Commercial Trials Research Articles

Abstract 2504: Determining tumour homologous recombination repair status in PDX and clinical samples using automated RAD51 scoring

Abstract PARP inhibitors (PARPi) as monotherapy are approved in a wide variety of cancers that show genetic alterations that result in homologous recombination repair (HRR) deficiency. Current genomic scar tests for HRR deficiency (HRD) are predictive of response to PARPi on a population scale but they may fail to provide a real-time functional status of HRR in an individual. RAD51 is a critical DNA repair factor that functions in HRR to safeguard the integrity of the genome and could be a useful patient selection biomarker for PARPi response.During HRR, RAD51 forms filamentous structures to facilitate repair, which can be visualised by direct immunofluorescence (IF) as nuclear foci. Quantification of these RAD51 foci has been shown to be a functional readout of HRR status, however current manual counting of foci is challenging and can result in high inter-observer variability. In order to standardise RAD51 quantification, we aimed to develop an image analysis solution.Tumour samples from patient derived xenograft (PDX) studies and human tissues from commercial sources and clinical trials were co-stained with IF for RAD51 and geminin, as a marker of cells in S/G2 phase of the cell cycle. Manual scoring was performed as reported previously. Visiopharm was used to create and image analysis pipeline in allowing delineate tumour epithelial areas, detection of the geminin positive nuclei and RAD51 foci within these and the quantification of the foci.We have successfully developed an image analysis solution to select geminin positive proliferating tumour cells from PDX and clinical material, then quantify the RAD51 foci within these cells. There is a good correlation with manual scores with a similar accuracy to the manual inter-observer variability (PDX: R2 = 0.76, F1 = 0.95 [n=34]; breast cancer samples: R2 = 0.72, F1 = 0.92 [n=33]). Developing and image analysis solution has challenges due to several factors such as pan-nuclear staining of non-focus forming RAD51 being variable across samples, manual scoring using a wider Z-plane, susceptibility of RAD51 to pre-analytical factors and the fact that a duplex IF stain with geminin is required to mark actively replicating cells.The frequent inactivation of HRR is known to sensitise cancer cells to PARP inhibitors, we demonstrate a quantitative functional readout of HRR competency using RAD51 foci staining and an image analysis algorithm. This solution may enable the use of RAD51 foci as a patient selection biomarker for PARP inhibitors by providing an objective, robust and reproducible algorithm for scoring. Citation Format: Jack Robertson, Jack Ashton, Gemma N. Jones, Gordon Mills, Tugba Y. Ozmen, Matthew J. Rames, Soonyoung Park, Paul Waring, Natalia Lukashchuk, Elizabeth Harrington. Determining tumour homologous recombination repair status in PDX and clinical samples using automated RAD51 scoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2504.

Neurologijos srityje vartojamų vaistinių preparatų klinikinių tyrimų tendencijos Lietuvoje ir Europoje

Background. As the global burden of neurological diseases has been increasing, clinical trials have become more important. Yet, no systematic analysis of clinical trials of neurological medicinal products has been done in Europe and, specifically, in Lithuania. The aim of this study is to evaluate the tendencies of characteristics and registration dynamics of clinical trials of neurological medicines in Europe and Lithuania.Materials and methods. Analysis of data from the clinical trials register of the European Union drug regulatory authorities (EudraCT) has been performed. Applications of clinical trials of neurological medicines included in the register during the period between 2012–2021 have been reviewed. The following aspects have been evaluated: the phase of the trial, the sponsor status, the neurological condition (indication), the expected sample size of the trial, the trial design, and the number of member countries.Results. 2,242 clinical trials of neurological medicines have been registered in Europe during the period of 2012–2021, and they comprised 6.49% of all clinical trials registered in Europe. The annual registration rates did not change significantly during the period of 2012–2021 (R² = 0.039; p = 0.606). The majority of the trials (72.18%) were sponsored by commercial pharmaceutical companies. Most trials (31.73%) were registered as phase I trials. The majority of the trials (363 (17.20%)) were clinical trials for Alzheimer’s disease and other dementias. During the period of 2012–2021, there was a significant decrease in the annual registration rate of clinical trials for Alzheimer’s disease and other dementias (R² = 0.751, p = 0.001) and an increase of clinical trials for myoneural junction and muscle diseases and motor neuron disease (R² = 0.582, p = 0.010 and R² = 0.635, p = 0.006, accordingly). Commercial trials had a higher planned number of subjects (p = 0.014). Multiple member states participated in commercial trials more frequently (p < 0.001). Fifty-five clinical trials of neurological medicines were registered in Lithuania during the period of 2012–2021, and they comprised 8.08% of all clinical trials registered in Lithuania. The annual registration rate has decreased significantly (R² = 0.401, p = 0.049). Almost all trials in Lithuania (53 out of 55) were sponsored by commercial companies. The majority of trials (23 (42%)) were trials for demyelinating diseases of the CNS.Conclusions. The annual registration rates of trials of neurological medicines remain stable in Europe while decreasing in Lithuania. Commercial clinical trials have more participants, and are more commonly conducted in multiple member states.

