Publications by authors named "Laura Baker"

237 Publications

Investigating Predictors of Preserved Cognitive Function in Older Women Using Machine Learning: Women's Health Initiative Memory Study.

J Alzheimers Dis 2021 Oct 7. Epub 2021 Oct 7.

Department of Social Sciences & Health Policy, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Background: Identification of factors that may help to preserve cognitive function in late life could elucidate mechanisms and facilitate interventions to improve the lives of millions of people. However, the large number of potential factors associated with cognitive function poses an analytical challenge.

Objective: We used data from the longitudinal Women's Health Initiative Memory Study (WHIMS) and machine learning to investigate 50 demographic, biomedical, behavioral, social, and psychological predictors of preserved cognitive function in later life.

Methods: Participants in WHIMS and two consecutive follow up studies who were at least 80 years old and had at least one cognitive assessment following their 80th birthday were classified as cognitively preserved. Preserved cognitive function was defined as having a score ≥39 on the most recent administration of the modified Telephone Interview for Cognitive Status (TICSm) and a mean score across all assessments ≥39. Cognitively impaired participants were those adjudicated by experts to have probable dementia or at least two adjudications of mild cognitive impairment within the 14 years of follow-up and a last TICSm score <  31. Random Forests was used to rank the predictors of preserved cognitive function.

Results: Discrimination between groups based on area under the curve was 0.80 (95%-CI-0.76-0.85). Women with preserved cognitive function were younger, better educated, and less forgetful, less depressed, and more optimistic at study enrollment. They also reported better physical function and less sleep disturbance, and had lower systolic blood pressure, hemoglobin, and blood glucose levels.

Conclusion: The predictors of preserved cognitive function include demographic, psychological, physical, metabolic, and vascular factors suggesting a complex mix of potential contributors.
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http://dx.doi.org/10.3233/JAD-210621DOI Listing
October 2021

Diet Effects on Cerebrospinal Fluid Amino Acids Levels in Adults with Normal Cognition and Mild Cognitive Impairment.

J Alzheimers Dis 2021 Sep 28. Epub 2021 Sep 28.

Department of Internal Medicine- Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Background: Exploration of cerebrospinal fluid (CSF) amino acids and the impact of dietary intake on central levels may provide a comprehensive understanding of the metabolic component of Alzheimer's disease.

Objective: The objective of this exploratory study was to investigate the effects of two diets with varied nutrient compositions on change in CSF amino acids levels in adults with mild cognitive impairment (MCI) and normal cognition (NC). Secondary objectives were to assess the correlations between the change in CSF amino acids and change in Alzheimer's disease biomarkers.

Methods: In a randomized, parallel, controlled feeding trial, adults (NC, n = 20; MCI, n = 29) consumed a high saturated fat (SFA)/glycemic index (GI) diet [HIGH] or a low SFA/GI diet [LOW] for 4 weeks. Lumbar punctures were performed at baseline and 4 weeks.

Results: CSF valine increased and arginine decreased after the HIGH compared to the LOW diet in MCI (ps = 0.03 and 0.04). This pattern was more prominent in MCI versus NC (diet by diagnosis interaction ps = 0.05 and 0.09), as was an increase in isoleucine after the HIGH diet (p = 0.05). Changes in CSF amino acids were correlated with changes in Alzheimer's disease CSF biomarkers Aβ42, total tau, and p-Tau 181, with distinct patterns in the relationships by diet intervention and cognitive status.

Conclusion: Dietary intake affects CSF amino acid levels and the response to diet is differentially affected by cognitive status.
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http://dx.doi.org/10.3233/JAD-210471DOI Listing
September 2021

Validity of Using Billing Codes From Electronic Health Records to Estimate Skin Cancer Counts.

JAMA Dermatol 2021 Sep;157(9):1089-1094

Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Patients can develop multiple skin cancers, and their medical data can be spread over multiple health care systems. This fragmented care, combined with the lack of skin cancer registries, has limited our ability both to provide accurate estimates of incidence and to study the pathogenesis of multiple skin cancers.

Objective: To assess whether standard diagnostic and procedural codes present in the electronic health records at a single health care system are a valid proxy for estimating the number of overall skin cancers.

Design, Setting, And Participants: Retrospective cohort study of patients seen at a single-center tertiary care hospital (ie, Vanderbilt University Medical Center) between July 1, 2008, and June 30, 2018. All patients with at least 1 electronic health record-based diagnostic or procedural code for any skin cancer and at least 1 pathology report of a skin cancer.

Exposure: The number of International Classification of Disease (ICD) or Current Procedural Terminology (CPT) codes relating to skin cancer.

Main Outcomes And Measures: Pearson correlation coefficient and R2 were calculated for the total number of ICD or CPT codes for skin cancer and histologically verified skin cancers.

Results: In this cohort study of 35 901 patients, the mean (SD) age was 70.4 (14.4) years, 20 404 (56.8%) were men, and 31 623 (88.1%) were White individuals. Of these patients, 6307 had at least 1 ICD or CPT code or pathology report for a skin cancer, of whom 5688 patients had both a CPT code related to skin malignancy and a histologically verified skin cancer. There was a strong linear correlation between the number of CPT codes and pathology records (r = 0.87). There was a poor correlation between the number of ICD codes and pathology records (r = 0.22).

Conclusions And Relevance: This cohort study found that the use of ICD codes was a poor proxy measure for the number of skin cancers per patient. In contrast, CPT codes accounted for more than 75% of the variability in the number of skin cancers (R2 = 0.76) and were a better proxy measure for the total number of skin cancers per patient.
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http://dx.doi.org/10.1001/jamadermatol.2021.2856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358802PMC
September 2021

A Systematic Review and Meta-analysis of Randomized Controlled Trials Comparing Intraoperative Red Blood Cell Transfusion Strategies.

Ann Surg 2021 May 12. Epub 2021 May 12.

Department of Surgery, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.

Objective: The objective of this work was to carry out a meta-analysis of RCTs comparing intraoperative RBC transfusion strategies to determine their impact on postoperative morbidity, mortality, and blood product use.

