Modification Trial Research Articles

Successful collaborative trials of simple gear modifications to reduce entanglement of whales and other megafauna in Scotland’s static pot (creel) fisheries

Abstract Entanglement in ropes associated with static fishing gear (pots/traps/creels) is a welfare and conservation concern for minke whales (Balaenoptera acutorostrata), humpback whales (Megaptera novaeangliae), basking sharks (Cetorhinus maximus), and other megafauna in Scottish waters. The Scottish Entanglement Alliance estimated that six humpback whales and 30 minke whales become entangled annually. Where entanglement type was known, 83% of minke whales, 50% of humpback whales, and 76% of basking sharks were caught in floating groundlines between pots. We collaborated with fishers on Scotland’s west coast to trial sinking groundline (which lies on the seabed) to assess its practicality. A total of 15 Nephrops (langoustine) and crab fishers re-roped 61 sets of creel gear and fished the gear for ∼15 months, reporting on each haul. Over 1500 hauls were reported; the fishers encountered few problems, in some cases preferring the modified gear. We also deployed depth sensors/accelerometers and filmed a range of sinking and floating rope configurations with a Remotely Operated Vehicle (ROV) to collect data on performance underwater. This project is encouraging, both because of its results—that there may be a simple option to greatly reduce entanglement risk—and because of the successful, bottom-up, partnership approach with Scottish creel fishers.

Long-Term Randomized Controlled Trials of Diet Intervention Reports and Their Impact on Cancer: A Systematic Review.

Most randomized controlled trials (RCTs) assessing the impact of diet on cancer have been short term (<1 year), mostly evaluating breast cancer survivors. Given the many-year interval that is generally required for an intervention to have an impact on cancer risk or prognosis, as well as the fact that lifestyle strategies such as diet modification frequently fail due to lack of adherence over the long term, we focused this systematic review only on longer-term (≥1 year) intervention reports. Diet intervention reports focused on reducing cancer risk in overweight and obese individuals target caloric restriction (every day, some days, or most hours of each day). This study is a systematic review of RCTs lasting at least 1 year, testing dietary interventions with a primary or secondary endpoint of cancer or a biomarker linked to cancer. Fifty-one reports met our review criteria. Twenty of fifty-one (39%) reports are RCTs where the primary endpoint was cancer or a cancer-related biomarker, while the other reports evaluated reports where cancer or a cancer-related biomarker was a secondary endpoint. Thirteen of twenty (65%) primary reports evaluated isocaloric, and the remaining eight evaluated low-calorie diets. All but one of the primary and two secondary isocaloric diet reports evaluated the benefit of a low-fat diet (LFD), with the other three evaluating a Mediterranean diet (MedD). More LCD vs. isocaloric diet primary reports (71% vs. 38%) demonstrated cancer or cancer-related biomarker benefit; the difference in chance of benefit with secondary reports was 85% for LCD vs. 73% for isocaloric diets. Three of three MedD reports demonstrated benefit. Sixty-nine percent (20/29) of the secondary reports came from two large reports: the WHI diet modification trial (15 secondary reports) and the polyp prevention trial (5 secondary reports). Nineteen of twenty-two (86%) primary reports enrolled only women, and three enrolled both men and women. No study that met our criteria enrolled only men, comprising 1447 men in total vs. 62,054 women. Fifteen of twenty (75%) primary reports focus on healthy women or women with breast cancer. Adherence findings are discussed when provided. More long-term RCTs evaluating cancer and cancer-related biomarker endpoints are needed, especially for cancers at sites other than the breast.

412.5: Outcomes of the RIVASTIM: Rapamycin randomized controlled trial of immunosuppression modification to improve vaccine responses in kidney transplant recipients.

412.5: Outcomes of the RIVASTIM: Rapamycin randomized controlled trial of immunosuppression modification to improve vaccine responses in kidney transplant recipients.

Exploring Analysis Approaches for Using the Dopamine Transporter Striatal Binding Ratio in Early- to Mid-Stage Parkinson's Disease Modification Trials.