Cattle, carcass, economic, and estimated emission impacts of feeding finishing steers lubabegron or ractopamine hydrochloride

Abstract Lubabegron (Experior; Elanco, Greenfield, IN, USA) is the first U.S. Food and Drug Administration approved feed additive for reducing gas emissions from feedlot animals or their waste; it does not have live or carcass performance claims. Our primary objective was to determine the effect of lubabegron on feedlot performance and carcass traits in finishing beef steers compared to ractopamine hydrochloride (Optaflexx; Elanco, Greenfield, IN, USA). A commercial feedlot trial using crossbred beef steers (n = 2,117; 373 ± 15 kg initial body weight [BW]) was completed with a randomized complete block design. Treatments consisted of two feed additives: 1) OPT targeted to deliver 300 mg/animal/d of ractopamine hydrochloride for 28 ± 7 d out from harvest and 2) EXP targeted to deliver 36 mg/animal/d of lubabegron 56 ± 7 d out from harvest and a 4-d pre-slaughter withdrawal period. Twenty 70-142 hd pens with 10 pens per treatment were used. Cattle were weighed at arrival processing and at harvest and fed for an average of 167 days. Data were used to calculate production metrics, partial budgets, and estimated greenhouse gas emissions using published methods, and were analyzed using linear mixed models with pen as the experimental unit and block as a random intercept. A statistical significance threshold of α = 0.05 was determined a priori. There was no evidence for statistically significant differences between treatments for initial BW (P = 0.70), health related outcomes (P values ≥ 0.43), or mobility scores (P = 0.09). Cattle fed EXP had increased final BW, ADG, G:F, and decreased DMI (P values ≤ 0.01) compared to OPT. Carcasses were 11 ± 1.76 kg (HCW) heavier in EXP group (P < 0.01), and differed between treatments for both YG and QG distributions (P values ≤ 0.01). Cattle fed EXP had a shift toward more YG 1 and 2, select and sub-select carcasses compared to OPT, which had as shift toward more YG 3, 4, 5, prime and choice carcasses. With increased beef production and efficiency compared to OPT, the estimated CO2 equivalent emissions from production were reduced 6.2% per unit of carcass weight for EXP (P ≤ 0.01). Estimated net returns/animal shipped were $56.61 ± 9.37 more for EXP than OPT (P ≤ 0.01). In conclusion, when cattle were fed for the same total number of days, feeding EXP compared to OPT increased net returns, feedlot performance, and efficiency, but resulted in carcass yield and quality characteristics that may impact marketing programs.

A comparison of the potential of Clinical Trials Centers within both public and commercial trial facilities

Abstract Clinical trials are an integral part of the process of developing new drugs, diagnostic methods and medical devices. Clinical trials offer patients the chance to access alternative treatment methods, thereby improving their quality of life, and even achieving recovery. Additionally, clinical trials provide the opportunity for regular contact with a specialist doctor and easier access to diagnostics, ensuring a faster therapeutic path for the patient. One of the key aspects of conducting clinical trials is choosing the right investigator and research center so as to meet specific criteria and guarantee high quality of the conducted studies. Therefore, the aim of the current study was to evaluate the differences between conducting clinical trials in public and commercial centers. A diagnostic survey was used in the study and the research tool chosen was a proprietary questionnaire belonging to the research technique as survey questionnaire. Questionnaires were constructed for the appropriate stakeholders/respondents, namely: doctors and employees of pharmaceutical companies and CROs. The analysis showed that employees of pharmaceutical companies, given the choice, prefer to cooperate with commercial centers. They choose public centers only when they need a center for phase one trials or those requiring hospitalization. The research obtained shows that public centers should improve administrative processes in order to optimize tasks such as contracting or obtaining a study.