Summary Of Background Data: RBC transfusions are common in surgery and associated with widespread variability despite adjustment for casemix. Evidence-based recommendations guiding RBC transfusion in the operative setting are limited.

Methods: The search strategy was adapted from a previous Cochrane Review. Electronic databases were searched from January 2016 to February 2021. Included studies from the previous Cochrane Review were considered for eligibility from before 2016. RCTs comparing intraoperative transfusion strategies were considered for inclusion. Co-primary outcomes were 30-day mortality and morbidity. Secondary outcomes included intraoperative and perioperative RBC transfusion. Meta-analysis was carried out using random-effects models.

Results: Fourteen trials (8641 patients) were included. One cardiac surgery trial accounted for 56% of patients. There was no difference in 30-day mortality [relative risk (RR) 0.96, 95% confidence interval (CI) 0.71-1.29] and pooled postoperative morbidity among the studied outcomes when comparing restrictive and liberal protocols. Two trials reported worse composite outcomes with restrictive triggers. Intraoperative (RR 0.53, 95% CI 0.43-0.64) and perioperative (RR 0.70, 95% CI 0.62-0.79) blood transfusions were significantly lower in the restrictive group compared to the liberal group.

Conclusions: Intraoperative restrictive transfusion strategies decreased perioperative transfusions without added postoperative morbidity and mortality in 12/14 trials. Two trials reported worse outcomes. Given trial design and generalizability limitations, uncertainty remains regarding the safety of broad application of restrictive transfusion triggers in the operating room. Trials specifically designed to address intraoperative transfusions are urgently needed.
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http://dx.doi.org/10.1097/SLA.0000000000004931DOI Listing
May 2021

Mediterranean and Western diet effects on Alzheimer's disease biomarkers, cerebral perfusion, and cognition in mid-life: A randomized trial.

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: Mid-life dietary patterns are associated with Alzheimer's disease (AD) risk, although few controlled trials have been conducted.

Methods: Eighty-seven participants (age range: 45 to 65) with normal cognition (NC, n = 56) or mild cognitive impairment (MCI, n = 31) received isocaloric diets high or low in saturated fat, glycemic index, and sodium (Western-like/West-diet vs. Mediterranean-like/Med-diet) for 4 weeks. Diet effects on cerebrospinal fluid (CSF) biomarkers, cognition, and cerebral perfusion were assessed to determine whether responses differed by cognitive status.

Results: CSF amyloid beta (Aβ) ratios increased following the Med-diet, and decreased after West-diet for NC adults, whereas the MCI group showed the reverse pattern. For the MCI group, the West-diet reduced and the Med-diet increased total tau (t-tau), whereas CSF Aβ /t-tau ratios increased following the West-diet and decreased following the Med-diet. For NC participants, the Med-diet increased and the West-diet decreased cerebral perfusion.

Discussion: Diet response during middle age may highlight early pathophysiological processes that increase AD risk.
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http://dx.doi.org/10.1002/alz.12421DOI Listing
July 2021

Recruitment of a multi-site randomized controlled trial of aerobic exercise for older adults with amnestic mild cognitive impairment: The EXERT trial.

Alzheimers Dement 2021 Jul 23. Epub 2021 Jul 23.

Department of Internal Medicine-Geriatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: Effective strategies to recruit older adults with mild cognitive impairment (MCI) into nonpharmacological intervention trials are lacking.

Methods: Recruitment for EXERT, a multisite randomized controlled 18-month trial examining the effects of aerobic exercise on cognitive trajectory in adults with amnestic MCI, involved a diverse portfolio of strategies to enroll 296 participants.

Results: Recruitment occurred September 2016 through March 2020 and was initially slow. After mass mailings of 490,323 age- and geo-targeted infographic postcards and brochures, recruitment rates increased substantially, peaking at 16 randomizations/month in early 2020. Mass mailings accounted for 52% of randomized participants, whereas 25% were recruited from memory clinic rosters, electronic health records, and national and local registries. Other sources included news broadcasts, public service announcements (PSA), local advertising, and community presentations.

Discussion: Age- and geo-targeted mass mailing of infographic materials was the most effective approach in recruiting older adults with amnestic MCI into an 18-month exercise trial.
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http://dx.doi.org/10.1002/alz.12401DOI Listing
July 2021

Association of Vascular Risk Scores and Cognitive Performance in a Diverse Cohort: The Multi-Ethnic Study of Atherosclerosis.

J Gerontol A Biol Sci Med Sci 2021 Jul 3. Epub 2021 Jul 3.

Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine.

Background: Vascular risk scores are associated with incident dementia. Information regarding their association with cognitive performance and decline in racially/ethnically diverse cohorts is lacking.

Methods: In 4392 Multi-Ethnic Study of Atherosclerosis participants (aged 60.1±9.4 years; 53% women; 41% white, 11% Chinese-American, 26% African-American, 21% Hispanic), we compared associations of Exam 1 (2000-02) Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke (FSRP), and atherosclerotic disease pooled cohort equation (ASCVD-PCE) risk scores with Exam 5 (2010-12) Cognitive Abilities Screening Instrument (CASI), Digit Symbol Coding (DSC), and Digit Span (DS) cognitive test performance using multivariable linear regression, and examined racial/ethnic interactions. In 1838 participants with repeat CASI data at Exam 6 (2016-18), we related risk scores to odds of a 1-standard deviation (SD) decline in CASI performance using multivariable logistic regression.

Results: SD increments in each risk score were associated with worse cognitive performance. CAIDE had stronger associations with CASI performance than the FSRP and ASCVD-PCE, but associations of ASCVD-PCE with the DSC and DS were similar to CAIDE (difference in β [95% CI] = -0.57 [-1.48, 0.34] and -0.21 [-0.43, 0.01], respectively). Race/ethnicity modified associations. For example, associations between CAIDE and CASI were greater in African-Americans and Hispanics than whites (difference in β = 0.69 [0.02, 1.36] and 1.67 [0.95, 2.39], respectively). Risk scores were comparably associated with decline in CASI performance.

