Risks of peri- and postoperative complications with glucagon-like peptide-1 receptor agonists.

AIM: To assess whether adults with diabetes on oral hypoglycaemic agents undergoing general endotracheal anaesthesia during nine common surgical procedures who are glucagon-like peptide-1 receptor agonist (GLP1-RA) users, compared with non-users, are at increased risk of six peri- and post-procedure complications. MATERIALS AND METHODS: A retrospective observational cohort analysis of over 130 million deidentified US adults with diabetes (defined as being on oral hypoglycaemic agents) from a nationally representative electronic health dataset between 1 January 2015 and 1 April 2023 was analysed. Cohorts were matched by high-dimensionality propensity scoring. We compared the odds of six peri- and postoperative complications in GLP1-RA users and non-users. A sensitivity analysis compared these odds in GLP1-RA users to non-users with diabetes and obesity. We measured the odds of (a) a composite outcome of postoperative decelerated gastric emptying, including antiemetic use, ileus within 7 days post-procedure, gastroparesis diagnosis, gastric emptying study; (b) postoperative aspiration or pneumonitis; (c) severe respiratory failure; (d) postoperative hypoglycaemia; (e) inpatient mortality; and (f) 30-day mortality. RESULTS: Among 13 361 adults with diabetes, 16.5% were treated with a GLP1-RA. In the high-dimensionality propensity score-matched cohort, GLP1-RA users had a lower risk of peri- and postoperative complications for decelerated gastric emptying and antiemetic use compared with non-users. The risk of ileus within 7 days, aspiration/pneumonitis, hypoglycaemia and 30-day mortality were not different. A sensitivity analysis showed similar findings in patients with diabetes and obesity. CONCLUSION: No increased risk of peri- and postoperative complications in GLP1-RA users undergoing surgery with general endotracheal anaesthesia was identified.

Chondrocyte Invasion May Be a Mechanism for Persistent Staphylococcus Aureus Infection In Vitro.

BACKGROUND: Recurrent bone and joint infection with Staphylococcus aureus is common. S. aureus can invade and persist in osteoblasts and fibroblasts, but little is known about this mechanism in chondrocytes. If S. aureus were able to invade and persist within chondrocytes, this could be a difficult compartment to treat. QUESTION/PURPOSE: Can S. aureus infiltrate and persist intracellularly within chondrocytes in vitro? METHODS: Cell lines were cultured in vitro and infected with S. aureus. Human chondrocytes (C20A4) were compared with positive controls of human osteoblasts (MG63) and mouse fibroblasts (NIH3T3), which have previously demonstrated S. aureus invasion and persistence (human fibroblasts were not available to us). Six replicates per cell type were followed for 6 days after infection. Cells were treated daily with antibiotic media for extracellular killing. To determine whether S. aureus can infiltrate chondrocytes, fluorescence microscopy was performed to qualitatively assess the presence of intracellular bacteria, and intracellular colony-forming units (CFU) were enumerated 2 hours after infection. To determine whether S. aureus can persist within chondrocytes, intracellular CFUs were enumerated from infected host cells each day postinfection. RESULTS: S. aureus invaded human chondrocytes (C20A4) at a level (2.8 x 105 ± 5.5 x 104 CFUs/mL) greater than positive controls of human osteoblasts (MG63) (9.5 x 102 ± 2.5 x 102 CFUs/mL; p = 0.01) and mouse fibroblasts (NIH3T3) (9.1 x 104 ± 2.5 x 104 CFUs/mL; p = 0.02). S. aureus also persisted within human chondrocytes (C20A4) for 6 days at a level (1.4 x 103 ± 5.3 x 102 CFUs/mL) greater than that of human osteoblasts (MG63) (4.3 x 102 ± 3.5 x 101 CFUs/mL; p = 0.02) and mouse fibroblasts (NIH3T3) (0 CFUs/mL; p < 0.01). S. aureus was undetectable within mouse fibroblasts (NIH3T3) after 4 days. There were 0 CFUs yielded from cell media, confirming extracellular antibiotic treatment was effective. CONCLUSION: S. aureus readily invaded human chondrocytes (C20A4) in vitro and persisted viably for 6 days after infection, evading extracellular antibiotics. Chondrocytes demonstrated a greater level of intracellular invasion and persistence by S. aureus than positive control human osteoblast (MG63) and mouse fibroblast (NIH3T3) cell lines. CLINICAL RELEVANCE: Chondrocyte invasion and persistence may contribute to recurrent bone and joint infections. Additional research should assess longer periods of persistence and whether this mechanism is present in vivo.