Geospatial technology on road, terrace and planting point for oil palm cultivation in hilly terrain

One of marginal area for oil palm cultivation is on hilly terrain, which pose various agro-management problems start from planting preparation, during oil palm growth/maintenance and up to the harvesting and transporting of the fresh fruit bunches. Geospatial technology was used to help designing road system with focuses on 1) road gradient of less than 7°, 2) road density of less than 200 m/ha and 3) carry distance of about 100m along the terraces. Commercial trial in Pelalawan Riau showed that the design can be implemented resulting average road gradient of 4.7°, road density of 234 m/ha and average carry distance of 143m. Geospatial technology was also used to help designing terraces where digital terrain model was used to produce suitable rajah line location. On planting point, improved Gawthorn and Violle method was introduced incorporating geospatial analysis in detection of potential etiolation areas. The method produced stand per ha of 142 palm/ha (and 145 in commercial) with minimized potential etiolation area to 6%.

A Simple and Cost-Effective Technique to Monitor the Sublimation Flow During Primary Drying of Freeze-Drying Using Shelf Inlet/Outlet Temperature Difference or Chamber to Condenser Pressure Drop

As lyophilization continues to be a critical step in the manufacturing of sensitive biopharmaceuticals, challenges often arise during the scale up to commercial scale or the transfer from one manufacturing site to another. While data from the small-scale development of the lyophilization cycle is abundant it is typically much more difficult to extract important information from commercial scale cycles, due to the lack of process analytical technologies available on the commercial line. There is often a reluctance to include wireless temperature or pressure probes during GMP operations due to the additional contamination risk, and retrofitting equipment such as the TDLAS can be prohibitively expensive. Further, as products become more advanced, the cost of consuming the product or even the availability of material may limit the opportunities to run commercial scale trials. This paper presents two novel methods to garner critical cycle information to allow for the evaluation of cycle performance without the need for expensive analytical equipment, costly revalidation and line downtime. Critically, this can be achieved using commonly available temperature and capacitance probes on existing commercial scale equipment. The first method is a calorimetric method, based on quantifying the differences in heat transfer liquid temperature between the shelf inlet and shelf outlet. This change in temperature results from the on-going sublimation, an endo-thermic reaction occurring during lyophilization. The second method uses the differential pressure between the chamber and condenser resulting from the vapor flow from vial to condenser during primary drying. As stated by the authors both methods align well and provide valuable cycle characterization data.

Registration of ‘CLL17’ rice

Abstract‘CLL17’ (Reg. no. CV‐160; PI 693941), a high‐yielding long‐grain rice (Oryza sativa L.) cultivar, was developed by the Louisiana State University Agricultural Center at the H. Rouse Caffey Rice Research Station near Crowley, LA, and approved for release in 2020. CLL17 contains the herbicide‐resistant gene for use in the Clearfield rice production system. The Clearfield rice production system is defined as the brand of rice cultivars that are tolerant to imidazolinone herbicides. CLL17 was derived from the cross ‘CL131’/‘Trenasse’. It showed good yield potential and favorable agronomic characteristics in the 2015 Clearfield Preliminary Yield Trial. In 2016, it was evaluated in the uniform regional rice nursery trial across four southern states. From 2017 to 2022, CLL17 was evaluated in 50 replicated trials across 10 locations in Louisiana. Three high‐yielding commercial cultivars were included as checks: ‘Cheniere’, ‘CL153’, and ‘CL111’. The grain yield of CLL17 was 9.0 t ha−1 compared with 8.9 t ha−1 for CL153, 8.3 t ha−1 for CL111, and 8.2 t ha−1 for Cheniere across 25 commercial advanced trials from 2017 to 2020. CLL17 had a similar plant height to CL111, 2‐cm taller than CL153, and 5‐cm taller than Cheniere. It exhibits typical US long‐grain rice cooking quality with intermediate amylose and gel temperature. CLL17 is susceptible to sheath blight [caused by Rhizoctonia solani Kuhn ], resistant to Cercospora spp., leaf blast [caused by Magnaporthe grisea (T.T. Hebert)], and neck blast, and moderately susceptible to bacterial panicle blight (caused by Burkholderia glumae).

