Cisplatin induces BDNF downregulation in middle-aged female rat model while BDNF enhancement attenuates cisplatin neurotoxicity.

Cancer-related cognitive impairments (CRCI) are neurological complications associated with cancer treatment, and greatly affect cancer survivors' quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning and memory. The reduction of BDNF is associated with the decrease in cognitive function in various neurological disorders. Few pre-clinical studies have reported on the effects of chemotherapy and medical stress on BDNF levels and cognition. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive function in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected 24 weeks after cisplatin initiation. In cultured hippocampal neurons, we screened three neuroprotective agents, riluzole (an approved treatment for amyotrophic lateral sclerosis), as well as the ampakines CX546 and CX1739. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD-95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD-95. Ampakines (CX546 and CX1739) and riluzole did not affect the antitumor efficacy of cisplatin in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels on cognitive function, although future studies are warranted to assess the efficacy of BDNF enhancement in vivo on synaptic plasticity. Collectively, our results indicate that cancer treatment exerts long-lasting changes in BDNF levels, and support BDNF enhancement as a potential preventative approach to target CRCI with therapeutics that are FDA approved and/or in clinical study for other indications.

A Prospective Multicenter Comparison of Trauma and Injury Severity Score, American Society of Anesthesiologists Physical Status, and National Surgical Quality Improvement Program Calculator's Ability to Predict Operative Trauma Outcomes.

BACKGROUND: Trauma outcome prediction models have traditionally relied upon patient injury and physiologic data (eg, Trauma and Injury Severity Score [TRISS]) without accounting for comorbidities. We sought to prospectively evaluate the role of the American Society of Anesthesiologists physical status (ASA-PS) score and the National Surgical Quality Improvement Program Surgical Risk-Calculator (NSQIP-SRC), which are measurements of comorbidities, in the prediction of trauma outcomes, hypothesizing that they will improve the predictive ability for mortality, hospital length of stay (LOS), and complications compared to TRISS alone in trauma patients undergoing surgery within 24 hours. METHODS: A prospective, observational multicenter study (9/2018-2/2020) of trauma patients ≥18 years undergoing operation within 24 hours of admission was performed. Multiple logistic regression was used to create models predicting mortality utilizing the variables within TRISS, ASA-PS, and NSQIP-SRC, respectively. Linear regression was used to create models predicting LOS and negative binomial regression to create models predicting complications. RESULTS: From 4 level I trauma centers, 1213 patients were included. The Brier Score for each model predicting mortality was found to improve accuracy in the following order: 0.0370 for ASA-PS, 0.0355 for NSQIP-SRC, 0.0301 for TRISS, 0.0291 for TRISS+ASA-PS, and 0.0234 for TRISS+NSQIP-SRC. However, when comparing TRISS alone to TRISS+ASA-PS (P = .082) and TRISS+NSQIP-SRC (P = .394), there was no significant improvement in mortality prediction. NSQIP-SRC more accurately predicted both LOS and complications compared to TRISS and ASA-PS. CONCLUSIONS: TRISS predicts mortality better than ASA-PS and NSQIP-SRC in trauma patients undergoing surgery within 24 hours. The TRISS mortality predictive ability is not improved when combined with ASA-PS or NSQIP-SRC. However, NSQIP-SRC was the most accurate predictor of LOS and complications.

Comparison of National Surgical Quality Improvement Program Surgical Risk Calculator and Trauma and Injury Severity Score Risk Assessment Tools in Predicting Outcomes in High-Risk Operative Trauma Patients.

BACKGROUND: The Trauma and Injury Severity Score (TRISS) uses anatomic/physiologic variables to predict outcomes. The National Surgical Quality Improvement Program Surgical Risk Calculator (NSQIP-SRC) includes functional status and comorbidities. It is unclear which of these tools is superior for high-risk trauma patients (American Society of Anesthesiologists Physical Status (ASA-PS) class IV or V). This study compares risk prediction of TRISS and NSQIP-SRC for mortality, length of stay (LOS), and complications for high-risk operative trauma patients. METHODS: This is a prospective study of high-risk (ASA-PS IV or V) trauma patients (≥18 years-old) undergoing surgery at 4 trauma centers. We compared TRISS vs NSQIP-SRC vs NSQIP-SRC + TRISS for ability to predict mortality, LOS, and complications using linear, logistic, and negative binomial regression. RESULTS: Of 284 patients, 48 (16.9%) died. The median LOS was 16 days and number of complications was 1. TRISS + NSQIP-SRC best predicted mortality (AUROC: .877 vs .723 vs .843, P = .0018) and number of complications (pseudo-R2/median error (ME) 5.26%/1.15 vs 3.39%/1.33 vs 2.07%/1.41, P < .001) compared to NSQIP-SRC or TRISS, but there was no difference between TRISS + NSQIP-SRC and NSQIP-SRC with LOS prediction (P = .43). DISCUSSION: For high-risk operative trauma patients, TRISS + NSQIP-SRC performed better at predicting mortality and number of complications compared to NSQIP-SRC or TRISS alone but similar to NSQIP-SRC alone for LOS. Thus, future risk prediction and comparisons across trauma centers for high-risk operative trauma patients should include a combination of anatomic/physiologic data, comorbidities, and functional status.

