Ongoing Studies Research Articles

Neuro-oncology Treatment Strategies for Primary Glial Tumors.

Primary brain tumors underwent reclassification in the 2021 World Health Organization update, relying on molecular findings (especially isocitrate dehydrogenase mutations and chromosomal changes in 1p, 19q, gain of chromosome 7 and loss of chromosome 10). Newer entities have also been described including histone 3 mutant midline gliomas. These updated pathologic classifications improve prognostication and reliable diagnosis, but may confuse interpretation of prior clinical trials and require reclassification of patients diagnosed in the past. For patients over seventy, multiple studies have now confirmed the utility of shorter courses of radiation, and the risk of post-operative delirium. Ongoing studies are comparing proton to photon radiation. Long term follow up of prior clinical trials have confirmed the roles and length of chemotherapy (mainly temozolomide) in different tumors, as well as the wearable novottf device. New oral isocitrate dehydrogenase inhibitors have also shown efficacy in clinical trials.

Occupational health and safety regulatory interventions to improve the work environment: An evidence and gap map of effectiveness studies.

Unsafe and unhealthy working conditions lead to injuries and financial losses across the globe, resulting in a need for research into effective work environment interventions. The objective of this evidence and gap map (EGM) is to provide an overview of existing systematic reviews and primary studies examining the effects of occupational health and safety regulatory interventions. Relevant studies are identified through searches in published and unpublished literature performed up to January 2023. The population for this EGM is workers above the age of 15 and their workplaces within the OECD. We include randomised controlled trials, non-randomised studies with a comparison of two or more groups of participants, and systematic reviews of effects. The map has been populated based on information about interventions and outcomes, study design, OECD country, and publication status. We have performed critical appraisal of included systematic reviews using an adjusted version of the AMSTAR-2 tool. The included studies for this report consist of six systematic reviews, 28 primary effect studies, and three on-going studies. The interactive map shows that the largest cluster of studies is located in the inspection activity domain, while the sickness absence outcome domain and the intervention categories for training initiatives and formulation of regulatory standards are only scarcely populated. Additionally, the AMSTAR-appraisal suggests a lack of rigorous systematic reviews and meta-analyses. More research in the form of primary studies and rigorous systematic reviews is needed to provide stakeholders with better guidance as to what constitutes the most efficient regulatory approaches to improve the work environment.

Up-regulation by overexpression of c-MET in fibroblastic foci of usual interstitial pneumonia.

Usual interstitial pneumonia (UIP) is the radiologic and histologic hallmark of idiopathic pulmonary fibrosis (IPF) and the commonest histologic pattern of other progressive fibrosing interstitial lung diseases (e.g., fibrotic hypersensitivity pneumonia). Analogous to lung cancer, activation of epithelial-to-mesenchymal transition (EMT) is one of the main molecular pathways recently identified by transcriptomic studies in IPF. Fibroblastic foci (FF) are considered the active/trigger component of UIP pattern. The proto-oncogene C-MET is a key gene among molecules promoting EMT against which several inhibitors are currently available or promising in ongoing studies on lung cancer. Twenty surgical cases of diffuse fibrosing interstitial lung diseases (fILD) with UIP pattern and FF-rich (17 IPF and 3 patients with fibrotic hypersensitivity pneumonia, fHP) were retrospectively selected. FF were manually microdissected and analysed for c-MET gene alterations (FISH amplification and gene hot-spot mutations Sanger sequencing) and tested with a c-MET companion diagnostic antibody (clone SP44 metmab) by immunohistochemistry. FF are characterized by upregulation of c-MET as shown by overexpression of the protein in 80% of cases, while no gene amplification by FISH or mutations were detected. C-MET upregulation of FF was observed either in IPF and fHP, with a tropism for the epithelial cell component only. Upregulation of c-MET in FF of ILD with UIP pattern further confirms the key role of the proto-oncogene c-MET in its pathogenesis, possibly representing an interesting and easily-detectable molecular target for selective therapy using specific inhibitors in future clinical trials, similar to lung cancer. It is reasonable to speculate that molecular alterations in FF can also be detected in FF by transbronchial cryobiopsy.

