Evaluation Period Research Articles

Co-development and evaluation of the Musculoskeletal Telehealth Toolkit for physiotherapists.

In-person physiotherapy services are not readily available to all individuals with musculoskeletal conditions, especially those in rural regions or with time-intensive responsibilities. The COVID-19 pandemic highlighted that telehealth may facilitate access to, and continuity of care, yet many physiotherapists lack telehealth confidence and training. This project co-developed and evaluated a web-based professional development toolkit supporting physiotherapists to provide telehealth services for musculoskeletal conditions. A mixed-methods exploratory sequential design applied modified experience-based co-design methods (physiotherapists [n=13], clinic administrators [n=2], and people with musculoskeletal conditions [n=7]) to develop an evidence-informed toolkit. Semi-structured workshops were conducted, recorded, transcribed, and thematically analysed, refining the toolkit prototype. Subsequently, the toolkit was promoted via webinars and social media. The usability of the toolkit was examined with pre-post surveys examining changes in confidence, knowledge, and perceived telehealth competence (19 statements modelled from the theoretical domains framework) between toolkit users (>30min) and non-users (0min) using chi-squared tests for independence. Website analytics were summarised. Twenty-two participants engaged in co-design workshops. Feedback led to the inclusion of more patient-facing resources, increased assessment-related visual content, streamlined toolkit organisation, and simplified, downloadable infographics. Three hundred and twenty-nine physiotherapists from 21 countries completed the baseline survey, with 172 (52%) completing the 3-month survey. Toolkit users had greater improvement in knowledge, confidence, and competence than non-users in 42% of statements. Seventy-two percentage of toolkit users said it changed their practice, and 95% would recommend the toolkit to colleagues. During the evaluation period, the toolkit received 5486 total views. The co-designed web-based Musculoskeletal Telehealth Toolkit is a professional development resource that may increase physiotherapist's confidence, knowledge, and competence in telehealth.

OP167 An Analysis Of Medication Exclusion Reports In The Health Technology Assessment Process For The Brazilian Unified Health System

IntroductionThe National Committee for Health Technology Incorporation of the Brazilian Public Health System (Conitec), which was created in 2011 by federal law, defines the criteria for incorporating and excluding health technologies in the Brazilian health system. For technology evaluation proposals a recommendation report is carried out, which finds the best scientific evidence about the efficacy, accuracy, effectiveness, and safety of the technology being analyzed. The report also provides a comparative economic evaluation of the technologies already in the health system to promote and protect public health, achieve the best allocation of resources, and reduce regional inequalities.MethodsThis exploratory, descriptive, and retrospective study aimed to identify the criteria considered for the exclusion of medicines within the Brazilian health system from 2012 to November 2022. Data were extracted from Conitec’s website into a specific extraction form and analyzed using descriptive statistics.ResultsDuring the evaluation period, 763 technology recommendations by Conitec were identified, of which 75 (10%) related to the exclusion of medicines. Several criteria were identified among the exclusion recommendations, including protocol updates, expiry or lack of registration in the National Health Surveillance Agency, and drugs whose clinical indication was not included in the list of drugs registered for treatments in the health system.ConclusionsAlthough there is no standardization of criteria in Conitec for recommendations on the exclusion of health technologies, this study contributes to a better understanding of these technologies. Disinvestment of technologies positively impacted the population because it resulted in better allocation of resources in the health system, and some of the excluded technologies presented a greater risk of interactions and undesirable adverse reactions.

Clinical relevance of pre- and coseasonal sublingual immunotherapy with a 300 index of reactivity 5-grass SLIT tablet in allergic rhinoconjunctivitis.

There is considerable interest in improving the scoring methods for evaluating the efficacy of allergen immunotherapy (AIT) and to show if this is associated with clinically meaningful results from the patient's perspective. We aimed to assess the efficacy and clinical relevance of a 300 index of reactivity (IR) 5-grass pollen sublingual immunotherapy (SLIT) tablet in children, adolescents and adults with moderate to severe grass-induced allergic rhinoconjunctivitis (ARC) with or without controlled asthma using the combined symptom and medication score CSMS0-36 . The data of the European population that participated in 3 Phase III, international, randomized double-blind placebo-controlled clinical trials were analyzed post hoc. A total of 864 patients randomized to 300 IR 5-grass tablet or placebo were analyzed. Over the primary evaluation period, the difference in CSMS0-36 between the 300 IR and placebo groups was statistically significant (point estimates: -2.51, CI95% [-3.88; -1.14], p<0.0001 in clinical trial1; -2.31, CI95% [-3.39; -1.23], p<0.0001 in CT2; and -2.31, CI95% [-3.58; -1.03], p=0.0004 in CT3). The relative differences between the 300 IR 5-grass tablet and placebo were -29.7%, -33.8%, and -26.3%, respectively. The results based on CSMS0-36 were consistent with those obtained with the primary endpoints of the trials and support the consideration of the 2-point threshold of the CSMS0-36 for clinical relevance of AIT. Post hoc analysis of 3 CTs with the 300 IR 5-grass SLIT tablet confirmed its significant and clinically relevant effect in the European population with grass pollen-induced ARC with or without controlled asthma.