Analisis Pengaruh Suplementasi 25-Hydroxycholecalciferol terhadap Performa Pertumbuhan Ayam Broiler dalam Kondisi Komersial di Jawa Barat, Indonesia

A large-scale commercial production trial was conducted to evaluate the effect of supplemental 25-hydroxycholecalciferol (25(OH)D3) on the growth performance of broilers.  A total of 100,000 day-old mixed-sex Cobb 500 broilers were allocated equally to 20 farms with 5000 broilers each.  Two experimental diets were prepared:  1) Control diet [(3000 IU D3 kg diet-1 + 2760 IU D3 kg diet-1) = total 5760 IU D3 kg diet-1] and 2) Experimental diet [(3000 IU D3 kg diet-1 + 69 mcg 25(OH)D3 kg diet-1 = 2760 IU D3 equivalent kg diet-1) = total 5760 IU D3 kg diet-1].   The design used a randomized block design with Multivariate Analysis of Covariance analysis method The results showed that broilers chickens fed supplemental 25(OH)D3 significantly gained faster, more efficient feed conversion and lower mortality rate from 0 to 14 days when compared to those fed without 25(OH)D3 supplementation.   Moreover, the relative growth on the diet supplemented with 25(OH)D3 at 7 days was significantly (p<0.05) greater than that without supplementation. At 14 days to harvest, growth parameters including the Production Efficiency Index of broilers supplemented with 25(OH)D3 were 3-4% better than that of the control diet.  Significantly lower mortality rates (p<0.05) were observed in broilers fed 25(OH)D3-supplemented diets compared to unsupplemented diets. It can be concluded of this study demonstrated the positive impact of supplemental 25(OH)D3 on broilers raised under commercial conditions in West Java, Indonesia.
 Key words:  broiler performance, commercial condition, mortality, 25 hydroxycholecalciferol

Defining the Boundaries of Patient Perception in Spinal Cord Stimulation Programming

ObjectivesRecent developments in spinal cord stimulation (SCS) programming have initiated new modalities of imperceptible stimulation. However, the boundaries of sensory perception are not well defined. The BEnchtop NEuromodulation Following endIng of Trial study aimed to create a map of perceptual threshold responses across a broad range of SCS parameters and programming to inform subperception therapy design. Materials and MethodsThis multicenter study was conducted at seven US sites. A total of 43 patients with low back and/or leg pain who completed a percutaneous commercial SCS trial were enrolled. Test stimulation was delivered through trial leads for approximately 90 minutes before removal. SCS parameters, including amplitude, frequency, pulse width (PW), electrode configuration, cycling, and multifrequency stimulation were varied during testing. Paresthesia threshold (PT), comfort level (CL), perceptual coverage area, and paresthesia quality (through patient selection of keywords) were collected. Differences were evaluated with analysis of variance followed by post hoc multiple comparisons using t-tests with Bonferroni correction. ResultsPT was primarily determined by PW and was insensitive to frequency for constant frequency stimulation (range: 20 Hz–10 kHz; F(1284) = 69.58, p < 0.0001). For all tests, CL was approximately 25% higher than PT. The dominant variable that influenced paresthesia quality was frequency. Sensations described as comfortable and tingling were most common for frequencies between 60 Hz and 2.4 kHz; unpleasant sensations were generally more common outside this range. Increasing distance between active electrodes from 7 mm to 14 mm, or cycling the SCS waveform at 1 Hz, decreased PT (p < 0.0001). Finally, PT for a low-frequency stimulus (ie, 60 Hz) was unaffected by mixing with a sub-PT high-frequency stimulus. ConclusionsIn contrast to previous work investigating narrower ranges, PW primarily influenced PT, independently of frequency. Paresthesia quality was primarily influenced by pulse frequency. These findings advance our understanding of SCS therapy and may be used to improve future novel neuromodulation paradigms.

