The TOTAL trial for weight management participation: A randomized controlled trial protocol.

BACKGROUND: The three types of evidence-based treatment options for adults with overweight and obesity - behavioral weight management, anti-obesity medications (AOM), and bariatric surgery - are underutilized in the Veterans Health Administration (VHA) system. Our objective in this manuscript is to describe the study protocol for an adequately powered randomized controlled trial (RCT) of a behavioral intervention: TOTAL (Teaching Obesity Treatment Options to Adult Learners) to increase patient uptake of obesity treatment. METHODS: In this multi-site, parallel, RCT, eligible Veterans with a body mass index [BMI] ≥ 27 who had not received obesity treatment within the past 12 months were randomly assigned to TOTAL or usual care. TOTAL involves watching an 18-min video that highlights obesity health risks, pros/cons of all three evidence-based obesity treatments, and expected treatment outcomes. It also includes motivational sessions delivered via televideo at 2 weeks, 6 months, and 12 months after the video (target n = 494 participants). The primary outcome is initiation of behavioral weight management treatment within 18 months of randomization. Secondary outcomes include sustained behavioral weight management treatment, initiation of AOM, bariatric surgery referral, and weight change across 18 months. CONCLUSION: TOTAL, which seeks to increase delivery of weight management treatment within the largest integrated health system in the U.S., combines patient education with motivational interviewing components. If efficacious in this trial, further evaluation of intervention effectiveness and implementation throughout the VHA and other healthcare systems would be warranted.

Qualitative Message Development to Motivate Quitting Smoking in Older Adults: Dementia May Motivate Quitting.

Compared to younger adults, older adults who smoke cigarettes are half as likely to make a quit attempt, but more likely to maintain abstinence using evidence-based smoking treatments (EBSTs), illustrating the need for motivational messages to promote cessation through EBSTs. It is unclear whether messaging regarding the association between smoking and dementia might motivate older adults to quit. We conducted 90-min semi-structured qualitative interviews and surveys via telephone with 24 U.S. older adults who smoke (ages 50-75) with no cognitive impairment history. Rapid content analysis revealed the most reported health-related concern of aging was dementia/cognitive loss/loss of functioning. However, most participants were unaware of the association between cognitive decline and smoking. Participants had seen previous smoking cessation advertisements, but most did not feel motivated to quit by them. The majority found a message about smoking raising dementia risk and quitting decreasing that risk to be motivational for cessation. Exact message content preference varied, but 2 broad categories arose: hope- and fear-based messages. Most participants stated willingness to use some cessation pharmacotherapy and half were willing to use cessation counseling. Participants preferred messages to come from older adults who were successful quitters. To our knowledge, this was the first study to explore potential motivational messages targeting older adult smokers, including the potential acceptability of a dementia-related message in this context. This work supports patient desire for targeted motivational messages for older adult smokers. Messages highlighting the link between smoking and dementia are perceived to be motivational for this group; future work should compare a hope- to fear-based messages.

A scoping review of the unmet needs of patients diagnosed with idiopathic pulmonary fibrosis (IPF).

AIMS: Patients diagnosed with idiopathic pulmonary fibrosis (IPF) have a high symptom burden and numerous needs that remain largely unaddressed despite advances in available treatment options. There is a need to comprehensively identify patients' needs and create opportunities to address them. This scoping review aimed to synthesise the available evidence and identify gaps in the literature regarding the unmet needs of patients diagnosed with IPF. METHODS: The protocol for the review was registered with Open Science Framework (DOI 10.17605/OSF.IO/SY4KM). A systematic search was performed in March 2022, in CINAHL, MEDLINE, Embase, PsychInfo, Web of Science Core Collection and ASSIA Applied Social Science Index. A comprehensive review of grey literature was also completed. Inclusion criteria included patients diagnosed with IPF and date range 2011-2022. A range of review types were included. Data was extracted using a data extraction form. Data was analysed using descriptive and thematic analysis. A total of 884 citations were reviewed. Ethical approval was not required. RESULTS: 52 citations were selected for final inclusion. Five themes were identified: 1.) psychological impact of an IPF diagnosis. 2.) adequate information and education: at the right time and in the right way. 3.) high symptom burden support needs. 4.) referral to palliative care and advance care planning (ACP). 5.) health service provision-a systems approach. CONCLUSION: This review highlights the myriad of needs patients with IPF have and highlights the urgent need for a systems approach to care, underpinned by an appropriately resourced multi-disciplinary team. The range of needs experienced by patients with IPF are broad and varied and require a holistic approach to care including targeted research, coupled with the continuing development of patient-focused services and establishment of clinical care programmes.

