Publications by authors named "Keith Anderson"

147 Publications

Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury.

Cell Death Dis 2021 Apr 7;12(4):379. Epub 2021 Apr 7.

Department of Neuroscience, Genentech, South San Francisco, 94080, CA, USA.

RIP1 kinase-mediated inflammatory and cell death pathways have been implicated in the pathology of acute and chronic disorders of the nervous system. Here, we describe a novel animal model of RIP1 kinase deficiency, generated by knock-in of the kinase-inactivating RIP1(D138N) mutation in rats. Homozygous RIP1 kinase-dead (KD) rats had normal development, reproduction and did not show any gross phenotypes at baseline. However, cells derived from RIP1 KD rats displayed resistance to necroptotic cell death. In addition, RIP1 KD rats were resistant to TNF-induced systemic shock. We studied the utility of RIP1 KD rats for neurological disorders by testing the efficacy of the genetic inactivation in the transient middle cerebral artery occlusion/reperfusion model of brain injury. RIP1 KD rats were protected in this model in a battery of behavioral, imaging, and histopathological endpoints. In addition, RIP1 KD rats had reduced inflammation and accumulation of neuronal injury biomarkers. Unbiased proteomics in the plasma identified additional changes that were ameliorated by RIP1 genetic inactivation. Together these data highlight the utility of the RIP1 KD rats for target validation and biomarker studies for neurological disorders.
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http://dx.doi.org/10.1038/s41419-021-03651-6DOI Listing
April 2021

A Systematic Review of Interventions to Increase Physical Activity Among American Indian and Alaska Native Older Adults.

Gerontologist 2021 Feb 19. Epub 2021 Feb 19.

Department of Medicine and Biobehavioral Health, University of Minnesota, Duluth, Minnesota, USA.

Background And Objectives: Physical activity (PA) is a powerful protective factor known to reduce risk for chronic conditions across the lifespan. PA levels are lower among American Indians and Alaska Natives (AIANs) when compared with other racial/ethnic groups and decrease with age. This evidence justifies a synthesis of current intervention research to increase PA levels among AIANs. This systematic review examines completed interventions to increase PA among AIAN older adults and considers recommended practices for research with Indigenous communities.

Research Design And Methods: The systematic review was designed in accordance with the PRISMA statement for systematic review protocols and reporting guidelines. Electronic databases PubMed, Web of Science, and PsycINFO were searched for academic literature. Trials investigating interventions to increase PA among AIAN adults ages 50+ were eligible. The Quality Assessment Tool for Quantitative Studies was used to evaluate the quality of evidence.

Results: Three published trials were identified, including one group-level, clinic-based and two individual-level, home-based interventions. All were 6-weeks in duration, took place in urban areas, and used self-report PA measures. Findings indicated an overall increase in PA levels, improved PA-related outcomes, and improved psychosocial health among participants. None described a community-engaged or culture-centered research strategies.

Discussion And Implications: The narrow yet promising evidence represents a need for expanded research and a call to action for using culture-centered strategies. An advanced understanding of cultural and contextual aspects of PA may produce more impactful interventions, supporting health and mobility across the lifespan.
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http://dx.doi.org/10.1093/geront/gnab020DOI Listing
February 2021

The peptide symporter SLC15a4 is essential for the development of systemic lupus erythematosus in murine models.

PLoS One 2021 14;16(1):e0244439. Epub 2021 Jan 14.

DiCE Molecules, South San Francisco, CA, United States of America.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease representing a serious unmet medical need. The disease is associated with the loss of self-tolerance and exaggerated B cell activation, resulting in autoantibody production and the formation of immune complexes that accumulate in the kidney, causing glomerulonephritis. TLR7, an important mediator of the innate immune response, drives the expression of type-1 interferon (IFN), which leads to expression of type-1 IFN induced genes and aggravates lupus pathology. Because the lysosomal peptide symporter slc15a4 is critically required for type-1 interferon production by pDC, and for certain B cell functions in response to TLR7 and TLR9 signals, we considered it as a potential target for pharmacological intervention in SLE. We deleted the slc15a4 gene in C57BL/6, NZB, and NZW mice and found that pristane-challenged slc15a4-/- mice in the C57BL/6 background and lupus prone slc15a4-/- NZB/W F1 mice were both completely protected from lupus like disease. In the NZB/W F1 model, protection persisted even when disease development was accelerated with an adenovirus encoding IFNα, emphasizing a broad role of slc15a4 in disease initiation. Our results establish a non-redundant function of slc15a4 in regulating both innate and adaptive components of the immune response in SLE pathobiology and suggest that it may be an attractive drug target.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808665PMC
January 2021

Comparison of patients satisfaction with aesthetic outcomes following lower extremity reconstruction: Muscle vs. fasciocutaneous free flaps.

