Coffee, PI3K signaling pathway, and prostate cancer: a prospective study in the Health Professionals Follow-up Study.

BACKGROUND: Higher coffee intake has been associated with reduced risk of prostate cancer, particularly aggressive forms. The activation of the PI3K signaling pathway plays an important role in prostate carcinogenesis. OBJECTIVE: To evaluate associations between pre-diagnostic coffee intake and a PI3K activation score, the expression/presence of PI3K regulators, and downstream effectors in tumor tissue from men with prostate cancer in the Health Professionals Follow-up Study, a prospective cohort study conducted in the US. DESIGN: A case-only study design was applied. Coffee intake was assessed using validated food frequency questionnaires completed in 1986 and every four years thereafter until prostate cancer diagnosis. PARTICIPANTS/SETTING: Study participants comprised 1,242 men diagnosed with prostate cancer from 1986 to 2009 and with tumor markers assessed from tissue microarrays constructed from tumor specimens. MAIN OUTCOME MEASURES: The outcomes include the PI3K activation score; expression of insulin receptor and IGF1 receptor; angiogenesis markers; and presence of the tumor suppressor PTEN, chronic and acute inflammation, simple atrophy, and post-atrophic hyperplasia. STATISTICAL ANALYSES PERFORMED: Multivariable linear or logistic regression was conducted to estimate associations between coffee intake and tumor marker expression/presence. RESULTS: Among coffee drinkers (86.6% of the population), median (25th-75th) coffee intake was 2 (1-3) cups/day. The associations between coffee consumption and the tumor markers of interest were generally weak with modest precision. When comparing men who drank >3 cups/day of coffee with nondrinkers, the absolute percent difference in the PI3K activation score and angiogenesis markers ranged from 0.6% to 3.6%. The odds ratios for PTEN loss, IGF1 receptor and insulin receptor expression, and presence of chronic and acute inflammation, simple atrophy, and post-atrophic hyperplasia also were not statistically significant, were imprecise, and ranged from 0.82 to 1.58. CONCLUSIONS: Coffee intake was not observed to be associated with PI3K activation, related regulators, and several effectors in prostate tumor tissue. Studies exploring alternative pathways or earlier steps in carcinogenesis are needed to investigate the underlying mechanisms of the coffee and prostate cancer association.

Exploring communication preferences and risk thresholds of clinicians and parents of febrile infants under 90 days presenting to the emergency department: a qualitative study.

BACKGROUND: Febrile infants under 3 months of age are at higher risk of invasive bacterial illness (IBI) when compared with older children. Increasingly sequential assessment based on age, clinical appearance and biomarkers is used to determine the risk of IBI, and appropriateness of invasive procedures such as lumbar puncture. The purpose of this qualitative study is to report parents and clinicians' opinions on communication of risks and benefits of sequential assessment and tailored treatment. METHODS: 18 parents enrolled in the Febrile Infant Diagnostic Assessment and Outcomes study and seven clinicians from England, Wales and Northern Ireland were purposively selected to participate in virtual qualitative interviews. Data were analysed thematically. RESULTS: Tailored treatment plans were widely supported. Confidence in the clinician was central to parents' attitude towards management recommendations. Parents' decision-making preferences change throughout their child's clinical journey, with an initial preference for clinician-led decisions evolving towards collaborative decision-making as their stress and anxiety reduce. There were widespread differences in preferences for how risk was discussed. Parents self-reported poor retention of information and felt communication adjuncts helped their understanding. Clinicians were generally positive about the use of clinical decision aids as a communication tool, rather than relying on them for decision-making. DISCUSSION: Parents want to feel informed, but their desire to be involved in shared decision-making evolves over time.Clinicians appear to use their clinical judgement to provide individualised information, evolving their communication in response to perceived parental needs.Poor information retention highlights the need for repetition of information and use of communication adjuncts. TRIAL REGISTRATION NUMBER: NCT05259683.

Clinical outcomes in patients switching from agalsidase beta to migalastat: A Fabry Registry analysis.