What to do after smoking relapse? A sequential multiple assignment randomized trial of chronic care smoking treatments.

AIM: To compare effects of three post-relapse interventions on smoking abstinence. DESIGN: Sequential three-phase multiple assignment randomized trial (SMART). SETTING: Eighteen Wisconsin, USA, primary care clinics. PARTICIPANTS: A total of 1154 primary care patients (53.6% women, 81.2% White) interested in quitting smoking enrolled from 2015 to 2019; 582 relapsed and were randomized to relapse recovery treatment. INTERVENTIONS: In phase 1, patients received cessation counseling and 8 weeks nicotine patch. Those who relapsed and agreed were randomized to a phase 2 relapse recovery group: (1) reduction counseling + nicotine mini-lozenges + encouragement to quit starting 1 month post-randomization (preparation); (2) repeated encouragement to quit starting immediately post-randomization (recycling); or (3) advice to call the tobacco quitline (control). The first two groups could opt into phase 3 new quit treatment [8 weeks nicotine patch + mini-lozenges plus randomization to two treatment factors (skill training and supportive counseling) in a 2 × 2 design]. Phase 2 and 3 interventions lasted ≤ 15 months. MEASUREMENTS: The study was powered to compare each active phase 2 treatment with the control on the primary outcome: biochemically confirmed 7-day point-prevalence abstinence 14 months post initiating phase 2 relapse recovery treatment. Exploratory analyses tested for phase 3 counseling factor effects. FINDINGS: Neither skill training nor supportive counseling (each on versus off) increased 14-month abstinence rates; skills on versus off 9.3% (14/151) versus 5.2% (8/153), P = 0.19; support on versus off 6.6% (10/152) versus 7.9% (12/152), P = 0.73. Phase 2 preparation did not produce higher 14-month abstinence rates than quitline referral; 3.6% (8/220) versus 2.1% [3/145; risk difference = 1.5%, 95% confidence interval (CI) = -1.8-5.0%, odds ratio (OR) = 1.8, 95% CI = 0.5-6.9]. Recycling, however, produced higher abstinence rates than quitline referral; 6.9% (15/217) versus 2.1% (three of 145; risk difference, 4.8%, 95% CI = 0.7-8.9%, OR = 3.5, 95% CI = 1.0-12.4). Recycling produced greater entry into new quit treatment than preparation: 83.4% (181/217) versus 55.9% (123/220), P < 0.0001. CONCLUSIONS: Among people interested in quitting smoking, immediate encouragement post-relapse to enter a new round of smoking cessation treatment ('recycling') produced higher probability of abstinence than tobacco quitline referral. Recycling produced higher rates of cessation treatment re-engagement than did preparation/cutting down using more intensive counseling and pharmacotherapy.

Exploration of the unmet needs of patients diagnosed with idiopathic pulmonary fibrosis: a scoping review protocol.

INTRODUCTION: Interstitial lung diseases consist of a range of lung disorders, the most prevalent being idiopathic pulmonary fibrosis (IPF). IPF is a chronic, progressive disease, resulting in loss of lung function and potentially significant impacts on quality of life. There is an increasing need to address unmet needs in this population as there is evidence that unmet needs may impact quality of life and health outcomes. The key objective of this scoping review is to define the unmet needs of patients living with a diagnosis of IPF and to identify gaps in the literature relating to unmet needs. Findings will inform the development of services and the introduction of patient-centred clinical care guidelines for IPF. METHODS AND ANALYSIS: This scoping review is guided by the methodological framework for conducting scoping reviews developed by the Joanna Briggs Institute. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist is used for guidance. The following databases will be searched: CINAHL, MEDLINE, PsycINFO, Web of Science, Embase and ASSIA and include a comprehensive grey literature search. The review will report on adult patients >18 with a diagnosis of IPF or pulmonary fibrosis and be limited to publications from 2011 onwards, with no language restrictions applied. Two independent reviewers will screen articles in consecutive stages for relevance against the inclusion and exclusion criteria. Data will be extracted using a predefined data extraction form and analysed using descriptive and thematic analysis. Findings will be presented in tabular form, coupled with a narrative summary of the evidence. ETHICS AND DISSEMINATION: Ethics approval is not required for this scoping review protocol. We will disseminate our findings using traditional approaches that include open access peer-reviewed publications and scientific presentations.

