Effect of dynamic exclusion and the use of FAIMS, DIA and MALDI-mass spectrometry imaging with ion mobility on amyloid protein identification.

Amyloidosis is a disease characterized by local and systemic extracellular deposition of amyloid protein fibrils where its excessive accumulation in tissues and resistance to degradation can lead to organ failure. Diagnosis is challenging because of approximately 36 different amyloid protein subtypes. Imaging methods like immunohistochemistry and the use of Congo red staining of amyloid proteins for laser capture microdissection combined with liquid chromatography tandem mass spectrometry (LMD/LC-MS/MS) are two diagnostic methods currently used depending on the expertise of the pathology laboratory. Here, we demonstrate a streamlined in situ amyloid peptide spatial mapping by Matrix Assisted Laser Desorption Ionization-Mass Spectrometry Imaging (MALDI-MSI) combined with Trapped Ion Mobility Spectrometry for potential transthyretin (ATTR) amyloidosis subtyping. While we utilized the standard LMD/LC-MS/MS workflow for amyloid subtyping of 31 specimens from different organs, we also evaluated the potential introduction in the MS workflow variations in data acquisition parameters like dynamic exclusion, or testing Data Dependent Acquisition combined with High-Field Asymmetric Waveform Ion Mobility Spectrometry (DDA FAIMS) versus Data Independent Acquisition (DIA) for enhanced amyloid protein identification at shorter acquisition times. We also demonstrate the use of Mascot's Error Tolerant Search and PEAKS de novo sequencing for the sequence variant analysis of amyloidosis specimens.

Do sociodemographic risk profiles for adolescents engaging in weekly e-cigarette, cigarette, and dual product use differ?

BACKGROUND: E-cigarette use represents a contemporary mode of nicotine product use that may be changing the risk profile of participating adolescents. Understanding differences in sociodemographic characteristics of adolescents engaging in contemporary e-cigarette use and traditional cigarette use is important for effectively developing and targeting public health intervention programs. The objective of this study was to identify and compare sociodemographic risk profiles for exclusive e-cigarette use and dual-product use among a large sample of Canadian youth. METHODS: A survey of 46,666 secondary school students in the 2021-22 wave of the COMPASS study measured frequency of past month e-cigarette and cigarette use as well as age, sex, gender, racial or ethnic background, spending money, relative family affluence, and having one's own bedroom. Rates of cigarette-only, e-cigarette-only, and dual product use were calculated, and separate classification trees were run using the CART algorithm to identify sociodemographic risk profiles for weekly dual-product use and weekly e-cigarette-only use. RESULTS: Over 13% of adolescents used only e-cigarettes at least weekly, 3% engaged in weekly dual e-cigarette and cigarette use, and less than 0.5% used only cigarettes. Available spending money was a common predictor of dual-product and e-cigarette-only use. Gender diverse youth and youth with lower perceived family affluence were at higher risk for dual-product use, while white and multiethnic adolescents were at greater risk of e-cigarette-only use. Two high-risk profiles were identified for e-cigarette-only use and four high-risk profiles were identified for dual product use. CONCLUSIONS: This study used a novel modelling approach (CART) to identify combinations of sociodemographic characteristics that profile high-risk groups for exclusive e-cigarette and dual-product use. Unique risk profiles were identified, suggesting that e-cigarettes are attracting new demographics of adolescents who have not previously been considered as high-risk for traditional cigarette use.

What Is the Optimal Stenting Duration After Ureteroscopy and Stone Intervention? Impact of Dwell Time on Postoperative Emergency Department Visits.