Fabry Registry data were analyzed among 83 agalsidase beta-treated patients with Fabry disease who switched to migalastat. Outcomes (estimated glomerular filtration rate [eGFR], urine protein-creatinine ratio [UPCR], plasma globotriaosylceramide [GL-3], plasma globotriaosylsphingosine [lyso-GL-3], interventricular septal wall thickness [IVST], left posterior wall thickness [LPWT], left ventricular mass index [LVMI]) were assessed using linear mixed models to estimate annual change over time in the pre- and postswitch periods. eGFR decreased throughout both periods (preswitch: -0.85 mL/min/1.73 m2/year; postswitch: -1.96 mL/min/1.73 m2/year; both p < 0.0001), with steeper decline postswitch (ppre/post = 0.01) in both classic and late-onset patients. UPCR increased significantly postswitch (ppre/post = 0.003) among classic patients and was stable in both periods among late-onset patients. GL-3 trajectories worsened postswitch across phenotypes (ppre/post = 0.0005 classic, 0.02 late-onset). LPWT was stable preswitch (0.07 mm/year, p = 0.25) and decreased postswitch (-0.51 mm/year, p = 0.0005; ppre/post = 0.0009), primarily among late-onset patients. IVST and LVMI slopes varied significantly by phenotype. Among classic patients, IVST and LVMI were stable and decreasing, respectively preswitch and increasing postswitch (ppre/post = 0.02 IVST, 0.01 LVMI). Among late-onset patients, IVST significantly decreased postswitch (ppre/post = 0.0003); LVMI was stable over time (ppre/post = 0.89). Ultimately, eGFR and GL-3 trajectories worsened postswitch across phenotypes, while UPCR and cardiac measures worsened among classic and stabilized/improved among late-onset patients. These findings indicate variability in long-term outcomes after switching from ERT to migalastat, underscoring the importance of careful monitoring.

Reach and Weight Loss Among Comparison Group Participants Who Enrolled in the Active Intervention After a Diabetes Prevention Trial.

We examined participation rates, engagement, and weight-loss outcomes of comparison group participants in a diabetes prevention trial who enrolled in a digitally delivered diabetes prevention program (ie, an active intervention) after the original trial ended. We evaluated these outcomes by using the Wilcoxon signed-rank test and 1-sample z test. We found a high participation rate (73%) among comparison group participants and comparable weight-loss outcomes at 12 months (6.8 lb) after initiating participation in the active intervention relative to intervention group participants during the original trial. Findings support providing evidence-based interventions for comparison or control group participants post-trial. Findings also support examining the cost-effectiveness of post-trial interventions, regardless of the limitations of acquiring post-trial data on weight in an uncontrolled setting.

Changes in forced vital capacity over ≤ 13 years among patients with late-onset Pompe disease treated with alglucosidase alfa: new modeling of real-world data from the Pompe Registry.

BACKGROUND: Chronic respiratory insufficiency from progressive muscle weakness causes morbidity and mortality in late-onset Pompe disease (LOPD). Previous Pompe Registry (NCT00231400) analyses for ≤ 5 years' alglucosidase alfa treatment showed a single linear time trend of stable forced vital capacity (FVC) % predicted. METHODS: To assess longer term Pompe Registry data, piecewise linear mixed model regression analyses estimated FVC% predicted trajectories in invasive-ventilator-free patients with LOPD aged ≥ 5 years. We estimated annual FVC change 0-6 months, > 6 months-5 years, and > 5-13 years from treatment initiation, adjusting for baseline age, sex, and non-invasive ventilation. FINDINGS: Among 485 patients (4612 FVC measurements; 8.3 years median follow-up), median ages at symptom onset, diagnosis, and alglucosidase alfa initiation were 34.3, 41.1, and 44.9 years, respectively. FVC% increased during the first 6 months' treatment (slope 1.83%/year; 95% confidence interval: 0.66, 3.01; P = 0.0023), then modestly declined -0.54%/year (-0.79, -0.30; P < 0.0001) during > 6 months-5 years, and -1.00%/year (-1.36, -0.63; P < 0.0001) during > 5-13 years. The latter two periods' slopes were not significantly different from each other (Pdifference = 0.0654) and were less steep than published natural history slopes (-1% to -4.6%/year). Estimated individual slopes were ≥ 0%/year in 96.1%, 30.3%, and 13.2% of patients during the 0-6 month, > 6 month-5 year, and > 5-13 year periods, respectively. CONCLUSION: These real-world data indicate an alglucosidase alfa benefit on FVC trajectory that persists at least 13 years compared with published natural history data. Nevertheless, unmet need remains since most individuals demonstrate lung function decline 5 years after initiating treatment. Whether altered FVC trajectory impacts respiratory failure incidence remains undetermined. TRIAL REGISTRATION: This study was registered (NCT00231400) on ClinicalTrials.gov on September 30, 2005, retrospectively registered.