Subcutaneous (SC) lecanemab is predicted to achieve comparable efficacy and improved safety compared to lecanemab IV in early Alzheimer’s disease (AD)

AbstractBackgroundLecanemab is an anti‐amyloid antibody that has been approved by the United States FDA for treatment of early AD under the accelerated approval pathway. Lecanemab 10 mg/kg every 2 weeks (Q2W) intravenously (IV) was shown in the CLARITY‐AD trial to slow the progression of AD. Pharmacokinetic/pharmacodynamic (PK/PD) modeling demonstrated that lecanemab average steady‐state concentrations (Cav,ss) are associated with amyloid plaque lowering and efficacy, while maximum steady‐state concentrations (Cmax,ss) are correlated with the incidence of amyloid‐related imaging abnormalities‐edema (ARIA‐E). SC lecanemab is being developed to improve patient convenience and safety profile by lowering the rate of ARIA‐E.MethodTwo single‐dose studies (NCT05045716 and NCT05533801) were conducted in healthy subjects to establish absolute bioavailability of a drug‐in‐vial (SC vial) formulation and to compare PK of SC vial and autoinjector (AI). In the first study, subjects were administered 10 mg/kg IV Q2W or 700 mg SC vial once‐weekly (QW) lecanemab (n = 30/arm). In the second study, subjects were administered 720 mg SC vial or 720 mg AI lecanemab (n = 80/arm). Serum lecanemab concentrations were measured for 50 days, and noncompartmental PK parameters were calculated.ResultThe absolute bioavailability of SC vial was 49.7% (90%CI:43.5‐56.8). Cmax following SC vial was 22.8% of IV (59.8 vs 262 µg/mL). AI had 20% higher AUC than SC vial (20900 vs 17400 µg.h/mL). PK modeling demonstrated that Cav,ss following 720 mg QW, administered by SC vial or AI, is similar to 10 mg/kg IV lecanemab. Cmax,ss following SC vial or AI will be approximately half that of IV. Based on these results, exposure‐response models predict similar amyloid plaque lowering and efficacy for IV, SC vial and AI. ARIA‐E rates are expected to be reduced with SC formulations (APOE4 carriers, IV:14.0%, SC Vial:4.8%, AI:5.6%; APOE4 noncarriers, IV:5.4%, SC Vial:1.7%, AI:2.0%).Conclusion720mg QW using SC vial or AI results in comparable Cav,ss to 10 mg/kg Q2W IV lecanemab and is expected to have similar amyloid plaque lowering and efficacy. SC lecanemab has the potential to substantially lower incidence of ARIA‐E compared to IV. Ongoing studies will confirm the safety and efficacy profiles of SC lecanemab.

Abstract IA019: Implementation science as an opportunity to address cancer equity

Abstract The past decade of research has continued to identify and understand health disparities for cancer prevention and control. Although emerging, progress in addressing these disparities continues to fall short achieving equity. Specifically, for cancer prevention and control, Khan and colleagues in 2021 showed a 15-year lag in implementation of evidence-based interventions (i.e., HPV vaccinations, cancer screenings, etc.). This gap highlights the lack of attention towards the implementation of scientific evidence, the complexity and fragmentation of health systems, and lays bare the structural causes of inequities that continue to persist from a population perspective. Integrating implementation science in cancer prevention and control research can provide a pathway to reduce the time to translation while addressing and advancing cancer equity. Implementation science is defined as the study of methods to promote the adoption and integration of evidence-based practices, interventions, and policies into routine health care and public health settings to improve the impact on population health. Implementation science has pushed the cancer prevention and control field to pay close attention to how we dissemination scientific information towards the adoption of interventions (i.e., dissemination research) and how we systematically study strategies (i.e., the building blocks) that aid in the implementation, scale-up, and sustainability of interventions (i.e., implementation science). With implementation research, there has been a push towards hybrid designs that considers intervention effectiveness and its implementation within the same study. Given the dearth of literature around the implementation of interventions, the science of implementation continues to build on a foundational theoretical base that further provide important opportunities for the promoting equitable outcomes for cancer prevention and control research. In this educational session, we will discuss why and how applying a health equity lens to implementation science is crucial to achieve equity in cancer prevention and control. Using ongoing and completed research studies as examples, this session will help attendees learn about core elements of implementation science including theories, models, and frameworks; implementation strategies; and focal areas of adaptations and de-implementation. Citation Format: Prajakta Adsul. Implementation science as an opportunity to address cancer equity [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr IA019.

Abstract C139: The robustness of a targeted methylation-based multi-cancer early detection (MCED) test to population differences in self-reported ethnicity

