Modest Improvement Research Articles

Combined polygenic scores for ischemic stroke risk factors aid risk assessment of ischemic stroke

BackgroundCurrent risk assessment for ischemic stroke (IS) is limited to clinical variables. We hypothesize that polygenic scores (PGS) of IS (PGSIS) and IS-associated diseases such as atrial fibrillation (AF), venous thromboembolism (VTE), coronary artery disease (CAD), hypertension (HTN), and Type 2 diabetes (T2D) may improve the performance of IS risk assessment. MethodsIncident IS was followed for 479,476 participants in the UK Biobank who did not have an IS diagnosis prior to the recruitment. Lifestyle variables (obesity, smoking and alcohol) at the time of study recruitment, clinical diagnoses of IS-associated diseases, PGSIS, and five PGSs for IS-associated diseases were tested using the Cox proportional-hazards model. Predictive performance was assessed using the C-statistic and net reclassification index (NRI). ResultsDuring a median average 12.5-year follow-up, 8374 subjects were diagnosed with IS. Known clinical variables (age, gender, clinical diagnoses of IS-associated diseases, obesity, and smoking) and PGSIS were all independently associated with IS (P < 0.001). In addition, PGSIS and each PGS for IS-associated diseases was also independently associated with IS (P < 0.001). Compared to the clinical model, a joint clinical/PGS model improved the C-statistic for predicting IS from 0.71 to 0.73 (P < 0.001) and significantly reclassified IS risk (NRI = 0.017, P < 0.001), and 6.48% of subjects were upgraded from low to high risk. ConclusionsAdding PGSs of IS and IS-associated diseases to known clinical risk factors statistically improved risk assessment for IS, demonstrating the supplementary value of inherited susceptibility measurement . However, its clinical utility is likely limited due to modest improvements in predictive values.

Screening and Management of Pediatric High Blood Pressure-Challenges to Implementing the Clinical Practice Guideline.

Elevated blood pressure (BP) and hypertension in childhood convey risk for hypertension and cardiovascular events in adulthood. Early recognition of abnormal BPs is key to preventing or lessening this risk. However, the process for making the diagnosis of hypertension is complex, and overall adherence to the 2017 American Academy of Pediatrics Clinical Practice Guidelines (CPG) is poor. We will review obstacles to adherence to the CPG and approaches designed to improve the diagnosis and management of hypertension in children. Baseline data from the multi-center quality improvement intervention, "Boosting Primary Care Awareness and Treatment of Hypertension" (BP-CATCH), demonstrate that childhood hypertension remains underdiagnosed. Other studies confirm a lack of compliance with the process outlined in the CPG. The provision of electronic prompts, coaching, and education results in modest improvements. The combination of embedded medical record tools and education seems to offer the most hope for improvement.

Peripheral nerve decompression for pain relief in the setting of previous obstetrical brachial plexus injury: a retrospective case series.

In children with previous obstetrical brachial plexus injury (OBPI), upper extremity pain is present in 45 to 66% of patients. Recent literature reports this as musculoskeletal or neuropathic in nature. The purpose of the study is to demonstrate that peripheral nerve decompression, and neurolysis may be an effective treatment for patients with upper extremity pain in the context of previous OBPI. A retrospective chart review was performed on patients undergoing peripheral nerve decompression and neurolysis after OBPI by senior author. The primary outcome assessed was pain, and secondary outcome measure was range of motion of the wrist and elbow. Outcome measures were assessed preoperatively as well as at their subsequent follow-up. Six patients were included, with a mean age of 14years old at time of decompression. Three patients underwent median nerve, two patients underwent ulnar nerve, and one patient underwent posterior interosseous nerve decompression. There was a substantial improvement in pain post-operatively, demonstrated by reduction or resolution of subjective pain in all patients and resolution of Tinel's sign. There was a modest improvement in range of motion. This study demonstrates an improvement in subjective pain and range of motion after decompression and neurolysis in small subset of OBPI patients. It generates the hypothesis that peripheral nerve compression is a source of pain that can be addressed in this population. Future research should focus on confirming this hypothesis and assessing treatment options on a larger scale.