Adolescent use and co-use of tobacco and cannabis in California: The roles of local policy and density of tobacco, vape, and cannabis retailers around schools.

Adolescent tobacco use (particularly vaping) and co-use of cannabis and tobacco have increased, leading some jurisdictions to implement policies intended to reduce youth access to these products; however, their impacts remain unclear. We examine associations between local policy, density of tobacco, vape, and cannabis retailers around schools, and adolescent use and co-use of tobacco/vape and cannabis. We combined 2018 statewide California (US) data on: (a) jurisdiction-level policies related to tobacco and cannabis retail environments, (b) jurisdiction-level sociodemographic composition, (c) retailer locations (tobacco, vape, and cannabis shops), and (d) survey data on 534,176 middle and high school students (California Healthy Kids Survey). Structural equation models examined how local policies and retailer density near schools are associated with frequency of past 30-day cigarette smoking or vaping, cannabis use, and co-use of tobacco/vape and cannabis, controlling for jurisdiction-, school-, and individual-level confounders. Stricter retail environment policies were associated with lower odds of past-month use of tobacco/vape, cannabis, and co-use of tobacco/vape and cannabis. Stronger tobacco/vape policies were associated with higher tobacco/vape retailer density near schools, while stronger cannabis policies and overall policy strength (tobacco/vape and cannabis combined) were associated with lower cannabis and combined retailer densities (summed tobacco/vape and cannabis), respectively. Tobacco/vape shop density near schools was positively associated with tobacco/vape use odds, as was summed retailer density near schools and co-use of tobacco, cannabis. Considering jurisdiction-level tobacco and cannabis control policies are associated with adolescent use of these substances, policymakers may proactively leverage such policies to curb youth tobacco and cannabis use.

Comparison of National Surgical Quality Improvement Program Surgical Risk Calculator, Trauma and Injury Severity Score, and American Society of Anesthesiologists Physical Status to predict operative trauma mortality in elderly patients.

BACKGROUND: The Trauma and Injury Severity Score (TRISS) uses anatomical and physiologic variables to predict mortality. Elderly (65 years or older) trauma patients have increased mortality and morbidity for a given TRISS, in part because of functional status and comorbidities. These factors are incorporated into the American Society of Anesthesiologists Physical Status (ASA-PS) and National Surgical Quality Improvement Program Surgical Risk Calculator (NSQIP-SRC). We hypothesized scoring tools using comorbidities and functional status to be superior at predicting mortality, hospital length of stay (LOS), and complications in elderly trauma patients undergoing operation. METHODS: Four level I trauma centers prospectively collected data on elderly trauma patients undergoing surgery within 24 hours of admission. Using logistic regression, five scoring models were compared: ASA-PS, NSQIP-SRC, TRISS, TRISS-ASA-PS, and TRISS-NSQIP-SRC.Brier scores and area under the receiver operator characteristics curve were calculated to compare mortality prediction. Adjusted R2 and root mean squared error were used to compare LOS and predictive ability for number of complications. RESULTS: From 122 subjects, 9 (7.4%) died, and the average LOS was 12.9 days (range, 1-110 days). National Surgical Quality Improvement Program Surgical Risk Calculator was superior to ASA-PS and TRISS at predicting mortality (area under the receiver operator characteristics curve, 0.978 vs. 0.768 vs. 0.903; p = 0.007). Furthermore, NSQIP-SRC was more accurate predicting LOS (R2, 25.9% vs. 13.3% vs. 20.5%) and complications (R2, 34.0% vs. 22.6% vs. 29.4%) compared with TRISS and ASA-PS. Adding TRISS to NSQIP-SRC improved predictive ability compared with NSQIP-SRC alone for complications (R2, 35.5% vs. 34.0%; p = 0.046). However, adding ASA-PS or TRISS to NSQIP-SRC did not improve the predictive ability for mortality or LOS. CONCLUSION: The NSQIP-SRC, which includes comorbidities and functional status, had superior ability to predict mortality, LOS, and complications compared with TRISS alone in elderly trauma patients undergoing surgery. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level III.