Abstract Background: DNA methylation (Me) is known to vary by race and ethnicity; cell-free DNA-based MCED tests must detect cancer-specific Me in the presence of this variation to be useful as a screening tool. Clinical study cohorts, however, often do not reflect the screening population. Additionally, underserved populations who may benefit most from improved cancer screening are often underrepresented. We sought to evaluate the robustness of an MCED test to detect cancer-specific Me patterns across self-reported ethnicity (SRE) in the training (N = 4487) and validation (N = 5309) datasets from the 15254-participant (pts) Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study. Methods: To understand MCED test performance across SRE, we assessed concordance between ancestry and SRE by genotype in CCGA. We then conducted two in silico experiments to assess the robustness of the MCED test to differences in SRE. First, MCED test classifier scores from 1254 non-cancer pts from the validation cohort were regressed against covariates of sex and SRE, with smoking status and age included as potential confounders. Two SRE groups were considered for the analysis: White, non-Hispanic (W; 996 pts) and all other non-White SRE (NW; 258 pts). Second, to evaluate classifier generalization across SRE, two experimental MCED test classifiers (single SRE, S; multiple SRE, M) were trained similarly to the MCED test with intentionally skewed SRE compositions: S with 100% W pts and M with all available NW pts (20% NW). The training sets for both classifiers further included pts from STRIVE (NCT03085888) and matched on demographics (age, sex, smoking status), number of pts, samples, cancer type and stage. Sensitivity (at 99.4% specificity) and accuracy of cancer signal origin (CSO) prediction for the two classifiers were assessed in a separate held out population of 507 NW cancer pts. Results: Ancestry and SRE by genotype were in good agreement with >95% concordance in CCGA study pts. Neither sex, smoking status, nor SRE were significantly correlated with MCED classifier scores; age was weakly (r2 < 0.01) associated. In the classifier training experiment, both S and M performed nearly identically for sensitivity (S: 57% [95% CI: 53-62], 290/507 vs M: 57% [52-61], 288/507; McNemar test, P > 0.5) and CSO prediction accuracy (S: 90% [86-93] 262/290 vs M: 91% [88-94] 263/288) in a diverse population of NW cancer pts, despite the relatively large difference in SRE training composition. Neither analysis detected a significant contribution from Me patterns associated with SRE on classifier performance. Conclusions: Though DNA Me differences are known to occur across SRE, MCED classifier scores were comparable across non-cancer pts in SRE groups. Similarly, cancer signal detection in a NW population was comparable regardless of classifier training exposure. These findings indicate that detection of invasive cancer by the MCED test is not strongly influenced by SRE. Ongoing interventional studies of the MCED test are targeting enrollment of population-representative SRE. Citation Format: Oliver Venn, Joerg Bredno, Alexis Thornton, Earl Hubbell, Kathryn Kurtzman, John Beausang, Charles Swanton. The robustness of a targeted methylation-based multi-cancer early detection (MCED) test to population differences in self-reported ethnicity [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C139.

Abstract B129: The association of Covid-19 pandemic restrictions with patient-reported outcomes and lifestyle behaviors among breast cancer survivors: Evidence from a cohort of Black and Hispanic breast cancer survivors in New Jersey

Abstract Purpose: The onset of COVID-19 pandemic restrictions in the US since March 2020 has worsened the disproportionate burden of physical and mental health challenges faced by vulnerable Black and Hispanic breast cancer (BrCa) patients. BrCa survivors experienced delays in their cancer treatments and limited access to supportive care, which may lead to further physical, and psychosocial challenges during an already difficult time. This study aimed to evaluate the association of the COVID-19 pandemic restrictions with patient-reported outcomes (PROs) (i.e. health-related quality of life (HRQoL), sleep, perceived stress, coping and financial toxicity), and lifestyle behaviors (i.e. obesity, smoking, and alcohol) among Black and Hispanic BrCa survivors participating in the Women’s Circle of Health Follow-Up 1 (WCHSFU1) and the New Jersey Breast Cancer Survivors Study (NJBCS), two ongoing population-based studies in New Jersey. Methods: The NJBCS followed similar methods to those in the WCHSFU1. We included a total of 447 Black (npre=364 and npost=83) and 182 Hispanic (npre=102 and npost=80) BrCa survivors who completed a home interview ~24 months post-diagnosis, from 2017 to 2023. The COVID-19 pandemic era was defined as pre- (recruited prior to March 2020) and post-(recruited after March 2020) pandemic. To assess the association of the pandemic with PROs and lifestyle behaviors we employed multivariable adjusted Poisson regression models with robust standard errors to estimate prevalence ratios with 95%CI. Results: Compared to the pre-pandemic group, Black survivors in the post-pandemic group were more likely to be educated, to have higher income, and to be foreign-born, while Hispanic women were significantly more likely to have private insurance and higher HRQoL, physical and emotional well-being mean scores (p<0.05 for all). Adjusted Poisson models indicated that Hispanic women in the post-pandemic group had 1.53 times higher prevalence of low resilience (vs high resilience) (PR:1.53 95% CI: 1.15-2.04), compared to the pre-pandemic group. Whereas Black women in the post-pandemic group reported a higher prevalence of clinically significant sleep disturbance and efficiency (PR: 1.43 95% CI: 1.23-1.68 and PR:1.50 95% CI: 1.30 – 1.73, respectively), compared to the pre-pandemic group. Both Hispanic and Black women in the post-pandemic group showed significantly less perceived stress and a lower prevalence of alcohol consumption. Conclusion: We found heterogeneity in the prevalence of PROs and lifestyle behaviors by pandemic era among Black and Hispanic survivors. Notably, we also noticed differences in demographic characteristics of women participating after the onset of the pandemic, which highlights the importance of considering the impact of the pandemic in all aspects of research, including the interpretation of findings. Continuing research to untangle important factors contributing to racial and ethnic differences in patient characteristics, PROs and lifestyle behaviors post-pandemic in cancer survivorship is warranted. Citation Format: Carola T. Sanchez-Diaz, Nur Zeinomar, Hari S. Iyer, Marley Perlstein, Chi-Chen Hong, Bo Qin, Elisa V. Bandera. The association of Covid-19 pandemic restrictions with patient-reported outcomes and lifestyle behaviors among breast cancer survivors: Evidence from a cohort of Black and Hispanic breast cancer survivors in New Jersey [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B129.