Clinical performance of bonded partial lithium disilicate restorations: The influence of preparation characteristics on survival and success

ObjectivesThe aim of this study was to investigate the influence of preparation characteristics on the survival, success, and clinical performance of partial indirect lithium disilicate restorations with immediate dentin sealing. MethodsThis retrospective clinical study evaluated partial indirect lithium disilicate restorations placed in conjunction with Immediate Dentin Sealing (IDS) in (pre)molar teeth between March 2018 and May 2021. The restorations were luted using pre-heated composite. The study focused on survival, success, and clinical performance, which was evaluated using the modified United States Public Health Service (USPHS) criteria. Results were analyzed using the Kaplan-Meier estimates, log-rank tests, and Fisher exact tests. ResultsPartial indirect lithium disilicate restorations (N = 454) were evaluated in 214 patients. The mean evaluation time was 37 months, with a cumulative survival rate of 99.2 % and a cumulative success rate of 97.6 %. Fourteen failures occurred, with endodontic pathology as the predominant failure mode, followed by secondary caries, debonding, and tooth fracture. No statistically significant influence of the preparation variables on survival and success was observed (p > .05). The short-term clinical performance was clinically acceptable in > 90 % of the evaluations. ConclusionsThis retrospective study on partial indirect lithium disilicate restorations in conjunction with IDS demonstrates survival and success rates of 99.2 and 96.7 % over a mean evaluation period of 37 months. A marked influence of the studied preparation characteristics on the survival, success and clinical performance of lithium disilicate partial restorations could not be demonstrated. Partial lithium disilicate restorations exhibit good clinical performance in >90 % of the cases. Clinical significanceThe results of this study suggest that preparation characteristics had no significant impact on the survival, success, and clinical performance of partial lithium disilicate restorations in conjunction with IDS. Results show good clinical performance and high survival and success rates, regardless of preparation characteristics.

PP152 Evaluation Of Reimbursement Periods In The Turkish Biosimilar Product Market (1995-2022)

IntroductionBiosimilar products that would enhance the patient’s access to treatments have emerged as a product group that is becoming more widespread globally. Since Turkiye is an emerging market in the pharmaceutical area in the Middle East and North Africa region, and being a reference country in pricing processes for some countries, the number of products in the market and reimbursement decisions are important. The aim of this study is to evaluate duration of inclusion of biosimilars into reimbursement lists after registration in Turkiye.MethodsThis study used website-based information (Turkish Medicine and Medical Devices Agency Registered Products List and Detailed Pharmaceutical Price List, Social Security Institution Reimbursed Product List) to analyze the reimbursement approval duration for registered biosimilars in Turkiye after receiving registration approval. A study has been conducted on the launch period of biosimilar products to patients access with reimbursement and the evaluation period of reimbursement applications after registration approval. Even though they might not be active on the reimbursement list right now, products that have previously been approved for payment have been included.ResultsBetween 1995-2022, biosimilars of 13 active substances in total were registered by the Ministry of Health in Turkiye. Thirty-three different brands and 105 biosimilars with all pharmaceutical forms are registered. As of November 2022, 72 biosimilars were in the reimbursement list. Twenty-two of reimbursed biosimilars were deactivated or excluded from reimbursement. It is calculated that the average evaluation and approval timeline for reimbursement of biosimilars between 2009 and 2022 is 9 months. When biosimilars in the European Medicines Agency (EMA) and Turkiye are compared, 13 biosimilar active substances are licensed in Turkiye compared to 19 for the EMA. When the total number of brands is compared, it has been observed that while 33 brands are registered in Turkiye, this number is 73 for the EMA.ConclusionsThis study, in which reimbursement approval dates for registered biosimilars in Turkiye have been compared based on years and access timelines of biotechnological products, shows that biosimilars have been launched to patients access with reimbursement much faster than biotechnological products.

Increasing the Vase Life of Chrysanthemum Cut Flowers by Using Silver and Zinc Nanoparticles.

Cut flowers are horticultural products that have great potential to be developed. Efforts to maintain quality and extend the shelf life of cut flowers are very important to obtain a product that is accepted in the market. The main problems of chrysanthemum cut flowers are the leaves easily turning yellow, wilting, and failure to fully open flowers. This study aimed to obtain the best pulsing solution formulation that increases vase life and maintains the freshness of chrysanthemum cut flowers. Pulsing solution treatment was carried out on chrysanthemum cut flowers during the evaluation period. Pulsing solution treatment consisted of control, AgNO3, nano-Ag (NAg), ZnO, and nano-Zn (NZn). The results showed that NAg20 treatment increased the vase life of chrysanthemum cut flowers up to 23 days, which was 19 days longer than the control. Nano-Ag inhibits bacterial growth, flower wilting, color degradation, and carotenoids. In addition, nano-Ag increased the size of the bloom-flower diameter. Considering the results of all postharvest quality parameters mentioned above, NAg20 extends the vase life of chrysanthemum cut flowers.

