Commercial Trials Research Articles

The 59th Annual Meeting of the Society for Low Temperature Biology, 20-22 September 2023, Vigo, Spain

Involving patients and their tissues in the research pathway is crucial for future heath innovations. There are many challenges including sustainability, logistical organisation whilst maintaining robust ethical oversight. For over a decade, TAPb has developed to become a research infrastructure to facilitate patient-centric studies across the research pipeline (from bench science, translation to human tissue and the sample component of interventional clinical trials). The TAPb platform groups researchers across academic, commercial and clinical trial sectors, and clinical services. This spreads the costs of the core team, and introduces capacity to provide specialised research services in an incremental way. TAPb is a not-for-profit, full cost recovery model that has been implemented across 7 patient clinical services within the Royal Free London NHS Foundation Trust. It supports an office of 6 fulltime staff, complemented by a number (currently about 7) part-time staff, to reflect the fluctuations in research demand. The researcher journey starts with TAPb linking NHS standard of care and research requirements to aid study design and feasibility. TAPb then provides suitable ethics and project management to develop timescales and delivery methodologies according to evolving research requirements, throughout the delivery phase. Samples and link-anonymised clinical data, and disease interpretation is provided to place samples in the correct research context. This presentation will provide an overview of the important steps which TAPb office have learnt which can make the infrastructure sustainable. Some examples of the significant research impact will be given as an illustration.

Medical researchers' perception of sharing of metadata from case report forms

AbstractIntroductionPublishing medical metadata stored in case report forms (CRFs) is a prerequisite for the development of a learning health system (LHS) by fostering reuse of metadata and standardization in health research. The aim of our study was to investigate medical researchers' (MRs) willingness to share CRFs, to identify reasons for and against CRF sharing, and to determine if and under which conditions MRs might consider sharing CRF metadata via a public registry.MethodsWe examined CRF data sharing commitments for 1842 interventional trials registered on the German Clinical Trials Registry (DRKS) from January 1, 2020, to December 31, 2021. We invited 1360 individuals registered as contacts on DRKS to participate in a web‐based survey between May 10, 2022, and June 30, 2022.ResultsOnly 0.3% (5/1842) of data sharing commitments in DRKS included a plan to share blank CRFs. Survey results showed high support for CRF sharing. More than 70% of respondents (223/301) were willing to share their CRFs, and 83.7% (252/301) were interested in CRF reuse. The most frequently reported reason for CRF sharing was improvement of comparability and interpretability of patient data (244/301; 81.0%). The most frequently reported reason against CRF sharing was missing approval by the sponsor (160/301; 53.2%). Researchers conducting commercial trials were significantly less likely to share CRFs than those conducting noncommercial trials (63.3% vs. 76.2%, OR 0.54, 95% CI 0.32–0.92) and they were less likely to reuse CRFs (78.5% vs. 84.6%, OR 0.66, 95% CI 0.35–1.24). The most frequently mentioned prerequisite for publication of CRFs in a public registry was its trustworthiness (244/301, 81.1%).ConclusionData sharing commitments in DRKS revealed a low awareness of CRF sharing. Survey results showed generally strong support for CRF sharing, including the willingness to publish CRFs in a public registry, although legal and practical barriers were identified.

Performability of Valuation Adjustment Mechanism: Value Judgements at the Normative Level

On the occasion of a valuation adjustment mechanism, the main conflict of profit occurs between the shareholders of the repurchasable shares and the creditors of the target company. Since the introduction of the Minutes of the national courts' civil and commercial trial work conference (Minutes), the academic debate on the valuation adjustment mechanism has centred on the enforceability of the share repurchase clause therein. If the dispute is dealt with according to the literal meaning of Article 5(2) of the Minutes, it is not only detrimental to the maintenance of transaction security, but also systematically in conflict with Article 579 of the Civil Code of the Peoples Republic of China (hereinafter referred to as Civil Code) systematically. Therefore, by means of systemic interpretation, Article 5(2) of the Minutes can be limited to the case of insufficient distributable profits in order to achieve the harmonisation of the normative system.

Characterization of a new dwarf watercress (Nasturtium officinale R Br.) ‘Boldrewood’ in commercial trials reveals a consistent increase in chemopreventive properties in a longer-grown crop

We describe ‘Boldrewood’, a new accession of watercress (Nasturtium officinale R. Br.) that was initially found to be of short stature with high antioxidant capacity (Payne et al. 2015). This was of particular commercial interest because it offered the potential to develop a novel watercress product with fork-friendly size and improved health-benefits. In two commercial trials comparing Boldrewood to a control, we confirmed that Boldrewood exhibits a dwarf phenotype with a significantly shorter stem and consistently produced more leaves per stem area alongside comparable crop biomass. The antioxidant and chemopreventive capacity of Boldrewood were comparable to the commercial crop. For the first time, we observed a novel increase in glucosinolate concentrations and cytotoxicity to cancer cells, characterised as decreased IC50 (half-maximal concentration of an inhibitor), associated with increased crop age at harvest. This suggests that a slower-growing and longer to harvest crop provides a significant improvement in health benefits gained in this leafy crop which is already known to be highly nutrient dense and with considerable chemopreventive ability.