The dopamine transporter striatal binding ratio (DAT SBR) has been used as an outcome measure in Parkinson's disease (PD) trials of potential disease-modifying therapies; however, both patient characteristics and analysis approach potentially complicate its interpretation. The aim was to explore how well DAT SBR reflects PD motor severity across different striatal subregions and the relationship to disease duration, and side of onset. DAT SBR for the anterior and posterior putamen and caudate in both hemispheres was obtained using validated automated quantitative software on baseline scans of 132 patients recruited for the Exenatide PD2 and PD3 trials. Associations between mean and lateralized SBR subregions (posterior and anterior putamen and caudate) and summed and lateralized motor characteristics were explored using regression analysis. Analyses were repeated considering disease duration and limiting analysis to the less-affected hemisphere. Lateralized bradykinesia was most consistently associated with the loss of DAT uptake in the contralateral anterior putamen. There was much higher variance in the posterior putamen, and in all regions in those with longer duration disease, although bradykinesia remained robustly associated with anterior putaminal DAT uptake even in longer-duration patients. Restricting analyses to the less-affected side did not usefully reduce the variance compared to the overall cohort. These data suggest that DAT SBR could be a useful biomarker in disease-modifying trials, but a focus on anterior striatal subregions and incorporating disease duration into analyses may improve its utility.

Using polygenic risk modification to improve breast cancer prevention: study protocol for the PRiMo multicentre randomised controlled trial

IntroductionEstablished personal and familial risk factors contribute collectively to a woman’s risk of breast or ovarian cancer. Existing clinical services offer genetic testing for pathogenic variants in high-risk genes to...

A randomized trial of dietary modification with exercise in women who are class 2 obese with non-metastatic breast cancer.

e22542 Background: As overweight and obesity increases worldwide, associated risks of breast cancer parallel. A higher body mass index (BMI) has been linked with at least seventeen types of solid tumors, including 9% of all breast cancer cases. Weight gain post-diagnosis is associated with greater morbidity and may increase cancer recurrence risk by 30-40%. Exercise and diet modifications carry potential to lower risk of recurrence. Herein, we report a 6-month pilot study at Piedmont Fayette Hospital in women with nonmetastatic breast cancer with diet modification. Methods: Women with non-metastatic breast cancer, class 2 obesity were recruited to participate in a six-month pilot study at the Thomas F. Chapman Family Cancer Wellness Program at Piedmont Fayette Hospital. Following consent, participants were randomized into either: ARM 1- Dietary coaching including Caloric Counting/Food Tracking with Exercise Coaching ARM 2- Dietary coaching including Carbohydrate Cycling/Intermittent Fasting/Caloric Counting/Food Tracking with Exercise Coaching. The primary goal of this pilot study is to evaluate and compare the feasibility and preliminary efficacy of two weight loss interventions. Results: As of December 2023, 20 patients were enrolled in the dietary modification study. 11 patients completed 6 months of dietary modification. Of the 11 evaluable patients, 6 were randomized to arm 1 and 5 patients were randomized to arm two, table 1. There was not a substantial weight loss in arm 1 at 6 months. However, patients on arm 2 had a median 17-pound weight loss. Conclusions: Although this was a small pilot study performed at the community hospital, we were able to demonstrate dietary modification is feasible in women with nonmetastatic breast cancer and class II obesity. Furthermore, carbohydrate cycling, and intermittent fasting seemed to be a more effective method at weight loss over calorie restriction. We plan to further expand this pilot study to other Piedmont Wellness Centers. [Table: see text]