J Plast Reconstr Aesthet Surg 2021 01 20;74(1):65-70. Epub 2020 Sep 20.

Plastic Surgery Department, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, 303 Hills Rd, Cambridge, CB2 0XY, United Kingdom.

Background: The microsurgical reconstruction of complex lower limb defects has become a routine procedure with high success rates. The emphasis has changed from ensuring flap 'success' to providing a reconstruction, which is also aesthetically pleasing. The aim of this study was to compare patients' satisfaction with aesthetic outcomes, following muscle or fasciocutaneous free flap reconstruction to the lower limb.

Methods: Data were collected retrospectively between July, 2013 and May, 2018 at a single institution. The inclusion criteria were adult patients who had successful free tissue transfers to the lower limb following any aetiology. A Likert Scale questionnaire was sent to all patients who met these criteria. The questionnaire included questions related to the reconstruction and donor site.

Results: Questionnaires were sent to 83 patients who met the inclusion criteria. Forty-seven (57%) patients responded, of which 22 (47%) underwent reconstruction with muscular flap and 25 (53%) with fasciocutaneous flap. A statistically significant difference between the two groups was found in relation to flap texture (p = 0.003). Patients with fasciocutaneous flap reconstruction being more satisfied. No significant difference was observed for contour, similarity to the contralateral side, bulkiness of flap, colour match, scar, or overall appearance. The comparison of donor site results revealed no significant difference between the two groups CONCLUSIONS: Despite increase in success in lower extremity reconstruction, many patients still find aesthetic results suboptimal and this affects an individual's global sense of well-being. Aesthetic restoration should be viewed as an integral part of lower limb reconstruction.

Level Of Evidence: Therapeutic, III.
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http://dx.doi.org/10.1016/j.bjps.2020.08.110DOI Listing
January 2021

The use of community advisory boards in pragmatic clinical trials: The case of the adult day services plus project.

Home Health Care Serv Q 2021 Jan-Mar;40(1):16-26. Epub 2020 Aug 31.

School of Public Health, University of Minnesota , Minneapolis, Minnesota, USA.

Community advisory boards (CABs) have become increasingly common and important in translational research in health care including studies focusing on home and community-based services. CABs are composed of stakeholders who share interest in research projects and typically include patients/clients, practitioners, community members, policymakers, and researchers. CABs advise researchers on issues ranging from research design and recruitment to implementation and dissemination. In this article, the researchers detail their experiences with the CAB for a pragmatic clinical trail of Adult Day Services (ADS) Plus, an education and support intervention for family caregivers of older adults with dementia using adult day services. Lessons learned, guidelines, and best practices are then presented for developing and working with a CAB in healthcare research.
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http://dx.doi.org/10.1080/01621424.2020.1816522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855735PMC
August 2020

Nursing Home Social Workers Perceptions of Preparedness and Coping for COVID-19.

J Gerontol B Psychol Sci Soc Sci 2021 03;76(4):e219-e224

School of Social Work, University of Texas at Arlington.

Objectives: Social work has a long history of responding to the needs of vulnerable populations during times of crisis and disaster. Social workers are working at the front lines responding to the current COVID-19 pandemic in a variety of health care practice settings, including nursing homes; however, it is unclear how social workers perceive their preparedness during this time.

Methods: This study employed a cross-sectional survey to nursing home social workers via social media on feelings of preparedness for COVID-19, what has been most professionally helpful for social workers during these times in their role in COVID-19, as well as demographic questions. Demographic data were analyzed using SPSS and qualitative data were analyzed using the rigorous and accelerated data reduction technique.

Results: Data are based on a sample of 63 (N = 63) nursing home social workers. Findings revealed that while some social workers felt prepared for the coronavirus, many respondents stated that they were unprepared to meet the demands and challenges they were facing. Moreover, participants shared that professional support was critically important to get through COVID-19.

Discussion: These findings are important, as social workers are tasked with ensuring each resident attains their highest level of psychosocial well-being, which can be achieved only when nursing home staff are supported. Findings from the present study suggest that additional support for nursing home staff ought to include peer mentoring and mutual support. Additionally, improved leadership across health care settings is worth assessing.
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http://dx.doi.org/10.1093/geronb/gbaa143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499712PMC
March 2021

The Overall Poor Specificity of MRCP in the Preoperative Evaluation of the Jaundiced Patient Will Increase the Incidence of Nontherapeutic ERCP.

Am Surg 2020 Aug 18;86(8):1022-1025. Epub 2020 Aug 18.