A Comparison of the Prevalence of Diabetes between Aging Rural and Urban Indians.

AbstractBackgroundDiabetes is one of the important modifiable risk factors for dementia. Its prevalence has been increasing rapidly in the past few decades across the world, particularly in India. However, among Indians, there are prominent lifestyle differences between rural and urban residents. Hence, understanding diabetes prevalence in these two distinct populations is essential to understand the differential risk for dementia in rural and urban Indians.MethodCross‐sectional (baseline) clinical data from two ongoing prospective cohort studies, namely Srinivaspura Aging, Neuro Senescence and Cognition (SANSCOG) study in rural India and Tata Longitudinal Study of Aging (TLSA) in urban India was utilized for the present study. A total of 6002 participants – 4913 rural (SANSCOG) and 1089 urban (TLSA) were included. Diagnosis of diabetes was made using self‐reported history and / or fasting blood glucose level of > 126 mg/dl. Chi‐square test of independence was used to assess the group differences between the rural and urban participants – both overall and gender‐wise and age group‐wise.ResultThe mean age of participants was 63.93 ± 9.56 years and 58.74 ± 9.88 years for the urban and rural cohorts, respectively. Prevalence of diabetes was significantly higher in urban than rural subjects – overall (33.6% vs. 19.3%, p<0.001) as well as among males (38.4% vs. 24.1%, p<0.001) and females (28.7% vs. 14.8%, p<0.001). Similarly, on age stratification, urban subjects had significantly higher prevalence than rural subjects in the age groups <65 years (28.1% vs. 18.3%, p<0.001) and ≥65 years (39.5%vs. 21.3%, p<0.001).ConclusionUrban subjects had significantly higher diabetes prevalence than rural subjects across both genders and age groups. In view of the association of diabetes with dementia risk, these findings could imply that urban Indians may be at higher risk for pathological cognitive impairment and dementia as compared to their rural counterparts. However, longitudinal follow of these participants with cognitive monitoring is required to establish a causal association.

Homocysteine, vitamin B12, folic acid levels and its association with Mild Cognitive Impairment in urban and rural dwelling Indians

AbstractBackgroundHomocysteine (Hcy) is a sulfur containing amino acid generated in the metabolism of methionine involving co‐factors such as B vitamins and folic acid. Deficiency of these co‐factors have been associated with increased Hcy levels (Hutto, 1997). Relationship between differing levels of plasma Hcy, vitamin B12, folic acid and cognitive impairment is inconclusive.MethodCross sectional analysis was done using the baseline data from two ongoing longitudinal studies such as Tata Longitudinal Study of Ageing (TLSA, N = 984) and Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG, N = 4404), an urban and rural cohorts (Sundarakumar et al, 2020) respectively. Hcy, vitamin B12, folic acid levels were compared between the subjects of both cohorts. Comparison of these levels between healthy and MCI (Mild Cognitive Impairment) subjects within and across the cohorts were done. CDR (Clinical Dementia Rating) scale was used to classify subjects having normal cognition and MCI, considering score of 0.5 as MCI. Mann‐Whitney U test was used to compare these levels between the groups.ResultHcy, vitamin B12, folic acid levels between the two cohorts showed significant difference, with higher levels of Hcy (median (IQR)) = (17.08 (11) vs 14.63 (10); p <0.001), vitamin B12 (247 (252) vs 220 (143); p <0.001) and folic acid (8.55 (9) vs 5.55(4); p <0.05) in TLSA than SANSCOG. Significant difference seen in Hcy (17.73(11) vs 14.73 (10); p <0.001), vitamin B12 (246 (249) vs 220 (136); p <0.001) and folic acid (8.42 (9) vs 5.53 (4): p <0.001) levels for healthy subjects between cohorts, higher levels were seen in TLSA subjects. Hcy (16.08 (8) vs 14.43 (12); p <0.001) vitamin B12 (305 (341) vs 216 (174); p = 0.03) and folic acid (8.52 (9) vs 5.34 (4): p <0.001) levels were significantly high in TLSA than SANSCOG for MCI subjects. However, these levels were not significantly different between healthy and MCI subjects within cohorts.ConclusionConsistently elevated levels of Hcy was observed in urban cohort. Though elevated level of Hcy was observed with normal vitamin B12 and folic acid, it was not associated with MCI.