Evaluation of mangrove restoration effectiveness using remote sensing indices - a case study in Guangxi Shankou Mangrove National Natural Reserve, China

As one of the most productive marine ecosystems in the coastal wetlands, mangrove forests have been severely threatened by intensive human activities. Many countries and regions have carried out mangrove restoration projects. The evaluation of mangrove restoration effectiveness is of great significance for scientific decision-making for restoration engineering and wetland management. In this study, we presented a remote-sensing-based Mangrove Restoration Effectiveness Index (MREI) to evaluate mangrove restoration effectiveness. We took the Guangxi Shankou Mangrove National Natural Reserve (GSMNNR) in China, a UNESCO Biosphere Reserve, as our study area, where four phases of afforestation were implemented during 1990-2022. The MREI was developed based on Landsat-series images by considering the change in mangrove area and the Normalized Difference Vegetation Index (NDVI) from the start year to the end year of each afforestation phase (evaluation period). We further evaluated the Persistence of Restoration Effectiveness (PRE) based on the MREI change trajectory during the whole evaluation period, and the Process-based Restoration Effectiveness Index (PREI) was developed to evaluate the restoration effectiveness at village scale. The results showed that MREI can effectively represent the trajectory of mangrove restoration and showed consistent pattern with high-spatial-resolution imagery. From 1990 to 2022, the mangrove forest area increased from 235.26 ha in 1990 to 873.27 ha in 2022, and 84.59% of the mangrove forest was converted from tidal flats in the reserve. The average value of MREI in the five evaluation phases were 0.48, 0.24, 0.29, 0.17, and 0.72, respectively. The dynamic change of MREI showed that 5.24% of the zones had poor PRE, 44.17% of the zones had excellent PRE. From the perspective of spatial distribution, the Zones with PREI values ranging from high to low were follows: Zone A, E, J, G, C, H, I (D), F, B. Overall, the high value zones of PREI were mainly distributed in the central of the Dandou Sea and the northern part of the Yingluo Bay. The low value zones were distributed in the northwest of the Dandou Sea. We expect the MREI and PREI have great potential to be applied to other regions to evaluate mangrove restoration effectiveness.

Hypoglycemic Effect of Orally Delivered Insulin Nanoparticles Compared to Subcutaneous Recombinant Human Soluble Insulin in Hyperglycemic Male Rats

Background: Insulin is available as an injectable drug and remains the mainstay of therapy. Researchers have attempted to develop an oral formulation of insulin, particularly utilizing nanoparticles (NPs). Objective: To assess the efficacy and safety of insulin-loaded D-α-Tocopherol polyethylene glycol succinate (TPGS)-emulsified PEG-capped PLGA NP in comparison to insulin-loaded PLGA NP and subcutaneous (SC) insulin in an in vitro and in vivo diabetic rat model. Methods: Two biocompatible and biodegradable NPs were used, in which 20 IU/kg of recombinant human soluble insulin was incorporated. NP1 was PLGA-loaded with human insulin, while NP2 was PLGA-PEG-TPGS-loaded with human insulin. The physical characteristics of the NPs were examined in an in vitro and in vivo study on a hyperglycemic rat model for a 24-hour duration. Results: For the first 3 hours, SC insulin showed a better reduction in serum glucose levels (SG) compared to both NP1 and NP2. A smooth, sustained reduction in SG was observed and maintained till the end of 24 hours with both NPs. NP1 maintained SG reduction for 6 hours before experiencing an increase, while NP2 demonstrated superior sustained reduction in SG beyond the 12-hour evaluation period. Conclusions: PLGA-PEG-TPGS NP can act as a potential carrier for oral insulin delivery and maintain good glycemic control for up to 24 hours.

The Role of Intravenous Immunoglobulin (IVIG) in Reducing Infection Risk in Multiple Myeloma (MM) Patients Receiving Immune-Based Therapies: A Single Center Experience

