Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC. METHODS: Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality. RESULTS: In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+ T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+ B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1-) eomesodermin (EOMES+)) CD8+ T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+ EOMES+) CD8+ T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation. CONCLUSION: Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors. TRIAL REGISTRATION NUMBER: NCT02562898.

Closing the Infrastructure Gap for Decarbonization: The Case for an Integrated Mineral Supply Agreement.

Significant amounts of feedstock metals will be required to build the infrastructure for the green energy transition. It is currently estimated, however, that the world may be facing an "infrastructure gap" that could prevent us from meeting United Nations Sustainable Development Goal targets. Prior investigations have focused on the extractive aspects of the mining industry to meet these targets and on looming bottlenecks and regional challenges in these upstream market segments. Scant attention has been paid to the downstream processing segments of the raw materials value chain, which also has a high degree of market concentration. Growing international tensions and geopolitical events have resulted in a shift toward "reshoring" and "near-shoring" of mining processing capabilities as regional powers attempt to make metal supply chains more secure. While increasing resilience, these shifts can also dilute the overall effectiveness of the global mining supply network and subsequently hamper the world's ability to close the green energy infrastructure gap. We argue that broadening the remit of the International Renewable Energy Agency (IRENA) to include coordinating these mission-critical metal processing functions can mitigate these issues. The G20 is one potential forum for enabling an integrated mineral processing agreement under the auspices of IRENA.

Single-Group Trial of an Internet-Delivered Insomnia Intervention Among Higher-Intensity Family Caregivers: Rationale and Protocol for a Mixed Methods Study.

BACKGROUND: Family caregivers are more likely to experience insomnia relative to noncaregivers but have significant barriers to accessing gold standard cognitive behavioral therapy for insomnia treatment. Delivering interventions to caregivers through the internet may help increase access to care, particularly among higher-intensity caregivers who provide assistance with multiple care tasks over many hours per week. Although there are existing internet interventions that have been thoroughly studied and demonstrated as effective in the general population, the extent to which these interventions may be effective for caregivers without tailoring to address this population's unique psychosocial needs has not been studied. OBJECTIVE: The goal of this trial is to determine what tailoring may be necessary for which caregivers to ensure they receive optimal benefit from an existing evidence-based, internet-delivered cognitive behavioral therapy for insomnia program named Sleep Healthy Using the Internet (SHUTi). Specifically, we will test the association between caregivers' engagement with SHUTi and their caregiving context characteristics (ie, caregiving strain, self-efficacy, and guilt) and environment (ie, proximity to care recipient; functional status, cognitive status, and problem behavior of care recipient; and type of care provided). Among caregivers using the program, we will also test the associations between change in known treatment mechanisms (sleep beliefs and sleep locus of control) and caregiving context factors. METHODS: A total of 100 higher-intensity caregivers with significant insomnia symptoms will be recruited from across the United States to receive access to SHUTi in an open-label trial with mixed methods preassessments and postassessments. At postassessment (9 weeks following preassessment completion), participants will be categorized according to their engagement with the program (nonusers, incomplete users, or complete users). Study analyses will address 3 specific aims: to examine the association between caregivers' engagement with SHUTi and their caregiving context (aim 1a); to describe caregivers' barriers to and motivations for SHUTi engagement from open-ended survey responses (aim 1b); and among caregivers using SHUTi, to determine whether cognitive mechanisms of change targeted by SHUTi are associated with differences in caregiving context (aim 2). RESULTS: Institutional review board approvals have been received. Data collection is anticipated to begin in December 2021 and is expected to be completed in 2023. CONCLUSIONS: Findings will inform the next research steps for tailoring and testing SHUTi for optimal impact and reach among caregivers. Beyond implication to the SHUTi program, the findings will be translatable across intervention programs and will hold significant promise to reduce inefficiencies in developing digital health interventions for caregivers while also increasing their impact and reach for this underserved population. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04986904; https://clinicaltrials.gov/ct2/show/NCT04986904?term=NCT04986904. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/34792.