The Effect of Stem Cell Infusion on Immune Effector Cell Associated Hematotoxicity with BCMA CAR T in Multiple Myeloma

Introduction: In recent pivotal clinical trials and real-world studies of patients undergoing BCMA CAR-therapy for multiple myeloma (MM), a significant percentage have exhibited persistent Immune Effector Cell Associated Hematotoxicity (ICAHT). The resulting, sometimes profound and long lasting cytopenias, are associated with increased morbidity, such as high rates of infections and bleeding and complicate further anti-MM therapy once the patient relapses post CAR-T cell therapy. While growth factor support is widely applied in patients with ICAHT, the effects are usually short lived. Consequently, the use of CD34 selected stem cell boost in ICAHT as a more permanent solution has been described, however studies have been limited by small patient numbers and short follow up. Herein, we report on our multi-institutional experience at ICAHT in patients who received autologous BCMA CAR T therapy both in commercial and clinical trial settings. Methods: We included recipients of autologous BCMA CAR T therapy at 2 large academic centers between 2020 and 2023. For this study, neutropenia was defined as an absolute neutrophil count (ANC) of ≤ 1000, thrombocytopenia as platelet counts ≤ 70,000 and anemia as hemoglobin ≤9 g/dL. ICAHT was characterized by the presence of any of these hematological abnormalities. The variables were assessed at 21 days, 3 months, and 6 months post CAR-T infusion. Median follow up time was 23 months. Results : A total of 108 patients received BCMA CAR T therapy, 42 (39%) were treated on a clinical trial, 52 (48%) received commercial Idecabtagene vicleucel and 14/108 (13%) commercial Ciltacabtagene autoleucel. Baseline characteristics of the whole patient cohort are shown in table 1. The median age was 68 (range 57-69) years, with 63/107 (60%) being male. About 11% (n=12) patients were Black. 97/108 (90%) received at least one prior ASCT and the median prior lines of therapy was 5 (range 4-6). At D+21, ICAHT was observed in 68% (n=69/102) of patients, which reduced to 35% (n=30/86) and 27% (n=21/78) at the 3-month and 6-month assessments, respectively. Risk factors for ICAHT were the following: history of a prior ASCT, higher number of prior lines of therapy, a decreased platelet count prior to lymphodepletion and history of ICANS, which interestingly occurred in 11/69 (16%) patients who developed ICAHT but was not seen in those without ICAHT. About 97%(n=67/69) of patients with ICAHT had stem cells in storage and 26% (n=17/69) received a stem cell boost. The median time to stem cell boost following CAR T infusion was 116 (range 49-166) days. The median dose of stem cell infused was 3.91 (range 2.11-5.12) x10 6 CD34/kg cells. Unsurprisingly, patients with ICAHT who received a stem cell boost had significantly worse cytopenias prior to stem cell boost compared to those ICAHT patients without stem cell infusions at 120 days. Hgb was 8.4g/dL vs 10.2g/dL, p=0.02, and mean platelet levels were 30x10 9/L vs 54x10 9/L, p=0.01, compared to ICAHT patients without stem cell support. ANC levels were not significantly different between those two ICAHT groups (1700/mL vs 1500/mL), likely due to a higher use G-CSF support in ICAHT patients who received stem cell support (75% vs 55%, NS). Stem cell infusion significantly improved Hgb levels at 3 and 6 months follow up with an increase to 10.6g/dL, p=0.002, and 10.5g/dl, p=0.02, respectively. Similarly, platelet counts at 3- and 6-months post stem cell boost improved significantly to 131x10 9/L, p=&amp;lt;0.001, and 150x10 9/L, p=&amp;lt;0.001, respectively. ANC levels showed a nonsignificant increase to 2.8/mL and 3.9/mL at 3 and 6 months, yet, G-CSF support was no longer required. We further investigated whether the occurrence of secondary AML/MDS was associated with ICAHT, however these events were rare and developed in only 2 patients, one who had no ICAHT and the other one who had ICAHT without stem cell boost. Conclusion: Nearly one-third of the patients who underwent BCMA CAR T therapy continued to experience ICAHT even at the 6-month post-infusion period. The utilization of a stem cell boost for managing ICAHT lead to significantly improved Hgb and platelet counts at 3 and 6 months follow up with also substantial improvement in ANC without further G-CSF requirements. These results suggest that the use of stem cell infusions in CAR-T cell induced ICAHT can improve cytopenia associated morbidities and facilitate further anti MM therapy post CAR-T relapse.