PURPOSE: AUA stone management guidelines recommend stenting duration following ureteroscopy be minimized to reduce morbidity; stents with extraction strings may be used for this purpose. However, an animal study demonstrated that short dwell time results in suboptimal ureteral dilation, and a pilot clinical study showed this increases postprocedure events. Using real-world practice data we examined stent dwell time after ureteroscopy and its association with postoperative emergency department visits. MATERIALS AND METHODS: We used the Michigan Urological Surgery Improvement Collaborative registry to identify ureteroscopy and stenting procedures (2016-2019). Pre-stented cases were excluded. Stenting cohorts with and without strings were analyzed. Using multivariable logistic regression we evaluated the risk of an emergency department visit occurring on the day of, or day after, stent removal based on dwell time and string status. RESULTS: We identified 4,437 procedures; 1,690 (38%) had a string. Median dwell time was lower in patients with a string (5 vs 9 days). Ureteroscopy in younger patients, smaller stones, or renal stone location had a higher frequency of string use. The predicted probability of an emergency department visit was significantly greater in procedures with string, compared to without string, when dwell times were less than 5 days (P < .01) but were not statistically significant after. CONCLUSIONS: Patients who had ureteroscopy and stenting with a string have short dwell times. Patients are at increased risk of a postoperative emergency department visit around the time of stent removal if dwell time is ≤4 days. We recommended stenting duration of at least 5 days in nonpre-stented patients.

Youth Vaping During the Early Stages of the COVID-19 Pandemic Period: Adjusted Annual Changes in Vaping Between the Pre-COVID and Initial COVID-Lockdown Waves of the COMPASS Study.

BACKGROUND: Adolescence is a critical period for vaping onset. The purpose of this article was to examine the effect of the early stages of the COVID-19 pandemic period on youth vaping. METHODS: We used 3-year linked data from the COMPASS study, including 7585 Canadian (Quebec, Ontario) adolescents from which 1949 completed all three survey waves (pre-COVID-19 [2018, 2019] and online [2020] during the early pandemic period [May-July 2020]) and provided vaping data. Structural equation modeling (SEM) and difference-in-difference (DD) models were used to estimate pre-COVID-19 to initial COVID-19 pandemic period change (2019-2020) in vaping (monthly, weekly, daily) compared with 2018-2019 change to adjust for age-related effects. Models were adjusted for age of entry into the cohort and sociodemographic characteristics. RESULTS: In the SEM and DD models, the proportion of youth who were monthly and weekly vaping increased from 2018 to 2019 but decreased from 2019 to 2020; daily vaping increased across all waves. However, for all vaping outcomes modeled, the expected increases from the pre-COVID-19 wave (2019) to the initial COVID-19 period wave (2020) were lesser relative to the changes seen across the 2018 to 2019 waves. CONCLUSION: The early stages of the COVID-19 pandemic period appear to be associated with a reduction in the proportion of youth who were monthly and weekly vapers in our adjusted longitudinal models. While daily vaping increased over this same period of time, the magnitude of the increase in our adjusted longitudinal models appears attenuated by the early stages of the pandemic. IMPLICATIONS: This large prospective study of youth that included pre-pandemic data is unique in that we were able to identify that the early stages of the COVID-19 pandemic period was associated with a reduction in the proportion of youth who were monthly and weekly vapers in our adjusted longitudinal models. Conversely, the proportion of youth who were daily vaping increased over this same period of time, but the magnitude of the increase appears smaller than expected during the early stages of the pandemic in our adjusted longitudinal models. This study provides novel robust evidence that the patterns of vaping most aligned with onset and progression (i.e., monthly and weekly use) appear attenuated during the initial pandemic period.

Precision medicine in chronic obstructive pulmonary disease: how far have we come?

PURPOSE OF REVIEW: In this review, we will discuss the current status and recent developments in precision medicine in chronic obstructive pulmonary disease (COPD) through the lens of treatable traits. RECENT FINDINGS: Although the term 'treatable traits' in the treatment of COPD is relatively recent, this concept has been used for many years if one considers interventions such as long-term oxygen therapy or alpha-1 antitrypsin replacement therapy. Recent advances have included expanding the definition of COPD to include a broader population of people with lower respiratory disease but not meeting the strict criteria for obstruction, advances in imaging to aid in the diagnosis and treatment of COPD, advances in understanding symptoms and exacerbations to define severity, using biomarkers to guide therapy and better understanding and addressing polymorbidity and frailty. In addition, there is a concerted effort to use these concepts to identify COPD patients earlier in the disease process wherein disease modification may be possible. SUMMARY: Focusing on subsets of patients with COPD with certain characteristics should lead to better outcomes and fewer adverse effects from treatment. VIDEO ABSTRACT: http://links.lww.com/COPM/A30.