A Panel of 6 Biomarkers Significantly Improves the Prediction of Type 2 Diabetes in the MONICA/KORA Study Population.

CONTEXT: Improved strategies to identify persons at high risk of type 2 diabetes are important to target costly preventive efforts to those who will benefit most. OBJECTIVE: This work aimed to assess whether novel biomarkers improve the prediction of type 2 diabetes beyond noninvasive standard clinical risk factors alone or in combination with glycated hemoglobin A1c (HbA1c). METHODS: We used a population-based case-cohort study for discovery (689 incident cases and 1850 noncases) and an independent cohort study (262 incident cases, 2549 noncases) for validation. An L1-penalized (lasso) Cox model was used to select the most predictive set among 47 serum biomarkers from multiple etiological pathways. All variables available from the noninvasive German Diabetes Risk Score (GDRSadapted) were forced into the models. The C index and the category-free net reclassification index (cfNRI) were used to evaluate the predictive performance of the selected biomarkers beyond the GDRSadapted model (plus HbA1c). RESULTS: Interleukin-1 receptor antagonist, insulin-like growth factor binding protein 2, soluble E-selectin, decorin, adiponectin, and high-density lipoprotein cholesterol were selected as the most relevant biomarkers. The simultaneous addition of these 6 biomarkers significantly improved the predictive performance both in the discovery (C index [95% CI], 0.053 [0.039-0.066]; cfNRI [95% CI], 67.4% [57.3%-79.5%]) and the validation study (0.034 [0.019-0.053]; 48.4% [35.6%-60.8%]). Significant improvements by these biomarkers were also seen on top of the GDRSadapted model plus HbA1c in both studies. CONCLUSION: The addition of 6 biomarkers significantly improved the prediction of type 2 diabetes when added to a noninvasive clinical model or to a clinical model plus HbA1c.

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease-a comparison in the MONICA/KORA study.

BACKGROUND: Biomarkers may contribute to our understanding of the pathophysiology of various diseases. Type 2 diabetes (T2D) and coronary heart disease (CHD) share many clinical and lifestyle risk factors and several biomarkers are associated with both diseases. The current analysis aims to assess the relevance of biomarkers combined to pathway groups for the development of T2D and CHD in the same cohort. METHODS: Forty-seven serum biomarkers were measured in the MONICA/KORA case-cohort study using clinical chemistry assays and ultrasensitive molecular counting technology. The T2D (CHD) analyses included 689 (568) incident cases and 1850 (2004) non-cases from three population-based surveys. At baseline, the study participants were 35-74 years old. The median follow-up was 14 years. We computed Cox regression models for each biomarker, adjusted for age, sex, and survey. Additionally, we assigned the biomarkers to 19 etiological pathways based on information from literature. One age-, sex-, and survey-controlled average variable was built for each pathway. We used the R2PM coefficient of determination to assess the explained disease risk. RESULTS: The associations of many biomarkers, such as several cytokines or the iron marker soluble transferrin receptor (sTfR), were similar in strength for T2D and CHD, but we also observed important differences. Lipoprotein (a) (Lp(a)) and N-terminal pro B-type natriuretic peptide (NT-proBNP) even demonstrated opposite effect directions. All pathway variables together explained 49% of the T2D risk and 21% of the CHD risk. The insulin-like growth factor binding protein 2 (IGFBP-2, IGF/IGFBP system pathway) best explained the T2D risk (about 9% explained risk, independent of all other pathway variables). For CHD, the myocardial-injury- and lipid-related-pathways were most important and both explained about 4% of the CHD risk. CONCLUSIONS: The biomarker-derived pathway variables explained a higher proportion of the T2D risk compared to CHD. The ranking of the pathways differed between the two diseases, with the IGF/IGFBP-system-pathway being most strongly associated with T2D and the myocardial-injury- and lipid-related-pathways with CHD. Our results help to better understand the pathophysiology of the two diseases, with the ultimate goal of pointing out targets for lifestyle intervention and drug development to ideally prevent both T2D and CHD development.