Higher dose alglucosidase alfa is associated with improved overall survival in infantile-onset Pompe disease (IOPD): data from the Pompe Registry.

BACKGROUND: Studies indicate that doses of alglucosidase alfa (ALGLU) higher than label dose (20 mg/kg every other week) improve clinical outcomes in infantile-onset Pompe disease (IOPD). We investigated data from the Pompe Registry to determine the association between ALGLU dose and survival in IOPD. RESULTS: We included 332 IOPD patients from the Registry as of January 2022 who had cardiomyopathy and were first treated at age < 1 year. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between ALGLU as a time-varying exposure and survival, adjusting for age at first treatment, sex, and cross-reactive immunologic material (CRIM)/immune tolerance induction (ITI) status. Dose was measured as average relative dose received over time (in multiples of label dose, range > 0 to 4 times label dose), current dose, and lagged dose. 81% patients received label dose at treatment initiation. Over time, 52% received a higher dose. Higher ALGLU dose over time was associated with improved survival: adjusted HR 0.40 (95% CI 0.22-0.73, p = 0.003) per 1-unit increase in average relative dose, with similar results for invasive ventilation-free survival (adjusted HR 0.48, 95% CI 0.28-0.84; p = 0.010). The association was consistent in patients first treated before or after 3 months of age and did not vary significantly by CRIM status. Results for current and lagged dose were similar to average dose. CONCLUSIONS: Higher ALGLU doses were associated with significantly improved overall and invasive ventilator-free survival in IOPD. Results were consistent across sensitivity analyses.

Applying clinical decision aids for the assessment and management of febrile infants presenting to emergency care in the UK and Ireland: Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study protocol.

INTRODUCTION: Febrile infants 90 days and younger are at risk of invasive bacterial infections (bacteraemia and meningitis) and urinary tract infections. Together this is previously termed serious bacterial infection with an incidence of approximately 10-20%. The National Institute for Health and Care Excellence guidance advocates a cautious approach with most infants requiring septic screening, parenteral broad-spectrum antibiotics and hospital admission. Internationally, variations exist in the approach to febrile infants, with European and North American guidance advocating a tailored approach based on clinical features and biomarker testing. None of the available international clinical decision aids (CDAs) has been validated in the UK and Irish cohorts. The aim of the Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study is to prospectively validate a range of CDAs in a UK and Irish population including CDAs that use procalcitonin testing. METHODS AND ANALYSIS: The FIDO Study is a prospective multicentre mixed-methods cohort study conducted in UK and Irish hospitals. All infants aged 90 days and younger presenting with fever or history of fever (≥38°C) are eligible for inclusion. Infants will receive standard emergency clinical care without delay. Clinical data and blood samples will be collected, and consent will be obtained at the earliest appropriate opportunity using research without prior consent methodology. The performance and cost-effectiveness of CDAs will be assessed. An embedded qualitative study will explore clinician and caregiver views on different approaches to care and perceptions of risk. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Office for Research Ethics Committees Northern Ireland-Health and Social Care Research Ethics Committee B, Public Benefit and Privacy Panel for Health and Social Care Scotland, and Children's Health Ireland Research and Ethics Committee Ireland. The results of this study will be presented at academic conferences and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05259683.

Evaluation of statin use and renal cell carcinoma risk identifies sex-specific associations with RCC subtypes.

Background: The association between statin use and risk of renal cell carcinoma (RCC) has been debated. We aimed to evaluate whether statin use is associated with RCC risk.Material and methods: We studied 100,195 women in the Nurses' Health Study (NHS) from 1994 to 2016; 91,427 women in the Nurses' Health Study II (NHS II) from 1999 to 2015; and 45,433 men in the Health Professionals Follow-up Study (HPFS) from 1990 to 2016. Statins and covariate data were collected at baseline and then biennially. Outcome was measured as incidence of total RCC and clinically relevant disease subgroups. Cox proportional hazards models estimated covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).Results: During follow-up, 661 participants developed RCC. There was no significant association between the use of statins and the risk of overall RCC, fatal RCC, or advanced or localized disease. Across cohorts, the adjusted HR for ever vs. never users was 0.97 (95% CI 0.81-1.16). Female ever users of statins were at increased risk of high-grade disease in the NHS only (HR 1.75, 95% CI 1.07-2.85). Among men only, ≥4 years of statin use was associated with an increased risk of clear cell RCC (HR 1.65, 95% CI 1.10-2.47).Conclusions: Statin use was not associated with the overall risk of RCC. However, it was associated with an increased risk of high-grade disease among women in the NHS cohort and an increased risk of clear cell RCC among men. The reasons for these inconsistent results by sex are unclear.