Introduction Immune-based therapies, including the anti-CD38 antibody daratumumab (Dara), and most recently bispecific antibodies (BsAb) targeting CD3 and BCMA, GPRC5D or FCRH5 are increasingly important strategies used to treat Multiple Myeloma. However, there are concerns that the prolonged use of these therapies predisposes patients (pts) to increased rates of infection, partly due to hypogammaglobulinaemia. To this date, most clinical trials on Dara and BsAb do not consistently capture rates of hypogammaglobulinaemia and leaves the use of intravenous immunoglobulin (IVIg) as prophylaxis to individual investigator discretion. There are currently a paucity of studies documenting IVIg as a means to reduce infection risk in these pts. Patient and Methods All patients with MM who started Dara or BsAb therapy at St Vincent's Hospital Melbourne from Jan 2021 to Dec 2022 were included in this retrospective chart review. Patients who received more than 2 months of treatment were included. The evaluation period for each patient began at the time of first Dara or BsAb dose and ended at the cut-off date of 28 th June 2023. The two time periods were “ON IVIg” defined as any time within 30 days of last IVIg administration and “OFF IVIg” defined as any time &amp;gt;30 days from last IVIg administration. The primary outcome was the incidence rate of all grade infections (expressed in events/person-year) during periods of ON IVIg vs OFF IVIg. Secondary outcomes included incidence rate of severe infection (CTCAE Grade 3-5). Incidence rate ratios (IRR) and the corresponding 95% confidence intervals were calculated using the Exact Poisson method. Results A total of 52 Dara or BsAb treated pts were identified of which 7 were excluded due to treatment cessation from progressive disease within 2 months. The remaining 45 pts were included in the study of which 16 were on Dara, 16 on a BCMA BsAb and 13 on a non-BCMA BsAb. All 16 of the patients on Dara received Dara as a triplet combination. Median age was 65 (IQR 59-70), 25 (56%) were male and median prior lines of therapy received was 1 (IQR 1-3). At the start of treatment, 34 pts (76%) had documented hypogammaglobinaemia of which 12 (27%) had severe hypogammaglobinaemia (defined uninvolved IgG &amp;lt;4.0 g/L). Median functional IgG was 5.0 g/L (IQR 3.9-6.5). Eleven pts (24%) were already on IVIG prior to Dara or BsAb therapy and a further 18 (40%) were commenced on IVIG during the course of treatment. At the cut-off date, 30 (67%) pts were still receiving Dara or BsAb therapy. Median time on treatment was of 8.94 months (IQR 5.06-14.30). The proportion of time ON IVIg for the cohort was 53%. Patient receiving BsAb spent a greater proportion of time ON IVG than patients receiving Dara-based therapy (56% vs 42%, p &amp;lt;0.002). There were 95 all grade infections during the evaluated period, most commonly in the respiratory tract; upper respiratory tract infections (36%), lower respiratory tract infections (31%) and COVID-19 (12%). There were 15 documented severe infections of which 10 occurred during the OFF IVIG period. There were no infection related deaths. The median time to first infection from commencement of Dara or BsAb was 3.12 (IQR 1.25-5.61) months. The rate of all grade infections ON IVIG was 1.54 (95% CI 1.07-2.15) per person years and lower compared to 2.56 (1.95-3.29) per person years OFF IVIG with IRR of 0.60 (95% CI 0.39-0.93; p=0.016) (figure 1). Rate of severe infections was 0.22 (0.07-0.51) and 0.43 (0.20-0.78) per person years respectively with IRR of 0.52 (0.14-1.66; p=0.234). BsAb therapy had a higher all grade infection rate vs Dara-based therapy; 2.86 (2.23-3.62) vs 1.39 (0.91-2.03) per person years respectively; IRR 2.06 (1.30-3.38; p=0.001) Conclusion There are high rates of pre-existing hypogammaglobinaemia in MM patients even during early lines of treatment. The use of IVIG during immune-based therapies appears to significantly reduce the yearly rate of all grade infections by 40% in our cohort. Differences between the rates of severe infection ON IVIg and OFF IVIg are not significant due to small number of events. Further prospective studies are needed to confirm these findings, towards an evidence-based approach in IVIg support for patients with myeloma on novel immunotherapies.

AKATSUKI 48-Week Interim Analysis: Emicizumab and Immune Tolerance Induction in People with Hemophilia A and Factor VIII Inhibitors