26520 Department of Surgery, Mountain Area Health Education Center (MAHEC), Asheville, NC, USA.

Laparoscopic cholecystectomy remains one of the most common surgical operations. Common bile duct stones (CBDS) are estimated to be present in 10%-20% of individuals with symptomatic gallstones. Preoperative magnetic resonance cholangiopancreatography (MRCP) and intraoperative cholangiography (IOC) remain the most common methods of evaluation, with subsequent endoscopic retrograde cholangiopancreatography (ERCP) for stone extraction if positive for CBDS. We examined our experience with preoperative MRCP versus IOC for the management of the jaundiced patient with cholelithiasis. This is a retrospective single-institution study that examined all laparoscopic cholecystectomies performed over a 15-month period between 2017 and 2018. Outpatient elective cases were excluded from the analysis. Charts were reviewed for demographics, operative details, and whether an MRCP, IOC, or ERCP was performed. Data were evaluated using a 2-sample -test. A total of 460 patients underwent laparoscopic cholecystectomy over a 15-month period. Of those, 147 underwent either an MRCP or an IOC for clinical suspicion for CBDS. ERCP after MRCP was nontherapeutic in 11/32 (34%) compared with 2/12 (17%) of patients following IOC. The sensitivity and specificity of MRCP were 91% and 80%, respectively, with a positive predictive value of 66% and a negative predictive value of 96%. The sensitivity and specificity of IOC were 83% and 97%, respectively, with a positive predictive value of 83% and a negative predictive value of 97%. MRCP and IOC have unique advantages and disadvantages. MRCP has greater sensitivity, but poor specificity, resulting in unnecessary ERCPs with associated morbidity and increased costs to the patient.
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http://dx.doi.org/10.1177/0003134820942139DOI Listing
August 2020

CODEL: phase III study of RT, RT + TMZ, or TMZ for newly diagnosed 1p/19q codeleted oligodendroglioma. Analysis from the initial study design.

Neuro Oncol 2021 03;23(3):457-467

Department of Neurosurgery, Cleveland Clinic, Cleveland, Ohio, USA.

Background: We report the analysis involving patients treated on the initial CODEL design.

Methods: Adults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm.

Results: Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months.

Conclusions: TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.
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http://dx.doi.org/10.1093/neuonc/noaa168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992874PMC
March 2021

Considerations for Developing Online Bereavement Support Groups.

J Soc Work End Life Palliat Care 2020 Apr-Jun;16(2):99-115. Epub 2020 Mar 28.

Social Work, University of Texas at Arlington, School of Social Work, Arlington, Texas, USA.

The loss of a family member or friend can have profound psychological and physical implications, particularly for individuals without bereavement support services. Online support groups can be an effective means of extending services beyond the traditional modes of delivery. This is especially true for populations that include isolated individuals and those with limited support networks, limited transportation, challenging time commitments, or reside in communities with limited services available. The literature over the last 10 years was reviewed to discern the potential opportunities and challenges of providing online bereavement support group services. Discussed are challenges for recruitment of participants, availability of technology resources, addressing privacy and confidentiality issues, participants' knowledge of technical equipment, legal considerations, ethical considerations, accessibility, and other best practices. Diverse populations such as adolescents, older adults, and rural communities must be uniquely considered when using online support groups.
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http://dx.doi.org/10.1080/15524256.2020.1745727DOI Listing
April 2021

Blockade of the Phagocytic Receptor MerTK on Tumor-Associated Macrophages Enhances P2X7R-Dependent STING Activation by Tumor-Derived cGAMP.

Immunity 2020 02 11;52(2):357-373.e9. Epub 2020 Feb 11.

Genentech Inc., South San Francisco, CA, USA. Electronic address:

Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTK treatment was lost in Sting mice, but not in Cgas mice. Abolishing cGAMP production in Cgas tumor cells, depletion of extracellular ATP, or inactivation of the ATP-gated P2X7R channel also compromised the effects of MerTK blockade. Mechanistically, extracellular ATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophages and subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicity and potentiates anti-tumor immunity, which has implications for cancer immunotherapy.
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http://dx.doi.org/10.1016/j.immuni.2020.01.014DOI Listing
February 2020

CD96 functions as a co-stimulatory receptor to enhance CD8 T cell activation and effector responses.

Eur J Immunol 2020 06 20;50(6):891-902. Epub 2020 Feb 20.

Department of Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080.