Comparison of Anthropometry Measures between Urban and Rural Aging Cohort in India

AbstractBackgroundAnthropometric characteristics of individuals and populations are simple and strong predictors of nutrition, future ill health, functional impairment and mortality (WHO‐TRS 854). Our objective was to observe differences in various anthropometric measurements between urban and rural aging participants in India. The Tata Longitudinal Study of Aging (TLSA) and Srinivaspura Aging Neurosenescence and COGnition (SANSCOG) study are ongoing, large‐scale, prospective, population‐based cohort studies in urban and rural India respectively (Sundarakumar J et.al 2020).MethodA cross‐sectional comparative study that included 1089 urban and 4913 rural participants of both the genders aged 45 years and above were selected from ongoing TLSA and SANSCOG studies. Anthropometric measurements such as Height, Weight, Waist circumference, Hip circumference, Waist‐Hip ratio, Waist‐Height ratio, Body fat and Visceral fat of both the groups were obtained through a structured clinical protocol by trained physicians and nurses and Tanita body composition analyzer. Chi‐square and Mann Whitney U tests were used to analyze the results as the data was not normally distributed.ResultUrban participants were older and had more years of education. The proportion of males and females did not differ between both cohorts as shown in Table 1. Mann‐Whitney U test was conducted to determine whether there was a difference in various anthropometric measures between Urban and Rural cohorts. The results indicate significant difference between the groups as shown in Table 2.ConclusionUrban participants were observed to have comparatively high range of anthropometric measurements compared to rural participants. This difference may be because mean age of rural cohort was less where they mostly engage in more physically demanding occupation such as farming while their urban counterparts were elder and may engage in sedentary occupation.

Abstract C169: AVA3996, a novel pre|CISION™ medicine, targets a warhead to the tumor microenvironment via Fibroblast Activation Protein (FAP) mediated cleavage to elicit tumor cell kill

Abstract AVA3996 is a therapeutic product based on proprietary pre|CISION™ technology which incorporates a substrate that is sensitive to cleavage by FAP. The pre|CISION™ substrate can be utilized in a drug conjugate linker or to generate chemotherapeutics that are only activated in the tumor microenvironment. AVA3996 consists of a proteasome inhibitor (PI) warhead covalently bonded to a peptide containing a cleaving sequence (D-Ala-L-Pro), which is designed to be susceptible to hydrolysis by Fibroblast Activation Protein α (FAP) but is resistant to hydrolysis by both closely related and wider mammalian peptidases. FAP, a post-prolyl endopeptidase, is overexpressed on the surface of activated fibroblastic cells which are abundant in the supporting stroma of over 90% of malignant epithelial cancers. Proteasome inhibitors are a first line of treatment for certain hematologic indications such as multiple myeloma. However, clinical utility of proteasome inhibitors is limited by severe dose-limiting toxicities, including peripheral neuropathy. We have demonstrated that the pre|CISION™ substrate is exquisitely sensitive to FAP and is not cleaved by related proteases. The active PI warhead is released from AVA3996 following FAP cleavage in the tumor microenvironment, reducing systemic exposure and hence associated toxicities. Here we show that exposure of tumor cell line/fibroblast cell co-cultures to AVA3996 results in tumor cell death which is dependent on the presence of FAP on the fibroblasts. AVA3996 also shows potent tumor growth inhibition in vivo with the active warhead accumulating at high levels in the tumor with little in the plasma relative to parent drug AVA3996. A DRF/MTD study established that the maximum tolerated dose in rats was around 6-fold higher for AVA3996 compared to warhead alone. This provides further evidence that AVA3996 can be dosed at higher levels than proteasome inhibitor alone, with the potential for greater tumor targeting and improved therapeutic index. This disease positioning data presented here, including in vivo models, immunohistochemical analysis of clinical material and ongoing safety studies, further validate the efficacy and tolerability profile of AVA3996 and supports further development of this drug. Overall, the data supports wider utility of the pre|CISION™ platform to target warheads to the tumor while reducing systemic dose-limiting toxicities. Citation Format: David Jones, Curtis Rink, Sergi Marco, Marine Houee, Hanna Buist, Folake Orafidiya, Francis Wilson, Chiara Braconi, Fiona McLaughlin. AVA3996, a novel pre|CISION™ medicine, targets a warhead to the tumor microenvironment via Fibroblast Activation Protein (FAP) mediated cleavage to elicit tumor cell kill [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C169.

