Awake versus Asleep Anesthesia in Deep Brain Stimulation Surgery for Parkinson's Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Deep brain stimulation (DBS) is a well-established surgical therapy for patients with Parkinsons' Disease (PD). Traditionally, DBS surgery for PD is performed under local anesthesia, whereby the patient is awake to facilitate intraoperative neurophysiological confirmation of the intended target using microelectrode recordings. General anesthesia allows for improved patient comfort without sacrificing anatomic precision and clinical outcomes. METHODS: We performed a systemic review and meta-analysis on patients undergoing DBS for PD. Published randomized controlled trials, prospective and retrospective studies, and case series which compared asleep and awake techniques for patients undergoing DBS for PD were included. A total of 19 studies and 1,900 patients were included in the analysis. RESULTS: We analyzed the (i) clinical effectiveness - postoperative UPDRS III score, levodopa equivalent daily doses and DBS stimulation requirements. (ii) Surgical and anesthesia related complications, number of lead insertions and operative time (iii) patient's quality of life, mood and cognitive measures using PDQ-39, MDRS, and MMSE scores. There was no significant difference in results between the awake and asleep groups, other than for operative time, for which there was significant heterogeneity. CONCLUSION: With the advent of newer technology, there is likely to have narrowing differences in outcomes between awake or asleep DBS. What would therefore be more important would be to consider the patient's comfort and clinical status as well as the operative team's familiarity with the procedure to ensure seamless transition and care.

Exposure Among Middle and High School Students to Warning Labels on E-Cigarette Packages Before and After an FDA Requirement, 2018-2019.

Introduction: Beginning August 10, 2018, a US Food and Drug Administration (FDA) rule required all e-cigarette packages to have a health warning. We examined exposure among middle and high school students to e-cigarette warnings before and after the compliance date of the FDA's deeming rule, a rule allowing the FDA to regulate e-cigarettes, cigars, and other products. Methods: We analyzed data from middle and high school students participating in the 2018 and 2019 National Youth Tobacco Survey. We generated weighted prevalence estimates for any exposure ("rarely," "sometimes," "most of the time," or "always") and high exposure ("most of the time" or "always") to warnings. We used independent 2-sided t tests to examine differences in exposure between 2018 and 2019 and χ2 tests to examine differences in any exposure and high exposure by demographic characteristics and tobacco use behaviors in 2019. Analyses excluded respondents who reported they had not seen an e-cigarette package. Results: In 2019, 68.0% (vs 67.7% in 2018) of students reported any past 30-day exposure to e-cigarette warning labels and 35.0% (vs 28.7% in 2018) reported high exposure; we observed differences in the proportion of students reporting any and high exposure to warning labels across demographic characteristics and tobacco use behaviors. From 2018 to 2019, report of any and high exposure to e-cigarette warning labels increased among students who currently used any tobacco product and e-cigarettes. We observed increases in high exposure to e-cigarette warning labels overall, and among male students, female students, non-Hispanic White students, and middle and high school students. Conclusion: After implementation of the health warnings per the FDA's deeming rule, the percentage of current tobacco users and e-cigarette users among middle and high school students who reported any and high exposure to e-cigarette warning labels increased. Continued monitoring of reactions can inform if warnings are achieving their regulatory goal.

Receipt and use of prohibited free samples of tobacco products among US adults who use cigarettes, cigars and smokeless tobacco, 2020.

OBJECTIVES: In the USA, tobacco product free samples (FS) are prohibited, except for smokeless tobacco samples distributed under certain conditions in qualified adult-only facilities. We examined prevalence and frequency of FS receipt among adults who use tobacco, channels of FS distribution and the potential effect of FS use on subsequent product purchase. METHODS: From 15 April through 12 July 2020, a total of 1989 adult participants in the National Panel of Tobacco Consumer Studies completed a mixed-mode survey on receipt and use of FS of cigarettes, cigars, smokeless tobacco, e-cigarettes and hookah tobacco. We estimated weighted proportions, population totals and 95% CIs. We used χ2 tests to assess differences between FS recipients and non-recipients. RESULTS: An estimated 11.0% of US adults who use tobacco received an FS in 2020. Similar proportions received FS of cigarettes (3.8%), cigars (3.3%), smokeless tobacco (3.2%) and e-cigarettes (2.7%). Approximately 60.0% of FS recipients used it, and 68.1% of those who used FS said they were likely to purchase the product. More than half (54.2%) received FS on two or more occasions in the past 12 months, most commonly at retail outlets and tobacco specialty stores. CONCLUSIONS: While prevalence of adults who use tobacco receiving FS is relatively low, findings indicate that FS distribution continues to occur for cigarettes, cigars, smokeless tobacco and e-cigarettes, though in-person FS of smokeless tobacco may be legally distributed under certain conditions in qualified adult-only facilities. Findings suggest that FS are often used by recipients, which can affect future purchase decisions.