Diagnosis and treatment of dyslipidemia in children and adolescents

Background: Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality worldwide, including in South Korea. Dyslipidemia is an independent risk factor for the development of atherosclerotic cardiovascular diseases. There is strong evidence that atherosclerosis begins early in life and that elevated lipid levels in childhood predict elevated lipid levels into adulthood.Current Concepts: A universal approach for cholesterol screening in all children is recommended. Lipid profiles should be studied for all children aged 9 to 11 years and then for those aged 17 to 21 years, as cholesterol levels may vary after puberty. The non-fasting lipid profile can be as useful in detecting severe genetic dyslipidemias as the fasting lipid profile and thus can be used as a first-line screening in children. The initial treatment for dyslipidemia in a child always begins with a 6-month trial of lifestyle modifications, such as improvements in dietary and physical activity patterns. Statins are as effective in children as in adults and can lower low-density lipoprotein cholesterol levels by up to 50%. Therefore, they are considered first-line therapy for children who meet the criteria for pharmacological therapy.Discussion and Conclusion: Statins and non-statin lipid-lowering agents can lower cholesterol levels with minimal adverse effects in children and adolescents with hypercholesterolemia. However, limited data is currently available on the long-term safety and efficacy of lipid-lowering agents in the pediatric population. Furthermore, non-statin lipid-lowering agents are used far less frequently in children. Therefore, further long-term safety and efficacy studies on lipid-lowering agents in pediatric populations and clinical trials with non-statin lipid-lowering agents are required.

Twelve Years of Drug Prioritization to Help Accelerate Disease Modification Trials in Parkinson's Disease: The International Linked Clinical Trials Initiative.

In 2011, the UK medical research charity Cure Parkinson's set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson's disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.

Abstract P492: Polygenic Risk for Obesity and Race Modify the Effect of a Low Fat Dietary Clinical Trial on Weight Loss

Introduction: Research populations harbor innate and acquired characteristics that can introduce substantial treatment response heterogeneity. Weight loss interventions show this variability, likely due to behavioral and physiological characteristics. Genetic risk for obesity is a potential but largely unexplored factor in weight loss trials. We examined whether genetic risk for obesity modified the effect of a low-fat diet on weight change in a randomized controlled trial. Methods: A data from the Women’s Health Initiative Dietary Modification Trial, including 10,353 postmenopausal women aged 50-79 with genotype data [63% European American (EAs), 37% African American (AAs)] were randomized into control and low-fat diet groups. The outcome was visit-specific weight difference (kg) from baseline. The Polygenic Risk Score of body mass index (PRS BMI ) was computed using the PRS-CS method and an independent trans-ancestry genome-wide association study of BMI (N = ~ 2M; 79 % EAs and 4 % AAs). We operationalized PRS BMI as a binary variable, distinguishing individuals in the 95 th percentile from the remaining individuals. Association was tested using generalized estimated equations with a 3-way interaction term (PRS х randomization х time), adjusting for 10 principal components, age, baseline BMI, and follow-up status. Analyses were performed separately by race/ethnicity, because body weight is influenced by ancestral diversity, which affects both linkage disequilibrium, PRS effect sizes, and cultural factors (e.g., racism). Results: Baseline, we had 6,473 EAs (mean age: 65.4 ± 6.6 years, mean BMI: 29.5 ± 6.5 kg/m 2 ) and 3,880 AAs (mean age: 60.9 ± 6.7years, mean BMI: 32.1 ± 6.8 kg/m 2 ) and mean follow-up was 6.0 ± 1.8 years. PRS BMI explained 12% of the variance in the baseline BMI measure in EAs and 8% in AAs. During the first year of intensive dietary intervention (18 sessions/yr), the low-fat diet group experienced 2.1 kg and 1.1 kg weight loss in European and AAs respectively, with no differences in PRS BMI . During years 1-7 with reduced intervention intensity (4 sessions/yr), the rate of weight change in both race/ethnic groups were modified by PRS BMI , although in different directions. EAs with high PRS (95 th percentile) in the intervention group rebounded towards initial weight (0.35 kg/year, p&lt;0.001) nearly twice as fast as those women with PRS &lt; 95 th percentile (0.19 kg/year, p&lt;0.001). Conversely, high PRS African American women in the intervention group maintained their weight loss without rebound (-0.10 kg/year, p=0.48), distinctly different from those with PRS &lt; 95 th percentile, who gained 0.25 kg annually (p&lt;0.001). Conclusions: Impact of long-term low-fat dietary intervention on weight change was modified by genetic risk and race/ethnicity. Genetic predisposition and other contextual factors may be considered in the design and analysis of relevant clinical trials.