Light Exposure as a Nonpharmacological Intervention for Alzheimer’s Disease

AbstractBackgroundIn recent years, significant advances have been made in our understanding of the non‐visible biological impact of light (Vetter et al, 2021). Many of these advances can be traced to the 2002 discovery of a previously unknown retinal photoreceptor known as the intrinsically photosensitive retinal ganglion cell, or ipRGC, which is now known to be connected directly to our master circadian clock in our superchiasmatic nucleus (SCN). Now a growing body of clinical and applied research has shown how light spectrum, intensity, and timing can be used to promote circadian entrainment, leading to significant improvements in human health outcomes, including for people with Alzheimer’s disease and related dementia (ADRD).MethodMany of these clinical studies have used lighting interventions in elder care facilities to evaluate the impact of lighting as a nonpharmacological intervention to improve mood, anxiety, sleep quality, falls and other health metrics for ADRD populations. These studies typically gather light exposure and health metric information during control periods or with control populations using traditional lighting approaches and compare results to periods or populations under “circadian‐enhanced” lighting conditions, which generally means brighter and bluer lighting during the day and dimmer and redder light in the evening and night hours.ResultThe results from these studies have consistently demonstrated significant improvements in circadian entrainment, sleep quality, mood, anxiety, falls and other health metrics for ADRD populations under circadian‐enhanced lighting conditions.ConclusionThis talk will provide an overview of our current understanding of how light exposure impacts human physiology. We will discuss several completed and ongoing clinical studies conducted with ADRD populations, including several studies on which the speaker has been the Principal Investigator. We will cover what questions remain in this area and what studies can be developed in the future to address them. Finally, we will close with a discussion of tools, products, building designs and daily routines that can be applied today by clinicians and caregivers that are most likely to improve the health and wellbeing of ADRD patients based on what is known today about the impact of light exposure.

Investigating the role of structural variants in Alzheimer’s Disease and AD‐Related traits

AbstractBackgroundAlthough recent advances have led to a greater understanding of the genetics of Alzheimer’s Disease (AD), there remains a discrepancy between the predicted and observed genetic heritability estimates when using single nucleotide polymorphisms (SNPs) and small indel data. Large genomic rearrangements, known as structural variants (SVs), have the potential to account for this missing genetic heritability.MethodHere, we investigate the role of SVs in AD and AD‐related dementias (ADRD) by leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). We analyzed over 25,000 SVs discovered using whole genome sequencing (WGS) data of 1,106 participants and tested for association with multiple indices for AD/ADRD, including measurements of cognitive decline, amyloid beta, neuronal neurofibrillary tangles, TDP‐43, cerebral amyloid angiopathy, and resilience.ResultOur findings revealed five associations reaching genome‐wide significance. These included a 106 bp insertion (chr21:17,134,448; MAF = 0.01), located in the intronic region of the gene USP25, associated with a higher TDP‐43 burden (P‐value = 1.83×10−6). An 82 bp insertion at chr19:45,444,699 (MAF = 0.25), previously mapped as eQTL for APOC1 and sQTL for APOC2 in brain tissues, was linked to greater cerebral amyloid angiopathy (P‐value = 1.02×10−6). An 820 bp deletion chr15:26,003,040 (MAF = 0.031) overlapping a CTCF site near ATP10A was associated with greater odds of Lewy Body disease (P‐value = 1.03×10−6). A 55 bp insertion (chr12:131,797,376; MAF = 0.21) in an intergenic region was found to be associated with reduced vascular disease burden (P‐value = 2.96×10−7); and a 53 bp insertion (chr4:99,901,557; MAF = 0.014) mapped as protein QTL for ADH5 was linked to lower cognitive resilience (P‐value = 8.51×10−7).ConclusionThese findings provide evidence that common genetic variation, particularly SVs, can play a significant role in AD/ADRD traits. We are now investigating the functional impact of these SVs by integrating multi‐omics assays available from brain tissues of the same individuals. Our goal is to connect genetics to phenotype and gain a deeper understanding of the role of SVs in AD/ADRD.

Accelerating Indonesia Sustainable Infrastructure Development through ESG Initiatives in PPP Ecosystem

The Government of Indonesia committed to implement the Sustainable Development Goals (SDGs) aim to end poverty, inequality, and mitigate climate change. The submission of an Enhanced Nationally Defined Contribution (ENDC) to UNFCC strengthens Indonesia’s commitment in a low-carbon and climate-resilient economy development. The Minister of Finance has launched an ESG Framework to mainstreaming ESG through government support and facilities on infrastructure financing, in which IIGF (Indonesia Infrastructure Guarantee Fund) has a significant role in providing sovereign guarantee for Public-Private Partnership (PPP). Qualitative approach was used to examine the benefit of ESG and additional value of IIGF’s ESG integrated guarantee to support the acceleration of the Indonesia’s sustainable infrastructure development. This paper concludes that in addition to de-risking instrument, the guarantee will bring additional value in ensuring a fair ESG risk allocation, project structuring and long-term risk management and monitoring. This will allow privates to access green and sustainable financing. The challenges mainly on capacity building and alignment of policy and standards among stakeholders. However, IIGF has opportunity to link with stakeholders and build collaboration to fill gaps and connecting to suitable market. This paper, however, report initial findings of the ongoing comprehensive studies as part of IIGF ESG initiative roadmap.