Background: Immune tolerance induction (ITI) therapy, for the eradication of factor (F)VIII inhibitors, is indicated for people with hemophilia A (PwHA) with FVIII inhibitors. There are limited data regarding the safety of emicizumab treatment in combination with ITI, particularly regarding thrombotic events (TEs). This study, conducted in Japan, aims to evaluate the safety profile of emicizumab during and immediately after ITI. Methods: AKATSUKI is a Phase IV, open-label, non-randomized, interventional, multicenter study; the methods have been previously published (Matsushita et al. BMJ Open 2022). PwHA with FVIII inhibitors received an approved dose of emicizumab and ITI therapy. Any standard half-life (SHL) FVIII concentrate could be used for ITI, with a dosing regimen of 50IU/kg, three times a week; when using an extended half-life (EHL) FVIII concentrate, 50IU/kg twice a week was permitted. Those who achieved ITI partial success received prophylaxis with emicizumab and a FVIII concentrate starting from the date of their next study visit following investigator confirmation of partial success. Any FVIII concentrate could be used for post-ITI maintenance therapy, given as 50IU/kg once a week for the first 24 weeks followed by 50IU/kg once every 2 weeks for the next 24 weeks, followed by discontinuation of the FVIII concentrate at the investigator's discretion. The primary endpoint was evaluation of adverse events (AEs), with a key focus on TEs, and abnormal laboratory values over time during and immediately after ITI. The main secondary endpoints included number of treated bleeds and the proportion of participants meeting ITI success criteria. Partial success was achieved on the same date that the participant's blood sample showed normal FVIII recovery in addition to the participant receiving a negative FVIII inhibitor titer. Normalized FVIII recovery was defined as a FVIII recovery rate of ≥66% of the predicted value on two consecutive occasions ≥2 weeks apart, and a negative FVIII inhibitor titer was defined as achieving FVIII inhibitor levels of &amp;lt;0.6 BU/mL on two consecutive occasions ≥2 weeks apart. Results: Twelve participants, all of whom were male (median [range] age 2.5 [1-54] years) were included in this interim analysis (evaluation period, median [range]: 437.5 days [224-749]. Data cut-off date: December 22, 2022). Prior to the study, participants had received emicizumab (n=11), ITI (n=9), or both (n=7), and the median (range) duration of ITI in combination with emicizumab was 203.0 (7-1,002) days. Three participants used a SHL FVIII product for their ITI treatment regimen, and nine participants used an EHL FVIII product. Additional baseline characteristics are presented in Table 1. Overall, 30 AEs occurred, none of which were considered emicizumab- or FVIII concentrate-related. Two participants each experienced one serious AE: one case of pneumonia, initially caused by transmission of a viral infection, and one wound hemorrhage, which was recorded as accidental; both recovered. No participants experienced a TE. Three participants reported a total of 10 treated bleeds, all of which were categorized as traumatic and were treated with recombinant activated FVII. At data cut-off, one participant had achieved partial ITI success, having reached a negative inhibitor titer at Week 5 and normalized FVIII recovery by Week 17. This participant was then treated with emicizumab and FVIII concentrate (50IU/kg once a week). No bleeds or AEs were reported for this participant during the observational period. The changes in FVIII inhibitor titer across the study for all participants are presented in Figure 1. Conclusions: At this 48-week interim analysis, no new safety concerns or TEs were reported in PwHA receiving emicizumab and ITI. This study continues to evaluate the safety of emicizumab in conjunction with, and following, ITI therapy in PwHA with FVIII inhibitors.

A Phase I, Single-Arm, Open Label, Dose Escalation, Multicenter Study of Off-the-Shelf Natural Killer (NK) Cells (SAR445419) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)

Background and Significance: SAR445419 (SAR'419) is an allogeneic, off-the-shelf, donor-derived, natural killer (NK) cell investigational immunotherapy. NK cells in SAR'419 are expanded ex vivo using PM21 particles expressing membrane-bound interleukin-21 and 4-1BB ligand from the plasma membranes of feeder cells (Ciurea et al, Leukemia, 2022). Ex vivo, PM21 expansion allows for large numbers of hyperactive NK cells to be generated and administered, thereby increasing therapeutic potential to patients. It is hypothesized that mature, fully functional NK cells expanded ex vivo will have superior anti-tumor activity, favorable safety profile, and can induce remissions, enabling patients to receive curative allogeneic hematopoietic stem cell transplantation (HSCT), thereby improving outcomes in patients with R/R AML. Two phase 1/2 dose-escalation and expansion studies (NCT01787474, NCT02809092) of ex vivo expanded haploidentical donor NK cells infused as 6 doses over a course of 2 weeks, after fludarabine and cytarabine chemotherapy, demonstrated this approach to be feasible with favorable safety profile in patients with R/R AML. This study aims to determine the candidate dose(s), evaluate safety, tolerability, and preliminary anti-tumor activity of SAR'419 administered after fludarabine and cytarabine chemotherapy for adult patients with R/R AML. Study Design and Methods: This is a phase 1, single-arm, dose escalation study (NCT05712278). The primary objective is to determine the candidate dose(s) based on the evaluation of dose-limiting toxicities (DLTs). The DLT evaluation period is from start of chemotherapy (Day -6) until 28 days after the first administration of SAR'419, starting at the lowest dose. Eligible patients will be administered fludarabine, 30 mg/m 2/day and cytarabine, 2 g/m 2/day (Day -6 to Day -2) for 5 days followed by 6 doses of SAR'419 (intravenous) given thrice weekly over 2 weeks beginning on Day 1. Approximately 12 DLT-evaluable patients will be enrolled. The treatment period will start from the first administration of chemotherapy (Day -6) until end of treatment on Day 56, and subsequently patients will have follow-up visits every 2 months. Dose escalation will be guided by the modified toxicity probability interval 2 design. Key secondary objectives include characterization of overall safety, tolerability, HSCT rate, impact of SAR'419 on infection, and preliminary anti-leukemic activity of SAR'419 (as per international working group criteria). Biomarkers in whole blood (including serum and plasma) and bone marrow (aspirates-liquid, and biopsy-solid) will be evaluated to assess the impact of SAR'419 treatment. Key inclusion criteria are adult participants with confirmed diagnosis of R/R AML according to World Health Organization classification, including participants with relapsed AML in the bone marrow after allogeneic HSCT (including those who have received donor lymphocyte infusions); with or without concomitant or with isolated central nervous system or extramedullary disease who have received at least 1 prior line of therapy for AML. Key exclusion criteria are participants with a second primary malignancy requiring active therapy (adjuvant hormonal therapy is allowed); with known acquired immunodeficiency syndrome or human immunodeficiency virus disease requiring antiretroviral treatment or having active hepatitis B or C infection, or symptomatic severe acute respiratory syndrome coronavirus 2 infection; and who are receiving &amp;gt;10 mg/day of oral prednisone or equivalent. In the safety analyses, all DLT modeling will be performed on the DLT-evaluable population or those who experienced a DLT. All other safety analyses will be performed on the safety population using descriptive statistics. This study is actively recruiting at this time and is being conducted in the United States.