CD96 is a member of the poliovirus receptor (PVR, CD155)-nectin family that includes T cell Ig and ITIM domain (TIGIT) and CD226. While CD96, TIGIT, and CD226 have important roles in regulating NK cell activity, and TIGIT and CD226 have also been shown to regulate T cell responses, it is unclear whether CD96 has inhibitory or stimulatory function in CD8 T cells. Here, we demonstrate that CD96 has co-stimulatory function on CD8 T cells. Crosslinking of CD96 on human or mouse CD8 T cells induced activation, effector cytokine production, and proliferation. CD96 was found to transduce its activating signal through the MEK-ERK pathway. CD96-mediated signaling led to increased frequencies of NUR77- and T-bet-expressing CD8 T cells and enhanced cytotoxic effector activity, indicating that CD96 can modulate effector T cell differentiation. Antibody blockade of CD96 or genetic ablation of CD96 expression on CD8 T cells impaired expression of transcription factors and proinflammatory cytokines associated with CD8 T cell activation in in vivo models. Taken together, CD96 has a co-stimulatory role in CD8 T cell activation and effector function.
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http://dx.doi.org/10.1002/eji.201948405DOI Listing
June 2020

Final report from Intergroup NCCTG 86-72-51 (Alliance): a phase III randomized clinical trial of high-dose versus low-dose radiation for adult low-grade glioma.

Neuro Oncol 2020 06;22(6):830-837

Wake Forest Baptist Health, Winston-Salem, North Carolina.

Background: The optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma.

Methods: Between 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection.

Results: For all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2-10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3-6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter <5 cm and baseline Mini-Mental State Examination (MMSE) >27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter <5 cm, patients who had gross total resection, and patients with baseline MMSE >27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years.

Conclusions: Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.
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http://dx.doi.org/10.1093/neuonc/noaa021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283016PMC
June 2020

Behavioral characterization of a CRISPR-generated TRPA1 knockout rat in models of pain, itch, and asthma.

Sci Rep 2020 01 22;10(1):979. Epub 2020 Jan 22.

Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.

The transient receptor potential (TRP) superfamily of ion channels has garnered significant attention by the pharmaceutical industry. In particular, TRP channels showing high levels of expression in sensory neurons such as TRPV1, TRPA1, and TRPM8, have been considered as targets for indications where sensory neurons play a fundamental role, such as pain, itch, and asthma. Modeling these indications in rodents is challenging, especially in mice. The rat is the preferred species for pharmacological studies in pain, itch, and asthma, but until recently, genetic manipulation of the rat has been technically challenging. Here, using CRISPR technology, we have generated a TRPA1 KO rat to enable more sophisticated modeling of pain, itch, and asthma. We present a detailed phenotyping of the TRPA1 KO rat in models of pain, itch, and asthma that have previously only been investigated in the mouse. With the exception of nociception induced by direct TRPA1 activation, we have found that the TRPA1 KO rat shows apparently normal behavioral responses in multiple models of pain and itch. Immune cell infiltration into the lung in the rat OVA model of asthma, on the other hand, appears to be dependent on TRPA1, similar to was has been observed in TRPA1 KO mice. Our hope is that the TRPA1 KO rat will become a useful tool in further studies of TRPA1 as a drug target.
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http://dx.doi.org/10.1038/s41598-020-57936-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976688PMC
January 2020

Optimizing Whole Brain Radiation Therapy Dose and Fractionation: Results From a Prospective Phase 3 Trial (NCCTG N107C [Alliance]/CEC.3).

Int J Radiat Oncol Biol Phys 2020 02 22;106(2):255-260. Epub 2019 Oct 22.

CHUM, Montreal, QC, Canada.

Purpose: Whole brain radiation therapy (WBRT) remains a commonly used cancer treatment, although controversy exists regarding the optimal dose/fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits.

Methods And Materials: NCCTG N107C [Alliance]/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the dose/fractionation that would be used for all patients treated at that site (either 30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher's exact tests.

Results: Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fractions (53%), and 43 were treated with 37.5 Gy in 15 fractions (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology was more frequent with protracted WBRT: 72% vs 45%, P = .01), and 93% of patients completed the full course of WBRT. A more protracted WBRT dose regimen (37.5 Gy in 15 fractions) did not significantly affect time to cognitive failure (hazard ratio [HR], 0.9; 95% confidence interval [CI], 0.6-1.39; P = .66), surgical bed control (HR, 0.52 [95% CI, 0.22-1.25], P = .14), intracranial tumor control (HR, 0.56 [95% CI, 0.28-1.12], P = .09), or overall survival (HR, 0.72 [95% CI, 0.45-1.16], P = .18). Although there was no reported radionecrosis, there is a statistically significant increase in the risk of at least 1 grade ≥3 adverse event with 37.5 Gy in 15 fractions versus 30 Gy in 10 fractions (54% vs 31%, respectively, P = .03).

Conclusions: This post hoc analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with the lengthened course of WBRT. For patients with brain metastases where WBRT is recommended, shorter course hypofractionated regimens remain the current standard of care.
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http://dx.doi.org/10.1016/j.ijrobp.2019.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957747PMC
February 2020

Examiner accuracy in cognitive testing in multisite brain-tumor clinical trials: an analysis from the Alliance for Clinical Trials in Oncology.

Neurooncol Pract 2019 Jul 24;6(4):283-288. Epub 2018 Nov 24.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN.