Closure intracranial pressure is an objective intraoperative determinant of the adequacy of surgical decompression in traumatic acute subdural haematoma: a multicentre observational study.

PURPOSE: Acute subdural haematoma (ASDH) is associated with severe traumatic brain injury and poor outcomes. Although guidelines exist for the decompression of ASDH, the question of adequate decompression remains unanswered. The authors examined the relationship of intracranial pressure (ICP) on closure with outcomes to determine its utility in the determination of adequate ASDH decompression. METHODS: A multicentre retrospective review of 105 consecutive patients with ASDH who underwent decompressive surgery was performed. Receiver operating characteristic (ROC) analysis with internal validation was performed to determine an ICP threshold for the division of patients into the inadequate and good ICP groups. Multivariable analyses were performed for both inpatient and long-term outcomes. RESULTS: An ICP threshold of 10 mmHg was identified with a 91.5% specificity, 45.7% sensitivity, and a positive and negative predictive value of 80.8% and 68.4%. There were 26 patients (24.8%) and 79 patients (75.2%) in the inadequate and good ICP groups, respectively. After adjustment, the inadequate ICP group was associated with increased postoperative usage of mannitol (OR 14.2, p < 0.001) and barbiturates (OR 150, p = 0.001). Inadequate ICP was also associated with increased inpatient mortality (OR 24.9, p < 0.001), and a lower rate of favourable MRS at 1 year (OR 0.08, p = 0.008). The complication rate was similar amongst the groups. CONCLUSIONS: Closure ICP is a novel, objective, and actionable intraoperative biomarker that correlates with inpatient and long-term outcomes in ASDH. Various surgical manoeuvres can be undertaken to achieve this target safely. Large-scale prospective studies should be performed to validate this ICP threshold.

Adoption, Sustainability, and Dissemination of Chronic Disease Prevention Policies in Community-Based Organizations.

Introduction. Despite increasing interest in structural (policy, systems, and environmental) changes to improve health, little attention has focused on the adoption, implementation, sustainability, and potential for dissemination of these changes among local community-based organizations. Method. A mixed methods approach was used for this process evaluation. Representatives of nine community-based organizations were surveyed using closed-ended questions and in-depth qualitative interviews to describe 32 policy changes. Diffusion of Innovation theory was used to inform the development of survey questions and the interview guide. Results. Policies adopted by local community-based organizations concerned types of food/beverages provided to staff/clients, methods to encourage physical activity, breastfeeding support, and tobacco control. The majority of the policies were either fully (66%) or partially (31%) implemented 1 year after their initial adoption. In general, participants somewhat/strongly agreed that policies had characteristics that predict sustainability/diffusion (relative advantage, compatibility, complexity, trialability, observability). In-depth interview responses described a generally smooth process for policy adoption and high levels of optimism for continued sustainability but revealed few efforts to disseminate the policies beyond the original organization. Conclusions. Structural changes in community-based organizations are a valuable tool for encouraging healthy changes in communities and have great potential to be adopted, sustained, and diffused.

Flavored Tobacco Product Use Among Middle and High School Students - United States, 2014-2018.