Association of fetuin-A with incident type 2 diabetes: results from the MONICA/KORA Augsburg study and a systematic meta-analysis.

OBJECTIVE: We investigated the association of circulating fetuin-A with incident T2D particularly examining potential sex differences. Additionally, we determined whether putative associations were independent of subclinical inflammation, adiponectin and liver fat content. DESIGN: Case-cohort study plus systematic meta-analysis. METHODS: We investigated the association between baseline fetuin-A levels and incident T2D in the MONICA/KORA Augsburg study using Cox proportional hazards analyses. Furthermore, we conducted a systematic review within PubMed and EMBASE and pooled association estimates of eligible studies with the MONICA/KORA Augsburg data using a DerSimonian-Laird random effects model. RESULTS: Within MONICA/KORA Augsburg, 930 participants developed incident T2D (median follow-up: 14 years). We observed a significant association between fetuin-A and T2D risk after multivariable adjustment including C-reactive protein and adiponectin. The strength of the association was similar in males and females (P value for sex interaction >0.55). Seven eligible published studies were identified in addition to the MONICA/KORA Augsburg study for the meta-analysis. The pooled hazard ratio (95% CI) for incident T2D per 1 standard deviation (s.d.) increment of fetuin-A was 1.24 (1.14-1.34) for the multivariable adjusted model. Our sex-stratified meta-analysis yielded relative risk estimates per 1 s.d. of 1.19 (1.04-1.38) in males and 1.29 (1.15-1.46) in females. Further individual adjustment for subclinical inflammation, adiponectin and liver fat content had almost no impact on the strength of the association. CONCLUSIONS: Higher fetuin-A levels are associated with incident T2D in both males and females independently of subclinical inflammation, adiponectin and liver fat content.

Circulating Levels of Interleukin 1-Receptor Antagonist and Risk of Cardiovascular Disease: Meta-Analysis of Six Population-Based Cohorts.

OBJECTIVE: Interleukin (IL)-1ß represents a key cytokine in the development of cardiovascular disease (CVD). IL-1ß is counter-regulated by IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor. This study aimed to identify population-based studies on circulating IL-1RA and incident CVD in a systematic review, estimate the association between IL-1RA and incident CVD in a meta-analysis, and to test whether the association between IL-1RA and incident CVD is explained by other inflammation-related biomarkers in the MONICA/KORA Augsburg case-cohort study (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg). APPROACH AND RESULTS: We performed a systematic literature search and identified 5 cohort studies on IL-1RA and incident CVD in addition to the MONICA/KORA Augsburg case-cohort study for a meta-analysis based on a total of 1855 CVD cases and 18 745 noncases with follow-up times between 5 and 16 years. The pooled standardized hazard ratio (95% confidence interval) for incident CVD was 1.11 (1.06-1.17) after adjustment for age, sex, anthropometric, metabolic, and lifestyle factors (P<0.0001). There was no heterogeneity in effect sizes (I2=0%; P=0.88). More detailed analyses in the MONICA/KORA study showed that the excess risk for CVD was attenuated by ≥10% after additional separate adjustment for serum levels of high-sensitivity C-reactive protein, IL-6, myeloperoxidase, soluble E-selectin, or soluble intercellular adhesion molecule-1. CONCLUSIONS: Serum IL-1RA levels were positively associated with risk of CVD after adjustment for multiple confounders in a meta-analysis of 6 population-based cohorts. This association may at least partially reflect a response to triggers inducing subclinical inflammation, oxidative stress, and endothelial activation.

Wearable Technology to Garner the Perspective of Dementia Family Caregivers.