Profiles of Resilience, Distress, and Posttraumatic Growth in Parents of Children with Cancer and the Relation to Subsequent Parenting and Family Functioning.

OBJECTIVE: The aim of this study was to identify patterns of distress and growth in parents of children with cancer and examine associations with subsequent parenting, parent-child relationship, and family environment. METHODS: Participants included children with cancer history (8-17 years) stratified by time since diagnosis and their parent. At enrollment, parents (n = 254) reported depression and anxiety, and post-traumatic stress symptoms, posttraumatic growth (PTG), and benefit finding in relation to their child's cancer. Three years later, children (n = 214) reported parenting behavior, parent reactions to their distress, and family environment. Parents reported their reaction to children's distress and qualities of the parent-child relationship. RESULTS: Latent profile analysis empirically identified 3 cross-sectional profiles using baseline data: "Resilience, High Growth" (50%), characterized by the lowest distress and the highest PTG/benefit finding; "Moderate Distress with Growth" (33%), characterized by relatively high levels of all indicators; and "Resilience, Low Growth" (17%), characterized by relatively low distress with low PTG/benefit finding. Membership in profiles was associated with parent gender; parents' stressful life events; socioeconomic status; and child diagnosis, on versus off treatment status, and treatment intensity. Parent membership in the Moderate Distress with Growth profile was generally linked with poorer parenting behavior, parent-child relationship quality, and family functioning. CONCLUSION: The majority of parents exhibited resilience and growth. However, a subset of parents displaying moderate distress may be at risk for subsequent parenting and family functioning challenges. Findings further highlight the importance of screening for even moderate parent distress and the possible impact of parent psychosocial interventions indirectly on parenting and family functioning.

Effects of Lifestyle and Educational Bridging Programs before Bariatric Surgery on Postoperative Weight Loss: A Systematic Review and Meta-Analysis.

OBJECTIVE: To fulfill the requirements for bariatric surgery, patients often need to participate in mandatory preoperative lifestyle interventions. Currently, the efficacy of multi-month preoperative lifestyle intervention programs on body mass index (BMI) reduction from the start of the program (T0) through the immediate preoperative time point (T1) to 1 year post-surgery (T2) and how the amount of preoperative BMI reduction affects postoperative outcome (T1 to T2) is unclear. The aim of this meta-analysis was to analyze the effects of preoperative lifestyle interventions on BMI 1 year post-surgery. METHOD: A systematic literature search was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Randomized controlled trials that implemented preoperative lifestyle interventions lasting 1-8 months before bariatric surgery were included. The BMI of the intervention group was compared with that of a control group before participation in the preoperative lifestyle interventions (T0), after completion of the program before surgery (T1), and 1 year post-surgery (T2). Finally, the impact of successful BMI reduction at T1 on BMI at T2 was analyzed. RESULTS: N = 345 patients derived from 4 studies undergoing preoperative lifestyle interventions reduced their BMI at T1 by 1.5 units compared to the control group (95% CI: -2.73, -0.28). One year post-surgery, both groups had lost comparable BMI points. The influence of reduced BMI at T1 on weight status at T2 is unclear due to the lack of available studies. Other endpoints and subgroup analyses were rarely examined. CONCLUSIONS: Preoperative lifestyle interventions reduce BMI before bariatric surgery more effectively than usual care. These differences are not detectable 1 year post-surgery. Although a short-term energy reduction period before surgery is clearly important to minimize surgery risks, it is currently unclear whether, and if so, under what circumstances, participation in a preoperative lifestyle intervention is beneficial.

Prevalence and incidence of cancer amongst adults with intellectual disability - a systematic review and meta-analysis protocol.