Is Risk-Stratifying Patients with Colorectal Cancer Using a Deep Learning-Based Prognostic Biomarker Cost-Effective?

OBJECTIVES: Accurate risk stratification of patients with stage II and III colorectal cancer (CRC) prior to treatment selection enables limited health resources to be efficiently allocated to patients who are likely to benefit from adjuvant chemotherapy. We aimed to investigate the cost-effectiveness of a recently developed deep learning-based prognostic method, Histotyping, from the perspective of the Norwegian healthcare system. METHODS: Two partitioned survival models were developed to assess the cost-effectiveness of Histotyping for two treatment cohorts: patients with CRC stage II and III. For each of the two cohorts, Histotyping was used for risk stratification to assign adjuvant chemotherapy and was compared with the standard of care (SOC) (adjuvant chemotherapy to all patients). Health outcomes measured in the model were quality-adjusted life years (QALYs) and life years (LYs) gained. Deterministic and probabilistic sensitivity analyses were performed to determine the impact of uncertainty. Scenario analyses were performed to assess the impact of the parameters with the greatest uncertainty. RESULTS: Risk-stratifying patients with CRC stage II and III using Histotyping was dominant (less costly and more effective) compared to SOC. In patients with CRC stage II, the net monetary benefit of Histotyping was 270,934 Norwegian kroners (NOK) (year of valuation is 2021), and the net health benefit of Histotyping was 0.99. In stage III, the net monetary benefit of Histotyping was 195,419 NOK, and the net health benefit of Histotyping was 0.71. CONCLUSIONS:  Risk-stratifying patients with CRC using Histotyping prior to the administration of adjuvant chemotherapy is likely to be a cost-effective strategy in Norway.

Diabetes Technology Meeting 2023.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting from November 1 to November 4, 2023. Meeting topics included digital health; metrics of glycemia; the integration of glucose and insulin data into the electronic health record; technologies for insulin pumps, blood glucose monitors, and continuous glucose monitors; diabetes drugs and analytes; skin physiology; regulation of diabetes devices and drugs; and data science, artificial intelligence, and machine learning. A live demonstration of a personalized carbohydrate dispenser for people with diabetes was presented.

Latent profile analysis of college students' alcohol and cannabis co-use patterns after recreational cannabis legalization.

OBJECTIVE: Evidence is mixed on how young adults' cannabis and alcohol use and co-use patterns have changed following recreational cannabis legalization (RCL). Incorporating measures of frequency and intensity of use we examined changes in college students' use and co-use patterns following RCL. METHOD: Four-year college students (n = 845,589) ages 18-24 years participated in the National College Health Assessment between 2008 and 2018, including students from 7 states that enacted RCL and 42 that did not. Latent profile analyses identified six patterns of use from four indicator variables tapping frequency of cannabis use and frequency and intensity of alcohol use: Abstainers, Light Alcohol Only, Heavy Alcohol Only, Predominantly Heavy Cannabis Use, Moderate Co-use, and Heavy Co-use. RESULTS: Regression models that adjusted for time and person- and institution-level covariates indicated that students' exposure to RCL was associated with lower odds of being in the two alcohol-only use classes, higher odds of being in the Predominantly Heavy Cannabis Use, Heavy Co-Use and Abstainers classes, and was not significantly related to Moderate Co-Use class membership. CONCLUSIONS: RCL was positively associated with patterns of frequent cannabis use and frequent and intense co-use but also with abstinence. Use of alcohol-only became less prevalent after RCL. Research on how RCL influences the prevalence of problematic patterns of substance use will inform and improve prevention efforts.