Family caregivers of individuals with dementia typically have limited opportunity during brief clinical encounters to describe the dementia-related behaviors and interactions they find difficult to handle. Lack of objective data depicting the nature, intensity, and impact of these manifestations of the underlying disease further constrains the extent to which strategies recommended by nurses or other health care providers can be tailored to the situation. The current article describes a prototype wearable camera system used to gather image and voice data from the caregiver's perspective in a pilot feasibility intervention study conducted with 18 caregiving dyads. Several scenarios are presented that include salient events (i.e., behaviors or interactions deemed difficult by the caregiver or identified as concerning by the research team during screening) captured in the resulting video. The current authors anticipate future wearable camera systems and software will automate screening for salient events, providing new tools for assessment and intervention by nurses.

Clinically significant novel biomarkers for prediction of first ever myocardial infarction: the Tromsø Study.

BACKGROUND: Identification of individuals with high risk for first-ever myocardial infarction (MI) can be improved. The objectives of the study were to survey multiple protein biomarkers for association with the 10-year risk of incident MI and identify a clinically significant risk model that adds information to current common risk models. METHODS AND RESULTS: We used an immunoassay platform that uses a sensitive, sample-efficient molecular counting technology to measure 51 proteins in samples from the fourth survey (1994) in the Tromsø Study, a longitudinal study of men and women in Tromsø, Norway. A case control design was used with 419 first-ever MI cases (169 females/250 males) and 398 controls (244 females/154 males). Of the proteins measured, 17 were predictors of MI when considered individually after adjustment for traditional risk factors either in men, women, or both. The 6 biomarkers adjusted for traditional risk factors that were selected in a multivariable model (odds ratios [OR] per standard deviation) using a stepwise procedure were apolipoprotein B/apolipoprotein A1 ratio (1.40), kallikrein (0.73), lipoprotein a (1.29), matrix metalloproteinase 9 (1.30), the interaction term IP-10/CXCL10×women (0.69), and the interaction term thrombospondin 4×men (1.38). The composite risk of these biomarkers added significantly to the traditional risk factor model with a net reclassification improvement of 14% (P=0.0002), whereas the receiver operating characteristic area increased from 0.757 to 0.791, P=0.0004. CONCLUSIONS: Novel protein biomarker models improve identification of 10-year MI risk above and beyond traditional risk factors with 14% better allocation to either high or low risk group.

Preparedness for death and adjustment to bereavement among caregivers of recently placed nursing home residents.

BACKGROUND: Preparedness for death as a predictor of post-bereavement adjustment has not been studied prospectively. Little is known about pre-death factors associated with feeling prepared prior to the death of a loved one. OBJECTIVE: Our aim was to prospectively assess the role of preparedness for death as a predictor of post-bereavement adjustment in informal caregivers (CGs) who experienced the death of their loved one and to identify predictors and correlates of complicated grief, depression, and preparedness for death among informal CGs. METHODS: We conducted a prospective, longitudinal study using data collected for a randomized trial testing the efficacy of an intervention for CGs of recently placed care recipients (CRs). Subjects were 217 informal CGs of care recipients recently placed in nursing homes, and they were followed for 18 months. CGs were assessed in person by certified interviewers at 6-month intervals. Eighty-nine CGs experienced the death of their loved one in the course of the study. Measurements used included preparedness for death, advance care planning (ACP), complicated grief, depression, and sociodemographic characteristics. RESULTS: CGs who reported feeling more prepared for the death experienced lower levels of complicated grief post-bereavement. A multivariate ordinal logistic regression model showed that spouses as opposed to adult child CGs were less prepared for the death, depressed CGs were less prepared, and patients who engaged in ACP had CGs who felt more prepared. CR overt expressions about wanting to die was also related to higher levels of preparedness in the CG. CONCLUSIONS: We show prospectively that preparedness for death facilitates post-bereavement adjustment and identify factors associated with preparedness. ACP can be an effective means for preparing informal CGs for the death of their CRs.

Effects of a Psychosocial Intervention on Caregivers of Recently Placed Nursing Home Residents: A Randomized Controlled Trial.