Background: People with intellectual disabilities have poorer health and die earlier than their peers without identified disabilities. This difference represents a significant inequality. Until recently, it was considered that cancer was less common in this population, mainly because they did not live long enough to develop age-related cancers. However, recent evidence has identified that people with intellectual disabilities may be at an increased risk of developing cancer but more likely to present for medical treatment at a later stage when cancer has spread. Nonetheless, the evidence is lacking and there is a need to understand the prevalence and incidence of cancer and subtypes of cancer in adults with intellectual disabilities. Methods: A systematic review and meta-analysis will be undertaken to investigate the prevalence and incidence of cancer and subtypes of cancer in adults with an intellectual disability. The JBI Systematic reviews of prevalence and incidence and the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed to develop this protocol. Electronic databases will be searched using predefined search terms to identify relevant studies using the Condition Context Population (CoCoPop) framework. Eligible studies should be observational and have published baseline data that have estimated or presented data on the prevalence or incidence of cancer in adults with intellectual disabilities. To assess the methodological quality of studies included in this review a modified version of the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data will be used. Prevalence and incidence proportions will be analysed separately with individual study data being pooled using the DerSimonian-Laird proportion method and a random effects meta-analysis will be undertaken. Discussion: This review will advance the epidemiological evidence to identify where targeted cancer care interventions are needed to help reduce the inequalities that this population experiences. Systematic review registration: PROSPERO registration number: CRD42023423584.

Health-related quality of life, obesity, fragmented sleep, fatigue, and psychosocial problems among youth with craniopharyngioma.

OBJECTIVE: Youth with craniopharyngioma experience weight gain, fragmented sleep, excessive daytime sleepiness (EDS), fatigue, and psychosocial problems that negatively impact their overall health-related quality of life (HRQoL). Greater hypothalamic tumor involvement (HI) may be associated with higher rates or severity of these impairments; however, the direct and indirect impact of HI on the physical and psychosocial consequences associated with pediatric craniopharyngioma remain unclear. The purpose of the current study was to examine relations between HI, body mass index (BMI), fragmented sleep, EDS, fatigue, psychosocial problems, and HRQoL among youth with craniopharyngioma. METHODS: Eighty-four youth with craniopharyngioma (Mage  = 10.27 ± 4.3 years, 53.6% female, 64.3% White) were assessed with actigraphy, nocturnal polysomnography, and multiple sleep latency tests prior to proton therapy, when indicated. Caregivers completed measures of fatigue, psychosocial functioning, and HRQoL. RESULTS: Hypothalamic tumor involvement was associated with greater BMI (Est. = 2.97, p = 0.003) and daytime sleepiness (Est. = 2.53, p = 0.01). Greater fatigue predicted more psychosocial problems (Est. = 0.29, p < 0.001) and lower HRQoL (Est. = 0.23, p = 0.001). Psychosocial problems also predicted lower HRQoL (Est. = -0.34, p = 0.004). Fragmented sleep (Est. = 0.03, p = 0.04) and fatigue (Est. = 0.10, p = 0.02) indirectly predicted lower HRQoL through psychosocial problems. CONCLUSIONS: Youth with craniopharyngioma with greater HI may benefit from weight reduction interventions and management of excessive sleepiness. Patients should be prospectively monitored for sleep problems, fatigue, and psychosocial problems, as these patients may benefit from interventions targeting fatigue and psychosocial health to improve HRQoL.

Working memory training in pediatric brain tumor survivors after recent diagnosis: Challenges and initial effects.

Research shows promise for cognitive interventions for children diagnosed with brain tumors. Interventions have been delivered approximately 5 years postdiagnosis on average, yet recent evidence shows cognitive deficits may appear near diagnosis. The present study assessed the feasibility and initial effects of working memory training in children with brain tumors delivered soon after diagnosis and followed 2 years postdiagnosis. Children completed baseline assessments 10 months postdiagnosis and were randomized to complete adaptive or nonadaptive (i.e., control) Cogmed Working Memory Training. Children were administered the WISC-IV Working Memory Index (WMI) and NIH Toolbox Cognitive Battery (NTCB), and parents completed attentional and executive function measures at four time points. On average, participants completed half of prescribed Cogmed sessions. Retention for the three follow-up assessments proved difficult. For both Cogmed groups, WMI and NTCB scores significantly improved immediately postintervention compared to baseline scores. Significant differences were not maintained at the remaining follow-ups. There was preliminary evidence for improved executive function at the final follow-up on parent-reported measures. Working memory training closer to diagnosis proved difficult, though results suggest evidence of cognitive improvement. Future studies should continue to examine potentially efficacious interventions for children with brain tumors and optimal delivery windows to maximize impact.