Effect of impregnated organophilic (hydrophobic) nano clay on asphalt binder properties and performance

This research paper presents the effects of electrophilic modification on raw nano clay (which is hydrophilic in nature) through wet impregnation method to transform it into hydrophobic nature. The reactivity, adsorption capability, and compatibility of nano clay with hydrocarbon and organic materials are improved by entailing functional group (QAS) on raw nano clay surface. Impact of impregnated organophilic nano clay (hydrophobic) on asphalt binder properties and mixture’s performance are studied. Organophilic(hydrophobic) nano clay with 3–5% content to the weight of the binder were selected after extensive trials for modification of asphalt binder. To analyze the electrophilic changes in organophilic nano clay (ONC) and its bonding chemistry with asphalt binder, FTIR analysis, and X-ray diffraction techniques were utilized. In addition, viscosity, low & high-temperature stiffness, bitumen bond strength, and phase separation were studied in the lab. The effect of organophilic nano clay modified binder on asphalt mixture was also measured by deploying rut resistance, moisture susceptibility& fatigue resistance tests. The study revealed that raw nano clay showed chemical compatibility with asphalt binder after electrophilic modification through wet impregnation method. ONC modified binder had better rheological properties, homogenized composition, and storage stability than hydrophilic nature. Mixtures prepared with ONC showed better resistance to rutting, fatigue, and moisture susceptibility.

Effect of eight-week controlled dietary modification trial on nutritional biomarkers in young Indian athletes

Objective: Present study was intended to examine the effects of dietary modification on nutritional biomarkers in young Indian male athletes. Methods: Eighty-eight footballers and hockey players were randomly segregated into ad-libitum group (ALG) and nutrition counselling group (NCG). Eight weeks of dietary modification trial was implemented on NCG, resulting in 9.5, 2.6, and 2.1 g/kgbw/day of carbohydrate, protein, and fat respectively. Rate of changes in daily nutrient intake and nutrition biomarkers were captured. Results: NCG revealed significant increases in total serum protein (5.6%, p&lt;0.001), haemoglobin (3.9%, p&lt;0.001) and vitamin E (2.9%, p&lt;0.001). They also exhibited rises in serum vitamin C (6%, p=0.004), folate (4.5%, p=0.004), ferritin (4.8%, p=0.003), calcium (4.2%, p=0.009), serum vitamins B12 (3.9%, p=0.012) and D (12.3%, p&lt;0.001). Haemoglobin levels were positively correlated with daily protein (p&lt;0.01), iron (p&lt;0.05), vitamins B12 and vitamin C (p&lt;0.05 both) intakes. Serum calcium positively correlated with daily calcium (p&lt;0.01), phosphorus and protein (p&lt;0.05 both) intakes. Serum zinc was positively correlated with daily protein, calcium, vitamin B9 and vitamin D intake, while serum ferritin and vitamin B12 were positively correlated with protein and iron intake. Post-intervention, NCG reported optimal blood levels of calcium, zinc, protein, Hb, ferritin, vitamins B12, C and E, whereas the folate and vitamin D values were suboptimal. On the other hand, the ALG revealed marginal levels of zinc and total protein as well as noticeably low levels of calcium, folate, and vitamin D. Conclusion: Enhanced blood levels of nutritional biomarkers noted after eight-weeks of controlled dietary modification was supported by positive correlations observed with the daily nutrient intakes.

Dietary Intervention Favorably Influences Physical Functioning: The Women’s Health Initiative Randomized Dietary Modification Trial