The 2009 Family Smoking Prevention and Tobacco Control Act prohibits the inclusion of characterizing flavors (e.g., candy or fruit) other than tobacco and menthol in cigarettes; however, characterizing flavors are not currently prohibited in other tobacco products at the federal level.* Flavored tobacco products can appeal to youths and young adults and influence initiation and establishment of tobacco-use patterns (1). The Food and Drug Administration (FDA) and CDC analyzed data from the 2014-2018 National Youth Tobacco Surveys (NYTS) to determine prevalence of current (past 30-day) use of flavored tobacco products, including electronic cigarettes (e-cigarettes), hookah tobacco, cigars, pipe tobacco, smokeless tobacco, bidis, and menthol cigarettes among U.S. middle school (grades 6-8) and high school (grades 9-12) students. In 2018, an estimated 3.15 million (64.1%) youth tobacco product users currently used one or more flavored tobacco products, compared with 3.26 million (70.0%) in 2014. Despite this overall decrease in use of flavored tobacco products, current use of flavored e-cigarettes increased among high school students during 2014-2018; among middle school students, current use of flavored e-cigarettes increased during 2015-2018, following a decrease during 2014-2015. During 2014-2018, current use of flavored hookah tobacco decreased among middle and high school students; current use of flavored smokeless tobacco, cigars, pipe tobacco, and menthol cigarettes decreased among high school students. Full implementation of comprehensive tobacco prevention and control strategies, coupled with regulation of tobacco products by FDA, can help prevent and reduce use of tobacco products, including flavored tobacco products, among U.S. youths (2,3).

Obesity Prevention Practices and Policies in Child Care Settings Enrolled and Not Enrolled in the Child and Adult Care Food Program.

Objectives The United States Department of Agriculture's Child and Adult Care Food Program (CACFP) provides meals and snacks to low-income children in child care. This study compared nutrition and physical activity practices and policies as well as the overall nutrition and physical activity environments in a sample of CACFP and non-CACFP child care settings. Methods A random stratified sample of 350 child care settings in a large Midwestern city and its suburbs, was mailed a survey on obesity prevention practices and policies concerning menu offerings, feeding practices, nutrition and physical activity education, activity levels, training, and screen time. Completed surveys were obtained from 229 of 309 eligible child care settings (74.1 % response rate). Chi square tests were used to compare practices and policies in CACFP and non-CACFP sites. Poisson and negative binomial regression were used to examine associations between CACFP and total number of practices and policies. Results Sixty-nine percent of child care settings reported CACFP participation. A significantly higher proportion of CACFP sites reported offering whole grain foods daily and that providers always eat the same foods that are offered to the children. CACFP sites had 1.1 times as many supportive nutrition practices as non-CACFP sites. CACFP participation was not associated with written policies or physical activity practices. Conclusions for Practice There is room for improvement across nutrition and physical activity practices and policies. In addition to food reimbursement, CACFP participation may help promote child care environments that support healthy nutrition; however, additional training and education outreach activities may be needed.

Risk perceptions of smokeless tobacco among adolescent and adult users and nonusers.

The recent growth in smokeless tobacco (ST) consumption has raised questions about consumer risk perceptions of ST products, especially in high-risk vulnerable populations. This qualitative study examined risk perceptions of ST among adolescent and adult users and nonusers in Ohio Appalachia. Focus groups and interviews were held with adolescents (n = 53; M age = 17 years) and adults (n = 63; M age = 34 years) from four Ohio Appalachian counties. Participants were asked about their perceptions of ST-related health risks, ST safety, and the relative safety of ST compared with cigarettes. Transcriptions were coded independently by two individuals. Overall, participants were knowledgeable about health problems from ST use (e.g., oral cancers, periodontal disease). Nearly all participants stated that ST use is not safe; however, there was disagreement about its relative safety. Some perceived all tobacco products as equally harmful; others believed that ST is safer than cigarettes for either the user or those around the user. Disagreements about ST relative safety may reflect mixed public health messages concerning the safety of ST. Comprehensive consumer messages about the relative safety of ST compared with cigarettes are needed. Messages should address the effect of ST on the health of the user as well as those exposed to the user.

Adolescent and adult perceptions of traditional and novel smokeless tobacco products and packaging in rural Ohio.