Evaluating four motivation-phase intervention components for use with primary care patients unwilling to quit smoking: a randomized factorial experiment.

AIMS: To assess the effectiveness of intervention components designed to increase quit attempts and promote abstinence in patients initially unwilling to quit smoking. DESIGN: A four-factor, randomized factorial experiment. SETTING: Sixteen primary care clinics in southern Wisconsin. PARTICIPANTS: A total of 577 adults who smoke (60% women, 80% White) recruited during primary care visits who were currently willing to reduce their smoking but unwilling to try to quit. Interventions Four factors contrasted intervention components administered over a 1-year period: (i) nicotine mini-lozenge versus none; (ii) reduction counseling versus none; (iii) behavioral activation (BA) counseling versus none; and (iv) motivational 5Rs counseling versus none. Participants could request cessation treatment at any time. MEASUREMENTS: The primary outcome was 7-day point-prevalence abstinence at 52 weeks post enrollment; secondary outcomes were point-prevalence abstinence at 26 weeks and making a quit attempt by weeks 26 and 52. FINDINGS: No abstinence main effects were found but a mini-lozenge × reduction counseling × BA interaction was found at 52 weeks; P = 0.03. Unpacking this interaction showed that the mini-lozenge alone produced the highest abstinence rate (16.7%); combining it with reduction counseling produced an especially low abstinence rate (4.1%). Reduction counseling decreased the likelihood of making a quit attempt by 52 weeks relative to no reduction counseling (P = 0.01). CONCLUSIONS: Nicotine mini-lozenges may increase smoking abstinence in people initially unwilling to quit smoking, but their effectiveness declines when used with smoking reduction counseling or other behavioral interventions. Reduction counseling decreases the likelihood of making a quit attempt in people initially unwilling to quit smoking.

Cigarette Smoking Status, Cigarette Exposure, and Duration of Abstinence Predicting Incident Dementia and Death: A Multistate Model Approach.

BACKGROUND: To fully characterize the risk for dementia associated with cigarette smoking, studies must consider competing risks that hinder the observation of dementia or modify the chance that dementia occurs (i.e., death). Extant research examining the competing risks fails to account for the occurrence of death following dementia, limiting our understanding of the relation between smoking and dementia. OBJECTIVE: Examine the impact of smoking status, lifetime smoking exposure, and duration of abstinence on incident dementia, death following dementia, and death without dementia. METHODS: Multi-state models estimated hazard ratios (HR) for 95% confidence interval (CI) of 10,681 cognitively healthy adults for transition from baseline to dementia, baseline to death, and dementia to death based on smoking status, lifetime cigarette exposure, and abstinence duration. RESULTS: Compared to never smokers, current smokers had increased risk of dementia (HR = 1.66; 95% CI 1.18- 2.32; p = 0.004), and death from baseline (HR = 2.98; 95% CI 2.24- 3.98; p < 0.001) and incident dementia (HR = 1.88; 95% CI 1.08- 3.27; p = 0.03). Pack years increased risk of death from baseline (HR = 1.01; 95% CI 1.00- 1.01; p < 0.001), but not dementia risk (HR = 1.00; 95% CI 1.00- 1.00; p = 0.78) or death following dementia (HR = 1.01; 95% CI 1.00- 1.01; p = 0.05). Recent quitters (quit < 10 years), compared to never smokers, had increased risk of death after baseline (HR = 2.31; 95% CI 1.55- 3.43; p < 0.001), but not dementia (HR = 1.17; 95% CI 0.73- 1.88; p = 0.52) or death following dementia (HR = 1.01; 95% CI 0.42- 2.41; p = 0.99). CONCLUSION: Current smoking increases the risk for dementia and death, but dementia is better attributed to smoking recency than lifetime exposure. Smoking cessation at any age might reduce these risks for cognitively healthy individuals.

Possible New Symptoms of Tobacco Withdrawal III: Reduced Positive Affect-A Review and Meta-analysis.