Preferences of Type 1 Diabetic Patients on Devices for Islet Transplantation.

Transplantation of pancreatic islets within a biomaterial device is currently under investigation in clinical trials for the treatment of patients with type 1 diabetes (T1D). Patients' preferences on such implants could guide the designs of next-generation implantable devices; however, such information is not currently available. We surveyed the preferences of 482 patients with T1D on the size, shape, visibility, and transplantation site of islet containing implants. More than 83% of participants were willing to receive autologous stem cells, and there was no significant association between implant fabricated by one's own stem cell with gender (χ2 (1, n = 468) = 0.28; P = 0.6) or with age (χ2 (4, n = 468) = 2.92; P = 0.6). Preferred location for islet transplantation within devices was under the skin (52.7%). 48.3% preferred microscopic disks, and 32.3% preferred a thin device (like a credit card). Moreover, 58.4% preferred the implant to be as small as possible, 25.4% did not care about visibility, and 16.2% preferred their implants not to be visible. Among female participants, 81% cared about the implant visibility, whereas this number was 64% for male respondents (χ2 test (1, n = 468) = 16.34; P < 0.0001). 22% of those younger than 50 years of age and 30% of those older than 50 did not care about the visibility of implant (χ2 test (4, n = 468) = 23.69; P < 0.0001). These results suggest that subcutaneous sites and micron-sized devices are preferred choices among patients with T1D who participated in our survey.

New anthropometric classification scheme of preoperative nutritional status in children: a retrospective observational cohort study.

OBJECTIVE: WHO uses anthropometric classification scheme of childhood acute and chronic malnutrition based on low body mass index (BMI) ('wasting') and height for age ('stunting'), respectively. The goal of this study was to describe a novel two-axis nutritional classification scheme to (1) characterise nutritional profiles in children undergoing abdominal surgery and (2) characterise relationships between preoperative nutritional status and postoperative morbidity. DESIGN: This was a retrospective observational cohort study. SETTING: The setting was 50 hospitals caring for children in North America that participated in the American College of Surgeons National Surgical Quality Improvement Program Paediatric from 2011 to 2013. PARTICIPANTS: Children >28 days who underwent major abdominal operations were identified. INTERVENTIONS/MAIN PREDICTOR: The cohort of children was divided into five nutritional profile groups based on both BMI and height for age Z-scores: (1) underweight/short, (2) underweight/tall, (3) overweight/short, (4) overweight/tall and (5) non-outliers (controls). MAIN OUTCOME MEASURES: Multiple variable logistic regressions were used to quantify the association between 30-day morbidity and nutritional profile groups while adjusting for procedure case mix, age and American Society of Anaesthesiologists class. RESULTS: A total of 39 520 cases distributed as follows: underweight/short (656, 2.2%); underweight/tall (252, 0.8%); overweight/short (733, 2.4%) and overweight/tall (1534, 5.1%). Regression analyses revealed increased adjusted odds of composite morbidity (35%) and reintervention events (75%) in the underweight/short group, while overweight/short patients had increased adjusted odds of composite morbidity and healthcare-associated infections (43%), and reintervention events (79%) compared with controls. CONCLUSION: Stratification of preoperative nutritional status using a scheme incorporating both BMI and height for age is feasible. Further research is needed to validate this nutritional risk classification scheme for other surgical procedures in children.

Pallidal deep brain stimulation modulates excessive cortical high ß phase amplitude coupling in Parkinson disease.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are equally efficacious in the management of Parkinson disease (PD). Studies of STN-DBS have revealed a therapeutic reduction in excessive cortical ß-γ phase-amplitude coupling (PAC). It is unclear whether this is specific to STN-DBS and potentially mediated by modulation of the hyperdirect pathway or if it is a generalizable mechanism seen with DBS of other targets. Moreover, it remains unclear how cortical signals are differentially modulated by movement versus therapy. To clarify, the effects of GPi-DBS and movement on cortical ß power and ß-γ PAC were examined. METHODS: Right sensorimotor electrocorticographic signals were recorded in 10 PD patients undergoing GPi-DBS implantation surgery. We evaluated cortical ß power and ß-γ PAC during blocks of rest and contralateral hand movement (finger tapping) with GPi-DBS off and on. RESULTS: Movement suppressed cortical low ß power (P = 0.008) and high ß-γ PAC (P = 0.028). Linear mixed effect modeling (LMEM) showed that power in low and high ß bands are differentially modulated by movement (P = 0.022). GPi-DBS also results in a significant suppression of high ß-γ PAC but without power modulation in either ß sub-band (P = 0.008). Cortical high ß-γ PAC is significantly correlated with severity of bradykinesia (Rho = 0.59, P = 0.045) and changes proportionally with therapeutic improvement (Rho = 0.61, P = 0.04). CONCLUSIONS: Similar to STN-DBS, GPi-DBS reduces motor cortical ß-γ PAC, like that also reported with dopaminergic mediations, suggesting it is a generalizable symptom biomarker in PD, independent of therapeutic target or proximity to the hyperdirect pathway.