More support needed: Evaluating the impact of school e-cigarette prevention and cessation programs on e-cigarette initiation among a sample of Canadian secondary school students.

Given the recent increase in e-cigarette use among adolescents, there is a need to further explore how school programs are associated with e-cigarette initiation. The objective of this quasi-experimental study was to evaluate the impact of multiple school-based e-cigarette prevention and cessation programs on e-cigarette initiation among Canadian adolescents. This study used data from Year 6 (2017/18) and Year 7 (2018/19) of the COMPASS study in British Columbia, Alberta, Ontario, and Quebec, Canada. Students in grades 9 to 11 who had never tried e-cigarettes at baseline were included (n = 13,269). Schools (n = 88) reported whether they added programming that addressed e-cigarette or tobacco prevention or cessation. Generalized estimating equations were used to identify how added programs were associated with e-cigarette initiation at follow-up. At one-year follow-up (2018/19), 23% of schools added programs. Our evaluation results suggest that none of the activities taken by schools to prevent or reduce vaping among students significantly prevented vaping onset. In fact, female students at schools that reported adding a theme week had higher odds of e-cigarette initiation (OR 1.68 [95% CI 1.31-2.16]) and male students at schools that reported a cessation program had higher odds of e-cigarette initiation (OR 1.20 [95% CI 1.01-1.44]). These results suggest that schools may not know how to address e-cigarette use and that there can be risks to students if programs are not carefully implemented. Results point to the need for additional support to ensure that schools are taking evidence-based approaches that support all students.

Early adoption of heated tobacco products resembles that of e-cigarettes.

BACKGROUND: Heated tobacco products (HTP) generate nicotine-containing aerosol by heating tobacco rather than burning it. The US Food and Drug Administration (FDA) has recently authorised the sale of one HTP brand, iQOS, in the USA. This study examined the awareness, use and risk perceptions of HTP in the USA following FDA authorisation. METHODS: A national probability sample of 20 449 US adults completed an online survey between November 2019 and February 2020. In addition to assessing awareness and use of HTP, two ratios were calculated: the ratio of those who experimented with HTP given that they had heard about it (E/H) and the ratio of those who currently used HTP given experimentation (C/E). These ratios for HTP were compared against those for e-cigarettes from a similar national survey in 2012. RESULTS: Overall, 8.1% of respondents had heard of HTP. Only 0.55% had tried and 0.10% were current users. The rate of experimentation among those who heard about HTP and the rate of current use among experimenters were, however, similar to those for e-cigarettes in 2012: E/H and C/E for HTP were 6.8% and 18.2%, respectively; and 10.7% and 17.8%, respectively for e-cigarettes. The majority of respondents considered HTP either less harmful than (11.6%), or equally harmful as e-cigarettes (42.7%). CONCLUSIONS: Only a small fraction of US population in 2020 have tried any HTP. However, the similarity in early adoption rates following awareness, suggests that future adoption for HTP may be similar to that for e-cigarettes, if HTP are marketed more aggressively.

Changes in Cannabis Consumption Among Emerging Adults in Relation to Policy and Public Health Developments.

Background: Rates of cannabis use appear to be highest among emerging adults (EA). Evidence suggests that cannabis smoking, as well as alternate methods of cannabis use (e.g., vaping, edibles) have become a prevalent mode of consumption among this population. Substance use or misuse peaks during emerging adulthood and may be influenced by extreme economic, social and community developments, such as policy changes, public health concerns, and significant global events such as pandemics. For instance, it is highly likely that cannabis consumption trends among at-risk populations were influenced by the legalization of recreational cannabis in Canada, the declaration of the "e-cigarette or vaping product use associated lung injury" or "EVALI" outbreak, and the "COVID-19" pandemic. ObjectivesWe aimed to examine self-reported changes in frequency of cannabis use among EA in Canada (N = 312): pre-legalization, post-legalization; pre-EVALI, post-EVALI; pre-COVID-19, since-COVID-19. ResultsThere was a gradual increase in average frequency of smoking and vaping cannabis across the six different time intervals from the pre-legalization period (2018) to the COVID-19 pandemic period (2020). Males reported higher frequencies of cannabis smoking and vaping compared to females. ConclusionsDespite health concerns and expectations that EVALI and COVID-19 events would lead to decreased consumption, our results suggest an average increase in smoking and vaping cannabis, although the most notable increase was after legalization. There are important sex differences in behavioral factors of cannabis use in EA, though it appears that the "gender-gap" in cannabis consumption is closing. These findings may facilitate the development of intervention programs for policy measures to address cannabis-attributable outcomes in the face of contextual factors that promote use, such as public emergencies or changes in policy landscapes.