BackgroundIn the Women’s Health Initiative Dietary Modification randomized trial, the dietary intervention reduced breast cancer mortality by 21% (P = .02) and increased physical activity as well. ObjectiveTherefore, the aim was to examine whether or not these lifestyle changes attenuated age-related physical functioning decline. DesignIn a randomized trial, the influence of 8 years of a low-fat dietary pattern intervention was examined through 20 years of cumulative follow-up. Participants and settingFrom 1993 to 1998, 48,835 postmenopausal women, ages 50 to 79 years with no prior breast cancer and negative baseline mammogram were randomized at 40 US clinical centers to dietary intervention or usual diet comparison groups (40 out of 60). The intervention significantly reduced fat intake and increased vegetable, fruit, and grain intake. Main outcome measuresIn post hoc analyses, physical functioning, assessed using the RAND 36-Item Short Form Health Survey, evaluated quality or limitations of 10 hierarchical physical activities. Longitudinal physical functioning, reported against a disability threshold (when assistance in daily activities is required) was the primary study outcome. Statistical analyses performedSemiparametric linear mixed effect models were used to contrast physical functioning trajectories by randomization groups. ResultsPhysical functioning score, assessed 495,317 times with 11.0 (median) assessments per participant, was significantly higher in the intervention vs comparison groups through 12 years of cumulative follow-up (P = .001), representing a reduction in age-related functional decline. The intervention effect subsequently attenuated and did not delay time to the disability threshold. Among women in the dietary intervention vs comparison groups, aged 50 to 59 years, who were physically inactive at entry, a persistent, statistically significant, favorable influence on physical functioning with associated delay in crossing the disability threshold by approximately a year was seen (P value for interaction = .007). ConclusionsIn the Women’s Health Initiative Dietary Modification randomized trial, a dietary intervention that significantly reduced breast cancer mortality also significantly reduced age-related functional decline through 12 years, which was attenuated with longer follow-up.

P253 Knowledge and acceptability of the Lémann Index to measure progressive intestinal damage in Crohn’s disease: results from an international cross-sectional survey

Abstract Background Chronic inflammation in Crohn’s disease (CD) predisposes to progressive structural bowel damage (SBD). The Lémann index (LI) is a prospectively validated tool that captures extent and severity of strictures, penetrating disease and surgery to generate a SBD score.1 It is earmarked as a potential outcome measurement tool for CD modification trials. Understanding perceived barriers and knowledge gaps is critical to its wider adoption. Methods We conducted a multinational, cross-sectional study (March to October 2023) to determine SBD and LI knowledge, and LI acceptability. An online survey link (REDCap) was distributed to clinicians by email through GI professional societies and snowball sampling. The questionnaire included 23 items, 5 sections (demographic, SBD knowledge, LI perception and knowledge, future LI adoption, and optional case) and responses (binary, 5-point Likert scale, 10-point visual analogue scale (VAS) and free-text) were captured on Excel. Results From 170 respondants: 82 (48%) were female; 142 (82.4%) from Europe, 13 North America (7.6%) and 13 Asia (7.6%). Most were IBD specialists (121; 71.2%), General Gastroenterologists (36; 21.2%), managing &amp;gt;40 CD patients per month (60; 35.3%). 88 (51.8%) questionnaires were incomplete (≥1 questions were unanswered). From completed responses, 99 (92.5%) knew about SBD, 97 (90.7%) rated it ‘’very’’ and ‘’fairly’’ important to measure SBD in clinical trials and 82 (76.6%) in clinical practice; 5 (4.7%) felt it was ‘’not important’’. Most agreed LI would improve long-term outcomes in CD (55; 55%) and show achievement of treatment targets (74; 74.7%). More (43; 42.6%) replied it was ‘’very difficult’’ or ‘’difficult’’ to complete the LI for each patient; 36 (36%) felt that it took ‘’significant’’ or ‘’a lot’’ of effort (Figure 1). Most (86; 80.4%) were untrained in calculating the LI; 73 (68.2%) felt it was ‘’very’’ and ‘’fairly’’ important to receive training. Most reported intestinal ultrasound instead of MR enterography to be important (VAS scores 8-10) for encouraging LI calculation in future clinical trials (53; 54.6%) and clinical practice (49; 52.7%) (Figure 2). Lack of time (80.2%), automated calculation methods (64.2%) and dedicated radiologist (50.6%) were the top 3 perceived barriers to wider adoption. Conclusion Most respondents had baseline knowledge of SBD and perceived the LI to be important in future long term CD research and clinical practice. Interventions to improve training and automation are needed to facilitate wider adoption of the LI. Reference 1. Pariente B, et al.Validation and Update of the Lémann Index to Measure Cumulative Structural Bowel Damage in Crohn's Disease.Gastroenterology.2021 Sep;161(3):853-864.e13.