Advanced Glycation Endproducts: A Marker of Long-term Exposure to Glycemia.

This article examines the importance of advanced glycation endproducts (AGEs) and summarizes the structure of AGEs, pathological changes associated with AGEs, the contribution of AGEs to metabolic memory, and the value of AGEs as a predictor of diabetic complications and cardiovascular disease in people with and without diabetes. As a practical focus, skin autofluorescence (SAF) is examined as an attractive approach for estimating AGE burden. The measurement of AGEs may be of significant value to specific individuals and groups, including Black and Hispanic/Latino Americans, as they appear to have higher concentrations of hemoglobin A1c (HbA1c) than would be predicted by other metrics of mean glycemia. We hypothesize that if the amount of glycation of HbA1c is greater than expected from measured glucose levels, and if AGEs are accumulating, then this accumulation of AGEs might account for the increased rate of complications of diabetes in populations with high rates of vascular disease and other complications. Thus, identifying and modifying the burden of AGEs based on measurement of AGEs by SAF may turn out to be a worthwhile metric to determine individuals who are at high risk for the complications of diabetes as well as others without diabetes at risk of vascular disease. We conclude that available evidence supports SAF as both a clinical measurement and as a means of evaluating interventions aimed at reducing the risks of vascular disease and diabetic complications.

Prioritizing Patient Experiences in the Management of Diabetes and Its Complications: An Endocrine Society Position Statement.

Diabetes can be an arduous journey both for people with diabetes (PWD) and their caregivers. While the journey of every person with diabetes is unique, common themes emerge in managing this disease. To date, the experiences of PWD have not been fully considered to successfully implement the recommended standards of diabetes care in practice. It is critical for health-care providers (HCPs) to recognize perspectives of PWD to achieve optimal health outcomes. Further, existing tools are available to facilitate patient-centered care but are often underused. This statement summarizes findings from multistakeholder expert roundtable discussions hosted by the Endocrine Society that aimed to identify existing gaps in the management of diabetes and its complications and to identify tools needed to empower HCPs and PWD to address their many challenges. The roundtables included delegates from professional societies, governmental organizations, patient advocacy organizations, and social enterprises committed to making life better for PWD. Each section begins with a clinical scenario that serves as a framework to achieve desired health outcomes and includes a discussion of resources for HCPs to deliver patient-centered care in clinical practice. As diabetes management evolves, achieving this goal will also require the development of new tools to help guide HCPs in supporting PWD, as well as concrete strategies for the efficient uptake of these tools in clinical practice to minimize provider burden. Importantly, coordination among various stakeholders including PWD, HCPs, caregivers, policymakers, and payers is critical at all stages of the patient journey.

Multiplex analysis of intratumoural immune infiltrate and prognosis in patients with stage II-III colorectal cancer from the SCOT and QUASAR 2 trials: a retrospective analysis.