California School Staff Reports of Seeing Students Vaping at School and Disciplinary Actions.

Youth vaping is a concern and schools may use many approaches to discipline students caught vaping at school. This study identified the prevalence of school staff seeing vaping in schools and the measures used to discipline students. A state-wide sample of 7,938 staff from 255 middle and high schools reported whether they saw any students vaping at school in the last 30 days, whether they have caught any students vaping during class in the last semester, and what happened after catching a student vaping in class. Open-text responses were coded and themes were identified related to disciplinary approaches. 31.9% of staff reported seeing students vaping at school, and 11.9% of teachers reported catching a student vaping during class. Teachers described four categories of disciplinary approaches after catching students vaping in class: no consequences, punitive approaches, restorative approaches, and mixed approaches. Additional support is necessary to help schools address student vaping.

GSK-3ß regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIα.

Deregulation of GSK-3ß is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. To understand how GSK-3ß becomes dysregulated in these conditions, it is important to understand its physiological functions in the central nervous system. In this context, GSK-3ß plays a role in the induction of NMDA receptor-dependent long-term depression (LTD) and several substrates for GSK-3ß have been identified in this form of synaptic plasticity, including KLC-2, PSD-95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK-3ß, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type IIα (PI4KIIα) as a neuronal GSK-3ß substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KIIα in organotypic rat hippocampal slices. We found that knockdown of PI4KIIα has no effect on synaptic AMPA receptor-mediated synaptic transmission but substantially reduces NMDA receptor-mediated synaptic transmission. Furthermore, the ability of the selective GSK-3 inhibitor, CT99021, to reduce the amplitude of NMDA receptor-mediated currents was occluded in shRNA-PI4KIIα transfected neurons. The effects of knocking down PI4KIIα were fully rescued by a shRNA-resistant wild-type construct, but not by a mutant construct that cannot be phosphorylated by GSK-3ß. These data suggest that GSK-3ß phosphorylates PI4KIIα to stabilize NMDA receptors at the synapse.

Infection-related hospitalization following ureteroscopic stone treatment: results from a surgical collaborative.

BACKGROUND: Unplanned hospitalization following ureteroscopy (URS) for urinary stone disease is associated with patient morbidity and increased healthcare costs. To this effect, AUA guidelines recommend at least a urinalysis in patients prior to URS. We examined risk factors for infection-related hospitalization following URS for urinary stones in a surgical collaborative. METHODS: Reducing Operative Complications from Kidney Stones (ROCKS) is a quality improvement (QI) initiative from the Michigan Urological Surgery Improvement Collaborative (MUSIC) consisting of academic and community practices in the State of Michigan. Trained abstractors prospectively record standardized data elements from the health record in a web-based registry including patient characteristics, surgical details and complications. Using the ROCKS registry, we identified all patients undergoing primary URS for urinary stones between June 2016 and October 2017, and determined the proportion hospitalized within 30 days with an infection-related complication. These patients underwent chart review to obtain clinical data related to the hospitalization. Multivariable logistic regression analysis was performed to determine risk factors for hospitalization. RESULTS: 1817 URS procedures from 11 practices were analyzed. 43 (2.4%) patients were hospitalized with an infection-related complication, and the mortality rate was 0.2%. Median time to admission and length of stay was 4 and 3 days, respectively. Nine (20.9%) patients did not have a pre-procedure urinalysis or urine culture, which was not different in the non-hospitalized cohort (20.5%). In hospitalized patients, pathogens included gram-negative (61.5%), gram-positive (19.2%), yeast (15.4%), and mixed (3.8%) organisms. Significant factors associated with infection-related hospitalization included higher Charlson comorbidity index, history of recurrent UTI, stone size, intra-operative complication, and procedures where fragments were left in-situ. CONCLUSIONS: One in 40 patients are hospitalized with an infection-related complication following URS. Awareness of risk factors may allow for individualized counselling and management to reduce these events. Approximately 20% of patients did not have a pre-operative urine analysis or culture, and these findings demonstrate the need for further study to improve urine testing and compliance.