Conclusions: Antecedent vascular risk scores are associated with cognitive performance and decline in the four most common US racial/ethnic groups, but associations differ among risk scores and by race/ethnicity.
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http://dx.doi.org/10.1093/gerona/glab189DOI Listing
July 2021

Relationship Between Cerebrovascular Reactivity and Cognition Among People With Risk of Cognitive Decline.

Front Physiol 2021 31;12:645342. Epub 2021 May 31.

Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States.

Vascular risk factors (e.g., obesity and hypertension) are associated with cerebral small vessel disease, Alzheimer's disease (AD) pathology, and dementia. Reduced perfusion may reflect the impaired ability of blood vessels to regulate blood flow in reaction to varying circumstances such as hypercapnia (increased end-tidal partial pressures of CO). It has been shown that cerebrovascular reactivity (CVR) measured with blood-oxygen-level-dependent (BOLD) MRI is correlated with cognitive performance and alterations of CVR may be an indicator of vascular disfunction leading to cognitive decline. However, the underlying mechanism of CVR alterations in BOLD signal may not be straight-forward because BOLD signal is affected by multiple physiological parameters, such as cerebral blood flow (CBF), cerebral blood volume, and oxygen metabolism. Arterial spin labeling (ASL) MRI quantitatively measures blood flow in the brain providing images of local CBF. Therefore, in this study, we measured CBF and its changes using a dynamic ASL technique during a hypercapnia challenge and tested if CBF or CVR was related to cognitive performance using the Mini-mental state examination (MMSE) score. Seventy-eight participants underwent cognitive testing and MRI including ASL during a hypercapnia challenge with a RespirAct computer-controlled gas blender, targeting 10 mmHg higher end-tidal CO level than the baseline while end-tidal O level was maintained. Pseudo-continuous ASL (PCASL) was collected during a 2-min baseline and a 2-min hypercapnic period. CVR was obtained by calculating a percent change of CBF per the end-tidal CO elevation in mmHg between the baseline and the hypercapnic challenge. Multivariate regression analyses demonstrated that baseline resting CBF has no significant relationship with MMSE, while lower CVR in the whole brain gray matter ( = 0.689, = 0.005) and white matter ( = 0.578, = 0.016) are related to lower MMSE score. In addition, region of interest (ROI) based analysis showed positive relationships between MMSE score and CVR in 26 out of 122 gray matter ROIs.
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http://dx.doi.org/10.3389/fphys.2021.645342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201407PMC
May 2021

The Moderating Effects of Genetic Variations on Changes in Physical Activity Level and Cardiorespiratory Fitness in Response to a Life-Style Intervention: A Randomized Controlled Trial.

Psychosom Med 2021 06;83(5):440-448

From the Department of Social and Behavioral Sciences (Lee), Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Behavioral and Social Sciences (Lee, Dunsiger, Williams), Brown University School of Public Health; Department of Psychiatry and Human Behavior (McGeary), Brown Alpert Medical School; Genomics Laboratory (McGeary), Providence Veterans Affairs Medical Center; Centers for Behavioral and Preventive Medicine (Dunsiger), Miriam Hospital, Providence, Rhode Island; Department of Internal Medicine (Baker), Wake Forest School of Medicine, Winston-Salem, North Carolina; Department of Medicine-Endocrinology, Diabetes and Metabolism (Balasubramanyam), Baylor College of Medicine, Houston, Texas; and Diabetes Epidemiology and Clinical Research Section (Knowler), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

Objective: Prior studies identified single nucleotide polymorphisms (SNPs) associated with physical activity (PA) level in a natural environment and intervention study: rs978656-DNAPTP6, rs10887741-PAPSS2, rs7279064-C18orf2, and rs6265-BDNF. Using the four SNPs' polygenic score (PGS), we examined whether PGS moderates a life-style intervention's effect on changes in PA level and cardiorespiratory fitness (CRF).

Methods: This is a secondary analysis of Look AHEAD, a multicenter randomized controlled trial designed to test the health benefits of a life-style intervention among 2675 participants with overweight/obesity and type 2 diabetes (ages, 45-76 years). Using linear mixed-effects models, level of PA (Paffenbarger PA questionnaire) and treadmill-assessed CRF were each regressed on four SNPs' PGS, study time (baseline, year 1, and year 4), intervention arm, and interactions between the three. Models adjusted for age, sex, body mass index, ancestry principal components (population stratification), and study sites, with Bonferroni corrections for multiple testing (α < .005). Effect modification by age was examined.

Results: PGS was not predictive of change in CRF or PA level in response to intervention. In analyses without PGS by intervention by time, the relationships between PGS and PA phenotypes were modified by age (p interaction = .048 for CRF and .058 for PA), such that a 1-unit increase in PGS was associated with 24 kcal · wk-1 more in moderate-intensity PA and 0.004 MET higher CRF only among older groups (age >55 years for CRF, >60 years for PA level).

Conclusions: The effects of the intervention on PA and CRF were not moderated by the four SNPs. Future studies with extended SNP list should confirm the findings on effect modification by age.
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http://dx.doi.org/10.1097/PSY.0000000000000930DOI Listing
June 2021

Passive Versus Active Intra-Abdominal Drainage Following Pancreatic Resection: Does A Superior Drainage System Exist? A Systematic Review and Meta-Analysis.

World J Surg 2021 09 27;45(9):2895-2910. Epub 2021 May 27.

Division of General Surgery, Department of Surgery, University of Ottawa, Ottawa, Canada.