A Composite Index for Tracking the Evolution towards Energy Transition at Urban Scale: The Turin Case Study

Cities play a pivotal role in achieving worldwide carbon neutrality due to their significant contribution to global energy consumption and carbon emissions. Therefore, planning effective strategies and guiding evidence-based policymaking at the city scale becomes even more crucial. Composite indices serve as a valuable tool for monitoring urban energy transition trends. This paper aims to present a novel approach, robust and flexible even under conditions of data scarcity, for tracking the energy transition trend of a city by means of a composite index (UETI). The Turin case study is introduced to test the applicability of the proposed approach. Additionally, to demonstrate the robustness of the composite index framework, the paper includes the findings of correlation and sensitivity analyses. This study reveals a significant improvement in Turin’s environmental and energy domains, while the socio-economic domain shows more modest improvement. Furthermore, the study highlights the need to address the shortage of urban data to enhance the accuracy and reliability of metric-based frameworks and to extend the assessment to a larger sample of cities.

Early Results in Total Replacement of the Distal Radioulnar Joint.

Pathology of the distal radioulnar joint (DRUJ) including instability and arthritis presents a challenge for hand and upper extremity surgeons. Surgical options include a Darrach procedure and similar resections, soft tissue interposition arthroplasty, and a one-bone forearm. In 2005, a prosthesis for DRUJ arthroplasty was approved for use in the United States. The authors hypothesize that DRUJ arthroplasty will lead to improved pain and range of motion (ROM) with a moderate, but manageable, complication rate. A retrospective review of 46 patients who underwent DRUJ arthroplasty by a single private group of hand surgeons was performed. Demographics, complications, postoperative visual analog scale (VAS), and postoperative ROM were obtained and analyzed. The patients were followed up for a mean of 60 weeks. The implant was used both as primary surgical treatment for DRUJ pathology and as salvage for previous failed procedures. Twenty-two percent of patients experienced complications: 15% required revision surgery. No patients were converted to another type of implant, including those who underwent revision surgery. Prominent hardware was the most common indication requiring revision. Patients achieved an improvement in supination of 17° and extension of 5°. They additionally achieved a decrease in average VAS score from 7.1 to 2.3. Distal radioulnar joint arthroplasty reduces pain and improves ROM in patients with DRUJ pathology with a 22% complication rate. This cohort demonstrates improved pain, modest improvement in ROM, but a 22% complication rate for this implant. Further long-term studies are encouraged.

Does the Squeaky Wheel Get More Grease? The Direct and Indirect Effects of Citizen Participation on Environmental Governance in China

We conducted a nationwide field experiment in China to evaluate the direct and indirect impacts of assigning firms to public or private citizen appeals when they violate pollution standards. There are three main findings. First, public appeals to the regulator through social media substantially reduce violations and pollution emissions, while private appeals cause more modest environmental improvements. Second, public appeals appear to tilt regulators’ focus away from facilitating economic growth and toward avoiding pollution-induced public unrest. Third, pollution reductions by treated firms are not offset by control firms, based on randomly varying the proportion of treated firms at the prefecture level. (JEL D22, L82, P28, P31, Q52, Q53, Q58)

Changes in alcohol intake and serum urate changes: longitudinal analyses of annual medical examination database

IntroductionDespite the established cross-sectional association between alcohol intake and serum urate (SU), its longitudinal association remains unknown. This study aimed to determine whether changes in alcohol intake have a clinically...

Efficient Sampling of Cavity Hydration in Proteins with Nonequilibrium Grand Canonical Monte Carlo and Polarizable Force Fields.