Exploring the Predictive Validity of the Susceptibility to Smoking Construct for Tobacco Cigarettes, Alternative Tobacco Products, and E-Cigarettes.

INTRODUCTION: Within tobacco prevention programming, it is useful to identify youth that are at risk for experimenting with various tobacco products and e-cigarettes. The susceptibility to smoking construct is a simple method to identify never-smoking students that are less committed to remaining smoke-free. However, the predictive validity of this construct has not been tested within the Canadian context or for the use of other tobacco products and e-cigarettes. METHODS: This study used a large, longitudinal sample of secondary school students that reported never using tobacco cigarettes and noncurrent use of alternative tobacco products or e-cigarettes at baseline in Ontario, Canada. The sensitivity, specificity, and positive and negative predictive values of the susceptibility construct for predicting tobacco cigarette, e-cigarette, cigarillo or little cigar, cigar, hookah, and smokeless tobacco use 1 and 2 years after baseline measurement were calculated. RESULTS: At baseline, 29.4% of the sample was susceptible to future tobacco product or e-cigarette use. The sensitivity of the construct ranged from 43.2% (smokeless tobacco) to 59.5% (tobacco cigarettes), the specificity ranged from 70.9% (smokeless tobacco) to 75.9% (tobacco cigarettes), and the positive predictive value ranged from 2.6% (smokeless tobacco) to 32.2% (tobacco cigarettes). Similar values were calculated for each measure of the susceptibility construct. CONCLUSIONS: A significant number of youth that did not currently use tobacco products or e-cigarettes at baseline reported using tobacco products and e-cigarettes over a 2-year follow-up period. The predictive validity of the susceptibility construct was high and the construct can be used to predict other tobacco product and e-cigarette use among youth. IMPLICATIONS: This study presents the predictive validity of the susceptibility construct for the use of tobacco cigarettes among secondary school students in Ontario, Canada. It also presents a novel use of the susceptibility construct for predicting the use of e-cigarettes, cigarillos or little cigars, cigars, hookah, and smokeless tobacco among secondary school students in Ontario, Canada.

Natural History and Predictors of Parastomal Hernia after Robot-Assisted Radical Cystectomy and Ileal Conduit Urinary Diversion.

PURPOSE: We investigated the prevalence of and variables associated with parastomal hernia and its outcomes after robot-assisted radical cystectomy and ileal conduit creation for bladder cancer. MATERIALS AND METHODS: We retrospectively reviewed the records of patients who underwent robot-assisted radical cystectomy at our institution. Parastomal hernia was defined as the protrusion of abdominal contents through the stomal defect in the abdominal wall on cross-sectional imaging. Parastomal hernia was further described in terms of patient and hernia characteristics, symptoms, management and outcomes. The Kaplan-Meier method was used to determine time to parastomal hernia and time to surgery. Multivariate stepwise logistic regression was done to evaluate variables associated with parastomal hernia. RESULTS: A total of 383 patients underwent robot-assisted radical cystectomy and ileal conduit creation. Of the patients 75 (20%) had parastomal hernia, which was symptomatic in 23 (31%), and 11 (15%) underwent treatment. Median time to parastomal hernia was 13 months (IQR 9-22). Parastomal hernia developed in 9%, 23% and 32% of cases at 1, 2 and 3 years, respectively. Patients with parastomal hernia had a significantly higher body mass index (30 vs 28 kg/m2, p = 0.02), longer overall operative time (357 vs 340 minutes, p = 0.01) and greater blood loss (325 vs 250 ml, p = 0.04). On multivariate analysis operative time (OR 1.25, 95% CI 1.21-3.90, p <0.001), a fascial defect 30 mm or greater (OR 5.23, 95% CI 2.32-11.8, p <0.001) and a lower postoperative estimated glomerular filtration rate (OR 2.17, 95% CI 1.21-3.90, p = 0.01) were significantly associated with parastomal hernia. CONCLUSIONS: Symptoms develop in approximately a third of patients with parastomal hernia and 15% will require surgery. The risk of parastomal hernia plateaued after postoperative year 3. Longer operative time, a larger fascial defect and lower postoperative kidney function were associated with parastomal hernia.