Phase 1b Trial of Irak 1/4 Inhibition for Low-Risk Myelodysplastic Syndrome Refractory/Resistant to Prior Therapies: A Trial in Progress

Background and Significance: Chronic stimulation of both the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to promote a proinflammatory environment in the bone marrow that causes persistent cytopenia in patients with low-risk myelodysplastic syndrome (LR-MDS). The serine/threonine kinases IRAK1 and IRAK4 are critical for the signaling downstream of IL-1R and most TLRs that promotes production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis, leading to bone marrow inflammation and cell death. Therefore, inhibition of IRAK1/4 is a potential target for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow, allowing for restoration of hematopoiesis. R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. R835 is a potent and selective inhibitor of IRAK1 and IRAK4 kinases that inhibits TLR and IL-1R-dependent proinflammatory cytokine production in multiple cell types. In vivo, R835 blocks TLR4 and IL-1R-dependent systemic cytokine release in mice. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 study in healthy volunteers (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the phase 1 trial results supported the further study of R289. An open-label phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently recruiting patients. Study Design and Methods: The R289 phase 1b study (NCT05308264) is an open label, single arm, multi-center study, which includes a dose escalation phase (up to 12 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases will include patients ≥18 years with a definitive diagnosis of low-risk MDS (International Prognostic Scoring System-R ≤3.5) and ≤5% bone marrow myeloblasts. Patients must be relapsed or refractory/resistant or intolerant to prior MDS therapies. Exclusion criteria include prior MDS treatment(s) within 4 weeks of study treatment, clinically significant anemia (from iron deficiency, hemolysis, or GI bleeding), and chronic myelomonocytic leukemia. Dose Escalation Phase: A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD). An initial R289 dose of 250 mg qd, will be given orally, with or without food, progressing to 500 mg qd with dose limiting toxicity (DLT) assessed at both doses. The DLT evaluation period will be 28 days. After completion, patients not experiencing DLTs may remain at their respective dose levels as long as they demonstrate continued clinical benefit without toxicity. Dose Expansion Phase: Up to 10 additional patients with LR-MDS will be enrolled, with R289 administered to all patients at a dose not exceeding the MTD determined in the dose escalation phase. The primary endpoint of the study is safety and tolerability of R289, assessed by incidence of AEs, discontinuation/interruption of R289 due to AEs, and incidence of DLTs. Secondary endpoints include preliminary efficacy, assessed by red blood cell transfusion independence by Week 24 (% achieving ≥50% reduction in transfusions), and pharmacokinetics of R289. Change from baseline in plasma biomarkers, including C-reactive protein and TNFα, and bone marrow biomarkers will be assessed. Statistical analyses will be primarily descriptive. Tabulations will be produced for disposition, demographics, disease characteristics, safety, pharmacokinetics, pharmacodynamics, and clinical activity. For analyses of clinical activity, such as proportion of patients with RBC transfusion independence, complete responder rate, overall response rate, and proportion of subjects with hematologic improvements, the summary will be produced separately for the dose escalation phase and dose expansion phase. For the dose escalation phase, data will be summarized by dose level and overall. The trial is currently recruiting at 9 US sites. The study has enrolled 7 patients in the dose escalation phase.