Ethyl Formate as a New Sanitary Treatment for Disinfesting the Hitchhiking Insect Pest Halyomorpha halys on Imported Nonfood Agricultural Machinery

With an increase in the international trade of agricultural and non-agricultural products, there is an increase in the possibility of introducing hitchhiking insect pests such as Halyomorpha halys, which has been detected on imported vehicles and agricultural machinery. Although methyl bromide (MB) is provisionally used to control invasive pests, it is classified as a restricted chemical owing to its potential to deplete the ozone layer and pose health risks to humans in cases of inadequate ventilation, as well as concerns regarding consumer safety. Therefore, this study investigated ethyl formate’s (EF’s) efficacy against H. halys and its efficacy and sorption, as an alternative to MB, on main electronic components, including alternators, ignition coils, and motors. Fumigation with 35 and 70 g/m3 EF for 4 h at 15 °C had no damage on the main electronic components as evaluated using various operation tests. In a commercial trial, H. halys infestation was effectively controlled with 35 g/m3 EF fumigated for 4 h at 23 °C using a 30 m3 polyvinyl chloride tarpaulin fumigation chamber. After ventilation, the EF concentration decreased below the safety level within 10 min and reached the zero level within 40 min for worker safety. This novel sanitary treatment using EF fumigation on imported agricultural machinery could be an effective method without causing mechanical damage.

First Report of Alfalfa Mosaic Virus on Cowpea in the United States

Cowpea ( Vigna unguiculata) is grown on approximately 5,220 ha across California and several Midwestern and southern states. In August of 2020, a viral disease was observed infecting cowpea in commercial fields and research trials in Nebraska, United States. Based on RNA sequencing and serology, the virus species was identified as Alfalfa mosaic virus. To our knowledge, this is the first report of this virus on cowpea in the United States.

In Vivo Efficacy of Purified Quillaja Saponin Extracts in Protecting against Piscirickettsia salmonis Infections in Atlantic Salmon (Salmo salar).

Piscirickettsiosis, the main infectious disease affecting salmon farming in Chile, still has no efficient control measures. Piscirickettsia salmonis is a facultative intracellular bacterium that can survive and replicate within the host macrophages, evading the immune response. Triterpenic saponins obtained from the Quillaja saponaria tree have been widely studied, and have been shown to be immunomodulatory agents, suitable for feed and vaccine applications for veterinary and human uses. The impact of the oral administration of two extracts of Quillaja saponins on the infection of P. salmonis in Salmo salar and the corresponding gene expressions of immunomarkers were studied under three in vivo models. In the intraperitoneal challenge model, the group fed with Quillaja extracts showed lower mortality (29.1% treated vs. 37.5% control). Similar results were obtained in the cohabitation model trial (36.3% vs. 60.0%). In the commercial pilot trial, the results showed a significant reduction of 71.3% in mortality caused by P. salmonis (0.51% vs. 1.78%) and antibiotic use (reduction of 66.6% compared to untreated control). Also, Quillaja extracts significantly modulated the expression of IFN-II and CD8. These results represent evidence supporting the future use of purified Quillaja extracts as a natural non-pharmacological strategy for the prevention and control of P. salmonis infections in salmon.

Strength and environmental evaluation of building bricks using industrial waste for liveable environments

Researchers around the world have been enthusiastically using industrial waste to develop eco-friendly building materials. The main objective of this study was to explore the potential of using local industrial waste, such as Solid Waste Fly Ash (SWFA) and Paint Sludge (PS), as alternative to non-renewable laterite soil. During the preliminary stage, compacted cylinders of two systems were investigated: Laterite Soil (LS) and SWFA at 50:50 ratio, and a combination of LS, SWFA and PS (LSP) at 50:25:25 ratio. Traditional stabilisers Hydrated Lime (HL) and Ordinary Portland Cement (OPC), as well as Ground Granulated Blastfurnace Slag (GGBS), were used at different ratios (10%, 20%, 30% and 40%) for these cylinders. The cylinders were cured for 7, 28 and 60 days prior to strength and water absorption test. The results showed that 30% stabiliser dosage provided the best strength and economic benefits. Based on these findings, pilot industrial and commercial trials were conducted using full-sized unfired bricks. The LSP brick system with the blended stabiliser HL-GGBS performed exceptionally well in terms of engineering properties. The investigation suggests that SWFA and Paint Sludge can be promising substitutes for clay in unfired bricks production, promoting waste recycling and reducing the impact of landfills. Using local available waste materials to manufacture unfired bricks present a viable alternative to fired bricks, especially in low-load bearing situations. This research contributes to innovation, enhanced waste management, and the concept of green building. Moreover, it minimizes energy usage and hazardous emissions associated with brick firing, aligning with the Sustainable Development Goals (SDGs).