Perceived stress and progression of cardiometabolic risk factors among South Asians with prediabetes in a lifestyle intervention trial

AimsTo examine associations between perceived stress and cardiometabolic risk factors in South Asians with prediabetes and assess whether a diabetes prevention program mitigates the impact of stress on cardiometabolic health. MethodsWe conducted a secondary analysis of the Diabetes Community Lifestyle Improvement Program, a lifestyle modification trial for diabetes prevention in India (n = 564). Indicators for cardiometabolic health (weight, waist circumference, blood pressure, glucose, HbA1c, and lipids) were measured at each visit while perceived stress was assessed via questionnaire at baseline. Multivariable linear regression assessed associations between stress and cardiometabolic parameters at baseline and 3-year follow up. ResultsAt baseline, perceived stress was associated with higher weight (b=0.16; 95% CI: 0.04, 0.29) and waist circumference (b=0.11; 95% CI: 0.01, 0.21) but lower 30-minute postload glucose (b=−0.44; 95% CI: −0.76, −0.14) and LDL cholesterol (b=−0.40; 95% CI: −0.76, −0.03). Over the study period, perceived stress was associated with weight gain (b=0.20; 95% CI: 0.07, 0.33) and increased waist circumference (b=0.14; 95% CI: 0.04, 0.24). Additionally, higher perceived stress was associated with lower HDL cholesterol among the control arm (pinteraction = 0.02). ConclusionsBaseline stress was associated with negative cardiometabolic risk factor outcomes over time in those with prediabetes.

Adherence to a healthy lifestyle, genetic susceptibility to abdominal obesity, cardiometabolic risk markers, and risk of coronary heart disease

BackgroundLittle is known about whether the association between genetic susceptibility to high waist-to-hip ratio (WHR), a measure of abdominal obesity, and incident coronary heart disease (CHD) is modified by adherence to a healthy lifestyle. ObjectivesTo explore the interplay of genetic susceptibility to high WHR and adherence to a healthy lifestyle on incident CHD. MethodsThis study included 282,316 white British individuals from the UK Biobank study. Genetic risk for high WHR was estimated in the form of weighted polygenic risk scores (PRSs), calculated based on 156 single-nucleotide polymorphisms. Lifestyle scores were calculated based on 5 healthy lifestyle factors: regular physical activity, no current smoking, a healthy diet, <3 times/wk of alcohol consumption and 7–9 h/d of sleep. Incident CHD (n = 11,635) was accrued over a median 13.8 y of follow-up, and 12 individual cardiovascular disease risk markers assessed at baseline. ResultsAdhering to a favorable lifestyle (4–5 healthy factors) was associated with a 25% (hazard ratio: 0.75, 95% confidence interval: 0.70, 0.81) lower hazard of CHD compared with an unfavorable lifestyle (0–1 factor), independent of PRS for high WHR. Estimated 12-y absolute risk of CHD was lower for a favorable lifestyle at high genetic risk (1.73%) and medium genetic risk (1.67%) than for an unfavorable lifestyle at low genetic risk (2.08%). Adhering to a favorable lifestyle was associated with healthier levels of cardiovascular disease risk markers (except random glucose and high-density lipoprotein), independent of PRS for high WHR. ConclusionsIndividuals who have high or medium genetic risk of abdominal obesity but adhere to a healthy lifestyle may have a lower risk of developing CHD, compared with those who have low genetic risk and an unhealthy lifestyle. Future clinical trials of lifestyle modification could be implemented for individuals at high genetic risk of abdominal obesity for the primary prevention of CHD events.

How should we be using biomarkers in trials of disease modification in Parkinson's disease?