Postoperative pancreatic fistula (POPF) is a major source of morbidity following pancreatic resection. Surgically placed drains under suction or gravity are routinely used to help mitigate the complications associated with POPF. Controversy exists as to whether one of these drain management strategies is superior. The objective was to identify and compare the incidence of POPF, adverse events, and resource utilization associated with passive gravity (PG) versus active suction (AS) drainage following pancreatic resection. MEDLINE, EMBASE, CINAHL, and Cochrane Library databases were searched from inception to May 18, 2020. Outcomes of interest included POPF, post-pancreatectomy hemorrhage (PPH), surgical site infection (SSI), other major morbidity, and resource utilization. Descriptive qualitative and pooled quantitative meta-analyses were performed. One randomized control trial and five cohort studies involving 10 663 patients were included. Meta-analysis found no difference in the odds of developing POPF between AS and PG (p = 0.78). There were no differences in other endpoints including PPH (p = 0.58), SSI (wound p = 0.21, organ space p = 0.05), major morbidity (p = 0.71), or resource utilization (p = 0.72). The risk of POPF or other adverse outcomes is not impacted by drain management following pancreatic resection. Based on current evidence, a suggestion cannot be made to support the use of one drain over another at this time. There is a trend toward increased intra-abdominal wound infections with AS drains (p = 0.05) that merits further investigation.
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http://dx.doi.org/10.1007/s00268-021-06158-5DOI Listing
September 2021

Clinical and Histopathologic Characteristics of Metastatic and Locally Advanced Cutaneous Basal Cell Carcinomas.

Am J Dermatopathol 2021 May 17. Epub 2021 May 17.

Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN.

Abstract: Locally advanced or metastatic basal cell carcinomas (laBCCs or mBCCs) are rare, with few case series providing information on their epidemiology. We aimed to describe the clinical and histologic features of locally advanced and metastatic basal cell carcinomas. Forty cases of laBCC or mBCC were identified by searching Vanderbilt's database from 1984 to January 2019. A retrospective chart review was performed. Pathology slides were available for 23 cases (13 mBCCs and 10 laBCCs). Twenty-one of 23 cases were Clark level IV or V, with a mean depth of invasion of >7 mm for both types. The mean mitotic rate was 4.4 mitoses/mm2 for laBCCs and 3.3 mitoses/mm2 for mBCCs. Ulceration was identified in 7 laBCC and 8 mBCC cases. Perineural invasion was present in 2 laBCC and 6 mBCC cases, with 3 mBCCs invading nerves >0.1 mm. Of 13 mBCC cases, histologic subtypes included infiltrative (n = 9), nodular (n = 7), morpheaform (n = 4), and superficial (n = 2), with multiple patterns present in some specimens. 10 of 13 patients with mBCC had local recurrence before metastasis. In summary, we identified several potential markers of high-risk BCC, including perineural invasion, deep invasion, elevated mitotic rate, and local recurrence of the primary tumor.
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http://dx.doi.org/10.1097/DAD.0000000000001985DOI Listing
May 2021

Safety and efficacy of autologous whole cell vaccines in hematologic malignancies: A systematic review and meta-analysis.

Hematol Oncol 2021 Oct 8;39(4):448-464. Epub 2021 May 8.

Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada.

Autologous cell vaccines use a patient's tumor cells to stimulate a broad antitumor response in vivo. This approach shows promise for treating hematologic cancers in early phase clinical trials, but overall safety and efficacy remain poorly described. We conducted a systematic review assessing the use of autologous cell vaccination in treating hematologic cancers. Primary outcomes of interest were safety and clinical response, with secondary outcomes including survival, relapse rate, correlative immune assays and health-quality related metrics. We performed a search of MEDLINE, Embase and the Cochrane Register of Controlled Trials including any interventional trial employing an autologous, whole cell product in any hematologic malignancy. Risk of bias was assessed using a modified Institute of Health Economics tool. Across 20 single arm studies, only 341 of 592 enrolled participants received one or more vaccinations. Primary reasons for not receiving vaccination included rapid disease progression/death and manufacturing challenges. Overall, few high-grade adverse events were observed. One death was reported and attributed to a GM-CSF producing allogeneic cell line co-administered with the autologous vaccine. Of 58 evaluable patients, the complete response rate was 21.0% [95% CI, 10.4%-37.8%)] and overall response rate was 35.8% (95% CI, 24.4%-49.0%). Of 97 evaluable patients for survival, the 5-years overall survival rate was 64.9% (95% CI, 52.6%-77.2%) and disease-free survival was 59.7% (95% CI, 47.7%-71.7%). We conclude that, in hematologic malignancies, based on limited available data, autologous cell vaccines are safe and display a trend towards efficacy but that challenges exist in vaccine manufacture and administration.
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http://dx.doi.org/10.1002/hon.2875DOI Listing
October 2021

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

Genet Med 2021 06 3;23(6):1028-1040. Epub 2021 Mar 3.

Division of Medical Genetics, Nemours/A.I. DuPont Hospital for Children, Wilmington, DE, USA.

Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis.

Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes.

Results: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes.

Conclusion: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
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http://dx.doi.org/10.1038/s41436-021-01114-zDOI Listing
June 2021

Intraoperative Red Blood Cell Transfusion Decision-making: A Systematic Review of Guidelines.

Ann Surg 2021 07;274(1):86-96

Department of Surgery, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.

Objectives: The objective of this work was to carry out a systematic review of clinical practice guidelines (CPGs) pertaining to intraoperative red blood cell (RBC) transfusions, in terms of indications, decision-making, and supporting evidence base.

Summary Of Background Data: RBC transfusions are common during surgery and there is evidence of wide variability in practice.

Methods: Major electronic databases (MEDLINE, EMBASE, and CINAHL), guideline clearinghouses and Google Scholar were systematically searched from inception to January 2019 for CPGs pertaining to indications for intraoperative RBC transfusion. Eligible guidelines were retrieved and their quality assessed using AGREE II. Relevant recommendations were abstracted and synthesized to allow for a comparison between guidelines.

Results: Ten guidelines published between 1992 and 2018 provided indications for intraoperative transfusions. No guideline addressed intraoperative transfusion decision-making as its primary focus. Six guidelines provided criteria for transfusion based on hemoglobin (range 6.0-10.0 g/dL) or hematocrit (<30%) triggers. In the absence of objective transfusion rules, CPGs recommended considering other parameters such as blood loss (n = 7), signs of end organ ischemia (n = 5), and hemodynamics (n = 4). Evidence supporting intraoperative recommendations was extrapolated primarily from the nonoperative setting. There was wide variability in the quality of included guidelines based on AGREE II scores.