OBJECTIVE: As smokeless tobacco (ST) marketing increases and new products emerge on the market, very little is known about consumer perceptions of ST products. To inform development of future ST counter-marketing approaches, this qualitative study examined consumer perceptions of traditional and novel ST products and packaging. METHODS: Focus groups and qualitative interviews were held with adolescent (n=23; mean age of 17 years) and adult (n=38; mean age of 29 years) male ST users from rural Ohio counties. Participants were shown a variety of traditional (eg, Copenhagen, Timber Wolf) and novel (eg, Camel Snus, Orbs) ST products and asked about perceptions of these products and their packaging. Transcriptions were coded independently for common themes by two individuals. FINDINGS: Adolescents and adults generally had similar beliefs and reactions about ST products. While participants were familiar with a variety of traditional ST products, Copenhagen was the most frequently used product. Perceptions of quality and price of traditional products were closely tied to product taste and packaging material. Colours, design and size of ST packaging appealed to participants and influenced decisions to purchase. Adults believed novel ST products had a weak taste and were targeted at untraditional ST users. While the vast majority was unfamiliar with dissolvable tobacco, adolescents noted that they would be more convenient to use during school than traditional ST. CONCLUSIONS: Packaging has a significant role in shaping perceptions of ST and consumer behaviour. Regulation of product packaging such as shape, size and images should be part of comprehensive tobacco control.

Comprehensive smoke-free policies: a tool for improving preconception health?

Lower income women are at higher risk for preconception and prenatal smoking, are less likely to spontaneously quit smoking during pregnancy, and have higher prenatal relapse rates than women in higher income groups. Policies prohibiting tobacco smoking in public places are intended to reduce exposure to secondhand smoke; additionally, since these policies promote a smoke-free norm, there have been associations between smoke-free policies and reduced smoking prevalence. Given the public health burden of smoking, particularly among women who become pregnant, our objective was to assess the impact of smoke-free policies on the odds of preconception smoking among low-income women. We estimated the odds of preconception smoking among low-income women in Ohio between 2002 and 2009 using data from repeated cross-sectional samples of women participating in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). A logistic spline regression was applied fitting a knot at the point of enforcement of the Ohio Smoke-free Workplace Act to evaluate whether this policy was associated with changes in the odds of smoking. After adjusting for individual- and environmental-level factors, the Ohio Smoke-free Workplace Act was associated with a small, but statistically significant reduction in the odds of preconception smoking in WIC participants. Comprehensive smoke-free policies prohibiting smoking in public places and workplaces may also be associated with reductions in smoking among low-income women. This type of policy or environmental change strategy may promote a tobacco-free norm and improve preconception health among a population at risk for smoking.

Bone marrow adipogenic lineage precursors are the major regulator of bone resorption in adult mice.

Bone resorption by osteoclasts is a critical step in bone remodeling, a process important for maintaining bone homeostasis and repairing injured bone. We previously identified a bone marrow mesenchymal subpopulation, marrow adipogenic lineage precursors (MALPs), and showed that its production of RANKL stimulates bone resorption in young mice using Adipoq-Cre. To exclude developmental defects and to investigate the role of MALPs-derived RANKL in adult bone, we generated inducible reporter mice (Adipoq-CreER Tomato) and RANKL deficient mice (Adipoq-CreER RANKLflox/flox, iCKO). Single cell-RNA sequencing data analysis, lineage tracing, and in situ hybridization revealed that Adipoq+ cells contain not only MALPs but also late mesenchymal progenitors capable of osteogenic differentiation. However, RANKLmRNA was only detected in MALPs, but not in osteogenic cells. RANKL deficiency in MALPs induced at 3 months of age rapidly increased trabecular bone mass in long bones as well as vertebrae within 1 month due to diminished bone resorption but had no effect on the cortical bone. Ovariectomy (OVX) induced trabecular bone loss at both sites. RANKL depletion either before OVX or at 6 weeks post OVX protected and restored trabecular bone mass. Furthermore, bone healing after drill-hole injury was delayed in iCKO mice. Together, our findings demonstrate that MALPs play a dominant role in controlling trabecular bone resorption and that RANKL from MALPs is essential for trabecular bone turnover in adult bone homeostasis, postmenopausal bone loss, and injury repair.

Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib.

