical controls.

Measurements And Main Results: Seventy-two patients underwent robotic hysterectomies on the HBP and were compared with 66 controls. There were no differences in age, BMI, blood loss, number of comorbidities, or cancer diagnosis. Since the implementation of the HBP, there has been a decrease in anesthesia time (-57.0 minutes; p = .001) and total operating room time (-47.0 min; p = .020), as well as lower estimated blood loss (median 150 mL [interquartile range 100-200] vs 200 mL [interquartile range 100-300]; p = .002) and reduction in overnight hospital admissions (33.3% vs 63.6%; p <.001). In the HBP group, there were fewer all-cause complications (19.4% vs 37.9%; p = .023) and infectious complications (8.3% vs 33.3%; p = .001), and there was no increase in the readmission rates (p = .400). In multivariable analysis, the HBP reduced all-cause complications (odds ratio 0.353; p = .010) after controlling for the covariate (total time in the operating room).

Conclusion: The HBP is a feasible method of optimizing the outcome for patients classified as morbidly obese undergoing major gynecologic surgery. Initiation of the HBP can lead to decreased anesthesia and operating times, all-cause complications, and overnight hospital admissions without increasing readmission rates.
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http://dx.doi.org/10.1016/j.jmig.2021.06.005DOI Listing
June 2021

Ophthalmic changes in a spaceflight analog are associated with brain functional reorganization.

Hum Brain Mapp 2021 Sep 9;42(13):4281-4297. Epub 2021 Jun 9.

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.

Following long-duration spaceflight, some astronauts exhibit ophthalmic structural changes referred to as Spaceflight Associated Neuro-ocular Syndrome (SANS). Optic disc edema is a common sign of SANS. The origin and effects of SANS are not understood as signs of SANS have not manifested in previous spaceflight analog studies. In the current spaceflight analog study, 11 subjects underwent 30 days of strict head down-tilt bed rest in elevated ambient carbon dioxide (HDBR+CO ). Using functional magnetic resonance imaging (fMRI), we acquired resting-state fMRI data at 6 time points: before (2), during (2), and after (2) the HDBR+CO intervention. Five participants developed optic disc edema during the intervention (SANS subgroup) and 6 did not (NoSANS group). This occurrence allowed us to explore whether development of signs of SANS during the spaceflight analog impacted resting-state functional connectivity during HDBR+CO . In light of previous work identifying genetic and biochemical predictors of SANS, we further assessed whether the SANS and NoSANS subgroups exhibited differential patterns of resting-state functional connectivity prior to the HDBR+CO intervention. We found that the SANS and NoSANS subgroups exhibited distinct patterns of resting-state functional connectivity changes during HDBR+CO within visual and vestibular-related brain networks. The SANS and NoSANS subgroups also exhibited different resting-state functional connectivity prior to HDBR+CO within a visual cortical network and within a large-scale network of brain areas involved in multisensory integration. We further present associations between functional connectivity within the identified networks and previously identified genetic and biochemical predictors of SANS. Subgroup differences in resting-state functional connectivity changes may reflect differential patterns of visual and vestibular reweighting as optic disc edema develops during the spaceflight analog. This finding suggests that SANS impacts not only neuro-ocular structures, but also functional brain organization. Future prospective investigations incorporating sensory assessments are required to determine the functional significance of the observed connectivity differences.
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http://dx.doi.org/10.1002/hbm.25546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357001PMC
September 2021

Outcomes of Children With Firearm Injuries Admitted to the PICU in the United States.

Pediatr Crit Care Med 2021 Jun 7. Epub 2021 Jun 7.

Department of Pediatrics, Division of Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD. University of Maryland Medical Center, Baltimore MD. Graduate Medical Education, University of Maryland School of Medicine, Baltimore MD. Virtual Pediatric Systems, LLC.

Objectives: Firearm-related injury is the second leading cause of injury and death for children 1-18 years old in United States. The objective of our study was to analyze the outcomes of children admitted to the PICU with firearm injuries.

Design: Retrospective study.

Setting: PICUs in United States contributing data to Virtual Pediatric Systems, LLC, from January 2009 to December 2017.

Patients: Children age 1 month to 18 years old admitted to the PICU with firearm injury, identified by external cause of injury E-codes and International Classification of Diseases, 9th Edition and International Classification of Diseases, 10th Edition codes were identified.

Interventions: None.

Measurements And Main Results: There were 1,447 cases identified of which 175 (12%) died in the PICU. Unintentional firearm injury (67.7%) and assault with a firearm injury (20%) comprised 90% of the cases. Males comprised 78% of the cohort (1,122) and race distribution included 45% Black (646), 27% White (390), and 12% Hispanic (178). Among the children who died in the PICU, 55% were 13-18 years old. Children attempting suicide with a firearm were more likely to die in the PICU as compared to the other causes of firearm injury. Based on their Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores at discharge, there is high morbidity in children with firearm injuries.

Conclusions: Mortality rate of children with firearm injury admitted to the PICU is high. Children admitted to the PICU with suicide attempt with a firearm carried the highest mortality. Further studies may help further define the epidemiology of firearm injuries in children and plan interventions to minimize these unnecessary deaths.
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http://dx.doi.org/10.1097/PCC.0000000000002785DOI Listing
June 2021
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