Prediction of the hydration levels of protein cavities and active sites is important to both mechanistic analysis and ligand design. Due to the unique microscopic environment of these buried water molecules, a polarizable model is expected to be crucial for an accurate treatment of protein internal hydration in simulations. Here we adapt a nonequilibrium candidate Monte Carlo approach for conducting grand canonical Monte Carlo simulations with the Drude polarizable force field. The GPU implementation enables the efficient sampling of internal cavity hydration levels in biomolecular systems. We also develop an enhanced sampling approach referred to as B-walking, which satisfies detailed balance and readily combines with grand canonical integration to efficiently calculate quantitative binding free energies of water to protein cavities. Applications of these developments are illustrated in a solvent box and the polar ligand binding site in trypsin. Our simulation results show that including electronic polarization leads to a modest but clear improvement in the description of water position and occupancy compared to the crystal structure. The B-walking approach enhances the range of water sampling in different chemical potential windows and thus improves the accuracy of water binding free energy calculations.

Laser-assisted surface grinding of innovative superhard SiC-bonded diamond (DSiC) materials

Silicon carbide (SiC)-bonded diamond materials, comprising approximately 50% diamond by volume, represent innovative composites with exceptional mechanical and thermal properties, including high hardness, wear and corrosion resistance, and elevated thermal conductivity. Despite these advantageous properties, the machining of these composites presents formidable challenges due to their extremely high hardness. Grinding with diamond tools is commonly employed among the limited viable machining methods. However, the efficiency of this process is hindered by high grinding forces, elevated temperatures, and significantly high tool wear. Additionally, the surface integrity, form, and dimensional accuracy of the workpiece are compromised by the effects of tool wear and high cutting forces. To address these technological constraints in the grinding of SiC-bonded diamond materials, a laser-assisted grinding process has been developed. Ultra-short pulsed laser radiations were effectively utilized to induce material ablation with controlled structural damages, enhancing the productivity and efficiency of the grinding process through reduced grinding forces, temperatures, and tool wear. Furthermore, this study investigated the influence of grinding tools' specifications, design variations, and parameters on key aspects such as grinding forces, surface quality, and tool wear. Substantial reductions of up to 70% in tangential grinding forces, 83% in normal grinding forces, and a modest improvement in surface roughness achieved. The surface integrity analysis revealed a damage-free ground surface when utilizing laser assistance. Furthermore, there was a substantial enhancement in the grinding ratio (G-ratio), achieving an increase of up to 247%, concurrently with a noteworthy improvement in the actual removal depth, reaching up to 99%, when compared to conventional grinding processes. Compared to the utilized segmented metal bonded diamond grinding wheel, the vitrified bonded diamond grinding wheel induced lower grinding forces and higher actual removal rates.

Maternal mood, anxiety and mental health functioning after combined myo-inositol, probiotics, micronutrient supplementation from preconception: Findings from the NiPPeR RCT

Observational studies have reported associations between nutrition during pregnancy and mental wellbeing. As secondary outcomes, the NiPPeR double-blind randomized trial in women planning conception investigated whether a myo-inositol, probiotics and enriched micronutrients formulation (intervention) taken preconception and throughout pregnancy could improve mental wellbeing during pregnancy and post-delivery, compared with a standard micronutrient supplement (control). Mood and anxiety symptoms were ascertained (Edinburgh Postnatal Depression Scale (EPDS), State-Trait Anxiety Inventory (STAI-state)) at preconception (baseline), 7, 28 and 34 weeks gestation, 3-weeks and 6-months post-delivery. EPDS>=13 was categorised as low mood; STAI-state>=45 as high anxiety. Change in mental health functioning was assessed as difference between preconception baseline and 6-month post-delivery 12-item Short-Form Health Survey (SF-12v2) mental component scores. Adjusting for site, ethnicity and baseline scores, there were no robust differences in EPDS and STAI-state scores between intervention and control groups across pregnancy (n = 630) and post-delivery (n = 532). Compared to controls, intervention group women averaged a 1.21 (95 %CI 0.04,2.39) higher change in SF-12v2 mental component score from preconception to 6-months post-delivery. Taking a myo-inositol, micronutrient and probiotic supplement during preconception/pregnancy had no effect on mood and anxiety, but there was evidence of a modest improvement in mental health functioning from preconception to 6-months post-delivery.