Estimation of low-density lipoprotein cholesterol (LDL-C) using the Friedewald (FR) formula is often inaccurate when triglycerides are elevated or VLDL particle composition is altered. We hypothesized that LDL-C estimation by the FR formula and other measurement methods might also be inaccurate in individuals treated with a cholesteryl ester transfer protein (CETP) inhibitor. An assay comparison study was conducted using pre and posttreatment serum samples from 280 of the 811 patients treated with the CETP inhibitor anacetrapib in the DEFINE study (determining the efficacy and tolerability of CETP inhibition with anacetrapib). After 24 weeks of treatment with anacetrapib, mean LDL-C values by FR formula, Roche direct method (RDM) and Genzyme direct method (GDM) deviated from that measured by the ß-quantification (BQ) reference method by -12.2 ± 7.5, -10.2 ± 6.6, -10.8 ± 8.8 mg/dl, respectively. After treatment with anacetrapib, the FR formula and detergent-based direct methods provided lower LDL-C values than those obtained by the BQ reference method. The bias by the FR formula appeared to be due to an overestimation of VLDL-C by the TG/5 component of the formula. Evaluation of the clinical significance of these findings awaits comprehensive lipid and cardiovascular outcome data from ongoing Phase III clinical studies of anacetrapib.

Safety of anacetrapib in patients with or at high risk for coronary heart disease.

BACKGROUND: Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease or at high risk for coronary heart disease. Eligible patients who were taking a statin and who had an LDL cholesterol level that was consistent with that recommended in guidelines were assigned to receive 100 mg of anacetrapib or placebo daily for 18 months. The primary end points were the percent change from baseline in LDL cholesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and deaths were prospectively adjudicated. RESULTS: A total of 1623 patients underwent randomization. By 24 weeks, the LDL cholesterol level had been reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a reduction from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group (P<0.001)--a 39.8% reduction with anacetrapib beyond that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with an increase from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group (P<0.001)--a 138.1% increase with anacetrapib beyond that seen with placebo. Through 76 weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P = 0.40). The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability (confidence) of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with torcetrapib. CONCLUSIONS: Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an acceptable side-effect profile, and, within the limits of the power of this study, did not result in the adverse cardiovascular effects observed with torcetrapib. (Funded by Merck Research Laboratories; ClinicalTrials.gov number, NCT00685776.).

Management and Outcomes of Pediatric Craniopharyngioma: A 15-Year Experience in Singapore.

BACKGROUND: Craniopharyngiomas arise from the Rathke pouch and account for 1.2%-18.4% of pediatric primary brain tumors. Despite relatively good survival outcomes, patients face long-term morbidity from recurrences, visual impairment, and endocrinopathies, which reduce quality of life. We examined the management of pediatric craniopharyngiomas, their recurrences, and subsequent neuroendocrine sequelae in a tertiary center in South-East Asia. METHODS: A retrospective cohort of 12 paediatric patients (aged ≤18 years) with histologically confirmed diagnosis of craniopharyngioma treated from January 2002 to June 2017 was conducted. Data collected included demographics, clinical presentation, imaging data, treatment details, postoperative sequelae, and outcomes on mortality and recurrence. Survival analysis was conducted using Cox-proportional hazards model. RESULTS: The median follow-up time was 6.60 years (1.9-11.5 years). The mean age was 7.6 years (standard deviation 4.8) and 7 patients (58.3%) were male. The most common presenting symptoms were raised intracranial pressure (7, 58.3%), visual deficits (6, 50.0%), and preoperative endocrine abnormalities (2, 16.7%). Five patients underwent gross total resection (41.7%), and 7 underwent subtotal resection (58.3%). Overall survival was 75.0% (9 patients), and recurrence was 58.0% (7 patients). Median time-to-recurrence was 5.87 months (0.23-33.7, interquartile range 15.8), and median progression-free survival was 4.16 years (0.18-10.1, interquartile range 5.29). CONCLUSIONS: Long-term management of pediatric craniopharyngioma remains difficult, with multiple recurrences and long-term neuroendocrine sequelae impairing quality of life for patients. Further research into management of recurrences and neuroendocrine sequelae, as well as novel therapies to improve outcomes in these patients, may be warranted.

Factors influencing smokeless tobacco use in rural Ohio Appalachia.

The burden of smokeless tobacco (ST) use disproportionally impacts males in rural Ohio Appalachia. The purpose of this study was to describe the cultural factors contributing to this disparity and to articulate the way in which culture, through interpersonal factors (i.e. social norms and social networks) and community factors (i.e. marketing and availability), impacts ST initiation and use of ST among boys and men in Ohio Appalachia. Fifteen focus groups and 23 individual qualitative interviews were conducted with adult (n = 63) and adolescent (n = 53) residents in Ohio Appalachian counties to ascertain factors associated with ST use and the impact of ST marketing. Transcriptions were independently coded according to questions and themes. ST use appears to be a rite of passage in the development of masculine identity in Ohio Appalachian culture. Interpersonal factors had the greatest influence on initiation and continued use of ST. Ohio Appalachian boys either emulated current ST users or were actively encouraged to use ST through male family and peer networks. Users perceived their acceptance into the male social network as predicated on ST use. Community factors, including ST advertisement and access to ST, reinforced and normalized underlying cultural values. In addition to policy aimed at reducing tobacco marketing and access, interventions designed to reduce ST use in Ohio Appalachia should incorporate efforts to (1) shift the perception of cultural norms regarding ST use and (2) address male social networks as vehicles in ST initiation.