The recent validation of the α-synuclein seed amplification assay as a biomarker with high sensitivity and specificity for the diagnosis of Parkinson's disease has formed the backbone for a proposed staging system for incorporation in Parkinson's disease clinical studies and trials. The routine use of this biomarker should greatly aid in the accuracy of diagnosis during recruitment of Parkinson's disease patients into trials (as distinct from patients with non-Parkinson's disease parkinsonism or non-Parkinson's disease tremors). There remain, however, further challenges in the pursuit of biomarkers for clinical trials of disease modifying agents in Parkinson's disease, namely: optimizing the distinction between different α-synucleinopathies; the selection of subgroups most likely to benefit from a candidate disease modifying agent; a sensitive means of confirming target engagement; and the early prediction of longer-term clinical benefit. For example, levels of CSF proteins such as the lysosomal enzyme β-glucocerebrosidase may assist in prognostication or allow enrichment of appropriate patients into disease modifying trials of agents with this enzyme as the target; the presence of coexisting Alzheimer's disease-like pathology (detectable through CSF levels of amyloid-β42 and tau) can predict subsequent cognitive decline; imaging techniques such as free-water or neuromelanin MRI may objectively track decline in Parkinson's disease even in its later stages. The exploitation of additional biomarkers to the α-synuclein seed amplification assay will, therefore, greatly add to our ability to plan trials and assess the disease modifying properties of interventions. The choice of which biomarker(s) to use in the context of disease modifying clinical trials will depend on the intervention, the stage (at risk, premotor, motor, complex) of the population recruited and the aims of the trial. The progress already made lends hope that panels of fluid biomarkers in tandem with structural or functional imaging may provide sensitive and objective methods of confirming that an intervention is modifying a key pathophysiological process of Parkinson's disease. However, correlation with clinical progression does not necessarily equate to causation, and the ongoing validation of quantitative biomarkers will depend on insightful clinical-genetic-pathophysiological comparisons incorporating longitudinal biomarker changes from those at genetic risk with evidence of onset of the pathophysiology and those at each stage of manifest clinical Parkinson's disease.

Metabolomics-Based Biomarker for Dietary Fat and Associations with Chronic Disease Risk in Postmenopausal Women

BackgroundThe Women’s Health Initiative (WHI) randomized, controlled Dietary Modification (DM) trial of a low-fat dietary pattern suggested intervention benefits related to breast cancer, coronary heart disease (CHD), and diabetes. Here, we use WHI observational data for further insight into the chronic disease implications of adopting this type of low-fat dietary pattern. ObjectivesWe aimed to use our earlier work on metabolomics-based biomarkers of carbohydrate and protein to develop a fat intake biomarker by subtraction, to use the resulting biomarker to develop calibration equations that adjusts self-reported fat intake for measurement error, and to study associations of biomarker-calibrated fat intake with chronic disease risk in WHI cohorts. Corresponding studies for specific fatty acids will follow separately. MethodsProspective disease association results are presented using WHI cohorts of postmenopausal women, aged 50–79 y when enrolled at 40 United States clinical centers. Biomarker equations were developed using an embedded human feeding study (n = 153). Calibration equations were developed using a WHI nutritional biomarker study (n = 436). Calibrated intakes were associated with cancer, cardiovascular diseases, and diabetes incidence in WHI cohorts (n = 81,954) over an approximate 20-y follow-up period. ResultsA biomarker for fat density was developed by subtracting protein, carbohydrate, and alcohol densities from one. A calibration equation was developed for fat density. Hazard ratios (95% confidence intervals) for 20% higher fat density were 1.16 (1.06, 1.27) for breast cancer, 1.13 (1.02, 1.26) for CHD, and 1.19 (1.13, 1.26) for diabetes, in substantial agreement with findings from the DM trial. With control for additional dietary variables, especially fiber, fat density was no longer associated with CHD, with hazard ratio (95% confidence interval) of 1.00 (0.88, 1.13), whereas that for breast cancer was 1.11 (1.00, 1.24). ConclusionsWHI observational data support prior DM trial findings of low-fat dietary pattern benefits in this population of postmenopausal United States women. Trial registration numberThis study is registered with clinicaltrials.gov identifier: NCT00000611.

GM1 Ganglioside as a Disease-Modifying Therapeutic for Parkinson's Disease: A Multi-Functional Glycosphingolipid That Targets Multiple Parkinson's Disease-Relevant Pathogenic Mechanisms.