Transfer learning for auto-segmentation of 17 organs-at-risk in the head and neck: Bridging the gap between institutional and public datasets.

Auto-segmentation of organs-at-risk (OARs) in the head and neck (HN) on computed tomography (CT) images is a time-consuming component of the radiation therapy pipeline that suffers from inter-observer variability. Deep learning (DL) has shown state-of-the-art results in CT auto-segmentation, with larger and more diverse datasets showing better segmentation performance. Institutional CT auto-segmentation datasets have been small historically (n<50) due to the time required for manual curation of images and anatomical labels. Recently, large public CT auto-segmentation datasets (n>1000 aggregated) have become available through online repositories such as The Cancer Imaging Archive. Transfer learning is a technique applied when training samples are scarce, but a large dataset from a closely related domain is available. The purpose of this study was to investigate whether a large public dataset could be used in place of an institutional dataset (n>500), or to augment performance via transfer learning, when building HN OAR auto-segmentation models for institutional use. Auto-segmentation models were trained on a large public dataset (public models) and a smaller institutional dataset (institutional models). The public models were fine-tuned on the institutional dataset using transfer learning (transfer models). We assessed both public model generalizability and transfer model performance by comparison with institutional models. Additionally, the effect of institutional dataset size on both transfer and institutional models was investigated. All DL models used a high-resolution, two-stage architecture based on the popular 3D U-Net. Model performance was evaluated using five geometric measures: the dice similarity coefficient (DSC), surface DSC, 95th percentile Hausdorff distance, mean surface distance (MSD), and added path length. For a small subset of OARs (left/right optic nerve, spinal cord, left submandibular), the public models performed significantly better (p<0.05) than, or showed no significant difference to, the institutional models under most of the metrics examined. For the remaining OARs, the public models were inferior to the institutional models, although performance differences were small (DSC≤0.03, MSD<0.5mm) for seven OARs (brainstem, left/right lens, left/right parotid, mandible, right submandibular). The transfer models performed significantly better than the institutional models for seven OARs (brainstem, right lens, left/right optic nerve, left/right parotid, spinal cord) with a small margin of improvement (DSC≤0.02, MSD<0.4mm). When numbers of institutional training samples were limited, public and transfer models outperformed the institutional models for most OARs (brainstem, left/right lens, left/right optic nerve, left/right parotid, spinal cord, and left/right submandibular). Training auto-segmentation models with public data alone was suitable for a small number of OARs. Using only public data incurred a small performance deficit for most other OARs, when compared with institutional data alone, but may be preferable over time-consuming curation of a large institutional dataset. When a large institutional dataset was available, transfer learning with models pretrained on a large public dataset provided a modest performance improvement for several OARs. When numbers of institutional samples were limited, using the public dataset alone, or as a pretrained model, was beneficial for most OARs.

Mitigation of Shock-Induced Separation Using Square-Shaped Micro-Serrations—A Preliminary Study

Suppressing shock-induced flow separation has been a long-standing problem in the design of supersonic vehicles. To reduce the structural and design complexity of control devices, a passive control technique based on micro-serrations is proposed and its controlling effects are preliminarily investigated under test conditions in which the Mach number is 2.5 and the ramp creating an incident shock is 15 deg. Meanwhile, a vorticity-based criterion for assessing separation scales is developed to resolve the inapplicability of the zero skin friction criterion caused by wall unevenness. The simulations demonstrate that the height of the first stair significantly influences the separation length. Generally, the separation length is shorter at higher stairs, but when the height is greater than half of the thickness of the incoming boundary layer, the corresponding separation point moves upstream. A stair with a height of only 0.4 times the thickness of the boundary layer reduces the separation length by 2.69%. Further parametric analysis reveals that while the remaining serrations have limited effects on the flow separation, an optimization of their shape (depth and width) can create more favorable spanwise vortices and offer a modest improvement of the overall controlling performance. Compared to the plate case, a 9.13% reduction in the separation length can be achieved using a slightly serrated design in which the leading stair is 0.1 high and the subsequent serrations are 0.2 deep and 0.05 wide (nondimensionalized, with the thickness of the incoming boundary layer). Meanwhile, the micro-serration structure even brings less drag. Considering the minor modification to the structure, the proposed method has the potential for use in conjunction with other techniques to exert enhanced control on separations.