Multiphase Spinal Cord Stimulation in Participants With Chronic Back or Leg Pain: Results of the BENEFIT-02 Randomized Clinical Trial

ObjectiveThis study aimed to assess the safety and effectiveness of a new charge-distributed multiphase stimulation paradigm during an extended spinal cord stimulation (SCS) trial. Materials and MethodsThis prospective, multicenter, randomized, single-blind, feasibility study included participants with chronic low back and/or leg pain and baseline numerical rating scale (NRS) for overall pain intensity ≥6. After a successful commercial SCS trial, participants were randomized to multiphase SCS therapy A (approximately 600–1500 Hz) or B (approximately 300–600 Hz), delivered via an investigational external pulse generator and existing leads during an 11-to-12–day testing period. Primary end points were mean NRS change from baseline to final in-office visit for each multiphase therapy and between therapies. Secondary end points included mean NRS change from end of commercial trial to final study visit and incidence of device-related adverse events (AEs). Additional measures included patient-reported outcomes collected at home through electronic watches and written diaries. Power usage was compared between multiphase and commercial therapies. ResultsA total of 122 participants initiated a commercial trial; 77 were randomized to a multiphase arm, and 65 completed the study. Reductions in mean NRS scores from baseline to final study visit were significant for multiphase therapy A and B (−4.3 and −4.7, respectively; both p < 0.0001). There was no statistically significant difference in mean NRS reduction or percent pain relief between multiphase therapies. In an additional analysis, 63.9% of participants reported greater pain relief with multiphase than with commercial SCS therapy in the at-home setting. On average, multiphase required less power than did commercial devices. One non–serious device-related AE was reported, and no infections occurred during the extended trial. ConclusionsMultiphase SCS effectively reduced pain in participants with chronic low back and/or leg pain during a trial, with no unanticipated device-related AEs reported. Future studies should evaluate long-term effectiveness of multiphase stimulation. Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is NCT03594266.

Progress and Limitation of China's Foreign-related Civil and Commercial Jurisdiction Procedure

With the developing of economic globalization and the expansion of China's opening to the outside world, Chinese enterprises are becoming more active in cross-border transactions, and the number of disputes is increasing at the same time. In 2022, China released Provisions of the Supreme People's Court on Several Issues concerning Jurisdiction over Foreign-related Civil and Commercial Cases and Minutes of the National Symposium on the Foreign-related Commercial and Maritime Trial Work of Courts, making new Provisions over Foreign-related civil and commercial jurisdiction. Building on a case analysis and a systematic overview of the two newly issued documents, this article focuses on issues existing in the jurisdiction concerned with civil and commercial foreign-related cases. By referring to foreign legislative experiences and practices in the jurisdiction concerned with civil and commercial foreign-related cases, the author proposes suggestions to improve China's jurisdiction procedures for civil and commercial foreign-related cases, rooted in China's national conditions and realistic needs, for the purpose of strengthening China's existing judicial practice of the application of foreign-related civil laws, protecting the legitimate rights and interests of Chinese citizens and enterprises in participating in economic globalization, and achieving the coordinated development for both domestic and foreign rule of law.

Double phase culture system mediated enhanced protocol for shoot proliferation of Vanilla andamanica Rolfe. - an endemic wild relative of commercial Vanilla from the Andaman and Nicobar Islands

A liquid overlay culture system in micropropagation improved shoot proliferation in many species. In the present investigation, we have developed an enhanced shoot proliferation protocol using the double phase culture system (DPS) for Vanilla andamanica, an endemic species of the Andaman and Nicobar Islands recognized under the vulnerable category by the IUCN. In vitro generated nodal explants were used for shoot proliferation experiments and were tested in Murashige and Skoog medium augmented with various cytokinins (BAP, KIN, 2iP) and auxins (IBA, NAA, IAA) to produce a maximum of 3.24 ± 0.08 shoots per explant in 5 µM BAP and 5.23±0.67 roots per shoot in basal MS medium. A remarkable increase in shoot regeneration was observed when the nodal explant was cultured on DPS system with optimum cytokinin (5 µM BAP). On evaluation of the influence of DPS and conventional single-phase systems (SPS), (solid medium) exhibits an improved multiplication rate on a DPS with optimal BAP (5µM) with an average of 8.66 ± 0.17 shoots per explant, which represents a 2-fold increase over the rate of SPS + 5 µM BAP. The plantlets were rooted at 100% frequency in half-strength MS medium devoid of auxins and acclimatized with 100% success. A double-phase mediated enhanced shoot proliferating procedure could be employed for large scale multiplication and commercial breeding trials for better results with regard to V. andamanica.