Background: Cognitive function is an important outcome in brain-tumor clinical trials. Cognitive examiners are often needed across multiple sites, many of whom have no prior testing experience. To ensure quality, we looked at examiner errors in administering a commonly used cognitive test battery, determined whether the errors were correctable upon central review, and considered whether the same errors would be detected using onsite electronic data entry.

Methods: We looked at 500 cognitive exams administered for brain-tumor trials led by the Alliance for Clinical Trials in Oncology (Alliance). Of 2277 tests examined, 32 noncorrectable errors were detected with routine central review (1.4% of tests administered), and thus removed from the database of the respective trial. The invalidation rate for each test was 0.8% for each part of the Hopkins Verbal Learning Test-Revised, 0.8% for Controlled Oral Word Association, 1.8% for Trail Making Test-A and 2.6% for Trail Making Test-B. It was estimated that, with onsite data entry and no central review, 4.9% of the tests entered would have uncorrected errors and 1.3% of entered tests would be frankly invalid but not removed.

Conclusions: Cognitive test results are useful and robust outcome measures for brain-tumor clinical trials. Error rates are extremely low, and almost all are correctable with central review of scoring, which is easy to accomplish. We caution that many errors could be missed if onsite electronic entry is utilized instead of central review, and it would be important to mitigate the risk of invalid scores being entered.

Clinicaltrialsgov Identifiers: NCT01781468 (Alliance A221101), NCT01372774 (NCCTG N107C), NCT00731731 (NCCTG N0874), and NCT00887146 (NCCTG N0577).
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http://dx.doi.org/10.1093/nop/npy048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660817PMC
July 2019

Preliminary exploration of a computerized cognitive battery and comparison with traditional testing in patients with high-grade glioma.

Neurooncol Pract 2019 Jan 21;6(1):71-77. Epub 2018 May 21.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN.

Background: Cognitive function is an important outcome measure in many brain tumor clinical trials, and investigators are interested in employing the most efficient methods of cognitive assessment for this purpose. Computerized testing can be appealing because of the perceived ease of use and electronic data generated. Traditional tests may have the advantage of accumulated validity evidence and comparability across historic trials.

Methods: We evaluated feasibility of a Cogstate battery in 39 patients with high-grade glioma, and compared it with a commonly used paper-and-pencil battery.

Results: Both batteries were well tolerated and rated equally likeable. Correlations between the batteries were low to low-moderate. More patients showed impairment at baseline and decline across trials on traditional tests.

Conclusions: Both batteries were well tolerated, but the most complicated tasks (from both batteries) could not be completed by all subjects. Preliminary validity evidence for the Cogstate tasks was mixed, but a larger sample is needed.
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http://dx.doi.org/10.1093/nop/npy013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656319PMC
January 2019

A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance/North Central Cancer Treatment Group N0872.

Cancer 2019 11 10;125(21):3790-3800. Epub 2019 Jul 10.

Department of Neurology, University of Virginia Medical Center, Charlottesville, Virginia.

Background: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM.

Methods: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6).

Results: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P = .22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P = .93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P = .52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome.

Conclusions: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone.
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http://dx.doi.org/10.1002/cncr.32340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788934PMC
November 2019

Embedding caregiver support in community-based services for older adults: A multi-site randomized trial to test the Adult Day Service Plus Program (ADS Plus).

Contemp Clin Trials 2019 08 22;83:97-108. Epub 2019 Jun 22.

University of Minnesota, School of Nursing, 308 SE Harvard St, Minneapolis, MN 55455, United States of America. Electronic address:

There are over five million people in the United States living with dementia. Most live at home and are cared for by family. These family caregivers often assume care responsibilities without education about the disease, skills training, or support, and in turn become at risk for depression, burden, and adverse health outcomes when compared to non-dementia caregivers. Despite over 200 caregiver interventions with proven benefits, many caregivers lack access to these programs. One approach to enhance access is to embed evidence-based caregiver support programs in existing community-based services for people with dementia such as adult day services (ADS). Here we describe the protocol for an embedded pragmatic trial designed to augment standard ADS known as ADS Plus. ADS Plus provides family caregivers with support via education, referrals, and problem-solving techniques over 12 months, and is delivered on-site by existing ADS staff. Embedding a program in ADS requires an understanding of outcomes and implementation processes in that specific context. Thus, we deploy a hybrid design involving a cluster randomized two-group trial to evaluate treatment effects on caregiver wellbeing, ADS utilization, as well as nursing home placement. We describe implementation practices in 30 to 50 geographically and racially/ethnically diverse participating sites. Clinical trial registration #: NCT02927821.
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http://dx.doi.org/10.1016/j.cct.2019.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069225PMC
August 2019

The Gag protein PEG10 binds to RNA and regulates trophoblast stem cell lineage specification.