BACKGROUND: Tumour-infiltrating CD8+ cytotoxic T cells confer favourable prognosis in colorectal cancer. The added prognostic value of other infiltrating immune cells is unclear and so we sought to investigate their prognostic value in two large clinical trial cohorts. METHODS: We used multiplex immunofluorescent staining of tissue microarrays to assess the densities of CD8+, CD20+, FoxP3+, and CD68+ cells in the intraepithelial and intrastromal compartments from tumour samples of patients with stage II-III colorectal cancer from the SCOT trial (ISRCTN59757862), which examined 3 months versus 6 months of adjuvant oxaliplatin-based chemotherapy, and from the QUASAR 2 trial (ISRCTN45133151), which compared adjuvant capecitabine with or without bevacizumab. Both trials included patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1. Immune marker predictors were analysed by multiple regression, and the prognostic and predictive values of markers for colorectal cancer recurrence-free interval by Cox regression were assessed using the SCOT cohort for discovery and QUASAR 2 cohort for validation. FINDINGS: After exclusion of cases without tissue microarrays and with technical failures, and following quality control, we included 2340 cases from the SCOT trial and 1069 from the QUASAR 2 trial in our analysis. Univariable analysis of associations with recurrence-free interval in cases from the SCOT trial showed a strong prognostic value of intraepithelial CD8 (CD8IE) as a continuous variable (hazard ratio [HR] for 75th vs 25th percentile [75vs25] 0·73 [95% CI 0·68-0·79], p=2·5 × 10-16), and of intrastromal FoxP3 (FoxP3IS; 0·71 [0·64-0·78], p=1·5 × 10-13) but not as strongly in the epithelium (FoxP3IE; 0·89 [0·84-0·96], p=1·5 × 10-4). Associations of other markers with recurrence-free interval were moderate. CD8IE and FoxP3IS retained independent prognostic value in bivariable and multivariable analysis, and, compared with either marker alone, a composite marker including both markers (CD8IE-FoxP3IS) was superior when assessed as a continuous variable (adjusted [a]HR75 vs 25 0·70 [95% CI 0·63-0·78], p=5·1 × 10-11) and when categorised into low, intermediate, and high density groups using previously published cutpoints (aHR for intermediate vs high 1·68 [95% CI 1·29-2·20], p=1·3 × 10-4; low vs high 2·58 [1·91-3·49], p=7·9 × 10-10), with performance similar to the gold-standard Immunoscore. The prognostic value of CD8IE-FoxP3IS was confirmed in cases from the QUASAR 2 trial, both as a continuous variable (aHR75 vs 25 0·84 [95% CI 0·73-0·96], p=0·012) and as a categorical variable for low versus high density (aHR 1·80 [95% CI 1·17-2·75], p=0·0071) but not for intermediate versus high (1·30 [0·89-1·88], p=0·17). INTERPRETATION: Combined evaluation of CD8IE and FoxP3IS could help to refine risk stratification in colorectal cancer. Investigation of FoxP3IS cells as an immunotherapy target in colorectal cancer might be merited. FUNDING: Medical Research Council, National Institute for Health Research, Cancer Research UK, Swedish Cancer Society, Roche, and Promedica Foundation.

Youth Exposure to Recreational Cannabis Legalization: Moderation of Effects by Sex and Parental Cannabis Use during Adolescence.

OBJECTIVE: Few studies of recreational cannabis legalization (RCL) have assessed adolescents both before and after RCL or considered moderators of RCL effects. The present study tested whether RCL was more strongly associated with cannabis use for girls and among youth whose parents had a history of cannabis use during adolescence. METHOD: Data were pooled from 940 adolescents from three intergenerational studies that began in Washington (where RCL was enacted in 2012), Oregon (RCL year = 2015), and New York (RCL year = 2021). Youth were assessed repeatedly from ages 13 to 18 years (k = 3,650 person-years) from 1999 to 2020 (prior to RCL in New York). Parent cannabis use at or before age 18 years (yes/no) was assessed prospectively during the parent's adolescence. Multilevel models focused on the between-subjects effects of years of youth exposure to RCL on adolescents' mean cannabis use likelihood, and interactions with child sex and parent use history. RESULTS: Child exposure to RCL was associated with a higher likelihood of cannabis use if their parents had a history of adolescent use, (Estimate [SE] = 0.67 [0.25], p = 0.008), versus no such history (Estimate [SE] = -0.05 [0.28], p = 0.855). RCL effects were not moderated by child sex. CONCLUSIONS: The effects of RCL on adolescents' cannabis use may depend on their parents' history of using the drug. Identifying other moderators of RCL effects, and understanding the mechanisms of these risks and the ways that parents and communities can offset them, are prevention priorities.