Many caregivers continue to provide care and support to their care recipients after institutional placement. A two-group randomized controlled trial was carried out to test the efficacy of a psychosocial intervention for informal caregivers whose care recipients resided in a long-term care facility. The intervention was delivered during the 6 month period following baseline assessment. Follow-up assessments were carried out at 6, 12, and 18 months. Primary outcomes were caregiver depression, anxiety, burden, and complicated grief. Significant time effects were found for all three primary outcomes showing that caregiver depression, anxiety, and burden improved over time. No treatment effects were found for these outcomes. However, complicated grief was significantly lower for caregivers in the treatment condition.

High fish plus fish oil intake is associated with slightly reduced risk of venous thromboembolism: the Tromsø Study.

Current knowledge of the effect of fish consumption on risk of venous thromboembolism (VTE) is scarce and diverging. Therefore, the purpose of the present study was to investigate the impact of fish consumption and fish oil supplements on the risk of VTE in a population-based cohort. Weekly intake of fish for dinner and intake of fish oil supplements during the previous year were registered in 23,621 persons aged 25-97 y who participated in the Tromsø Study from 1994 to 1995. Incident VTE events were registered throughout follow-up (31 December 2010). Cox-regression models were used to calculate HRs for VTE, adjusted for age, body mass index, sex, triglycerides, HDL cholesterol, physical activity, and education level. During a median of 15.8 y of follow-up there were 536 incident VTE events. High fish consumption was associated with a slightly reduced risk of VTE. Participants who ate fish ≥3 times/wk had 22% lower risk of VTE than those who consumed fish 1-1.9 times/wk (multivariable HR: 0.78; 95% CI: 0.60, 1.01; P = 0.06). The addition of fish oil supplements strengthened the inverse association with risk of VTE. Participants who consumed fish ≥3 times/wk who additionally used fish oil supplements had 48% lower risk than those who consumed fish 1-1.9 times/wk but did not use fish oil supplements (HR: 0.52; 95% CI: 0.34, 0.79; P = 0.002). In conclusion, a high weekly intake (≥3 times/wk) of fish was associated with a slightly reduced risk of VTE, and the addition of fish oil supplements strengthened the inverse effect.

Enhancing the quality of life of dementia caregivers from different ethnic or racial groups: a randomized, controlled trial.

BACKGROUND: Caring for a family member with dementia is extremely stressful, contributes to psychiatric and physical illness among caregivers, and increases the risk for caregiver death. Finding better ways to support family caregivers is a major public health challenge. OBJECTIVE: To test the effects of a structured multicomponent intervention on quality of life and clinical depression in caregivers and on rates of institutional placement of care recipients in 3 diverse racial or ethnic groups. DESIGN: Randomized, controlled trial. SETTING: In-home caregivers in 5 U.S. cities. PARTICIPANTS: 212 Hispanic or Latino, 219 white or Caucasian, and 211 black or African-American caregivers and their care recipients with Alzheimer disease or related disorders. INTERVENTION: Caregivers within each racial or ethnic group were randomly assigned to an intervention or to a control group. The intervention addressed caregiver depression, burden, self-care, and social support and care recipient problem behaviors through 12 in-home and telephone sessions over 6 months. Caregivers in the control group received 2 brief "check-in" telephone calls during the 6-month intervention. MEASUREMENTS: The primary outcome was a quality-of-life indicator comprising measures of 6-month caregiver depression, burden, self-care, and social support and care recipient problem behaviors. Secondary outcomes were caregiver clinical depression and institutional placement of the care recipient at 6 months. RESULTS: Hispanic or Latino and white or Caucasian caregivers in the intervention group experienced significantly greater improvement in quality of life than those in the control group (P < 0.001 and P = 0.037, respectively). Black or African-American spouse caregivers also improved significantly more (P = 0.003). Prevalence of clinical depression was lower among caregivers in the intervention group (12.6% vs. 22.7%; P = 0.001). There were no statistically significant differences in institutionalization at 6 months. LIMITATIONS: The study used only a single 6-month follow-up assessment, combined heterogeneous cultures and ethnicities into a single group, and excluded some ethnic groups. CONCLUSIONS: A structured multicomponent intervention adapted to individual risk profiles can increase the quality of life of ethnically diverse dementia caregivers. ClinicalTrials.gov identifier: NCT00177489.