PLoS One 2019 5;14(4):e0214110. Epub 2019 Apr 5.

Physiological Chemistry Department, Genentech, South San Francisco, California, United States of America.

Peg10 (paternally expressed gene 10) is an imprinted gene that is essential for placental development. It is thought to derive from a Ty3-gyspy LTR (long terminal repeat) retrotransposon and retains Gag and Pol-like domains. Here we show that the Gag domain of PEG10 can promote vesicle budding similar to the HIV p24 Gag protein. Expressed in a subset of mouse endocrine organs in addition to the placenta, PEG10 was identified as a substrate of the deubiquitinating enzyme USP9X. Consistent with PEG10 having a critical role in placental development, PEG10-deficient trophoblast stem cells (TSCs) exhibited impaired differentiation into placental lineages. PEG10 expressed in wild-type, differentiating TSCs was bound to many cellular RNAs including Hbegf (Heparin-binding EGF-like growth factor), which is known to play an important role in placentation. Expression of Hbegf was reduced in PEG10-deficient TSCs suggesting that PEG10 might bind to and stabilize RNAs that are critical for normal placental development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214110PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450627PMC
December 2019

CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1.

Proc Natl Acad Sci U S A 2018 12 30;115(50):E11731-E11740. Epub 2018 Nov 30.

Department of Cancer Immunology, Genentech, Inc., South San Francisco, CA 94080;

Natural killer (NK) cell recognition of tumor cells is mediated through activating receptors such as CD226, with suppression of effector functions often controlled by negative regulatory transcription factors such as FOXO1. Here we show that CD226 regulation of NK cell cytotoxicity is facilitated through inactivation of FOXO1. Gene-expression analysis of NK cells isolated from syngeneic tumors grown in wild-type or CD226-deficient mice revealed dysregulated expression of FOXO1-regulated genes in the absence of CD226. In vitro cytotoxicity and stimulation assays demonstrated that CD226 is required for optimal killing of tumor target cells, with engagement of its ligand CD155 resulting in phosphorylation of FOXO1. CD226 deficiency or anti-CD226 antibody blockade impaired cytotoxicity with concomitant compromised inactivation of FOXO1. Furthermore, inhibitors of FOXO1 phosphorylation abrogated CD226-mediated signaling and effector responses. These results define a pathway by which CD226 exerts control of NK cell responses against tumors.
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http://dx.doi.org/10.1073/pnas.1814052115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294892PMC
December 2018

Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation.

J Exp Med 2018 09 22;215(9):2279-2288. Epub 2018 Aug 22.

Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA

Intracellular LPS sensing by caspase-4/5/11 triggers proteolytic activation of pore-forming gasdermin D (GSDMD), leading to pyroptotic cell death in Gram-negative bacteria-infected cells. Involvement of caspase-4/5/11 and GSDMD in inflammatory responses, such as lethal sepsis, makes them highly desirable drug targets. Using knock-in (KI) mouse strains, we herein provide genetic evidence to show that caspase-11 auto-cleavage at the inter-subunit linker is essential for optimal catalytic activity and subsequent proteolytic cleavage of GSDMD. Macrophages from caspase-11-processing dead KI mice ( ) exhibit defective caspase-11 auto-processing and phenocopy and caspase-11 enzymatically dead KI ( ) macrophages in attenuating responses to cytoplasmic LPS or Gram-negative bacteria infection. KI macrophages also fail to cleave GSDMD and are hypo-responsive to inflammasome stimuli, confirming that the GSDMD Asp residue is a nonredundant and indispensable site for proteolytic activation of GSDMD. Our data highlight the role of caspase-11 self-cleavage as a critical regulatory step for GSDMD processing and response against Gram-negative bacteria.
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http://dx.doi.org/10.1084/jem.20180589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122968PMC
September 2018

Erector Spinae Plane Block for Open-Heart Surgery: A Potential Tool for Improved Analgesia.

J Cardiothorac Vasc Anesth 2019 02 17;33(2):376-377. Epub 2018 Aug 17.

Department of Anesthesiology, Perioperative and Pain Medicine, Foothills Medical Centre, Cumming School of Medicine, University of Calgary and Libin Cardiovascular Institute, Alberta, Canada.

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http://dx.doi.org/10.1053/j.jvca.2018.07.015DOI Listing
February 2019

Acute Hemolytic Transfusion Reaction Due to Anti-Kpa Antibody.

S D Med 2018 May;71(5):222-223

Department of Family Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota.

Background: Kpa (KEL3, Penney) is a red blood cell antigen within the Kell system, first described in 1957, that occurs in less than 2 percent of the population. Although anti-Kpa antibodies were identified in 2-5 percent of those with alloantibodies among patients requiring chronic transfusion, only five previously published case reports of anti-Kpa reactions were identified.