INTRODUCTION: Most descriptions of tobacco withdrawal have not changed in >30 years despite new research. This meta-analysis tested whether abstinence leads to decreased positive affect (PA) because abstinence-induced symptom changes are a core feature of the tobacco withdrawal syndrome. In addition, we examined whether reduced PA was due to withdrawal (ie, temporary decrease in a "U-shaped" curve) or offset (ie, return to baseline) effect. METHODS: Our main inclusion criterion was a prospective within-participant test of change in PA during abstinence conditions among people who smoke cigarettes daily who were not using a cessation medication. Our search of PubMed, PsycINFO, and personal libraries yielded a total of 32 tests with 2054 participants. RESULTS: There was a medium effect size indicating an overall decrease in PA following abstinence from cigarettes (Cohen's d = -0.40, 95% CI = -0.30 to -0.49). There was large heterogeneity (I2 = 70.7%). Most (79%) of the 24 trials that conducted significance tests reported that reduction in PA was significant. Seven tests were adequately designed to detect a withdrawal versus offset effect. Over half (57%) displayed a U-shaped curve for abstinence-induced change in PA indicative of a withdrawal symptom rather than offset effect. CONCLUSIONS: Abstinence from cigarettes is associated with a decrease in PA. Whether low PA should be added to withdrawal measures and diagnostic criteria requires replication of the time-course of change in PA and tests of whether abstinence-induced changes in PA and negative affect occur independently. IMPLICATIONS: Though there was substantial heterogeneity among trials, our findings suggest that (1) abstinence from cigarettes decreases positive affect and (2) this decrease may represent a withdrawal effect (vs. an offset effect). However, it is unclear whether abstinence-induced losses in positive affect are independent from increased negative affect.

Time-varying effects of 'optimized smoking treatment' on craving, negative affect and anhedonia.

AIMS: To identify when smoking cessation treatments affect craving, negative affect and anhedonia, and how these symptoms relate to abstinence, to help evaluate the effects of particular intervention components in multi-component treatments and accelerate treatment refinement. DESIGN: Secondary analysis of data from a two-arm randomized controlled trial. SETTING: Seven primary care clinics in Wisconsin, United States. PARTICIPANTS: Adult primary care patients who smoked daily (n = 574). INTERVENTION AND COMPARATOR: Intervention was abstinence-optimized treatment (A-OT, n = 276) comprising 3 weeks of nicotine mini-lozenges pre-target quit day (TQD), 26 weeks of combination nicotine patch and mini-lozenges post-TQD and extensive psychosocial support. The comparator was recommended usual care (RUC, n = 298), comprising brief counseling and 8 weeks of nicotine patch post-TQD. MEASUREMENTS: Time-varying effect models examined dynamic effects of A-OT (versus RUC) on the primary outcomes of nightly cigarette craving, negative affect and anhedonia from 1 week pre- to 2 weeks post-TQD. Exploratory models examined within-person relations between nicotine medication use and same-day symptom ratings. Secondary logistic regression analyses examined associations between post-TQD craving, negative affect and anhedonia and 1-month post-TQD abstinence. FINDINGS: A-OT significantly suppressed pre- and post-TQD craving (ß = -0.27 to -0.46 across days) and post-TQD anhedonia (ß = -0.24 to -0.38 across days), relative to RUC. Within individuals, using patches was associated with lower negative affect in RUC (ß = -0.42 to -0.52), but not in A-OT. Using more mini-lozenges was associated with greater craving (ß = 0.04-0.07) and negative affect (ß = 0.03-0.05) early, and with lower anhedonia (ß = -0.06 to -0.12) later. Greater post-TQD craving (OR = 0.68) and anhedonia (OR = 0.85) predicted lower odds of abstinence 1 month post-TQD. CONCLUSION: Time-varying effect models showed that a multi-component treatment intervention for smoking cessation suppressed significant withdrawal symptoms more effectively than recommended usual care among daily adult smokers motivated to quit. The intervention reduced craving pre- and post-target quit day (TQD) and anhedonia post-TQD.

pHLARE: a new biosensor reveals decreased lysosome pH in cancer cells.