Comparison of two multivalent modified live viral/bacterial combination vaccines in feedlot calves at ultra-high risk of developing undifferentiated fever/bovine respiratory disease

Vaccine 1 (VAC1 group) and Vaccine 2 (VAC2 group) are com­mercially available vaccines labeled for the control of bovine respiratory disease (BRD) in beef cattle. There are limited data from large-scale commercial feedlot trials comparing VAC1 and VAC2 arrival processing vaccination pro­grams. The objective of this study was to evaluate the relative effects of VAC1 and VAC2 arrival processing vacci­nation programs on animal health, feedlot performance and carcass characteristic outcomes in feedlot calves at ultra-high risk of developing undifferentiated fever/BRD under large-scale commercial production conditions. Animals were randomly allocated at feedlot arrival to 1 of 2 experimental groups: VAC1 or VAC2. Animals in the VAC1 group (6 multi-pen lots; 3,001 animals) received a bovine rhinotracheitis-virus diarrhea-parainfluenza 3-respiratory syncytial virus-Mannheimia hae­molytica-Pasteurella multocida vaccine per animal once at allocation. Animals in the VAC2 group (6 multi-pen lots; 3,005 animals) received a bovine rhinotracheitis-virus diarrhea-parainfluenza 3-respiratory syncytial virus vaccine with a Mannheimia haemolytica toxoid per animal once at allocation. Vaccines differed regarding viral strains, bacterial protection, means for providing bacterial immunity, and adjuvant use. Animals were housed by experi­mental group in commercial feedlot pens and followed from allocation until slaughter. Although histophilosis mortality was higher in the VAC1 group compared to the VAC2 group (P = 0.040), no statistical differences were detected in overall mor­tality or any of the other outcome variables (P ≥ 0.050). The relative cost effectiveness of each arrival processing vaccina­tion program in the study population is therefore dependent on relative program cost.

Guidelines for the choice of stone fruit rootstocks

Rootstocks for stone fruits (Prunus spp.) provide numerous and diverse production benefits, not least of which is the ability to produce high quality improved clonal fruit varieties, but also for better adaptation to orchard site variations and adoption of improved production techniques. These include mitigation of potential abiotic (soil, climate) and biotic (disease, pest) production limitations, as well as modification of natural tree vigor, precocity, and canopy architecture. Stone fruit production has lagged far behind that of apples with regard to rootstock-based control of vigor, which has contributed to comparatively less efficient production methods. Sweet cherries were the first stone fruits to have to a full range of vigor-controlling rootstocks become commercially available, about 25 years ago. It is primarily over the past decade that rootstocks conferring an increasing range of vigor control have begun to look promising for the larger-fruited stone fruits (peaches, apricots, plums), based on various scientific and commercial evaluation trials. This is likely to be a significant component of the overdue adoption of improved orchard training systems, particularly planar or “fruiting wall” canopies that are more labor efficient for pruning, fruit thinning, and harvest, and often contribute to better and/or more uniform fruit coloration, ripening, and quality. Such training systems also facilitate new and developing orchard data acquisition technologies and precision management techniques. General guidelines for the choice of stone fruit rootstocks for both specific growing conditions and anticipated contemporary production systems are discussed.

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.

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.

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.

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%.

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).

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

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 cross-bred beef steers (n = 2,117; 373 ± 15kg initial body weight [BW]) was completed with a randomized complete block design. Treatments consisted of two feed additives: (1) OPT targeted to deliver 300mg/animal/d of ractopamine hydrochloride for 28 ± 7 d out from harvest and (2) EXP targeted to deliver 36mg/animal/d of lubabegron 56 ± 7 d out from harvest and a 4-d preslaughter withdrawal period. Twenty 70 to 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 d. 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 dry matter intake (P values ≤ 0.01) compared to OPT. Carcasses were 11 ± 1.76kg (hot carcass weight) heavier in EXP group (P < 0.01), and differed between treatments for both yield grades (YG) and quality grades 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 by 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.

Challenges and Emerging Strategies in ATMPs

Advanced therapy medicinal products (ATMPs) are a significant innovation in medicine, categorized by the European Medicines Agency into four types: gene therapy medicines, somatic cell therapy medicines, tissue-engineered medicines and combined ATMPs. They hold potential for treating various conditions, including rare diseases, degenerative diseases like Parkinson’s and Alzheimer’s and cancers. The global market for ATMPs was valued at US$9.28 billion in 2023 and is projected to reach US$22.80 billion by 2032, growing at a compound annual growth rate of 10.50%. Gene and cell therapies are advancing rapidly, with over 1,700 approved clinical trials worldwide. Notable successes include Glybera for lipoprotein lipase deficiency and Roctavian for haemophilia. Despite limited current approvals, many gene therapies are expected to gain market approval soon. Challenges include stringent regulatory requirements, safety and ethical concerns. For example, Glybera faced multiple rejections before approval due to safety issues. Current clinical studies are exploring immune-based therapies like CAR-T, cytotoxic T lymphocytes, natural killer cells and mesenchymal stromal cells. CAR-T cell therapies, such as Yescarta and Kymriah, have shown promise in treating B-cell lymphoma. However, high development and manufacturing costs limit accessibility, exemplified by Hemgenix, a gene therapy for haemophilia B priced at US$3.5 million. Increased ATMP sales have spurred investor interest in R&amp;D, leading to advancements in technology and manufacturing processes. Despite challenges, the future is promising with more academic and commercial ATMP clinical trials. There are now 32 approved gene therapies globally. To attract industries, the focus should shift from rare to common diseases, and alternative reimbursement models could help manage high costs. A trained workforce and public involvement are crucial for the successful delivery of ATMPs.

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&lt;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&lt;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.&#x0D; 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.

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).