Trends and characteristics of ocular exposures related to e-cigarettes and e-liquids reported to Poison Control Centers in the United States, 2010-2019.

INTRODUCTION: Ocular injuries and unintended exposures involving electronic nicotine delivery systems (ENDS), also known as e-cigarettes, have been reported. However, trends and characteristics of ENDS-related ocular exposures at the population level are not well documented. This study was designed to describe trends and characteristics of ENDS-related ocular exposure cases reported to poison control centers (PCCs) in the U.S. METHODS: We computed descriptive statistics of ENDS-related ocular exposure cases reported to PCCs between January 1, 2010 and December 31, 2019, including number of cases per year and the distribution of characteristics of those cases. We also summarized case narrative review findings. RESULTS: A total of 1,393 ENDS-related ocular exposure cases were reported to PCCs during the study period. Overall number of cases increased from two in 2010 to a peak of 389 in 2014, followed by a steady decline in 2015-2018. Of the 1,393 cases, 42.5% occurred among individuals aged 25 years and older; 20.4 and 17.7% occurred among young adults aged 18-24 years and children younger than five years, respectively. Nearly one quarter (23.8%) of the individuals experiencing ocular exposure sought or were recommended to seek medical attention. Case narrative review found that 59 of 127 (46.5%) cases were due, at least in part, to incorrect use or handling of the products. DISCUSSION AND CONCLUSIONS: Our study shows that more than 1,000 ENDS-related ocular exposure cases were reported to PCCs during the study period. Many of these cases involved young children; nearly half were due, at least in part, to incorrect use or handling of the products. Future efforts to prevent these exposures may focus on improving the awareness of the potential harmful effects of ENDS products and the importance of appropriate handling of ENDS products. Health care professionals may play an important role in educating patients and improving surveillance of ENDS-related ocular exposure cases.

Development and validation of an LC-MS/MS method for determination of a novel anticancer agent (CPI-613) in human plasma.

Background: This article describes the development and validation of a bioanalytical assay to quantify CPI-613 and its major metabolites, CPI-2850 and CPI-1810, in human plasma matrix using LC-MS/MS. Methodology: Sample extraction procedure following protein precipitation with acetonitrile was optimized to extract all three analytes from plasma with maximum recovery. The final extracted supernatants were diluted with water and injected onto an Xbridge C18 (50 × 2.1 mm; 5 µm) column for analysis. The analytes were separated by a gradient elution, and detection was performed on a triple quadrupole mass spectrometer (Sciex API 5000) operating in the negative ion mode. Results: The assay was linear over a range of 50-50,000 ng/ml for CPI-613, 250-250,000 ng/ml for CPI-2850 and 10-10,000 ng/ml for CPI-1810. Benchtop stability was established for 24 h, and four freeze-thaw cycles were evaluated for CPI-613 and its metabolites. Long-term freezer (-60 to -80°C) stability for about 127 days was established in this validation. Mean matrix recovery was more than 80% for all analytes. Conclusion: A robust LC-MS/MS method was developed for the quantification of CPI-613 and its major metabolites. The current assay will be used to support ongoing and future CPI-613 clinical trials.

To achieve the pharmacokinetic objectives of clinical trials, it was necessary to determine the concentrations of CPI-613 and its metabolites in human plasma samples. In this article, the authors describe the development and validation of a highly sensitive and selective LC-MS/MS assay method for the simultaneous quantification of CPI-613 and its major metabolites, CPI-2850 and CPI-1810, in human plasma. Concentration ranges were selected based on previous data where CPI-613 was detected using the HPLC method (rather than LC-MS/MS).

Electronic Nicotine Delivery System (ENDS) Device Types and Flavors Used by Youth in the PATH Study, 2016-2019.