Association between state Medicaid policies and accrual of Black and Hispanic patients to cancer clinical trials.

1510 Background: The U.S. Medicaid health insurance program may play a key role in mitigating racial and ethnic disparities in cancer clinical trial enrollment, given Medicaid’s disproportionate representation of these populations and its coverage of the routine costs of trial participation in some states. We sought to evaluate the effect of Medicaid expansion under the Affordable Care Act (ACA) on changes in the accrual of racial and ethnic minority patients in cancer clinical trials, across all states and specifically those mandating Medicaid coverage of routine trial costs. Methods: The study used anonymous enrollment data from Medidata Rave, a large commercial clinical trial data collection platform. We conducted a retrospective difference-in-differences (DID) analysis to examine accrual demographics in states that expanded Medicaid eligibility under the ACA compared with non-expansion states, before and after expansion; and assessed effect modification based on state-mandated Medicaid coverage of routine trial costs. Participants included adults enrolled in interventional cancer clinical trials from 2012-2019, located in U.S. hospital referral regions with &gt;5% Black or Hispanic population. The primary outcome was participant race/ethnicity, defined dichotomously as Black or Hispanic (vs non-Black, non-Hispanic). We used ordinary least squares regression to model participant race/ethnicity as a function of (1) an indicator for trial enrollment in an expansion state after policy implementation, (2) state fixed effects, and (3) year fixed effects, with standard errors clustered at the state level. To assess effect modification, we stratified the main model across states with and without coverage mandates of routine trial costs. Results: The study included 75,700 participants across 1,409 clinical trials and 351 sites. In expansion states, the proportion of participants who identified as Black and/or Hispanic increased from 13.4% before expansion to 13.8% after expansion (0.4 percentage-point [PP] change, 95% CI -0.8 to 1.7). In non-expansion states, this proportion decreased from 17.0% to 15.2% (-1.7 PP change, 95% CI -3.7 to 0.2). These trends yielded a non-significant DID estimate of 2.0 PP (95% CI -1.0 to 5.0). In stratified analyses, Medicaid expansion was associated with a 4.5 PP (95% CI 0.4 to 8.6) increase in the enrollment of Black and/or Hispanic participants in states with coverage mandates, but not in states without coverage mandates (1.1 PP, 95% CI -2.6 to 4.8). Conclusions: Medicaid expansion was associated with a significant increase in the proportion of Black and Hispanic oncology trial participants in states that mandated Medicaid coverage of the routine costs of trial participation, but not overall across all states. These findings suggest that Medicaid policies have the potential to advance equitable enrollment in cancer clinical trials.

ID: 214538 At-Home Versus In-Clinic Pain Reporting for SCS Patients: Post Hoc Analysis of the BENEFIT-02 Study

Inconsistencies between in-clinic and at-home pain intensity ratings in patients using spinal cord stimulation (SCS) may result in inaccurate representation of a patient’s real-world pain experience.1 This post hoc analysis was conducted to better understand potential differences between daily pain and pain reported at in-clinic assessments during the commercial SCS trial period of the BENEFIT-02 study.

Critical challenges and advances in recombinant adeno-associated virus (rAAV) biomanufacturing.

Gene therapy is a promising therapeutic approach for genetic and acquired diseases nowadays. Among DNA delivery vectors, recombinant adeno-associated virus (rAAV) is one of the most effective and safest vectors used in commercial drugs and clinical trials. However, the current yield of rAAV biomanufacturing lags behind the necessary dosages for clinical and commercial use, which embodies a concentrated reflection of low productivity of rAAV from host cells, difficult scalability of the rAAV-producing bioprocess, and high levels of impurities materialized during production. Those issues directly impact the price of gene therapy medicine in the market, limiting most patients' access to gene therapy. In this context, the current practices and several critical challenges associated with rAAV gene therapy bioprocesses are reviewed, followed by a discussion of recent advances in rAAV-mediated gene therapy and other therapeutic biological fields that could improve biomanufacturing if these advances are integrated effectively into the current systems. This review aims to provide the current state-of-the-art technology and perspectives to enhance the productivity of rAAV while reducing impurities during production of rAAV.