Concordance of race or ethnicity of interventionists and caregivers of dementia patients: relationship to attrition and treatment outcomes in the REACH study.

PURPOSE: We assess the effects of racial or ethnic concordance between caregivers and interventionists on caregiver attrition, change in depression, and change in burden in a multisite randomized clinical trial. DESIGN AND METHODS: Family caregivers of patients with Alzheimer's disease were randomized to intervention or control groups at six sites from 1996 to 2000. Interventionists provided psychosocial interventions aimed at decreasing caregiver depression and burden. This analysis included 694 caregivers who received face-to-face interventions from 36 interventionists at five sites. We modeled caregiver loss to follow-up at 12 months and changes in depression and burden from baseline by racial or ethnic concordance by using random effects logistic and linear regression models, controlling for caregiver age, gender, race or ethnicity, relation to care recipient, interventionist race or ethnicity, and care recipient activities of daily living. The loss to follow-up model also controlled for care recipient institutionalization and death. RESULTS: Overall, there was no difference in caregiver loss to follow-up or change in depression or burden by racial or ethnic concordance. African-American caregivers with an interventionist of the same race or ethnicity had greater decreases in depression than did African-American caregivers with interventionists of a different race or ethnicity. However, this finding has to be interpreted cautiously because there were only two African-American interventionists. IMPLICATIONS: Although these initial findings do not provide conclusive evidence on whether racial or ethnic concordance is associated with intervention outcomes for caregivers of Alzheimer's disease patients, these results, along with the paucity of research studies evaluating this issue, suggest that the effects of racial or ethnic concordance in research should be systematically examined in future studies.

Data and safety monitoring in social behavioral intervention trials: the REACH II experience.

BACKGROUND: Psychosocial and behavioral interventions trials targeting a broad range of complex social and behavioral problems such as smoking, obesity and family caregiving have proliferated in the past 30 years. At the same time the use of Data and Safety Monitoring Boards (DSMBs) to monitor the progress and quality of intervention trials and the safety of study participants has increased substantially. Most of the existing literature and guidelines for safety monitoring and reporting of adverse events focuses on medical interventions. Consequently, there is little guidance for investigators conducting social and behavior trials. PURPOSE: This paper summarizes how issues associated with safety monitoring and adverse event reporting were handled in the Resources for Enhancing Alzheimer's Caregiver Health (REACH II) program, a multi-site randomized clinical trial, funded by the National Institutes on Aging (NIA) and the National Institutes of Nursing Research (NINR), that tested the efficacy of a multicomponent social/behavioral intervention for caregivers of persons with Alzheimer's disease. METHODS: A task force was formed to define adverse events for the trial and protocols for reporting and resolving events that occurred. The task force conducted a review of existing polices and protocols for data and safety monitoring and adverse event reporting and identified potential risks particular to the study population. An informal survey regarding data and safety monitoring procedures with investigators on psychosocial intervention trials was also conducted. RESULTS: Two categories of events were defined for both caregivers and patients; adverse events and safety alerts. A distinction was also made between events detected at baseline assessment and those detected post-randomization. Standardized protocols were also developed for the reporting and resolution of events that occurred and training of study personnel. Results from the informal survey indicated wide variability in practices for data safety and monitoring across psychosocial intervention trials. CONCLUSIONS: Overall, the REACH II experience demonstrates that existing guidelines regarding safety monitoring and adverse event reporting pose unique challenges for social/behavioral intervention trials. Challenges encountered in the REACH II program included defining and classifying adverse events, defining "resolution" of adverse events and attributing causes for events that occurred. These challenges are highlighted and recommendations for addressing them in future studies are discussed.