Case Report: Reported here is a case of an elderly female who experienced an acute hemolytic transfusion reaction due to this antigen. Following initiation of blood transfusion, she experienced a sudden onset of rigorous chills, accompanied by elevated temperature, tachycardia, and hypertension. Laboratory studies showed uremia, elevated creatinine, positive direct Coomb's, and low haptoglobin. Serology revealed anti-Kpa antibody.

Conclusion: This report is only the sixth, to our knowledge, of a significant reaction attributable to anti-Kpa and only the second of an acute hemolytic reaction associated with it. It serves as a reminder of the potential of low incidence antigens causing severe reactions; this potential should be considered when evaluating acute hemolytic reaction.
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May 2018

Developing a Set of Uniform Outcome Measures for Adult Day Services.

J Appl Gerontol 2020 06 14;39(6):670-676. Epub 2018 Jun 14.

The Pennsylvania State University, University Park, USA.

Adult day services (ADS) provide care to adults with physical, functional, and/or cognitive limitations in nonresidential, congregate, community-based settings. ADS programs have emerged as a growing and affordable approach within the home and community-based services sector. Although promising, the growth of ADS has been hampered by a lack of uniform outcome measures and data collection protocols. In this article, the authors detail a recent effort by leading researchers and practitioners in ADS to develop a set of uniform outcome measures. Based upon three recent efforts to develop outcome measures, selection criteria were established and an iterative process was conducted to debate the merits of outcome measures across three domains-participant well-being, caregiver well-being, and health care utilization. The authors conclude by proposing a uniform set of outcome measures to (a) standardize data collection, (b) aid in the development of programming, and (c) facilitate the leveraging of additional funding for ADS.
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http://dx.doi.org/10.1177/0733464818782130DOI Listing
June 2020

Findings From a Prospective Randomized Controlled Trial of an Individualized Music Listening Program for Persons With Dementia.

J Appl Gerontol 2020 06 6;39(6):567-575. Epub 2018 Jun 6.

University of Wisconsin-Milwaukee, USA.

Music & Memory (M&M) is a passive music intervention that uses personalized music playlists delivered on digital music players. This program has been increasingly adopted in nursing homes across the United States to facilitate communication, engagement, and socialization among persons with dementia (PWDs); however, few studies have evaluated the program's effect on PWDs' outcomes. In the present study, a randomized controlled crossover design was used to examine the impact of the M&M program on 59 PWDs in 10 nursing homes over a 14-week period. Residents' evaluated outcomes included agitation, behavioral symptoms, and use of psychotropic medications. Although trends supported the positive effects of M&M, no statistically significant differences were found in any of the outcomes measured over time. Methodological limitations withstanding, these findings call into question the effectiveness of the M&M program and the ability of facility staff to implement this intervention with fidelity.
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http://dx.doi.org/10.1177/0733464818778991DOI Listing
June 2020

Constitutive Interferon Pathway Activation in Tumors as an Efficacy Determinant Following Oncolytic Virotherapy.

J Natl Cancer Inst 2018 10;110(10):1123-1132

Department of Molecular Medicine, Mayo Clinic, Rochester, MN.

Background: Attenuated measles virus (MV) strains are promising agents currently being tested against solid tumors or hematologic malignancies in ongoing phase I and II clinical trials; factors determining oncolytic virotherapy success remain poorly understood, however.

Methods: We performed RNA sequencing and gene set enrichment analysis to identify pathways differentially activated in MV-resistant (n = 3) and -permissive (n = 2) tumors derived from resected human glioblastoma (GBM) specimens and propagated as xenografts (PDX). Using a unique gene signature we identified, we generated a diagonal linear discriminant analysis (DLDA) classification algorithm to predict MV responders and nonresponders, which was validated in additional randomly selected GBM and ovarian cancer PDX and 10 GBM patients treated with MV in a phase I trial. GBM PDX lines were also treated with the US Food and Drug Administration-approved JAK inhibitor, ruxolitinib, for 48 hours prior to MV infection and virus production, STAT1/3 signaling and interferon stimulated gene expression was assessed. All statistical tests were two-sided.

Results: Constitutive interferon pathway activation, as reflected in the DLDA algorithm, was identified as the key determinant for MV replication, independent of virus receptor expression, in MV-permissive and -resistant GBM PDXs. Using these lines as the training data for the DLDA algorithm, we confirmed the accuracy of our algorithm in predicting MV response in randomly selected GBM PDX ovarian cancer PDXs. Using the DLDA prediction algorithm, we demonstrate that virus replication in patient tumors is inversely correlated with expression of this resistance gene signature (ρ = -0.717, P = .03). In vitro inhibition of the interferon response pathway with the JAK inhibitor ruxolitinib was able to overcome resistance and increase virus production (1000-fold, P = .03) in GBM PDX lines.