The Efficacy of Immune Checkpoint Inhibitors in Microsatellite Stable Colorectal Cancer: A Systematic Review.

The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer care, particularly in immune-inflamed tumors and tumors with a high mutational burden, like microsatellite instable colorectal cancer (CRC). However, their effectiveness in microsatellite stable (MSS) CRC is limited. This systematic review aims to evaluate the efficacy of ICIs in MSS CRC and explore promising combination strategies. A comprehensive search from the Web of Science, Medline, and Embase databases, for studies published until 14 November 2022, identified 53 clinical trials included in the review. ICI monotherapy or ICI-ICI combinations demonstrated limited clinical activity for patients with MSS CRC, with overall response rates below (ORR) 10% in most studies. The ICI and tyrosine kinase inhibitor (TKI) garnered ORRs ranging from 10% to 40% and indicated a higher benefit for patients, particularly those without active liver metastases. The combination of ICIs with anti-VEGF agents showed modest ORRs, especially in the earlier treatment lines and in combination with chemotherapy. While these combinations could lead to modest improvements, well-defined biomarkers for long-term benefit are yet to be delineated. Combinations involving BRAF inhibitors with ICIs were studied, showing promising responses with combination approaches in molecularly defined subgroups. In conclusion, while ICI monotherapy has limited efficacy in MSS CRC, combination strategies hold promise to enhance survival outcomes. Further research is necessary to identify optimal combination approaches, predictive biomarkers for treatment response, as well as enrollment according to tumor molecular characteristics.

Provider perceptions and use of mental health services in the Veterans Health Administration during the COVID-19 pandemic.

The COVID-19 pandemic significantly altered the way in which health care is delivered, challenging providers, and systems of care to innovate to maintain access to services. This article describes the delivery of mental health services during the pandemic in two Veterans Health Administration (VHA) regions that include 15 hospitals and over 100 outpatient facilities in the southern United States. Data were derived from (a) a survey of provider perspectives (n = 1,175) on delivering mental health care prior to and during the pandemic and (b) VHA administrative data on mental health service delivery. Providers reported that access, quality, and timeliness of services remained high during the pandemic; indicated increased use of telehealth services; and reported challenges in delivering evidence-based psychotherapies (EBPs) and measurement-based care (MBC). Administrative data indicated no drop in the number of Veterans receiving mental health care during the pandemic but showed fewer total visits relative to prepandemic levels and confirmed a dramatic increase in telehealth services during the first 6 months of the pandemic (+ 459% telephone and + 202% video) and a decrease in use of EBPs (-28%) and MBC (-31%). Data at 12 months showed a continued increase in video services (+ 357%) and modest improvement in EBP and MBC use. Rapid shifts in the use of telehealth services, coupled with organizational efforts, ensured that Veterans continued to have access to mental health services during the pandemic. Although mental health services remained accessible, challenges existed in the delivery of specialized mental health services, including EBPs and MBC. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Experimental study and performance enhancement of micro heat pipe PV/T system