Conclusion: This review has identified several clinical practice guidelines providing recommendations for intraoperative transfusion. The existing guidelines were noted to be highly variable in their recommendations and to lack a sufficient evidence base from the intraoperative setting. This represents a major knowledge gap in the literature.
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http://dx.doi.org/10.1097/SLA.0000000000004710DOI Listing
July 2021

Pursuing the developmental aims of the triarchic model of psychopathy: Creation and validation of triarchic scales for use in the USC: RFAB longitudinal twin project.

Dev Psychopathol 2021 Feb 15:1-16. Epub 2021 Feb 15.

Department of Psychology, Florida State University, Tallahassee, FL, USA.

The triarchic model was advanced as an integrative, trait-based framework for investigating psychopathy using different assessment methods and across developmental periods. Recent research has shown that the triarchic traits of boldness, meanness, and disinhibition can be operationalized effectively in youth, but longitudinal research is needed to realize the model's potential to advance developmental understanding of psychopathy. We report on the creation and validation of scale measures of the triarchic traits using questionnaire items available in the University of Southern California Risk Factors for Antisocial Behavior (RFAB) project, a large-scale longitudinal study of the development of antisocial behavior that includes measures from multiple modalities (self-report, informant rating, clinical-diagnostic, task-behavioral, physiological). Using a construct-rating and psychometric refinement approach, we developed triarchic scales that showed acceptable reliability, expected intercorrelations, and good temporal stability. The scales showed theory-consistent relations with external criteria including measures of psychopathy, internalizing/externalizing psychopathology, antisocial behavior, and substance use. Findings demonstrate the viability of measuring triarchic traits in the RFAB sample, extend the known nomological network of these traits into the developmental realm, and provide a foundation for follow-up studies examining the etiology of psychopathic traits and their relations with multimodal measures of cognitive-affective function and proneness to clinical problems.
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http://dx.doi.org/10.1017/S0954579420002060DOI Listing
February 2021

Inhibitor of Differentiation 4 (ID4) represses mammary myoepithelial differentiation via inhibition of HEB.

iScience 2021 Feb 20;24(2):102072. Epub 2021 Jan 20.

The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

Inhibitor of differentiation (ID) proteins dimerize with basic HLH (bHLH) transcription factors, repressing transcription of lineage-specification genes across diverse cellular lineages. ID4 is a key regulator of mammary stem cells; however, the mechanism by which it achieves this is unclear. Here, we show that ID4 has a cell autonomous role in preventing myoepithelial differentiation of basal cells in mammary organoids and . ID4 positively regulates proliferative genes and negatively regulates genes involved in myoepithelial function. Mass spectrometry reveals that ID4 interacts with the bHLH protein HEB, which binds to E-box motifs in regulatory elements of basal developmental genes involved in extracellular matrix and the contractile cytoskeleton. We conclude that high ID4 expression in mammary basal stem cells antagonizes HEB transcriptional activity, preventing myoepithelial differentiation and allowing for appropriate tissue morphogenesis. Downregulation of ID4 during pregnancy modulates gene regulated by HEB, promoting specialization of basal cells into myoepithelial cells.
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http://dx.doi.org/10.1016/j.isci.2021.102072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851187PMC
February 2021

Parental experiences of adolescent cancer-related distress: A qualitative study.

Eur J Cancer Care (Engl) 2021 Jul 29;30(4):e13417. Epub 2021 Jan 29.

Department of Psychology, University of Bath, Bath, UK.

Objective: Adolescents' cancer-related distress is more complex, severe, and long-lasting than that of children and adults. Parents adopt an active role in supporting their adolescent, reporting that adolescent cancer-related distress is the most problematic symptom parents experience. Research has predominantly focused on exploring adolescents' experiences of cancer-related distress, with little attention to how their parents experience their adolescent's cancer-related distress. Therefore, we aimed to explore parents' experiences of distress within the context of parenting an adolescent with cancer-related distress during or immediately subsequent to active treatment.

Methods: A total of 21 semi-structured interviews were conducted face-to-face or via telephone, with parents of adolescents aged 12-18 years from south-west England. Inductive reflexive thematic analysis was used to analyse the data.

Results: Three themes were generated: "The contagion of distress", "Navigating breaking point" and "Developmental disruption". Parental distress transcended from adolescent cancer-related distress, eliciting uncertainty and challenging parenting limits. Parental distress was perpetuated by feelings that their adolescent had missed out on "normal" adolescence during and just after active treatment.

Conclusion: Parental distress reflected the multi-faceted nature of their adolescent's cancer-related distress. Findings advocate the importance of providing a parental voice within adolescent oncology populations. Developing tailored interventions to address parental distress are suggested.
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http://dx.doi.org/10.1111/ecc.13417DOI Listing
July 2021

Effects of a Motor Imagery Task on Functional Brain Network Community Structure in Older Adults: Data from the Brain Networks and Mobility Function (B-NET) Study.

Brain Sci 2021 Jan 17;11(1). Epub 2021 Jan 17.

Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27103, USA.

Elucidating the neural correlates of mobility is critical given the increasing population of older adults and age-associated mobility disability. In the current study, we applied graph theory to cross-sectional data to characterize functional brain networks generated from functional magnetic resonance imaging data both at rest and during a motor imagery (MI) task. Our MI task is derived from the Mobility Assessment Tool-short form (MAT-sf), which predicts performance on a 400 m walk, and the Short Physical Performance Battery (SPPB). Participants ( = 157) were from the Brain Networks and Mobility (B-NET) Study (mean age = 76.1 ± 4.3; % female = 55.4; % African American = 8.3; mean years of education = 15.7 ± 2.5). We used community structure analyses to partition functional brain networks into communities, or subnetworks, of highly interconnected regions. Global brain network community structure decreased during the MI task when compared to the resting state. We also examined the community structure of the default mode network (DMN), sensorimotor network (SMN), and the dorsal attention network (DAN) across the study population. The DMN and SMN exhibited a task-driven decline in consistency across the group when comparing the MI task to the resting state. The DAN, however, displayed an increase in consistency during the MI task. To our knowledge, this is the first study to use graph theory and network community structure to characterize the effects of a MI task, such as the MAT-sf, on overall brain network organization in older adults.
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http://dx.doi.org/10.3390/brainsci11010118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830141PMC
January 2021

Novel genetic testing model: A collaboration between genetic counselors and nephrology.