Conclusions: These findings document a key mechanism of tumor resistance to oncolytic MV therapy and describe for the first time the development of a prediction algorithm to preselect for oncolytic treatment or combinatorial strategies.
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http://dx.doi.org/10.1093/jnci/djy033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186520PMC
October 2018

CRISPR off-target analysis in genetically engineered rats and mice.

Nat Methods 2018 07 21;15(7):512-514. Epub 2018 May 21.

Department of Molecular Biology, Genentech, Inc., South San Francisco, CA, USA.

Despite widespread use of CRISPR, comprehensive data on the frequency and impact of Cas9-mediated off-targets in modified rodents are limited. Here we present deep-sequencing data from 81 genome-editing projects on mouse and rat genomes at 1,423 predicted off-target sites, 32 of which were confirmed, and show that high-fidelity Cas9 versions reduced off-target mutation rates in vivo. Using whole-genome sequencing data from ten mouse embryos, treated with a single guide RNA (sgRNA), and from their genetic parents, we found 43 off-targets, 30 of which were predicted by an adapted version of GUIDE-seq.
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http://dx.doi.org/10.1038/s41592-018-0011-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558654PMC
July 2018

Applying a trauma-informed perspective to loss and change in the lives of older adults.

Soc Work Health Care 2018 May-Jun;57(5):355-375. Epub 2018 Mar 9.

b School of Social Work , University of Maryland Baltimore County , Missoula , MT , USA.

Traumatic events are widely acknowledged to have long-term impacts on individuals, yet only recently have health-care professionals begun to assess for and gain an understanding of trauma in the lives of older adults. For many older adults, trauma is often disenfranchised and overlooked as being either a distant past event (e.g., child abuse) or a normal part of aging (e.g., widowhood). Trauma-informed care, on the other hand, calls for health-care professionals to acknowledge that past and recent events may have been traumatic for older adults and to assess and care plan to reduce or prevent re-traumatization. In this article, we explore the impacts of trauma in later life through a case study of a patient admitted to a long-term care facility. Analysis of this case study suggests several important implications for social work practice in long-term care and the use of person-centered care practices in the care of older adults in general.
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http://dx.doi.org/10.1080/00981389.2018.1447531DOI Listing
January 2019

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572.

Cancer 2018 04 3;124(7):1455-1463. Epub 2018 Jan 3.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

Background: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma.

Methods: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi.

Results: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients.

Conclusions: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867230PMC
April 2018

Early versus late tracheostomy after decompressive craniectomy for stroke.

J Intensive Care 2018 4;6. Epub 2018 Jan 4.

Department of Neurosurgery, University of North Carolina School of Medicine, 170 Manning Drive, Campus Box 7025, Chapel Hill, NC 27599-7025 USA.

Background: Stroke patients requiring decompressive craniectomy are at high risk of prolonged mechanical ventilation and ventilator-associated pneumonia (VAP). Tracheostomy placement may reduce the duration of mechanical ventilation. Predicting which patients will require tracheostomy and the optimal timing of tracheostomy remains a clinical challenge. In this study, the authors compare key outcomes after early versus late tracheostomy and develop a useful pre-operative decision-making tool to predict post-operative tracheostomy dependence.

Methods: We performed a retrospective analysis of prospectively collected registry data. We developed a propensity-weighted decision tree analysis to predict tracheostomy requirement using factors present prior to surgical decompression. In addition, outcomes include probability functions for intensive care unit length of stay, hospital length of stay, and mortality, based on data for early (≤ 10 days) versus late (> 10 days) tracheostomy.

Results: There were 168 surgical decompressions performed on patients with acute ischemic or spontaneous hemorrhagic stroke between 2010 and 2015. Forty-eight patients (28.5%) required a tracheostomy, 35 (20.8%) developed VAP, and 126 (75%) survived hospitalization. Mean ICU and hospital length of stay were 15.1 and 25.8 days, respectively. Using GCS, SOFA score, and presence of hydrocephalus, our decision tree analysis had 63% sensitivity and 84% specificity for predicting tracheostomy requirement. The early group had fewer ventilator days (7.3 versus 15.2,  < 0.001) and shorter hospital length of stay (28.5 versus 44.4 days,  = 0.014). VAP rates and mortality were similar between the two groups. Withdrawal of treatment interventions shortly post-operatively confounded mortality outcomes.

Conclusion: Early tracheostomy shortens duration of mechanical ventilation and length of stay after surgical decompression for stroke, but it did not impact mortality or VAP rates. A decision tree is a practical tool that may be helpful in guiding pre-operative decision-making with patients' families.
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http://dx.doi.org/10.1186/s40560-017-0269-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753520PMC
January 2018