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of patients worldwide. Many therapeutics are available for treating PD symptoms but there is no disease-modifying therapeutic that has been unequivocally shown to slow or stop the progression of the disease. There are several factors contributing to the failure of many putative disease-modifying agents in clinical trials and these include the choice of patients and clinical trial designs for disease modification trials. Perhaps more important, however, is the choice of therapeutic, which for the most part, has not taken into account the multiple and complex pathogenic mechanisms and processes involved in PD. This paper discusses some of the factors contributing to the lack of success in PD disease-modification trials, which have mostly investigated therapeutics with a singular mechanism of action directed at one of the many PD pathogenic processes, and suggests that an alternative strategy for success may be to employ multi-functional therapeutics that target multiple PD-relevant pathogenic mechanisms. Evidence is presented that the multi-functional glycosphingolipid GM1 ganglioside may be just such a therapeutic.

A Multicenter, Phase II Trial of Schedule Modification for Nab-Paclitaxel in Combination with Ramucirumab for Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer: The B-RAX Trial (JACCRO GC-09).

This study investigated whether schedule modification of bi-weekly nanoparticle albumin-bound paclitaxel (nab-PTX) plus ramucirumab (RAM) is efficacious against gastric cancer (GC) or gastroesophageal junction cancer (GJC). Patients with unresectable GC or GJC who were previously treated with fluoropyrimidine-containing regimens received nab-PTX (100 mg/m2) on days 1, 8, and 15 and RAM (8 mg/kg) on days 1 and 15 of a 28-day cycle. Based on the incidence of severe adverse events (AEs) during the first cycle, patients were modified to bi-weekly therapy from the second cycle. The primary endpoint was progression-free survival (PFS) in the bi-weekly therapy population. Based on the hypothesis that bi-weekly nab-PTX plus RAM would improve PFS from 4.5 to 7.0 months, 40 patients were required for power of 0.8 with a one-sided α of 0.05. Of the 81 patients enrolled, 47 patients (58%) were assigned to bi-weekly therapy. Patient characteristics were Eastern Cooperative Oncology Group performance status of 1 (19%) and diffuse type (45%). Median PFS was 4.7 months (95% confidence interval [CI] 3.7-5.6 months) and overall response rate was 25% (95% CI 11-39%). Severe AEs of grade 3 or worse were mainly neutropenia (83%) and hypertension (23%). EQ-5D scores were maintained during the treatment. In patients who continued standard-schedule therapy, median PFS was 2.7 months (95% CI 1.8-4.0 months). The primary endpoint for PFS was statistically not met, but modification of nab-PTX plus RAM to a bi-weekly schedule might be a feasible treatment option as second-line treatment for advanced GC/GJC patients, especially elderly patients, with severe AEs during the first cycle.

Evaluating Statin Knowledge-Perceptions and Receptivity Following a Comprehensive Lifestyle Modification Program

Background Though clinical guidelines for cholesterol-lowering therapies advocate for both a trial of lifestyle modification and the initiation of statin medication when appropriate, the extent to which lifestyle modification may alter a patient’s knowledge-perceptions and receptivity towards statins remains unclear. Methods Following completion of a 6-month comprehensive lifestyle modification program, perceived changes in knowledge and receptivity towards statins were examined across prespecified subgroups of age, sex, and statin eligibility using a mixed-methods questionnaire. Quantitative and qualitative analyses incorporated binomial tests, McNemar’s test, and thematic analyses. Results Among 192 patients who completed the program and exit questionnaire between December 15, 2020 and July 2, 2021, 88.4% of patients indicated a perceived improvement in cholesterol and/or statin knowledge (P &lt; . 0001). 48.2% of patients acknowledged that their receptivity towards taking statins increased (P = . 61). Changes in receptivity were attributed to several identified program themes including improvements in health knowledge and awareness, motivation and empowerment. Patients who noted improvements in their mental health also reported significantly increased receptivity towards statins (P &lt; . 001). Conclusions Patients’ perceived knowledge and receptivity towards statins may improve following participation in a comprehensive therapeutic lifestyle modification program. Future research must evaluate the impact of these programs on statin uptake, compliance and outcomes.