Am J Med Genet A 2021 04 21;185(4):1142-1150. Epub 2021 Jan 21.

Precision Medicine/Genetic Testing Stewardship Program, Nemours A.I. duPont Hospital for Children Precision Medicine/Genetic Testing Stewardship Program, Wilmington, Delaware, USA.

Many barriers to genetic testing currently exist which delay or prevent diagnosis. These barriers include wait times, staffing, education, and cost. Specialists are able to identify patients with disease that may need genetic testing, but lack the genetics support to facilitate that testing in the most cost, time, and medically effective manner. The Nephrology Division and the Genetic Testing Stewardship Program at Nemours A.I. duPont Hospital for Children created a novel service delivery model in which nephrologists and genetic counselors collaborate in order to highlight their complementary strengths (clinical expertise of nephrologists and genetics and counseling skills of genetic counselors). This collaboration has reduced many barriers to care for our patients. This workflow facilitated the offering of genetic testing to 76 patients, with 86 tests completed over a 20-month period. Thirty-two tests were deferred. Twenty-seven patients received a diagnosis, which lead to a change in their medical management, three of whom were diagnosed by cascade family testing. Forty-two patients had a negative result and 16 patients had one or more variants of uncertain significance on testing. The inclusion of genetic counselors in the workflow is integral toward choosing the most cost and time effective genetic testing strategy, as well as providing psychosocial support to families. The genetic counselors obtain informed consent, and review genetic test results and recommendations with the patient and their family. The availability of this program to our patients increased access to genetic testing and helps to provide diagnoses and supportive care.
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http://dx.doi.org/10.1002/ajmg.a.62088DOI Listing
April 2021

Developmental Trajectories of Delinquent and Aggressive Behavior: Evidence for Differential Heritability.

Child Psychiatry Hum Dev 2021 Jan 15. Epub 2021 Jan 15.

Department of Psychology, University of Southern California, Los Angeles, USA.

The developmental course of antisocial behavior is often described in terms of qualitatively distinct trajectories. However, the genetic etiology of various trajectories is not well understood. We examined heterogeneity in the development of delinquent and aggressive behavior in 1532 twin youth using four waves of data collection, spanning ages 9-10 to 16-18. A latent class growth analysis was used to uncover relevant subgroups. For delinquent behavior, three latent classes emerged: Non-Delinquent, Low-Level Delinquent, and Persistent Delinquent. Liability for persistent delinquency had a substantial genetic origin (heritability = 67%), whereas genetic influences were negligible for lower-risk subgroups. Three classes of aggressive behavior were identified: Non-Aggressive, Moderate, and High. Moderate heritability spanned the entire continuum of risk for aggressive behavior. Thus, there are differences between aggressive behavior and non-aggressive delinquency with respect to heterogeneity of etiology. We conclude that persistent delinquency represents an etiologically distinct class of rule-breaking with strong genetic roots.
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http://dx.doi.org/10.1007/s10578-020-01119-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280243PMC
January 2021

Longitudinal tracking of skin dynamic stiffness to quantify evolution of sclerosis in chronic graft-versus-host disease.

Bone Marrow Transplant 2021 04 5;56(4):989-991. Epub 2020 Dec 5.

Dermatology Service and Research Service, Department of Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.

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http://dx.doi.org/10.1038/s41409-020-01158-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117134PMC
April 2021

Patient Satisfaction Following Level II Oncoplastic Breast Surgery: A Comparison with Mastectomy Utililizing the Breast-Q Questionnaire will be published in Surgical Oncology.

Surg Oncol 2020 Dec 13;35:556-559. Epub 2020 Nov 13.

Division of General Surgery, Department of Surgery, University of Ottawa, 501 Smyth Rd., Ottawa, Ontario, K1H 8L6, Canada.

Introduction: Oncoplastic breast surgery (OBS) is increasingly used to decrease the deformity in breast conserving therapy (BCT) for breast cancer. We aimed to evaluate patient reported satisfaction following level II OBS and mastectomy utilizing the BREAST-Q questionnaire.

Methods: Patients who underwent level II OBS BCT and those who underwent mastectomies were distributed the BREAST-Q post-reduction/mammoplasty module. Clinicopathological data were collected from review of patient charts. Results were scored using the standardized scoring system (Q-score). Results of the OBS group were compared to those in the mastectomy group.

Results: A total of 88 patients who underwent level II OBS and 101 patients who underwent mastectomy completed the questionnaire. Mann-Whitney odds estimator demonstrated higher satisfaction with breasts (1.51, 95% CI [1.04-2.25], p = 0.026) and higher psychosocial well-being (1.51, 95% CI [1.04-2.15], p = 0.022) in those who underwent OBS compared to mastectomy.

Conclusion: Results demonstrate a high satisfaction with breasts and improved psychosocial wellbeing in patients who underwent level II OBS compared to those undergoing mastectomy. These results demonstrate that OBS should be considered in patients where mastectomy otherwise would be necessary. Further larger multi-institutional studies are necessary to examine the effect of OBS on the quality of life of breast cancer patients.
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http://dx.doi.org/10.1016/j.suronc.2020.11.001DOI Listing
December 2020

Acute midgut volvulus in a septuagenarian with secondary jejunoileal diverticulitis and undiagnosed congenital malrotation: an unusual presentation.

J Surg Case Rep 2020 Nov 12;2020(11):rjaa449. Epub 2020 Nov 12.

Department of Surgery, The Ottawa Hospital, Ottawa, ON, Canada.