A decreased level of high-density lipoprotein is a possible risk factor for type 2 diabetes mellitus: A review.

Type 2 diabetes mellitus (T2DM) is characterized primarily by dyslipidemia and hyperglycemia due to insulin resistance. High-density lipoprotein (HDL) play a significant role in preventing the incidence of dyslipidemia and its complications. HDL has different protective functions, such as reducing oxidation, vascular inflammation, and thrombosis; additionally, its anti-diabetic role is one of the most significant recent discoveries about HDL and some of its constituent lipoproteins. This research reviews ongoing studies and preliminary investigations into the assessment of relation between decreased level of HDL and T2DM. The levels of HDL and its functions contribute to glucose hemostasis and the development of T2DM through four possible mechanisms, including insulin secretion by beta cells, peripheral insulin sensitivity, non-insulin-dependent glucose uptake, and adipose tissue metabolic activity. Additionally, the anti-oxidant properties of HDL protect beta cells from apoptosis caused by oxidative stress and inflammation induced by low-density lipoprotein, which facilitate insulin secretion. Therefore, HDL and its compositions, especially Apo A-I, play an important role in regulating glucose metabolism, and decreased levels of HDL can be considered a risk factor for DM. Different factors, such as hypoalphalipoproteinemia that manifests as a consequence of genetic factors, such as Apo A-I deficiency, as well as secondary causes arising from lifestyle choices and underlying medical conditions that decrease the level of HDL, could be associated with DM. Moreover, intricate connections between HDL and diabetic complications extend beyond glucose metabolism to encompass complications like cardiovascular disease and kidney disease. Therefore, the exact interactions between HDL level and DM should be evaluated in future studies.

Updated Appropriate Use Criteria for Amyloid and Tau PET

AbstractBackgroundThe Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging convened a Workgroup to update previous Appropriate Use Criteria (AUC) for amyloid PET (Johnson 2013) and develop the first AUC for tau PET. The AUC represent general guidelines and should not be considered a substitute for clinical judgment exercised in the care of individual patients.MethodThe Workgroup included 14 researchers with multidisciplinary expertise. Meetings were held between June 2020 and August 2021. Key research questions were identified using the PICOTS framework, triggering an independent systematic literature review. Using established methods (Fitch 2001), the Workgroup identified 17 clinical scenarios in which amyloid/tau PET may be considered. Appropriateness of amyloid and tau PET as independent, stand‐alone modalities were ranked for each scenario using a 9‐point scale (Table 1). Consensus was achieved using a modified Delphi process. Online surveys were completed iteratively by Workgroup members, followed by discussion, until all votes for each scenario fell within one of the following categories: Appropriate/Uncertain/Rarely Appropriate.ResultAs an over‐arching principle, amyloid/tau PET should be considered in patients who: (1) have undergone a comprehensive assessment by a dementia expert; (2) Alzheimer’s disease (AD) is a diagnostic possibility but uncertainty remains; and (3) knowledge of amyloid/tau PET results is expected to help establish diagnosis and guide patient management. Consensus ratings for clinical scenarios are shown in Table 2. More evidence was available to inform recommendations for amyloid than tau PET. Amyloid PET was considered “Appropriate” to inform diagnosis of MCI or dementia due to suspected AD; clarify diagnosis when CSF biomarkers are equivocal; to inform prognosis in MCI; and to determine eligibility for amyloid‐targeting therapies. Tau PET was considered “Appropriate” to clarify diagnosis in patients with MCI/dementia under age 65 or those with atypical presentations; and to inform prognosis in MCI or dementia due to suspected AD.ConclusionThe updated AUC highlight a growing role for amyloid PET and an emerging role for tau PET in the clinical evaluation of cognitively impaired patients. AUC are expected to further evolve based on data from ongoing studies of clinical utility and a rapidly developing therapeutic landscape.

Glia‐Selective Replacement of APOE4 with APOE2: Implications for AD‐Associated Pathologies