(1) Adolescents' use of cannabis may have intergenerational consequences, making it more likely their future offspring will use cannabis. (2) Whether or not recreational cannabis legalization influences adolescents' cannabis use may depend on their parents' cannabis use history. (3) Parenting in a state with liberalized cannabis policies may present new challenges and require that novel prevention resources be developed.

A probabilistic computation framework to estimate the dawn phenomenon in type 2 diabetes using continuous glucose monitoring.

In type 2 diabetes (T2D), the dawn phenomenon is an overnight glucose rise recognized to contribute to overall glycemia and is a potential target for therapeutic intervention. Existing CGM-based approaches do not account for sensor error, which can mask the true extent of the dawn phenomenon. To address this challenge, we developed a probabilistic framework that incorporates sensor error to assign a probability to the occurrence of dawn phenomenon. In contrast, the current approaches label glucose fluctuations as dawn phenomena as a binary yes/no. We compared the proposed probabilistic model with a standard binary model on CGM data from 173 participants (71% female, 87% Hispanic/Latino, 54 ± 12 years, with either a diagnosis of T2D for six months or with an elevated risk of T2D) stratified by HbA1c levels into normal but at risk for T2D, with pre-T2D, or with non-insulin-treated T2D. The probabilistic model revealed a higher dawn phenomenon frequency in T2D [49% (95% CI 37-63%)] compared to pre-T2D [36% (95% CI 31-48%), p = 0.01] and at-risk participants [34% (95% CI 27-39%), p < 0.0001]. While these trends were also found using the binary approach, the probabilistic model identified significantly greater dawn phenomenon frequency than the traditional binary model across all three HbA1c sub-groups (p < 0.0001), indicating its potential to detect the dawn phenomenon earlier across diabetes risk categories.

Evaluating Patient and Provider Preferences for a Once-Weekly Basal Insulin in Adults with Type 2 Diabetes.

Purpose: The global burden of disease of type 2 diabetes (T2D) is significant, and insulin currently plays a central role in T2D management. This study sought to assess the preferences of patients with T2D and healthcare providers (HCPs) involved in T2D care regarding a hypothetical once-weekly basal insulin in comparison to current basal insulin options. Patients and Methods: In a survey-based study in the United States that included a discrete choice experiment (DCE), patients with T2D (insulin naïve and current insulin users) and providers who treat individuals with T2D were asked to evaluate current basal insulins and identify attributes of importance regarding a hypothetical once-weekly basal insulin. A regression analysis was conducted to identify drivers of preference by relevant demographics, attitudes, and behaviors. Results: Most respondents (91% of patients with T2D and 89% of HCPs in the base case scenario) would choose a once-weekly basal insulin product over another type of basal insulin. Both patients with T2D and HCPs rated insulin type and delivery method to be attributes of highest importance in the discrete choice exercise. Current basal insulin users ("insulin experienced") reported higher levels of confidence that a once-weekly insulin would help them to achieve their desired blood sugar levels compared to their current basal insulin (5.7 vs 5.2 on a 7-point Likert scale). Most insulin-experienced respondents (88%) were likely to inquire about once-weekly basal insulin, and most HCPs (85%) indicated willingness to educate patients on management of their T2D using a once-weekly basal insulin. Conclusion: Discussing preferences for T2D medication management is important for patients and HCPs to ensure treatments are offered for patients based on their preferences. This study showed that patient and provider preferences are similar towards a once-weekly basal insulin over current basal insulin preparations.

Technology and health inequities in diabetes care: How do we widen access to underserved populations and utilize technology to improve outcomes for all?

Digital health technologies are being utilized increasingly in the modern management of diabetes. These include tools such as continuous glucose monitoring systems, connected blood glucose monitoring devices, hybrid closed-loop systems, smart insulin pens, telehealth, and smartphone applications (apps). Although many of these technologies have a solid evidence base, from the perspective of a person living with diabetes, there remain multiple barriers preventing their optimal use, creating a digital divide. In this article, we describe many of the origins of these barriers and offer recommendations on widening access to digital health technologies for underserved populations living with diabetes to improve their health outcomes.

Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. METHODS: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). RESULTS: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. CONCLUSIONS: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.

Multimodal digital phenotyping of diet, physical activity, and glycemia in Hispanic/Latino adults with or at risk of type 2 diabetes.

Digital phenotyping refers to characterizing human bio-behavior through wearables, personal devices, and digital health technologies. Digital phenotyping in populations facing a disproportionate burden of type 2 diabetes (T2D) and health disparities continues to lag compared to other populations. Here, we report our study demonstrating the application of multimodal digital phenotyping, i.e., the simultaneous use of CGM, physical activity monitors, and meal tracking in Hispanic/Latino individuals with or at risk of T2D. For 14 days, 36 Hispanic/Latino adults (28 female, 14 with non-insulin treated T2D) wore a continuous glucose monitor (CGM) and a physical activity monitor (Actigraph) while simultaneously logging meals using the MyFitnessPal app. We model meal events and daily digital biomarkers representing diet, physical activity choices, and corresponding glycemic response. We develop a digital biomarker for meal events that differentiates meal events into normal and elevated categories. We examine the contribution of daily digital biomarkers of elevated meal event count and step count on daily time-in-range 54-140 mg/dL (TIR54-140) and average glucose. After adjusting for step count, a change in elevated meal event count from zero to two decreases TIR54-140 by 4.0% (p = 0.003). An increase in 1000 steps in post-meal step count also reduces the meal event glucose response by 641 min mg/dL (p = 0.0006) and reduces the odds of an elevated meal event by 55% (p < 0.0001). The proposed meal event digital biomarkers may provide an opportunity for non-pharmacologic interventions for Hispanic/Latino adults facing a disproportionate burden of T2D.

NIH Fifth Artificial Pancreas Workshop 2023: Meeting Report: The Fifth Artificial Pancreas Workshop: Enabling Fully Automation, Access, and Adoption.

The Fifth Artificial Pancreas Workshop: Enabling Fully Automation, Access, and Adoption was held at the National Institutes of Health (NIH) Campus in Bethesda, Maryland on May 1 to 2, 2023. The organizing Committee included representatives of NIH, the US Food and Drug Administration (FDA), Diabetes Technology Society, Juvenile Diabetes Research Foundation (JDRF), and the Leona M. and Harry B. Helmsley Charitable Trust. In previous years, the NIH Division of Diabetes, Endocrinology, and Metabolic Diseases along with other diabetes organizations had organized periodic workshops, and it had been seven years since the NIH hosted the Fourth Artificial Pancreas in July 2016. Since then, significant improvements in insulin delivery have occurred. Several automated insulin delivery (AID) systems are now commercially available. The workshop featured sessions on: (1) Lessons Learned from Recent Advanced Clinical Trials and Real-World Data Analysis, (2) Interoperability, Data Management, Integration of Systems, and Cybersecurity, Challenges and Regulatory Considerations, (3) Adaptation of Systems Through the Lifespan and Special Populations: Are Specific Algorithms Needed, (4) Development of Adaptive Algorithms for Insulin Only and for Multihormonal Systems or Combination with Adjuvant Therapies and Drugs: Clinical Expected Outcomes and Public Health Impact, (5) Novel Artificial Intelligence Strategies to Develop Smarter, More Automated, Personalized Diabetes Management Systems, (6) Novel Sensing Strategies, Hormone Formulations and Delivery to Optimize Close-loop Systems, (7) Special Topic: Clinical and Real-world Viability of IP-IP Systems. "Fully automated closed-loop insulin delivery using the IP route," (8) Round-table Panel: Closed-loop performance: What to Expect and What are the Best Metrics to Assess it, and (9) Round-table Discussion: What is Needed for More Adaptable, Accessible, and Usable Future Generation of Systems? How to Promote Equitable Innovation? This article summarizes the discussions of the Workshop.