The integration of photovoltaic/thermal (PV/T) systems, which enable the simultaneous conversion of solar energy into both electricity and thermal energy, holds great promise in the solar-rich northwest region of China. This study aims to assess the performance of a micro heat pipe (MHP) PV/T system through comprehensive experiments conducted over the four seasons in Lanzhou. The experimental setup involved the measurement of various parameters including environmental temperature, surface temperature of the PV/T panel, back temperature of the PV/T panel, and water temperature, as well as the determination of the power collection efficiency (PCE) and thermal conversion efficiency (TCE). The PV/T system was installed at a tilt angle of 45°, resulting in an average PCE of 12.42 % and TCE of 34.7 %. To further understand the system performance, a two-dimensional mathematical model was developed and validated using the experimental data, demonstrating good agreement between the simulated and actual results. The simulation provided valuable insights into the temperature distribution across different components of the PV/T module, such as the glass cover, solar cell, and single shell of the MHP. The findings revealed that increasing the number of MHPs from 12 to 20 led to a modest improvement of 0.21 % and 2.72 % in the PCE and TCE, respectively. Similarly, raising the flow rate from 0.108 L/s to 0.128 L/s resulted in a corresponding increase of 0.25 % and 3.01 % in the PCE and TCE, respectively. These experimental investigations and numerical simulations established a solid scientific foundation and offered practical guidance for the implementation of MHP-PV/T systems, thereby facilitating the efficient utilization of solar energy in future applications.

Exploring hospital mealtime experiences of older inpatients, caregivers and staff using photovoice methods.

To gather and understand the experience of hospital mealtimes from the perspectives of those receiving and delivering mealtime care (older inpatients, caregivers and staff) using photovoice methods to identify touchpoints and themes to inform the co-design of new mealtime interventions. This study was undertaken on acute care wards within a single metropolitan hospital in Brisbane, Australia in 2019. Photovoice methods involved a researcher accompanying 21 participants (10 older patients, 5 caregivers, 4 nurses and 2 food service officers) during a mealtime and documenting meaningful elements using photographs and field notes. Photo-elicitation interviews were then undertaken with participants to gain insight into their experience. Data were analysed using inductive thematic analysis, involving a multidisciplinary research team including a consumer. Themes were identified across the three touchpoints: (1) preparing for the meal (the juggle, the anticipation), (2) delivering/receiving the meal (the rush, the clutter and the wait) and (3) experiencing the meal (the ideal, pulled away and acceptance). Despite a shared understanding of the importance of meals and shared vision of 'the ideal' mealtime, generally this was a time of tension, missed cares and dissatisfaction for staff, patients and caregivers. There was stark contrast in some aspects of mealtime experience, with simultaneous experiences of 'the rush' (staff) and 'the wait' (patients and caregivers). There was an overwhelming sense of acceptance and lack of control over change from all. This study identified themes during hospital mealtimes which have largely gone unaddressed in the design of mealtime interventions to date. This research may provide a framework to inform the future co-design of mealtime interventions involving patients, caregivers and multidisciplinary staff, centred around these key touchpoints. Mealtimes are experienced differently by patients, caregivers, nurses and food service officers across three key touchpoints: preparing for, delivering/receiving and experiencing the meal. Improving mealtime experiences therefore necessitates a collaborative approach, with co-designed mealtime improvement programs that include specific interventions focusing each touchpoint. Our data suggest that improvements could focus on reducing clutter, clarifying mealtime roles and workflows and supporting caregiver involvement. What problem did the study address? Mealtimes are the central mechanism to meet patients' nutritional needs in hospital; however, research consistently shows that many patients do not eat enough to meet their nutritional requirements and that they often do not receive the mealtime assistance they require. Interventions to improve hospital mealtimes have, at best, shown only modest improvements in nutritional intake and mealtime care practices. Gaining deeper insight into the mealtime experience from multiple perspectives may identify new opportunities for improvement. What were the main findings? Patients, caregivers and staff have shared ideals of comfort, autonomy and conviviality at mealtimes, but challenges of complex teamwork and re-prioritisation of mealtimes in the face of prevailing power hierarchies make it difficult to achieve this ideal. There are three discrete touchpoints (preparing for, delivering/receiving and experiencing the meal) that require different approaches to improvement. Our data suggests a need to focus improvement on reducing clutter, clarifying mealtime roles and workflows and supporting caregivers. Where and on whom will the research have an impact? The research provides a framework for multidisciplinary teams to begin co-designing improvements to mealtime care to benefit patients, caregivers and staff, while also providing a method for researchers to understand other complex care situations in hospital. This manuscript is written in adherence with the Standards for Reporting Qualitative Research. Patients and caregivers were involved in the conception and design of the study through their membership of the hospital mealtime reference group. A consumer researcher (GP) was involved in the team to advise on study conduct (i.e. recruitment methods and information), data analysis (i.e. coding transcripts), data interpretation (i.e. review and refinement of themes) and manuscript writing (i.e. review and approval of final manuscript).