AbstractBackgroundCompared to the ‘neutral’ E3, the E4 allele of Apolipoprotein E (APOE) confers up to a 15‐fold increase in Alzheimer’s Disease (AD) risk. Conversely, the neuroprotective E2 allele decreases AD risk by a similar degree. APOE’s strong risk profile and multitude of effects make it a promising therapeutic target. Here, we aimed to assess the therapeutic potential of allelic ‘switching’ by investigating the physiological changes associated with an inducible, in vivo APOE4 to APOE2 transition in a novel transgenic mouse model.MethodsThe APOE “switch mouse” (APOE4s2) uses the Cre‐loxP system to allow for inducible APOE allele switching from APOE4 to APOE2. These mice express a floxed human APOE4 coding region followed by the human APOE2 coding region. To study the effects of full body APOE switching, APOE4s2 mice were crossed to ubiquitous ROSA26‐CreERT1 mice. Gene expression and proteomic analyses were used to validate that the model worked as expected. Lipidomics and single‐cell RNAseq were used to measure physiological changes following the APOE4 to APOE2 allele switch.ResultmRNA and protein analyses confirm that APOE4s2 mice synthesize full‐length human APOE4/ApoE4 pre‐switch and that the inducible switch results in successful and efficient recombination and expression of human APOE2/ApoE2. Single‐cell RNAseq shows that global, genetic replacement of APOE4 with APOE2 results in distinct alterations to glial cell transcriptomes affecting pathways involved with lipid and mitochondrial metabolism, inflammation, blood‐brain barrier integrity, and amyloid beta. Excitingly, differentially expressed genes associated with an E4 to E2 ‘switch’ included several AD GWAS, and both aging‐ and AD‐associated pathways. Additionally, untargeted lipidomics reveals changes to several lipid classes in the brain, in particular glycerophospholipids.ConclusionTogether, these data suggest that a successful transition from APOE4 to APOE2 has broad impact on the cerebral transcriptome as well as peripheral and cerebral metabolism. Ongoing studies aim to determine whether cell‐specific replacement of APOE4 with APOE2 will rescue E4‐associated metabolic dysfunction, disease‐associated gene signatures, and AD pathology.

Axillary surgery in oncologic breast surgery: a narrative review.

With the improved survival for breast cancer there is now an increased focus on quality of life after treatment. Axillary surgery is known to be associated with significant risk of arm morbidity feared by the patients, and several studies have shown de-escalation is possible in different settings. In this review, an overview will be given on new techniques and procedures for de-escalation of axillary surgery in breast cancer patients and the subsequent implications for adjuvant systemic treatment. This study is a narrative review. PubMed was searched for relevant publications in English published between January 2018-June 2023. Only publications with major impact on clinical practice have been included with main emphasis on meta-analysis. In addition, Clinicaltrial.gov has been searched for on-going studies. New tracer techniques are described as well as the on-going reduction in axillary lymph node dissection (ALND) at primary surgery even in node positive patients, and the axillary staging possibilities after down-staging of the axilla by neoadjuvant treatment. Finally axillary staging at local recurrence and in case of ductal carcinoma in situ is described. ALND is no longer routinely recommended in many node positive patients and further de-escalation is investigated. The lack of knowledge on precise axillary status will require cooperating studies between oncologists and breast surgeons in order to avoid escalation of systemic treatment due to the lack of applicability of trial eligibility criteria. Furthermore, investigations on the use of axillary imaging for staging are needed.

Bridging Theory and Measurement of Student Engagement

Learner engagement is well-established as critical for learning online. Professional development for online instructors emphasizes techniques for engaging students, and learning technology products tout features intended to promote engagement (e.g., adaptive content, video, gamification). But the influence of particular instructor practices and of particular learning technology features on theory-based aspects of student engagement is infrequently tested empirically, and even more rarely with Black, Latine, and low-income students, who are more likely to face barriers to learning online. This paper first provides a research-based theoretical model of affective engagement developed in conjunction with ongoing studies of blended learning implementations of courseware designed to enhance learning and engagement among historically and systemically marginalized students. Next, the paper describes development of survey-based measures of four components of affective engagement and the use of responses from over 850 students in introductory statistics courses to evaluate the reliability and factor structure of those measures. We conclude with implications for use of the engagement measures in future improvement-oriented research and practice.

Treatment of type 2 diabetes mellitus with stem cells and antidiabetic drugs: a dualistic and future-focused approach.

Type 2 Diabetes Mellitus (T2DM) accounts for more than 90% of total diabetes mellitus cases all over the world. Obesity and lack of balance between energy intake and energy expenditure are closely linked to T2DM. Initial pharmaceutical treatment and lifestyle interventions can at times lead to remission but usually help alleviate it to a certain extent and the condition remains, thus, recurrent with the patient being permanently pharmaco-dependent. Mesenchymal stromal cells (MSCs) are multipotent, self-renewing cells with the ability to secrete a variety of biological factors that can help restore and repair injured tissues. MSC-derived exosomes possess these properties of the original stem cells and are potentially able to confer superior effects due to advanced cell-to-cell signaling and the presence of stem cell-specific miRNAs. On the other hand, the repository of antidiabetic agents is constantly updated with novel T2DM disease-modifying drugs, with higher efficacy and increasingly convenient delivery protocols. Delving deeply, this review details the latest progress and ongoing studies related to the amalgamation of stem cells and antidiabetic drugs, establishing how this harmonized approach can exert superior effects in the management and potential reversal of T2DM.