Many lysosome functions are determined by a lumenal pH of ∼5.0, including the activity of resident acid-activated hydrolases. Lysosome pH (pHlys) is often increased in neurodegenerative disorders and predicted to be decreased in cancers, making it a potential target for therapeutics to limit the progression of these diseases. Accurately measuring pHlys, however, is limited by currently used dyes that accumulate in multiple intracellular compartments and cannot be propagated in clonal cells for longitudinal studies or used for in vivo determinations. To resolve this limitation, we developed a genetically encoded ratiometric pHlys biosensor, pHLARE (pH Lysosomal Activity REporter), which localizes predominantly in lysosomes, has a dynamic range of pH 4.0 to 6.5, and can be stably expressed in cells. Using pHLARE we show decreased pHlys with inhibiting activity of the mammalian target of rapamycin complex 1 (mTORC1). Also, cancer cells from different tissue origins have a lower pHlys than untransformed cells, and stably expressing oncogenic RasV12 in untransformed cells is sufficient to decrease pHlys. pHLARE is a new tool to accurately measure pHlys for improved understanding of lysosome dynamics, which is increasingly considered a therapeutic target.

Centrality of the childhood cancer experience and its relation to post-traumatic stress and growth.

OBJECTIVE: Event centrality, the degree to which a traumatic event is perceived as central to one's identity, has been associated with post-traumatic stress (PTS) symptoms and post-traumatic growth (PTG) outcomes in various trauma samples. Trauma frameworks are widely used to understand the psychological impact of pediatric cancer; however, event centrality has not been studied in this population. We investigated event centrality in pediatric cancer survivors and healthy comparisons, and its relation with PTS and PTG outcomes. METHOD: Cancer survivors, age 13-23 (N = 196) and healthy comparisons (N = 131) completed the Centrality of Events Scale and PTS and PTG measures in reference to their most traumatic life event. Cancer survivors who first identified a non-cancer-related event repeated all measures in reference to cancer. RESULTS: Centrality scores were significantly higher when referencing cancer compared to non-cancer events, even in survivors for whom cancer was not rated as most stressful (53.1%). Centrality scores for non-cancer events were not significantly different between survivors and healthy comparisons. Event centrality showed significant positive relations to both PTS and PTG outcomes. CONCLUSION: The pediatric cancer experience is perceived as central to survivors' identity regardless of whether the experience is perceived as highly traumatic. Centrality of cancer is a significant predictor of both positive and negative psychological outcomes in cancer survivors.

Tobacco Withdrawal Symptoms Before and After Nicotine Deprivation in Veteran Smokers with Posttraumatic Stress Disorder and with Major Depressive Disorder.

INTRODUCTION: The high smoking prevalence amongst individuals with psychiatric disorders constitutes a major public health disparity. Negative reinforcement models of addiction posit that severe tobacco withdrawal symptoms, related to the affective vulnerabilities of these smokers, may thwart their quitting smoking successfully. However, relatively few studies have prospectively examined the effects of nicotine deprivation on withdrawal symptoms in these groups. METHODS: This study compared the level of withdrawal symptoms both before and after nicotine deprivation in those diagnosed with posttraumatic stress disorder (PTSD) or major depressive disorder (MDD) and in those without psychiatric diagnoses. Participants were US veterans who smoked (≥10 cigarettes/day) and met diagnostic criteria for PTSD (n = 38), MDD (n = 43), or no psychiatric diagnosis ("controls" n = 44). Participants attended study visits before and during 48-hour nicotine deprivation to report tobacco withdrawal symptoms. Analyses evaluated withdrawal symptom levels (baseline and during nicotine deprivation) and the change in symptoms related to nicotine deprivation and compared (1) participants with a psychiatric diagnosis versus controls, and (2) participants with PTSD versus MDD. RESULTS: Contrary to hypotheses, nicotine deprivation produced greater increases in most withdrawal symptoms amongst controls than in those with psychiatric diagnoses. Compared with controls, those with PTSD or MDD reported elevated symptom levels both before and after tobacco deprivation for most withdrawal symptoms. CONCLUSIONS: These findings suggest that chronically high levels of distress and craving, rather than acute increases in withdrawal symptoms because of nicotine deprivation, may account for the quitting difficulties of those with comorbid conditions such as PTSD and MDD. IMPLICATIONS: Severe tobacco withdrawal may account for the higher quitting difficulties of smokers with either posttraumatic stress disorder (PTSD) or major depressive disorder (MDD). Paradoxically, this study showed that individuals with no psychiatric diagnosis had greater increases in tobacco withdrawal severity because of nicotine deprivation than did those with either PTSD or MDD. Those with either PTSD or MDD showed high stable levels of withdrawal symptom severity both before and during two days of abstinence, suggesting that their quitting difficulties may be related to their chronically high levels of distress rather than nicotine deprivation per se.