The evolving electronic nicotine delivery system (ENDS) marketplace and recent regulatory actions may influence youth ENDS device preferences. Using data from Waves (W) 4, 4.5, and 5 (2016-2019) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study, this study estimated the prevalence of open and closed system primary ENDS use by youth (12-17 years) current (past 30-day) ENDS users, and compared demographics, tobacco use characteristics, and patterns of ENDS use, including flavors, by device type. Among current ENDS users, closed system use was significantly higher than open system use in W4.5 (68.3% vs. 31.7%) and W5 (60.5% vs. 39.5%). In W5, closed system users were more likely to have a regular ENDS brand, believe their ENDS had nicotine, and use tobacco and mint or menthol flavors in the past 30 days compared to open system users. In W5, users of closed systems were less likely to use fruit, non-alcoholic drink, and candy, desserts, or other sweets flavors in the past 30 days than users of open systems. Youth were more likely to use closed over open system ENDS in 2017-2019. Differences were observed between device types, particularly with flavor use, reflecting recent changes in flavored product availability.

Development of a panel of U.S. adult tobacco users to inform tobacco regulatory science.

The National Panel of Tobacco Consumer Studies (TCS Panel) is a probability-based panel of about 4,000 U.S. adult cigarette, cigar, and smokeless tobacco users developed by the U.S. Food and Drug Administration's Center for Tobacco Products to conduct observational and experimental studies to inform tobacco regulatory activities. This paper describes the methods and characteristics of the current panel. The TCS Panel employed a stratified 4-stage sample design and in-person screening of U.S. sampled households. Selected eligible adults participated in an enrollment interview and completed a baseline survey assessing tobacco use behaviors to enroll in the Panel; 3,893 individuals were enrolled from September 2016-August 2017. Replenishment occurred from July 2019-December 2019 with 2,260 new members, for a current panel of 3,929 members. Demographic and tobacco use characteristics of the current panel were analyzed in 2020. Most demographic characteristics of the TCS Panel are similar to those of U.S. tobacco users in the 2018 National Health Interview Survey, suggesting a lack of systematic bias in the Panel. Small, but statistically significant, differences were observed in the proportion of 18- to 25-year-olds; high school diploma and bachelor's degree/higher; never married and married (p < 0.05 for all). The TCS Panel appears to be representative of U.S. cigarette, cigar, and smokeless tobacco users; such panels can be a feasible method for conducting tobacco regulatory science research. The TCS Panel has been used to field studies examining purchasing behaviors, receipt and use of free samples/coupons, and the impact of a hypothetical tobacco product standard.

Intracranial Pressure as an Objective Biomarker of Decompression Adequacy in Large Territory Infarction: A Multicenter Observational Study.

Background: Decompressive craniectomy (DC) improves the survival and functional outcomes in patients with malignant cerebral infarction. Currently, there are no objective intraoperative markers that indicates adequate decompression. We hypothesise that closure intracranial pressure (ICP) correlates with postoperative outcomes. Methods: This is a multicentre retrospective review of all 75 DCs performed for malignant cerebral infarction. The patients were divided into inadequate ICP (iICP) and good ICP (gICP) groups based on a suitable ICP threshold determined with tiered receiver operating characteristic and association analysis. Multivariable logistic regression was performed for various postoperative outcomes. Results: An ICP threshold of 7 mmHg was determined, with 36 patients (48.0%) and 39 patients (52.0%) in the iICP and gICP group, respectively. After adjustment, postoperative osmotherapy usage was more likely in the iICP group (OR 6.32, p = 0.003), and when given, was given for a longer median duration (iICP, 4 days; gICP, 1 day, p = 0.003). There was no difference in complications amongst both groups. When an ICP threshold of 11 mmHg was applied, there was significant difference in the duration on ventilator (ICP ≥11 mmHg, 3-9 days, ICP <11 mmHg, 3-5 days, p = 0.023). Conclusion: Surgical decompression works complementarily with postoperative medical therapy to manage progressive cerebral edema in malignant cerebral infarctions. This is a retrospective study which showed that closure ICP, a novel objective intraoperative biomarker, is able to guide the adequacy of DC in this condition. Various surgical manoeuvres can be performed to ensure that this surgical aim is accomplished.