Variability and interpretation of communication taxonomy during robot-assisted surgery: do we all speak the same language?

OBJECTIVE: To investigate and analyse the different ways surgeons communicate with bedside assistants during robot-assisted surgery (RAS). METHODS: We retrospectively reviewed video and audio recordings of 26 RAS procedures (23 prostatectomies and three cystectomies). Three cameras and eight lapel microphones were used to record the operating theatre environment. We identified five common tasks and categorized them into 'specific', 'non-specific' and 'unclear' categories. We also determined the frequency, time to execute the task, inconveniences and acknowledgements associated with each category. The most efficient category was the one that took the shortest duration to accomplish and was associated with the fewest inconveniences. RESULTS: A total of 1 000 requests were made by three surgeons for six bedside assistants by three surgeons. The five identified tasks were: instrument change; clipping; suction; irrigation; and retraction. For instrument change, non-specific requests were the most frequent compared with the other categories (77% vs 18% vs 5%; P < 0.001). For suction, specific requests were the most frequently used of the three categories (73% vs 27% vs 0%; P < 0.001) and this task was associated with the fewest inconveniences (38% vs 62%; P = 0.01). For clipping, irrigation and retraction, both specific and non-specific requests were similar in terms of their frequency, action time and inconveniences. Comparing complete vs incomplete requests, incomplete requests had significantly shorter median action time (5 vs 8 s; P < 0.001) but did not significantly differ in terms of inconveniences and acknowledgement. CONCLUSION: To our knowledge, this is the first study to provide a detailed analysis of communication during RAS. It lays a foundation for standardized taxonomy to improve communication, surgical efficiency and patient safety.

Undiagnosed HIV and HCV Infection in a New York City Emergency Department, 2015.

OBJECTIVES: To measure undiagnosed HIV and HCV in a New York City emergency department (ED). METHODS: We conducted a blinded cross-sectional serosurvey with remnant serum from specimens originally drawn for clinical indications in the ED. Serum was deduplicated and matched to (1) the hospital's electronic medical record and (2) the New York City HIV and HCV surveillance registries for evidence of previous diagnosis before being deidentified and tested for HIV and HCV. RESULTS: The overall prevalence of HIV was 5.0% (250/4990; 95% confidence interval [CI] = 4.4%, 5.7%); the prevalence of undiagnosed HIV was 0.2% (12/4990; 95% CI = 0.1%, 0.4%); and the proportion of undiagnosed HIV was 4.8% (12/250; 95% CI = 2.5%, 8.2%). The overall prevalence of HCV (HCV RNA ≥ 15 international units per milliliter) was 3.9% (196/4989; 95% CI = 2.8%, 5.1%); the prevalence of undiagnosed HCV was 0.8% (38/4989; 95% CI = 0.3%, 1.3%); and the proportion of undiagnosed HCV was 19.2% (38/196; 95% CI = 11.4%, 27.0%). CONCLUSIONS: Undiagnosed HCV was more prevalent than undiagnosed HIV in this population, suggesting that aggressive testing initiatives similar to those directed toward HIV should be mounted to improve HCV diagnosis.

From Good to Great: The Role of Performance Coaching in Enhancing Tobacco-Dependence Treatment Rates.