Individual-level innovation in the upstream oil & gas industry: Insights from a global survey

The transition to a lower-carbon world is significantly underway, but oil & gas will likely continue to play an important role in the world's energy mix for many years to come. At the same time, though, the industry is undergoing significant change on several fronts, and technology and innovation will accordingly play a pivotal role in the future of the sector. Building upon the first Society of Petroleum Engineers Global Innovation Survey, this paper presents the findings from the follow-up survey to examine these processes again. However, whereas the first survey looked at innovation at the business unit level, this investigation explores this phenomenon from the point of view of individual people. Through the application of tools from the field of organizational psychology, this survey was designed to find out who the “explorers” are within the oil & gas sector that are hardwired to deliver tomorrow's bolder technologies, and who the “exploiters” are that are more inclined to prefer modest improvements to existing solutions. We found several potentially useful patterns in the data. First, respondents who have graduate degrees were more likely to engage in exploration kinds of behaviors than those who do not. Second, age had little bearing on whether or not a respondent exhibited exploration kinds of behaviors. Third, respondents who spent their formative years before the age of 18 in Norway, Russia, or Indonesia tended to engage in more exploration kinds of activity than most others. Fourth, respondents working in Brazil, China, Malaysia, Nigeria, and Venezuela at the time of the survey all reported lower levels of exploration-like behavior than their counterparts elsewhere. The paper concludes with recommendations for future investigations in this area.

Gastrodin Suppresses the Progression of Atherosclerosis and Vascular Inflammation by Regulating TLR4/NF-κB Pathway.

Elevated levels of plasma triglycerides (TG) and cholesterol have been shown to contribute to the pathogenesis of several cardiovascular risk factors, such as atherosclerosis, a primary cause of mortality. Gastrodin (Gas) is an effective polyphenol extracted from Chinese natural herbal Gastrodiae elata Blume, which has been documented to be effective against atherosclerosis. However, the related mechanisms remain largely unclear. The current investigation elucidated the involvement of Gas in the development of AS generated by a high-fat diet in mice lacking the apolipoprotein E gene (ApoE-/-). The findings of our study indicate that the administration of Gas had a beneficial effect on hyperlipidemia in mice that were given a high-fat diet and lacked the ApoE gene. Specifically, Gas supplementation resulted in a reduction in blood levels of oxidized low-density lipoprotein (ox-LDL), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α). Additionally, the administration of Gas resulted in the suppression of lesions in the en face aortas of ApoE KO mice, accompanied by a modest improvement in lipid profiles. The intervention demonstrated the capacity to impede the development of atherosclerotic lesions and promote characteristics associated with plaque stability. The administration of Gas prevented inflammation in the aorta by decreasing the expression of IL-6, TNF-α, and MCP-1. Additionally, Gas had a mitigating effect on TLR4/NF-κB pathway components in the aorta of ApoE-/- mice. Furthermore, it has been shown that Gas has the potential to mitigate the harm caused to human umbilical vein endothelial cells (HUVECs) by ox-LDL, perhaps via inhibiting inflammation through the TLR4/NF-κB pathway. This study shows that Gas may potentially mitigate the development of atherosclerosis via its pleiotropic effects, including improvements in lipid profiles and anti-inflammatory properties.