Cost and cost-effectiveness analysis of a digital diabetes prevention program: results from the PREDICTS trial.

Although technology-assisted diabetes prevention programs (DPPs) have been shown to improve glycemic control and weight loss, information are limited regarding relevant costs and their cost-effectiveness. To describe a retrospective within-trial cost and cost-effectiveness analysis (CEA) to compare a digital-based DPP (d-DPP) with small group education (SGE), over a 1-year study period. The costs were summarized into direct medical costs, direct nonmedical costs (i.e., times that participants spent engaging with the interventions), and indirect costs (i.e., lost work productivity costs). The CEA was measured by the incremental cost-effectiveness ratio (ICER). Sensitivity analysis was performed using nonparametric bootstrap analysis. Over 1 year, the direct medical costs, direct nonmedical costs, and indirect costs per participant were $4,556, $1,595, and $6,942 in the d-DPP group versus $4,177, $1,350, and $9,204 in the SGE group. The CEA results showed cost savings from d-DPP relative to SGE based on a societal perspective. Using a private payer perspective for d-DPP, ICERs were $4,739 and $114 to obtain an additional unit reduction in HbA1c (%) and weight (kg), and were $19,955 for an additional unit gain of quality-adjusted life years (QALYs) compared to SGE, respectively. From a societal perspective, bootstrapping results indicated that d-DPP has a 39% and a 69% probability, at a willingness-to-pay of $50,000/QALY and $100,000/QALY, respectively, of being cost-effective. The d-DPP was cost-effective and offers the prospect of high scalability and sustainability due to its program features and delivery modes, which can be easily translated to other settings.

Although technology-assisted DPPs have been shown to improve glycemic control and/or weight loss, information is limited on examining relevant costs and the cost-effectiveness of DPPs with the use of remote technologies within a randomized controlled trial design. We evaluated the costs associated with a d-DPP and further examined the cost-effectiveness of the d-DPP with an enhanced usual care condition. The d-DPP was cost-effective in achieving HbA1c reduction and weight loss and offers the prospect of high scalability and sustainability due to its program features and delivery modes, which can be easily translated to other settings.

Effects of a digital diabetes prevention program on cardiovascular risk among individuals with prediabetes.

OBJECTIVE: To examine changes in cardiovascular disease (CVD) risk outcomes of overweight/obese adults with prediabetes. METHODS: Using data from a randomized control trial of digital diabetes prevention program (d-DPP) with 599 participants. We applied the atherosclerotic CVD (ASCVD) risk calculator to predict 10-year CVD risk for d-DPP and small education (comparison) groups. Between-group risk changes at 4 and 12 months were compared using a repeated measures linear mixed-effect model. We examined within-group differences in proportion of participants over time for specific CVD risk factors using generalized estimating equations. RESULTS: We found no differences between baseline 10-year ASCVD risk. Relative to the comparison group, the d-DPP group experienced greater reductions in predicted 10-year ASCVD risk at each follow-up visit and a significant group difference at 4 months (-0.96%; 95% confidence interval: -1.58%, -0.34%) (but not at 12 months). Additionally, we observed that the d-DPP group experienced a decreased proportion of individuals with hyperlipidemia (18% and 16% from baseline to 4 and 12 months), high-risk total cholesterol (8% from baseline to 12 months), and being insufficiently active (26% and 22% from baseline to 4 and 12 months at follow-up time points. CONCLUSIONS: Our findings suggest that a digitally adapted DPP may promote the prevention of cardiometabolic disease among overweight/obese individuals with prediabetes. However, given the lack of maintenance of effect on ASCVD risk at 12 months, there may also be a need for additional interventions to sustain the effect detected at 4 months.

Assessment of Patient Diversity and Equity of Care in a Tertiary Referral Interventional Pain Medicine Clinic.