A 79-year-old male presented with abdominal pain, incidental umbilical hernia and acute midgut volvulus that was not detected until surgical exploration. When he presented to hospital, computed tomography (CT) findings indicated perforated jejunoileal diverticulitis; however, in the operating room clockwise volvulization of the jejunum and ileum, secondarily inflamed jejunoileal diverticula, incomplete malrotation (right-sided duodenojejunal flexure), right retroperitoneal adhesions (Ladd's bands) and numerous other congenital adhesive bands were found. A modified Ladd's procedure and umbilical hernia repair were completed including detorsion, division of Ladd's bands with medialization of the cecum and lysis of other congenital adhesions without appendectomy. The patient recovered to baseline function by 3 weeks postoperatively. Acute midgut volvulus is a life-threatening surgical emergency that is exceptionally rare in the elderly. CT is relatively insensitive, so misdiagnosis is common. A high index of suspicion is required, especially in patients with a history of congenital gastrointestinal abnormalities. Prompt surgical exploration for correction and prevention is crucial.
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http://dx.doi.org/10.1093/jscr/rjaa449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659920PMC
November 2020

Correction to: Postoperative Adverse Events are Associated with Oncologic Recurrence Following Curative‑intent Resection for Lung Cancer.

Lung 2020 Dec;198(6):983

Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada.

The original version of this article unfortunately contained a mistake in author names. The given and family names of all the authors was transposed. The author names are corrected with this correction. The original article has been corrected.
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http://dx.doi.org/10.1007/s00408-020-00409-3DOI Listing
December 2020

Development of Phenotyping Algorithms for the Identification of Organ Transplant Recipients: Cohort Study.

JMIR Med Inform 2020 Dec 10;8(12):e18001. Epub 2020 Dec 10.

Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, United States.

Background: Studies involving organ transplant recipients (OTRs) are often limited to the variables collected in the national Scientific Registry of Transplant Recipients database. Electronic health records contain additional variables that can augment this data source if OTRs can be identified accurately.

Objective: The aim of this study was to develop phenotyping algorithms to identify OTRs from electronic health records.

Methods: We used Vanderbilt's deidentified version of its electronic health record database, which contains nearly 3 million subjects, to develop algorithms to identify OTRs. We identified all 19,817 individuals with at least one International Classification of Diseases (ICD) or Current Procedural Terminology (CPT) code for organ transplantation. We performed a chart review on 1350 randomly selected individuals to determine the transplant status. We constructed machine learning models to calculate positive predictive values and sensitivity for combinations of codes by using classification and regression trees, random forest, and extreme gradient boosting algorithms.

Results: Of the 1350 reviewed patient charts, 827 were organ transplant recipients while 511 had no record of a transplant, and 12 were equivocal. Most patients with only 1 or 2 transplant codes did not have a transplant. The most common reasons for being labeled a nontransplant patient were the lack of data (229/511, 44.8%) or the patient being evaluated for an organ transplant (174/511, 34.1%). All 3 machine learning algorithms identified OTRs with overall >90% positive predictive value and >88% sensitivity.

Conclusions: Electronic health records linked to biobanks are increasingly used to conduct large-scale studies but have not been well-utilized in organ transplantation research. We present rigorously evaluated methods for phenotyping OTRs from electronic health records that will enable the use of the full spectrum of clinical data in transplant research. Using several different machine learning algorithms, we were able to identify transplant cases with high accuracy by using only ICD and CPT codes.
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http://dx.doi.org/10.2196/18001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759442PMC
December 2020

Parental Experiences of Adolescent Cancer-Related Fatigue: A Qualitative Study.

J Pediatr Psychol 2020 11;45(10):1093-1102

Department of Psychology, University of Bath.

Objective: Cancer-related fatigue is common, disabling, and chronic, but professional help is not necessarily sought. Parents can support symptom management and facilitate help-seeking. This study explored parental experiences of their adolescent's cancer-related fatigue and what they do to help.

Methods: Qualitative semi-structured interviews were conducted with 21 parents of 17 adolescents aged 12-18 who were previously diagnosed with cancer. Reflexive thematic analysis was used to analyze the data.

Results: Three high-order themes were generated. Firstly, "fatigue is inevitable and unpredictable." This encompassed parental perceptions of fatigue as variable, distinct from normal tiredness, and linked to sleep and mood. Fatigue was seen as arising from cancer, which rendered parents helpless. Secondly, "fatigue is disruptive to normal life" beyond cancer treatment, which is contrary to expectations. Thirdly, parents managed fatigue by trying to balance the adolescent's desires for normality and their own perception of what is realistic with encouraging activities, and by seeking support from others.

Conclusions: Parents see adolescent cancer-related fatigue as multi-faceted and experience it as unpredictable and attributed to cancer. They struggle to distinguish normal adolescent behavior from problematic fatigue, and to balance supporting and empowering the adolescent to live life to the fullest whilst also being realistic about the limitations imposed by fatigue and the benefits of activity. Parents try to manage fatigue practically but want more information about adolescent cancer-related fatigue to help establish their own and their adolescent's expectations.
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http://dx.doi.org/10.1093/jpepsy/jsaa080DOI Listing
November 2020

Postoperative Adverse Events are Associated with Oncologic Recurrence Following Curative-intent Resection for Lung Cancer.

Lung 2020 12 9;198(6):973-981. Epub 2020 Oct 9.

Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada.

Background: Up to 50% of patients suffer short-term postoperative adverse events (AEs) and metastatic recurrence in the long-term following curative-intent lung cancer resection. The association between AEs, particularly infectious in nature, and disease recurrence is controversial. We sought to evaluate the association of postoperative AEs on risk of developing recurrence and recurrence-free survival (RFS) following curative-intent lung resection surgery.

Methods: All lung cancer resections at a single institution (January 2008-July 2015) were included, with prospective collection of AEs using the Thoracic Morbidity & Mortality System. Cox proportional hazards models were used to estimate the effect of AEs on recurrence, with results presented as hazard ratio (HR) with 95% confidence interval (CI). An a priori, clinically driven approach to predictor variable selection was used. Kaplan-Meier curves were used examine the relationship between AE and RFS. p < 0.05 was considered statistically significant.