PURPOSE: The purpose of this study was to examine the incremental effect of performance coaching, delivered as part of a multicomponent intervention (Ottawa Model for Smoking Cessation [OMSC]), in increasing rates of tobacco-dependence treatment by primary care clinicians. METHODS: In a cluster-randomized controlled trial, 15 primary care practices were randomly assigned to 1 of the following active-treatment conditions: OMSC or OMSC plus performance coaching (OMSC+). All practices received support to implement the OMSC. In addition, clinicians in the OMSC+ group participated in a 1.5-hour skills-based coaching session and received an individualized performance report. All clinicians and a cross-sectional sample of their patients were surveyed before and 4 months after introduction of the interventions. The primary outcome measure was rates of tobacco-dependence treatment strategy (Ask, Advise, Assist, Arrange) delivery. Secondary outcomes were patient quit attempts and smoking abstinence measured at 6 months' follow-up. RESULTS: Primary care clinicians (166) and patients (1,990) were enrolled in the trial. Clinicians in the OMSC+ group had statistically greater rates of delivery for Ask (adjusted odds ratio [AOR] = 1.69; 95% CI, 1.05-2.72), Assist (AOR = 1.64; 95% CI, 1.08-2.49), and Arrange (AOR = 2.01; 95% CI, 1.22-3.31). Sensitivity analysis found that the rate of delivery for Advise was greater only among those clinicians who attended the coaching session (AOR = 1.65; 95% CI, 1.10-2.49; P = .02). No differences were documented between groups for cessation outcomes. CONCLUSIONS: Performance coaching significantly increased rates of tobacco-dependence treatment by primary care clinicians when delivered as part of a multicomponent intervention.

Electronic cigarette use and smoking initiation among youth: a longitudinal cohort study.

BACKGROUND: The influence of e-cigarette use on smoking initiation is a highly controversial issue, with limited longitudinal data available for examining temporal associations. We examined e-cigarette use and its association with cigarette-smoking initiation at 1-year follow-up within a large cohort of Canadian secondary school students. METHODS: We analyzed data from students in grades 9-12 who participated in 2 waves of COMPASS, a cohort study of purposefully sampled secondary schools in Ontario and Alberta, Canada, at baseline (2013/14) and 1-year follow-up (2014/15). We assessed cigarette smoking and e-cigarette use at baseline and follow-up using self-completed surveys. We used generalized linear mixed-effects models to examine correlates of past 30-day e-cigarette use at baseline and smoking initiation between waves within the longitudinal sample. RESULTS: Past 30-day e-cigarette use increased from 2013/14 to 2014/15 (7.2% v. 9.7%, p < 0.001), whereas past 30-day cigarette smoking decreased slightly (11.4% v. 10.8%, p = 0.02). Among the 44 163 students evaluated at baseline, past 30-day e-cigarette use was strongly associated with smoking status and smoking susceptibility. In the longitudinal sample (n = 19 130), past 30-day use of e-cigarettes at baseline was associated with initiation of smoking a whole cigarette (adjusted odds ratio [OR] 2.12, 95% confidence interval [CI] 1.68-2.66) and with initiation of daily smoking (adjusted OR 1.79, 95% CI 1.41-2.28) at follow-up. INTERPRETATION: E-cigarette use was strongly associated with cigarette smoking behaviour, including smoking initiation at follow-up. The causal nature of this association remains unclear, because common factors underlying the use of both e-cigarettes and conventional cigarettes may also account for the temporal order of initiation.

Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes.

α-Synuclein plays a central causative role in Parkinson's disease (PD). Increased expression of the P-type ATPase ion pump PARK9/ATP13A2 suppresses α-Synuclein toxicity in primary neurons. Our data indicate that ATP13A2 encodes a zinc pump; neurospheres from a compound heterozygous ATP13A2(-/-) patient and ATP13A2 knockdown cells are sensitive to zinc, whereas ATP13A2 over-expression in primary neurons confers zinc resistance. Reduced ATP13A2 expression significantly decreased vesicular zinc levels, indicating ATP13A2 facilitates transport of zinc into membrane-bound compartments or vesicles. Endogenous ATP13A2 localized to multi-vesicular bodies (MVBs), a late endosomal compartment located at the convergence point of the endosomal and autophagic pathways. Dysfunction in MVBs can cause a range of detrimental effects including lysosomal dysfunction and impaired delivery of endocytosed proteins/autophagy cargo to the lysosome, both of which have been observed in cells with reduced ATP13A2 function. MVBs also serve as the source of intra-luminal nanovesicles released extracellularly as exosomes that can contain a range of cargoes including α-Synuclein. Elevated ATP13A2 expression reduced intracellular α-Synuclein levels and increased α-Synuclein externalization in exosomes >3-fold whereas ATP13A2 knockdown decreased α-Synuclein externalization. An increased export of exosome-associated α-Synuclein may explain why surviving neurons of the substantia nigra pars compacta in sporadic PD patients were observed to over-express ATP13A2. We propose ATP13A2's modulation of zinc levels in MVBs can regulate the biogenesis of exosomes capable of containing α-Synuclein. Our data indicate that ATP13A2 is the first PD-associated gene involved in exosome biogenesis and indicates a potential neuroprotective role of exosomes in PD.