An Experimental Private Small Hydropower Plant Investments Selection Classification System

Investment selection problems and models are crucial for humans, communities, and states. Private small hydroelectric power/ hydropower plant investments (PSHPPIs) selection problem is a unique one in those problems and models. Many available scientific methods can be implemented on this research topic. One methods group is type-2 Mamdani’s type fuzzy inference systems (FISs). This study presents an experimental one-node general type-2 4-zslices Mamdani’s type FIS model for PSHPPIs selection. There are 3 input variables (total estimated electricity generation: M1, total estimated cost: M2, change in the average runoff: M3), 1 output variable (O1: selected/unselected, selection classification of PSHPPIs), and 49 rules. M1 is designed in 5 triangular and trapezoidal general type-2 4-zslices fuzzy membership functions (MFs), M2 in 5 triangular and trapezoidal general type-2 4-zslices fuzzy MFs, M3 in 5 Gaussian type-2 4-zslices fuzzy MFs, and O1 in 2 Gaussian type-2 4-zslices fuzzy MFs. All modeling details are finalized by a human-expert decision process. JuzzyOnline V2.0, a browser-based platform of Juzzy (a Java-based library: Juzzy toolkit), is used for all FIS modeling and calculation activities. Five PSHPPI options assumed to be in their very early investment stages in Turkiye are evaluated in an experimental application. It is clear that an improved, tuned, and fine-tuned version of this model will help private investors to take more convenient/satisfying actions/decisions in a very short evaluation period in their PSHPPIs decision processes. An automatic investment selection classification system can be built in an appropriate development period after experiencing many methods and models. This study is one of the open-science humanoid robot, robot and platform development activities entitled Global Power Robots and Platforms: GPRP/GPRAP (Global Power Plants Developers: GP2D/G2PD/GPPD, Global Power Plants Engineers: GP2E/G2PE/ GPPE, Global Power Plants Owners: GP2O/G2PO/GPOO, Global Power Prediction Systems: GP2S/G2PS/GPPS), Global Profile Analyses Systems, and Global Social Network Analyses Systems.

1228. Evaluation of the Practice of Switching from Intravenous to Oral Antimicrobial Therapy at King Abdulaziz University Hospital

Abstract Background Conversion from intravenous (IV) antibiotics to an oral (PO) in eligible patients is an important antimicrobial stewardship strategy. Recently, King Abdul-Aziz University Hospital (KAUH) in updated its IV to PO conversion policy. This policy describes eligibility criteria for patients to be switched to oral therapy from IV and it suggests PO alternative to IV medications. The aim of this prospective observational study is to observe IV to PO conversion practices on selected antimicrobials in selected ward after updating and implementing this policy. Methods Adult patients admitted to the medical, surgical, and hematology/oncology wards who received either metronidazole, ciprofloxacin or clindamycin IV were evaluated for antibiotic need and for eligibility for IV to PO conversion according to the policy. Evaluation period spanned from November 2021 – December 2022. Results 194 patients were evaluated. Of them, 154 (80%) had a clear indication for the antibiotic of which 98 (63%) required IV administration for the following reasons: impaired oral route (59%), impaired gastrointestinal absorption (15.3%), acute treatment phase of the infection (15.3%), and other reasons such as surgical prophylaxis (3%) and severe sepsis/septic shock (2%). The remaining 56 (36.7%) met the policy’s eligibility criteria for IV to PO conversion. Conclusion We found that most patients received antibiotics appropriately in the appropriate route for an existing indication. However, there are plenty of opportunities for improvement in discontinuing unnecessary antibiotics and de-escalating from IV to PO. Ideally, this discussion should be had while rounding on the patient for collective decision making at the point of care. Disclosures Nour Baghdady, PharmD, BCPS, MPH, BCIDP, CSL Seqirus: Advisor/Consultant|CSL Seqirus: Stocks/Bonds

Soil Health in an Integrated Production System in a Brazilian Semiarid Region

Soil health is directly related to sustainable development goals (SDGs) and can be affected by inadequate management practices. In this work, soil edaphic respiration and changes in microbial biomass promoted by cover crops in an integrated crop–livestock system (ICLS) were evaluated using soil health indicators with the respirometry method. The design was completely randomized in a 3 × 6 factorial arrangement, and multivariate principal components analysis (PCA) was performed according to MANOVA. Edaphic respiration was determined based on the respirometry technique. The results showed that edaphic soil respiration was significant in the nine evaluation periods, demonstrating the importance of grass cover in edaphic respiration arising from the biological activity of microorganisms, which is directly related to the amount of soil organic carbon. The cover crops increased soil organic matter and consequently microbial respiratory activity.

Evaluation of the Quality of the Age-Friendly Environment in Liaoning Province

The age friendliness of an environment is significant for improving the quality of life of the elderly. This metric is an important measure used by the international community to address the challenges of population aging. In order to explore effective ways to improve the quality of an age-friendly environment, this study considers the theoretical framework of the World Health Organization and combines China’s demographic and policy conditions to develop an urban-scale indicator system for the evaluation of the age-friendly environment (AFE) by including the dimensions of social and physical environments and municipal services. The entropy method and multiple linear regression were used to study the changes and influencing factors of the quality of AFE in 14 prefecture-level cities in Liaoning Province. The research results are as follows. First, temporally, the comprehensive quality of AFE in the cities in Liaoning Province was at a relatively low level, and the overall trend was decreasing. During the evaluation period, the level of age friendliness in various cities was generally low, with a relatively small number of cities scoring higher. Second, spatially, significant regional differences in the age friendliness of the environment existed, which showed spatial patterns of “high in the middle and low on both sides” and “strong in the south and weak in the north”. Third, the dimensions were in the order of physical environment &gt; municipal services &gt; social environment. The social environment was weak for the construction of AFEs in Liaoning Province, and efforts are required to strengthen it in the future. Fourth, aging rate was negatively correlated with the level of AFE. The positively correlated factors were in the order of expenditure for urban and rural community affairs &gt; per capita GDP &gt; per capita disposable income of urban residents. This study provides insights for cities to improve the quality of AFEs, actively respond to population aging, and help promote WHO initiatives in developing countries.