P1018 Population pharmacokinetic and exposure-response analyses for efficacy and safety of risankizumab in subjects with moderately to severely active Ulcerative Colitis

Abstract Background Risankizumab (RZB) has been evaluated in subjects with moderately to severely active ulcerative colitis (UC) in the INSPIRE and COMMAND trials. Population pharmacokinetic (PPK) and exposure-response (ER) analyses were conducted at the end of Phase 2b and following Phase 3 to characterize RZB PK and its relationship with clinical efficacy and safety to support Phase 3 induction dose selection, and the final dose recommendations for induction and maintenance treatment. Methods PPK analyses in UC used a previously developed PPK model for Crohn’s disease with additional evaluation of covariates relevant to UC. ER relationships between RZB exposures and efficacy endpoints at the end of induction (Week 12), re-induction (Week 24; exploratory only) and maintenance (Week 52) periods were established using exploratory graphical analyses and logistic regression modeling. ER analyses for safety were performed for key variables through Weeks 12, 24 and 52 using graphical analyses. Results A two-compartment model with first-order absorption for SC administration and first-order elimination adequately described RZB PK. Among the various covariates assessed, body weight, baseline (BL) serum albumin, BL high-sensitivity C-reactive protein, BL fecal calprotectin, sex, advanced therapy IR status, BL pancolitis and corticosteroid use were statistically correlated with RZB clearance but their impact on exposure was not clinically relevant for efficacy. ER analyses for efficacy using Phase 2b induction data showed that while incremental improvement in efficacy was predicted with doses increasing from 1200 to 1800 mg, the magnitude of difference in efficacy was modest especially for endoscopy-driven endpoints. Phase 3 ER analyses for efficacy showed statistically significant trends of exposure-dependent increase in efficacy following induction treatment with 1200 mg IV at Week 0, 4 and 8, with greater response rates observed with higher exposures across all evaluated endpoints at Week 12, in line with the results from Phase 2b. ER analyses for maintenance demonstrated an exposure-dependent increase in efficacy for Week 52 endpoints, with modest improvement in efficacy when increasing the dose from 180 mg to 360 mg, and largely overlapping confidence intervals. ER analyses for safety indicated no apparent exposure-dependent safety events over the induction or maintenance treatment. Conclusion The PPK and ER analyses of RZB in subjects with UC characterized the disposition of RZB and its relationship to efficacy and safety, as well as the lack of impact by intrinsic and extrinsic factors on PK and efficacy. Results supported the final dosing regimen recommendations for the treatment of moderately to severely active UC.

Effect of Hospital Cancer Designation on use of Multimodal Therapy and Survival of Metastatic Colorectal Cancer: A State-Wide Analysis.

Stage IV colorectal cancer (CRC) often requires multidisciplinary approach. However, multimodal treatment options (receipt of >1 type of treatment) may not be uniformly delivered across health systems. We characterized the association between center-level cancer center designation and receipt of multimodal treatment and survival. The Texas Cancer Registry was used to identify patients diagnosed with stage IV CRC from 2004-2017. We identified those who received care at either: a National Cancer Institute-designated (NCI-D), an American College of Surgeons-Commission on Cancer-designated (ACS-D), or an undesignated facility. We used multivariable logistic regression and Cox regression for analysis to assess receipt of one or more treatment modality and 5-year overall survival. Of 19,355 patients with stage IV CRC, 2955 (15%) received care at an NCI-D facility and 5871 (30%) received multimodal therapy. Both NCI-D (odds ratio [OR] 1.64; 95% confidence interval [CI] 1.49-1.81) and ACS-D (OR 1.37; 95% CI 1.27-1.48) were associated with increased likelihood of multimodal therapy compared with undesignated centers. NCI-D also was associated with significantly improved survival (hazard ratio [HR] 0.74; 95% CI 0.70-0.78), although ACS-D was associated with a modest improvement in survival (HR 0.95; 95% CI 0.92-0.99). Receipt of multimodal therapy was strongly associated with improved survival (HR 0.61; 95% CI 0.59-0.63). In patients with stage IV CRC, treatment at ACS-D and NCI-D facilities was associated with increased use of multimodality therapy and improved survival. However, only a small proportion of patients have access to these specialized centers, highlighting a need for expanded access to multimodal therapies at other centers.