OBJECTIVE: As an academic tertiary care interventional pain clinic, referrals are screened to ensure patients most likely to benefit from our services are accepted into the practice. The objective of this study is to assess for unconscious bias in the patient selection process. STUDY DESIGN: The demographic data of patients accepted into the practice was compared to patients not offered an appointment as a result of the screening process. SETTING: A university-based interventional pain center seeing patients referred from within the institution and broader community. METHODS: Three data management systems including an electronic health record, an appointment management system, and a financial records system, were queried to extract the patient characteristics and demographic data for all patients referred to the clinic between January 1, 2018, and December 31, 2019. Data were then analyzed for differences across these demographic characteristics to assess for unconscious bias. RESULTS: There were 3,465 patients meeting the criteria; 2975 were offered an appointment and 490 were not. The ages and genders were not clinically different between groups. There was a significant difference in the percentage of patients identifying as Hispanic being offered an appointment (1.82%) vs not being offered an appointment (3.88%) (P = 0.0016). There were no statistical differences in the race or preferred language of patients accepted for an appointment versus declined. CONCLUSIONS: While the screening process did not result in disparities across age, gender, race, or language preference, there was a statistical difference in patients identifying as Hispanic. As a result of this study, all patient identification has been removed from the review document to limit the likelihood of unconscious bias.

Growth in individuals with attenuated mucopolysaccharidosis type I during untreated and treated periods: Data from the MPS I registry.

Mucopolysaccharidosis Type I (MPS I) is caused by deficiency of α-L-iduronidase. Short stature and growth deceleration are common in individuals with the attenuated MPS I phenotype. Study objectives were to assess growth in individuals with attenuated MPS I enrolled in The MPS I Registry while untreated and after initiation of enzyme replacement therapy (ERT) with laronidase (recombinant human iduronidase). Individuals in the MPS I Registry with at least one observation for height and assigned attenuated MPS I phenotype as of September 2020 were included. The cohort included 142 males and 153 females 2-18 years of age. Age and sex adjusted standardized height-for-age z-scores during the natural history and ERT-treatment periods were assessed using linear mixed model repeated measures analyses. Growth curves were estimated during both periods and compared to standard growth charts from the Center for Disease Control (CDC). There was a significantly slower decline in height z-scores with age during the ERT-treated period compared to the natural history period. Estimated average height z-scores in the ERT-treatment versus the natural history period at age 10 were -2.4 versus -3.3 in females and -1.4 versus -2.9 in males (females first treated 3 year; males <4.1 year). While median height remained below CDC standards during both the natural history and ERT-treated periods for individuals with attenuated MPS I, laronidase ERT was associated with slower declines in height z-scores.

Obesity in Relation to Renal Cell Carcinoma Incidence and Survival in Three Prospective Studies.

To disentangle the "obesity paradox" in renal cell carcinoma (RCC), we examined associations of body mass index (BMI) and weight change with RCC risk and survival in the Health Professionals Follow-up Study (HPFS) and Nurses' Health Study (NHS) 1 and 2. We estimated cohort-specific and summary covariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for RCC incidence, as well as RCC-specific survival among cases in the pooled HPFS and NHS data. Cumulative average BMI was associated with a higher risk of total RCC (summary HR 2.16, 95% CI 1.77-2.63 for BMI ≥30 vs 18-<25 kg/m2; p trend <0.001) and fatal RCC (HR 2.03, 95% CI 1.37-3.01; p trend <0.001). Prediagnosis BMI was not associated with RCC death. However, first postdiagnosis BMI (HR 0.51, 95% CI 0.29-0.89; p trend 0.006) and prediagnosis to postdiagnosis weight change (HR 0.52, 95% CI 0.29-0.91; p trend 0.001) were significantly inversely associated with RCC death. These results support obesity as a risk factor for total and fatal RCC. They undermine the obesity paradox by suggesting that weight loss around diagnosis, and not low BMI itself, is associated with worse prognosis. PATIENT SUMMARY: We studied obesity in kidney cancer and found that obesity is associated with getting and dying from the disease. Body mass index at diagnosis is not an ideal factor for predicting prognosis, as patients who have lost weight are likely to have more aggressive cancer.

Racial Disparities in Prostate Cancer: Evaluation of Diet, Lifestyle, Family History, and Screening Patterns.