Prognostic Value of Percent Gleason Grade 4 at Prostate Biopsy in Predicting Prostatectomy Pathology and Recurrence.

PURPOSE: The importance of primary Gleason grade among men with Gleason score 7 disease has been well-defined. However, this dichotomization may oversimplify the continuous spectrum of absolute percent Gleason grade 4 disease (G4%). In this study we report the prognostic value of G4% in cancer related outcomes of men undergoing radical prostatectomy. MATERIALS AND METHODS: Patients who underwent radical prostatectomy for clinically localized Gleason 6-8 prostate cancer from 2005 to 2013 were included in the study. G4% was determined as biopsy tumor length containing Gleason pattern 4/total tumor length, which performed better than alternative quantifications of pattern 4 involvement. G4% was correlated with time to biochemical recurrence and presence of adverse radical prostatectomy pathology, defined as primary Gleason 4 or pT3 or greater, by multivariable Cox and logistic regressions. RESULTS: Of 1,691 patients 517 (30.6%) had adverse pathological features and 86 (5.6%) experienced biochemical recurrence. On multivariable analyses G4% was a significant predictor of adverse pathology (OR 1.04, 95% CI 1.03-1.05) and time to biochemical recurrence (HR 1.02, CI 1.01-1.03). G4% was also a significant independent predictor of adverse pathology in subsets of patients with Gleason score 7 (OR 1.05, 95% CI 1.03-1.06), 3+4 (OR 1.06, 95% CI 1.04-1.08) and 4+3 cancer (OR 1.05, 95% CI 1.03-1.06). We found a significantly increased risk of adverse pathology at potentially meaningful G4% thresholds (1% to 10% vs 20% to 30%). CONCLUSIONS: The incremental percentage of Gleason grade 4 disease in biopsy specimens is an important predictor of adverse pathology and biochemical recurrence across the entire range of G4% disease. Accounting for G4% can improve risk assessment even among those patients with Gleason 3+4 or 4+3 cancer and may help inform patient counseling.

Independent surgical validation of the new prostate cancer grade-grouping system.

OBJECTIVE: To report the independent prognostic impact of the new prostate cancer grade-grouping system in a large external validation cohort of patients treated with radical prostatectomy (RP). PATIENTS AND METHODS: Between 1994 and 2013, 3 694 consecutive men were treated with RP at a single institution. To investigate the performance of and validate the grade-grouping system, biochemical recurrence-free survival (bRFS) rates were assessed using Kaplan-Meier tests, Cox-regression modelling, and discriminatory comparison analyses. Separate analyses were performed based on biopsy and RP grade. RESULTS: The median follow-up was 52.7 months. The 5-year actuarial bRFS for biopsy grade groups 1-5 were 94.2%, 89.2%, 73.1%, 63.1%, and 54.7%, respectively (P < 0.001). Similarly, the 5-year actuarial bRFS based on RP grade groups was 96.1%, 93.0%, 74.0%, 64.4%, and 49.9% for grade groups 1-5, respectively (P < 0.001). The adjusted hazard ratios for bRFS relative to biopsy grade group 1 were 1.98, 4.20, 5.57, and 9.32 for groups 2, 3, 4, and 5, respectively (P < 0.001), and for RP grade groups were 2.09, 5.27, 5.86, and 10.42 (P < 0.001). The five-grade-group system had a higher prognostic discrimination compared with the commonly used three-tier system (Gleason score 6 vs 7 vs 8-10). CONCLUSIONS: In an independent surgical cohort, we have validated the prognostic benefit of the new prostate cancer grade-grouping system for bRFS, and shown that the benefit is maintained after adjusting for important clinicopathological variables. The greater predictive accuracy of the new system will improve risk stratification in the clinical setting and aid in patient counselling.