Personalizing adjuvant therapy for patients with colorectal cancer.

The current standard-of-care adjuvant treatment for patients with colorectal cancer (CRC) comprises a fluoropyrimidine (5-fluorouracil or capecitabine) as a single agent or in combination with oxaliplatin, for either 3 or 6 months. Selection of therapy depends on conventional histopathological staging procedures, which constitute a blunt tool for patient stratification. Given the relatively marginal survival benefits that patients can derive from adjuvant treatment, improving the safety of chemotherapy regimens and identifying patients most likely to benefit from them is an area of unmet need. Patient stratification should enable distinguishing those at low risk of recurrence and a high chance of cure by surgery from those at higher risk of recurrence who would derive greater absolute benefits from chemotherapy. To this end, genetic analyses have led to the discovery of germline determinants of toxicity from fluoropyrimidines, the identification of patients at high risk of life-threatening toxicity, and enabling dose modulation to improve safety. Thus far, results from analyses of resected tissue to identify mutational or transcriptomic signatures with value as prognostic biomarkers have been rather disappointing. In the past few years, the application of artificial intelligence-driven models to digital images of resected tissue has identified potentially useful algorithms that stratify patients into distinct prognostic groups. Similarly, liquid biopsy approaches involving measurements of circulating tumour DNA after surgery are additionally useful tools to identify patients at high and low risk of tumour recurrence. In this Perspective, we provide an overview of the current landscape of adjuvant therapy for patients with CRC and discuss how new technologies will enable better personalization of therapy in this setting.

State Alcohol Policy Environments of U.S. Colleges: Predictors of Sexual Assault and Alcohol-Related Arrest and Disciplinary Action.

INTRODUCTION: Binge drinking and sexual assault are serious inter-related public health problems faced by college students. State-level alcohol policy restrictiveness has been found to decrease binge drinking among college students and, therefore, may also reduce occurrences of alcohol-related criminal offenses. It was hypothesized that more restrictive state alcohol policy environments would be associated with fewer liquor law violations and sexual assault offenses on U.S. college campuses. METHODS: Data were aggregated across 3 academic years (2016-2017, 2017-2018, and 2018-2019) and represented n=1,290 institutions. Zero-inflated negative binomial regression modeling was performed in 2022-2023 to evaluate associations of state-level young adult binge drinking and the Alcohol Policy Scale (APS) with the numbers of campus-level alcohol-related arrests, alcohol-related disciplinary actions, rape offenses, and fondling offenses reported in national Campus Safety and Security data. RESULTS: Higher APS scores had direct associations with fewer alcohol-related arrests (1.79% decrease per one-unit increase in APS, p=0.05), alcohol-related disciplinary actions (2.27% decrease per one-unit increase in APS, p=0.027), and rape offenses (0.85% decrease per one-unit increase in APS, p=0.021). The associations APS scores had with disciplinary actions and rape offenses were partially and fully mediated, respectively, by state-level young adult binge drinking. No associations were found between APS and fondling offenses. CONCLUSIONS: This cross-sectional study presents evidence that more restrictive state alcohol policies are associated with fewer alcohol-related arrests and disciplinary actions, and rape offenses on college campuses. Future research should identify the alcohol policy domains that are most protective against these outcomes.

Children and young adults with profound and multiple learning disabilities: Evidence of intelligible subvocal language.