BACKGROUND: Racial disparities in prostate cancer incidence and mortality rates are considerable. We previously found in the Health Professionals Follow-up Study (HPFS) that African-American men had an 80% higher prostate cancer risk than White men. With 21 additional years of follow-up and four-fold increase in cases, we undertook a contemporary analysis of racial differences in prostate cancer incidence and mortality in HPFS. METHODS: For 47,679 men, we estimated HRs and 95% confidence intervals (CI) for the association between race and risk of prostate cancer through 2016 using Cox proportional hazards regression. Multivariable models (mHR) were adjusted for lifestyle, diet, family history, and PSA screening collected on biennial questionnaires. RESULTS: 6,909 prostate cancer cases were diagnosed in White, 89 in African-American, and 90 in Asian-American men. African-Americans had higher prostate cancer incidence (mHR = 1.31; 95% CI, 1.06-1.62) and mortality (mHR = 1.67; 95% CI, 1.00-2.78), and lower PSA screening prevalence than White men. The excess risk was greater in the pre-PSA screening era (HR = 1.68; 95% CI, 1.14-2.48) than the PSA screening era (HR = 1.20; 95% CI, 0.93-1.56). Asian-Americans had lower prostate cancer risk (mHR = 0.74; 95% CI, 0.60-0.92), but similar risk of fatal disease compared with white men. CONCLUSIONS: Racial differences in prostate cancer incidence and mortality in HPFS are not fully explained by differences in lifestyle, diet, family history, or PSA screening. IMPACT: Additional research is necessary to address the disproportionately higher rates of prostate cancer in African-American men.

5-Alpha Reductase Inhibitors and Prostate Cancer Mortality among Men with Regular Access to Screening and Health Care.

BACKGROUND: How 5-alpha reductase inhibitor (5-ARI) use influences prostate cancer mortality is unclear. The objective of this study was to determine whether men taking 5-ARIs with regular health care access have increased prostate cancer mortality. METHODS: We undertook two analyses in the Health Professionals Follow-up Study examining 5-ARI use, determined by biennial questionnaires, and prostate cancer. A cohort analysis followed 38,037 cancer-free men for prostate cancer incidence from 1996 through January 2017 and mortality through January 2019. A case-only analysis followed 4,383 men with localized/locally advanced prostate cancer for mortality over a similar period. HRs and 95% confidence intervals (CI) were calculated for prostate cancer incidence and mortality. RESULTS: Men using 5-ARIs underwent more PSA testing, prostate exams and biopsies. Over 20 years of follow-up, 509 men developed lethal disease (metastases or prostate cancer death). Among men initially free from prostate cancer, 5-ARI use was not associated with developing lethal disease [HR, 1.02; 95% confidence interval (CI), 0.71-1.46], but was associated with reduced rates of overall and localized disease (HR, 0.71; 0.60-0.83). Among men diagnosed with prostate cancer, there was no association between 5-ARI use and cancer-specific (HR, 0.78; 95% CI, 0.48-1.27) or overall survival (HR, 0.88; 95% CI, 0.72-1.07). CONCLUSIONS: Men using 5-ARIs were less likely to be diagnosed with low-risk prostate cancer, without increasing long-term risk of lethal prostate cancer or cancer-specific death after diagnosis. IMPACT: Our results provide evidence that 5-ARI use is safe with respect to prostate cancer mortality in the context of regular health care access. See related commentary by Hamilton, p. 1259.

Effects of a Digital Diabetes Prevention Program: An RCT.