Analysis of the performance and operation of a photovoltaic-battery heat pump system based on field measurement data

Photovoltaic-heat pump (PV-HP) combinations with battery and energy management systems are becoming increasingly popular due to their ability to increase the autarchy and utilization of self-generated PV electricity. This trend is driven by the ongoing electrification of the heating sector and the growing disparity between growing electricity costs and reducing feed-in tariffs in Germany. Smart control strategies can be employed to control and optimize the heat pump operation to achieve higher self-consumption of PV electricity. This work presents the evaluation results of a smart-grid ready controlled PV-HP-battery system in a single-family household in Germany, using 1-minute-high-resolution field measurement data. Within 12 months evaluation period, a self-consumption of 43 % was determined. The solar fraction of the HP amounts to 36 %, enabled also due to higher set temperatures for space heating and domestic hot water production. Accordingly, the SPF decreases by 4.0 % the space heating and by 5.7 % in the domestic hot water mode. The combined seasonal performance factor for the heat pump system increases from 4.2 to 6.7, when only considering the electricity taken from the grid and disregarding the locally generated electricity supplied from photovoltaic and battery units.

Development and Validation of the EFFAM Scale (Family Functioning Scale-Madrid)

Most models that analyse risk and protective factors during adolescence include the family system and family functionality as key elements. For this reason, Family Counselling Services play an important role in addressing adolescent problems. These services require quick and easy-to-apply assessment tools that integrate different dimensions of family functioning. To develop and validate a brief scale for use in Family Counselling Services, exploring and confirming its factorial structure and testing its psychometric properties. Confirmatory Factor Analysis using structural equation modeling. 441 family members in seven units. Results: A 5-factor structure was confirmed, with a good fit. All the Average Variance Extracted values were higher than the Maximum Shared Squared Variance values. The results confirm the structure of the Family Functioning Scale-Madrid. In addition, the scale demonstrates adequate psychometric properties and stable structure during two evaluation periods with different samples. The instrument is considered reliable and consistent for of assessing family intervention carried out in Family Counselling Services.

Choice for smart investment in mutual funds: Single- or multi-period performance ranks

This study presents strong evidence of fund performance persistence using a newly proposed multi-period performance rank (MR). The MR is the average of the performance ranks, calculated using multiple performance evaluation periods. With regard to 60-month returns to the performance rank, the performance persists over the next three years. This study explains performance persistence as a combination of fund investors’ behavior and fund managers’ abilities. The MR-based portfolios have low outflows and high turnover rates. MR-based investments are a smart choice for obtaining higher future returns.

Применение экстерьерной оценки в селекции крупного рогатого скота голштинской породы

Abstract. Evaluation of the conformation of cattle is an additional resource for selection. Exterior assessment allows you to level the herd, clarify the breeding value of animals, and identify the direction of breeding work. The purpose of the study is to evaluate the conformation of Holstein cattle in order to improve the herd in the future. Methods. The studies were carried out in 2019 and 2021. The conformation was evaluated in two generations of cows. The evaluation of the herd twice revealed the changes that had taken place. The assessment of the exterior was carried out by several methods: taking measurements; calculation of body indexes; linear assessment of the exterior according to systems A and B, taking into account the shortcomings and defects in the physique of animals [1]. The assessment of the exterior of cows of the first lactation was carried out in accordance with the method of linear assessment. The evaluation period is from 30 to 150 days of lactation. Results. Studies have shown that the conformation of a herd can change rather quickly under the influence of sires with a strong heredity. The studied herd veered towards the delicate body type within one generation. The receipt of tender animals is confirmed by the fact that the cows have become larger, but the width of the sternum (body strength) has not changed much. The bone development index decreased by 0.4 % (P &lt; 0.001) in cows in the 2021 group. The number of deficiencies in cows in 2021 has increased compared to cows in the 2019 group. This confirms the changes that have taken place in the herd. The linear assessment of the exterior of the cows turned out to be the most accurate, as it made it possible to characterize the cows and identify shortcomings in the physique. The scientific novelty of the study lies in the interpretation of the results of the study to develop recommendations that can be used to improve the herd. This will increase the efficiency of the use of cattle in the conditions of industrial milk production.