Osteoclast-expanded super-charged NK-cells preferentially select and expand CD8+ T cells.

Osteoclasts (OCs) and much less dendritic cells (DCs) induce significant expansion and functional activation of NK cells, and furthermore, the OC-expanded NK cells preferentially increase the expansion and activation of CD8+ T cells by targeting CD4+ T cells. When autologous OCs were used to expand patient NK cells much lower percentages of expanded CD8+ T cells, decreased numbers of expanded NK cells and decreased functions of NK cells could be observed, and the addition of allogeneic healthy OCs increased the patients' NK function. Mechanistically, OC-expanded NK cells were found to lyse CD4+ T cells but not CD8+ T cells suggesting potential selection of CD8+ T cells before their expansion by OC activated NK cells. In agreement, Increased IFN-γ secretion, and NK cell-mediated cytotoxicity and higher percentages of CD8+ T cells, in various tissue compartments of oral tumor-bearing hu-BLT mice in response to immunotherapy by OC-expanded NK cells were observed. Thus, our results indicate an important relationship between NK and CD8+ T cells.

Gut Microbiota, Probiotics and Psychological States and Behaviors after Bariatric Surgery-A Systematic Review of Their Interrelation.

The gastrointestinal (GI) microbiota plays an important role in health and disease, including brain function and behavior. Bariatric surgery (BS) has been reported to result in various changes in the GI microbiota, therefore demanding the investigation of the impact of GI microbiota on treatment success. The goal of this systematic review was to assess the effects of BS on the microbiota composition in humans and other vertebrates, whether probiotics influence postoperative health, and whether microbiota and psychological and behavioral factors interact. A search was conducted using PubMed and Web of Science to find relevant studies with respect to the GI microbiota and probiotics after BS, and later screened for psychological and behavioral parameters. Studies were classified into groups and subgroups to provide a clear overview of the outcomes. Microbiota changes were further assessed for whether they were specific to BS in humans through the comparison to sham operated controls in other vertebrate studies. Changes in alpha diversity appear not to be specific, whereas dissimilarity in overall microbial community structure, and increases in the abundance of the phylum Proteobacteria and Akkermansia spp. within the phylum Verrucomicrobia after surgery were observed in both human and other vertebrates studies and may be specific to BS in humans. Human probiotic studies differed regarding probiotic strains and dosages, however it appeared that probiotic interventions were not superior to a placebo for quality of life scores or weight loss after BS. The relationship between GI microbiota and psychological diseases in this context is unclear due to insufficient available data.

Searching for Personalized Medicine for Binge Drinking Smokers: Smoking Cessation Using Varenicline, Nicotine Patch, or Combination Nicotine Replacement Therapy.

OBJECTIVE: Heavy drinking is common among smokers and is associated with especially poor health outcomes. Varenicline may affect mechanisms and clinical outcomes that are relevant for both smoking cessation and alcohol use. The current study examines whether varenicline, relative to nicotine replacement therapy, yields better smoking cessation outcomes among binge drinking smokers. METHOD: Secondary data analyses of a comparative effectiveness randomized controlled trial of three smoking cessation pharmacotherapies (12 weeks of varenicline, nicotine patch, or nicotine patch and lozenge) paired with six counseling sessions were conducted. Adult daily cigarette smokers (N = 1,078, 52% female) reported patterns of alcohol use, cigarette craving, and alcohol-related cigarette craving at baseline and over 4 weeks after quitting. Smoking cessation outcome was 7-day biochemically confirmed point-prevalence abstinence. RESULTS: Binge drinkers had higher relapse rates than moderate drinkers at 4-week post-target quit day but not at the end of treatment or long-term follow up (12 and 26 weeks). Varenicline did not yield superior smoking cessation outcomes among binge drinkers, nor did it affect alcohol use early in the quit attempt. Varenicline did produce relatively large reductions in alcohol-related cigarette craving and overall cigarette craving during the first 4 weeks after quitting. CONCLUSIONS: Varenicline did not yield higher smoking abstinence rates or reduce alcohol use among binge drinkers. Varenicline did reduce alcohol-related cigarette craving but this did not translate to meaningful differences in smoking abstinence. Varenicline's effects on smoking abstinence do not appear to vary significantly as a function of drinking status.