INTRODUCTION: In light of the need to expand the reach and access of clinically proven digital Diabetes Prevention Programs (d-DPPs) and the need for rigorous evidence of effectiveness, the purpose of this study was to determine the effectiveness of a digital Diabetes Prevention Program for improving weight, HbA1c, and cardiovascular risk factors among people with prediabetes compared to enhanced standard care plus waitlist control. STUDY DESIGN: This was a single-blind RCT among participants at risk of developing type 2 diabetes and included 12 months of follow-up. SETTING/PARTICIPANTS: A total of 599 volunteer patients with prediabetes were recruited primarily through electronic medical records and primary care practices. INTERVENTION: Participants were randomized to either a d-DPP (n=299) or a single-session small-group diabetes-prevention education class (n=300) focused on action planning for weight loss. The d-DPPs consisted of 52 weekly sessions, lifestyle coaching, virtual peer support, and behavior tracking tools. MAIN OUTCOME MEASURES: The primary outcome was a change in HbA1c from baseline to 12 months using intent-to-treat analyses. On the basis of multiple comparisons of endpoints, 95% CIs are presented and 2-sided p<0.025 was required for statistical significance. Secondary outcomes included body weight and cardiovascular disease risk factors. RESULTS: Among 599 randomized participants (mean age=55.4 years, 61.4% women), 483 (80%) completed the study. The d-DPPs produced significantly greater reductions in HbA1c (0.08%, 95% CI= -0.12, -0.03) and percentage change in body weight (-5.5% vs -2.1%, p<0.001) at 12 months. A greater proportion of the d-DPPs group achieved a clinically significant weight loss ≥5% (43% vs 21%, p<0.001), and more participants shifted from prediabetes to normal HbA1c range (58% vs 48%, p=0.04). Engagement in d-DPPs was significantly related to improved HbA1c and weight loss. CONCLUSIONS: This d-DPPs demonstrated clinical effectiveness and has significant potential for widespread dissemination and impact, particularly considering the growing demand for telemedicine in preventive healthcare services. TRIAL REGISTRATION: This study is registered at www. CLINICALTRIALS: gov (ClinicalTrials.gov Identifier: NCT03312764).

Circulating Insulin-Like Growth Factor 1-Related Biomarkers and Risk of Lethal Prostate Cancer.

Background: Experimental and epidemiologic evidence supports the role of circulating insulin-like growth factor-1 (IGF-1) levels with the risk of prostate cancer. Most circulating IGF-1 is bound to specific binding proteins, and only about 5% circulates in a free form. We explored the relation of free IGF-1 and other components of the IGF system with lethal prostate cancer. Methods: Using prospectively collected samples, we undertook a nested case-only analysis among 434 men with lethal prostate cancer and 524 men with indolent, nonlethal prostate cancer in the Physicians' Health Study and the Health Professionals Follow-up Study. Prediagnostic plasma samples were assayed for free IGF-1 and total IGF-1, acid labile subunit, pregnancy-associated plasma protein A (PAPP-A), and intact and total IGF binding protein 4. We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the associations between IGF-1-related biomarkers and lethal prostate cancer using unconditional logistic regression models adjusted for age, height, and body mass index. Results: Men in the highest quartile of PAPP-A levels had 42% higher odds of lethal prostate cancer (pooled adjusted OR = 1.42, 95% CI = 1.04 to 1.92) compared with men in the lowest 3 quartiles. There were no statistically significant differences in the other plasma analytes. The positive association between PAPP-A and lethal prostate cancer was present among men with intact PTEN but not among those with tumor PTEN loss (2-sided P interaction = .001). Conclusions: Our study provides suggestive evidence that among men who later develop prostate cancer, higher plasma PAPP-A levels measured prior to diagnosis are associated with increased risk of lethal compared with indolent disease.

Does environmental message framing impact proportional reach and sample representativeness related to motivational characteristics?

Physical activity (PA) promotion messages are commonly used to engage target populations in PA programs. However, little is known about how recruitment messages impact program reach. Evidence suggests that framing messages to be congruent with individuals' motivational orientation can maximize effectiveness. This congruency effect has not been tested in the context of brief PA promotion messages used in a recruitment environment. It is plausible that framed messages attract certain individuals, while deterring others. The purpose of this study was to determine whether message framing influences representativeness of a sample recruited for a PA program with regards to motivational factors. Three messaging conditions (gain-framed, neutral, loss-framed) were counterbalanced across days of data collection in a primary care waiting room. Patients were asked to complete a questionnaire including surveys on personality and PA, and basic demographic questions. Respondents were offered the chance to participate in a low-burden PA program. Interested respondents were instructed to provide contact information. The proportion and representativeness, with respect to motivational orientation, of individuals volunteering for program participation was assessed using chi-squared tests, and two-way (condition × group) ANOVAs, respectively. After controlling for demographic and behavioral covariates, there was no effect of message framing on the motivational orientation of the resultant samples. Results did not support a congruency effect of a covert message-framing manipulation. More work should aim to understand how recruitment materials and strategies influence motivational characteristics of the resulting sample to maximize intervention outcomes, and target individuals who are more likely to engage in risky health behaviors.