INTRODUCTION: Literature to date describes people with Profound and Multiple Learning Disabilities (PMLD) as pre-linguistic. In contrast, this study explores the existence and use of meaningful sub vocal (SV) language by twenty PMLD participants. METHOD: The SV utterances of 20 PMLD participants were recorded and amplified. Recordings were investigated for evidence of language content and structure, listener intelligibility, and acoustic and phonetic features relative to normal speech and whisper. RESULTS: Language content and structure was identified. Listener intelligibility was demonstrated. Acoustic and phonetic features relative to normal speech and whisper were evident. CONCLUSION: Twenty PMLD participants produced meaningful SV language intelligible to listeners. This study requires further robust research to fully confirm its findings but highlights implications for clinical practice and for understanding of PMLD communication competencies. This paper is accompanied by audio samples and transcriptions of recorded utterances to demonstrate the SV language produced by the participants. The quality of the samples varies due to the difficulties in recording SV utterances and the difficulties for participants in articulating clearly. This is not normal speech, but it is normal language. The listener may need to replay samples where the quality of the recording is poor.

The Co-Occurrence of Conduct Problems and Depressive Symptoms From Childhood to Adulthood for Men: Stability Over Time and Prediction to Substance Use.

The dual pathway hypothesis of risk for substance use was tested by examining risk from symptoms of conduct problems and depressive symptoms in adolescence (from ages 10-11 to 17-18 years) to substance use-including tobacco, alcohol, cannabis, and other illicit drugs-in both early adulthood (approximately from ages 20 to 29 years) and middle adulthood (approximately from ages 29 to 38 years). Hypotheses were tested on a sample of boys who were at risk for conduct problems by virtue of the neighborhoods where they lived in childhood (the Oregon Youth Study; N = 206 at Wave 1). Dual-trajectory modeling (Latent Class Analysis) resulted in a 3-group solution of high, moderate, and low co-occurring symptoms. The latent class of boys with co-occurring symptoms in adolescence showed higher levels of substance use in adulthood; namely, higher levels of cannabis and illicit substance use during early adulthood compared to either of the moderate or low symptom classes, and higher use of cannabis in midadulthood than the low symptom class. Those with co-occurring symptoms also showed, overall, higher vulnerability to use of tobacco in these 2 periods, but not to higher use of alcohol. Regression analyses indicated that the higher substance use of the co-occur group of men was related to their adolescent conduct problems, but was not related to their adolescent depressive symptoms; however, these associations were nonsignificant when adolescent use of the respective substances were included in the models. Thus, the dual-trajectory hypothesis was not supported. However, the findings indicated that, as assessed in the present study, the psychopathology symptoms of boys with conduct problems in adolescence who show risk for later substance use may be complex, involving depressive symptoms.

Accounting for intensity variation in image analysis of large-scale multiplexed clinical trial datasets.

Multiplex immunofluorescence (mIF) imaging can provide comprehensive quantitative and spatial information for multiple immune markers for tumour immunoprofiling. However, application at scale to clinical trial samples sourced from multiple institutions is challenging due to pre-analytical heterogeneity. This study reports an analytical approach to the largest multi-parameter immunoprofiling study of clinical trial samples to date. We analysed 12,592 tissue microarray (TMA) spots from 3,545 colorectal cancers sourced from more than 240 institutions in two clinical trials (QUASAR 2 and SCOT) stained for CD4, CD8, CD20, CD68, FoxP3, pan-cytokeratin, and DAPI by mIF. TMA slides were multi-spectrally imaged and analysed by cell-based and pixel-based marker analysis. We developed an adaptive thresholding method to account for inter- and intra-slide intensity variation in TMA analysis. Applying this method effectively ameliorated inter- and intra-slide intensity variation improving the image analysis results compared with methods using a single global threshold. Correlation of CD8 data derived by our mIF analysis approach with single-plex chromogenic immunohistochemistry CD8 data derived from subsequent sections indicates the validity of our method (Spearman's rank correlation coefficients ρ between 0.63 and 0.66, p ≪ 0.01) as compared with the current gold standard analysis approach. Evaluation of correlation between cell-based and pixel-based analysis results confirms equivalency (ρ > 0.8, p ≪ 0.01, except for CD20 in the epithelial region) of both analytical approaches. These data suggest that our adaptive thresholding approach can enable analysis of mIF-stained clinical trial TMA datasets by digital pathology at scale for precision immunoprofiling.