Results: 892 patients underwent curative-intent resection. 342 (38.3%) patients experienced an AE; 69 (7.7%) patients developed infectious AEs. 17.6% (n = 157) of patients had disease recurrence after mean follow-up of 26.5 months. Severe (Grade IV) AEs were associated with increased risk of recurrence (3.40; 95% CI 1.56-7.41) and a trend to decreased RFS. Major infectious AEs were associated with increased risk of recurrence (HR 1.71; CI 1.05-2.8) and earlier time to recurrence (no infectious AE 66 months, minor infectious 41 months, major infectious 54 months; p = 0.02).

Conclusion: For patients undergoing curative-intent lung cancer resection, postoperative AEs associated with critical illness or major infection were associated with increased risk of oncologic recurrence.
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http://dx.doi.org/10.1007/s00408-020-00395-6DOI Listing
December 2020

Cancer-related fatigue in teenage and young adult cancer patients: Clinicians' perspectives, practice and challenges.

Eur J Cancer Care (Engl) 2021 Jan 4;30(1):e13337. Epub 2020 Oct 4.

University of Cambridge, Cambridge, UK.

Objective: Cancer-related fatigue (CRF) is a common and distressing symptom experienced by teenage and young adult cancer patients (TYAs). This study aimed to explore clinicians' perspectives, practices and challenges in supporting TYAs with CRF.

Method: Ten clinicians from a TYA multidisciplinary team (MDT) participated in semi-structured interviews which were thematically analysed.

Results: Clinicians perceived CRF as a common, but individual experience for TYAs and framed the broad impact of CRF in the context of TYAs' development. Clinicians' assessment and management of CRF for TYAs varied. Clinicians described a range of challenges affecting their practice in supporting TYAs with CRF, including limited knowledge, difficulties engaging TYAs, inadequate time in consultations and a lack of age-appropriate resources.

Conclusions: Despite clinicians' good insight into TYAs' unique experiences of CRF, the assessment and management of CRF for TYAs are complicated by numerous challenges. The development of evidence-based interventions and guidelines, clear pathways of care, and TYA-friendly resources, measures and programmes, is vital to support clinicians, and TYAs, in managing CRF.
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http://dx.doi.org/10.1111/ecc.13337DOI Listing
January 2021

Development of a novel cognitive composite outcome to assess therapeutic effects of exercise in the EXERT trial for adults with MCI: The ADAS-Cog-Exec.

Alzheimers Dement (N Y) 2020 9;6(1):e12059. Epub 2020 Sep 9.

Department of Internal Medicine-Geriatrics Wake Forest School of Medicine Winston-Salem North Carolina USA.

Introduction: Use of cognitive composites as primary outcome measures is increasingly common in clinical trials of preclinical and prodromal Alzheimer's disease (AD). Composite outcomes can decrease intra-individual variability, resulting in improved sensitivity to detect longitudinal change and increased statistical power. We developed a novel composite outcome, the ADAS-Cog-Exec, for use in the EXERT trial-a Phase 3 randomized, controlled, 12-month exercise intervention in mild cognitive impairment (MCI).

Methods: Three combinations of cognitive measures selected from the Alzheimer's Disease Assessment Scale-Cognitive Subscale version 13 (ADAS-Cog13), tests of executive function, and the Clinical Dementia Rating (CDR) were created based on previously documented sensitivity to longitudinal change in MCI and to the effects of exercise. Optimally weighted composites of each combination were modeled using data from the ADNI-1 MCI cohort. Ten-fold cross-validation was performed to obtain a bias-corrected mean to standard deviation ratio (MSDR). The cognitive composites were assessed for their sensitivity to detect 12-month change in MCI.

Results: The MSDR of 12-month change for each of the composite outcomes tested exceeded that of the ADAS-Cog13 total score. The composite with the highest MSDR (MSDR = 0.48) and associated statistical power included scores on ADAS-Cog13 Word Recall, Delayed Word Recall, Orientation, and Number Cancellation subtests; Trail-Making Tests A & B, Digit Symbol Substitution and Category Fluency; and cognitive components of the CDR (Memory, Orientation, Judgement & Problem Solving).

Discussion: An optimally weighted cognitive composite measure was identified and validated for use in EXERT. This composite contained selected subtests from the ADAS-Cog13, additional measures of executive function, and box scores for cognitive components of the CDR. Because this composite score demonstrated high sensitivity to longitudinal change in MCI it will be used as the primary outcome measure for the EXERT trial.
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http://dx.doi.org/10.1002/trc2.12059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507362PMC
September 2020

Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy.

Biomolecules 2020 09 8;10(9). Epub 2020 Sep 8.

Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India.

The basic helix-loop-helix (bHLH) transcription factors inhibitor of differentiation 1 () and inhibitor of differentiation 3 (referred to as ) have an important role in maintaining the cancer stem cell (CSC) phenotype in the triple-negative breast cancer (TNBC) subtype. In this study, we aimed to understand the molecular mechanism underlying control of CSC phenotype and exploit it for therapeutic purposes. We used two different TNBC tumor models marked by either depletion or expression in order to identify targets using a combinatorial analysis of RNA sequencing and microarray data. Phenotypically, Id protein depletion leads to cell cycle arrest in the G0/G1 phase, which we demonstrate is reversible. In order to understand the molecular underpinning of Id proteins on the cell cycle phenotype, we carried out a large-scale small interfering RNA (siRNA) screen of 61 putative targets identified by using genomic analysis of two Id TNBC tumor models. Kinesin Family Member 11 () and Aurora Kinase A (), which are critical cell cycle regulators, were further validated as Id targets. Interestingly, unlike in depletion conditions, and knockdown leads to a G2/M arrest, suggesting a novel cell cycle mechanism, which we will explore in further studies. Therapeutic targeting of to block the axis was carried out using small molecular inhibitor ispinesib. We finally leveraged our findings to target the pathway using the small molecule inhibitor ispinesib in the Id+ CSC results combined with chemotherapy for better response in TNBC subtypes. This work opens up exciting new possibilities of targeting targets such as in the TNBC subtype, which is currently refractory to chemotherapy. Targeting the molecular pathway in the Id1+ CSCs in combination with chemotherapy and small molecular inhibitor results in more effective debulking of TNBC.
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http://dx.doi.org/10.3390/biom10091295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565337PMC
September 2020
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