Palliative Care and Health Care Utilization for Patients With End-Stage Liver Disease at the End of Life.

BACKGROUND & AIMS: There has been increased attention on ways to improve the quality of end-of-life care for patients with end-stage liver disease; however, there have been few reports of care experiences for patients during terminal hospitalizations. We analyzed data from a large national database to increase our understanding of palliative care for and health care utilization by patients with end-stage liver disease. METHODS: We performed a cross-sectional, observational study to examine terminal hospitalizations of adults with decompensated cirrhosis using data from the National Inpatient Sample from 2009 through 2013. We collected data on palliative care consultation and total hospital costs, and performed multivariate regression analyses to identify factors associated with palliative care consultation. We also investigated whether consultation was associated with lower costs. RESULTS: Among hospitalized adults with terminal decompensated cirrhosis, 30.3% received palliative care; the mean cost per hospitalization was $48,551 ± $1142. Palliative care consultation increased annually, and was provided to 18.0% of patients in 2009 and to 36.6% of patients in 2013 (P < .05). The mean cost for the terminal hospitalization did not increase significantly ($47,969 in 2009 to $48,956 in 2013, P = .77). African Americans, Hispanics, Asians, and liver transplant candidates were less likely to receive palliative care, whereas care in large urban teaching hospitals was associated with a higher odds of receiving consultation. Palliative care was associated with lower procedure burden-after adjusting for other factors, palliative care was associated with a cost reduction of $10,062. CONCLUSIONS: Palliative care consultation for patients with end-stage liver disease increased from 2009 through 2013. Palliative care consultation during terminal hospitalizations is associated with lower costs and procedure burden. Future research should evaluate timing and effects of palliative care on quality of end-of-life care in this population.

Congenital and acquired mandibular asymmetry: Mapping growth and remodeling in 3 dimensions.

INTRODUCTION: Disordered craniofacial development frequently results in definitive facial asymmetries that can significantly impact a person's social and functional well-being. The mandible plays a prominent role in defining facial symmetry and, as an active region of growth, commonly acquires asymmetric features. Additionally, syndromic mandibular asymmetry characterizes craniofacial microsomia (CFM), the second most prevalent congenital craniofacial anomaly (1:3000 to 1:5000 live births) after cleft lip and palate. We hypothesized that asymmetric rates of mandibular growth occur in the context of syndromic and acquired facial asymmetries. METHODS: To test this hypothesis, a spherical harmonic-based shape correspondence algorithm was applied to quantify and characterize asymmetries in mandibular growth and remodeling in 3 groups during adolescence. Longitudinal time points were automatically registered, and regions of the condyle and posterior ramus were selected for growth quantification. The first group (n = 9) had a diagnosis of CFM, limited to Pruzansky-Kaban type I or IIA mandibular deformities. The second group (n = 10) consisted of subjects with asymmetric, nonsyndromic dentofacial asymmetry requiring surgical intervention. A control group (n = 10) of symmetric patients was selected for comparison. A linear mixed model was used for the statistical comparison of growth asymmetry between the groups. RESULTS: Initial mandibular shape and symmetry displayed distinct signatures in the 3 groups (P <0.001), with the greatest asymmetries in the condyle and ramus. Similarly, mandibular growth had unique patterns in the groups. The dentofacial asymmetry group was characterized by significant asymmetry in condylar and posterior ramal remodeling with growth (P <0.001). The CFM group was characterized by asymmetric growth of the posterior ramus (P <0.001) but relatively symmetric growth of the condyles (P = 0.47). CONCLUSIONS: Forms of CFM are characterized by active and variable growth of the dysplastic side, which has a distinct pattern from other disorders of mandibular growth.