Acceptable Tolerability Research Articles

Efficacy and tolerability of subcutaneous repository corticotropin injection in refractory ocular inflammatory diseases

Abstract Background Repository corticotropin injection (RCI) has been suggested to exert immunomodulatory and anti-inflammatory effects in ocular inflammation. The index retrospective study aimed to evaluate the efficacy and tolerability of subcutaneous RCI in patients with active scleritis or uveitis. Main body Medical records of patients who were diagnosed with different types of active scleritis or uveitis and received RCI for more than six months at a tertiary eye center were reviewed. Patient characteristics including age, sex, comorbidities, clinical findings, treatment details, and adverse events were recorded. A total of 17 eyes of 17 patients were included. Median age was 43 years old and 53% of patients were male. Mean treatment duration was 25.4 ± 15.5 months. Indications for RCI therapy were scleritis (7 anterior and 1 posterior) (47.8%), panuveitis (17.4%), retinal vasculitis (17.4%), chronic/recurrent anterior uveitis (13%), and posterior uveitis (4.35%). RCI was initiated at a dose of 40 to 80 units 3 times weekly. Given the adequate control of inflammation, RCI was successfully discontinued in four patients (23.5%). Prior to RCI therapy, 14 (82.3%) patients were on oral prednisone at an average of 10 mg daily (range 2.5–40 mg), and two (11.7%) patients discontinued prednisone immediately before initiating RCI due to side effects. After six months of therapy, the prednisone dose was reduced in four (23.5%) patients to an average of 3 mg daily (range 1–5 mg) and was stopped in eight (53%) patients. Concomitant immunomodulatory therapies (IMTs) included mycophenolate mofetil (23.5%) and methotrexate (23.5%), and adalimumab (23.5%). Ten patients were on IMTs prior to using RCI, and during the course of treatment, IMT was stopped in two patients and reduced in one. Side effects included insomnia (23%), hypertension (11.7%), lower extremity edema (11.7%), hyperglycemia (11.7%), weight gain (11.7%), and infection (5.8%). Conclusion RCI may be considered as a potential therapy with acceptable tolerability for patients with non-infectious scleritis or uveitis.

Evaluation of a weight‐based process for real‐time accurate confirmation of oral liquid controlled drug balances

AbstractTo meet legislative requirements in Australia, the balance of controlled drugs (CDs) must be confirmed after completion of each transaction. This is particularly challenging for liquid CD formulations, and over the years, health organisations have implemented various methods of performing this task, including the use of visual aids or conversion of bulk formulations to individual unit doses. These methods have a number of limitations. Therefore, this study aimed to evaluate the accuracy and feasibility of a weight‐based method for confirming oral liquid CD balances packed in multidose containers. This study was conducted in a palliative care ward of a metropolitan hospital over a 41‐day period. Morphine mixture 5 mg/1 mL transactions and balance checks were confirmed using weight calculations of the product bottle. The weights were then converted to volume using a locally developed electronic application, which was recorded in the relevant CD registers. The acceptable tolerance per transaction (±0.1 mL) was determined prior to commencement based on 80 test transactions. Throughout the trial period, 407 transactions were undertaken, among which there were no CD discrepancies. Nine nurses provided feedback via an anonymous online survey after the trial, mostly reporting that the new method was more accurate. However, participants also reported that it took on average 3 min longer to complete each transaction. In conclusion, utilising a weight‐based method of confirming liquid CD balances may present a feasible method of meeting legislative requirements related to the recording and accountability of CDs. This project was exempt due to the local policy requirements that constitute research by the Eastern Health Office of Research and Ethics (Reference no: QA24‐100‐111698). The justification for this ethics exemption was as follows: the study conformed with the National Health and Medical Research Council (NHMRC) Ethical considerations in quality assurance and evaluation activities and did not directly affect patient care; written consent was not required from participants per local requirements, however staff were provided verbal and written project information and were informed their participation in the survey was voluntary and anonymous.

The effect of zinc-containing calcium phosphate coating on the osseointegration of transcutaneous implants for limb prosthetics

Introduction Increasing the integration of transcutaneous implants is an important goal for their application in clinical practice.The purpose of the work was to evaluate the osseointegration of transcutaneous titanium implants with calcium-phosphate coating containing zinc ions.Materials and methods The studies were performed on 12 male rabbits, who underwent implantation of an original implant into the tibial stump. After implantation, a compression device was installed on the bone, maintaining a load of 3.5 N for 5 weeks. Duration of observation was 26 weeks. The animals were divided into two groups: a control group (n = 6) with an implant without coating and an experimental group (n = 6) with a zinc-substituted calcium-phosphate coated implant.Results The implant fell out in one case in animals from the control group; no cases of implant loss were noted in the experimental group. It was revealed that the weight concentration of Ca and P in all zones of the bone-implant block of the animals in the experimental group significantly exceeded similar indicators in the control group. In the control group, long-term persistence of high levels of C-reactive protein was noted, which was not observed in the experimental group.Discussion This series of studies has shown that an implant with a zinc-modified calcium-phosphate coating exhibited a more effective integration, in contrast to an uncoated product. The absence of serious adverse reactions to the tested products indicates acceptable tolerability and safety of its use.Conclusion The implants with a zinc-modified calcium-phosphate coating showed signs of more effective osseointegration compared to the product without additional coating.

Topology optimization and experimental validation of mass-reduced aircraft wing designs

Development and evaluation of a novel design of mass reduced aircraft wing ribs through topology optimization is reported herein. For comparison, the same examination is performed on ribs with normal internal geometry. The wing rib design is based on the Gulfstream G650 transonic jet. The rib is divided into three segments for analysis based around the positions of the two spars. Only the center section of the rib is mass optimized, while the leading and trailing edges of the ribs are kept solid. Methodology in this study includes the k-Ω shear stress transport turbulence model computational fluid dynamic simulation as well as static and transient finite element simulations. The optimized wing rib is found to be between 8% and 15% lighter than traditional wing ribs depending on configuration. Simulation of the wing showed a tip deflection of 13.8 cm upward at an angle of 1.1°. An experimental scaled model of the optimized wing subjected to near identical bending loads as identified in the FEA simulation is applied to validate stress concentrations and performance. It is found that in the simulations, average stress never exceeded the factor of safety prescribed by the FAA. While the average factor of safety on the full computational model was 2.649, the average factor of safety on the experimental model was 9.185. Four strain gauges attached to the experimental model are used to compare the strains at similar locations on the computational model. The experimental results validate the CFD simulation results with acceptable tolerances.

FcγR3A polymorphism influences natural killer cell activation and response to anti-PD-L1 (avelumab) in gestational trophoblastic neoplasia

BackgroundLow-risk gestational trophoblastic neoplasia (GTN) are currently receiving monochemotherapy as first-line therapy. In the case of a resistance, a second-line mono- or polychemotherapy is proposed. As an alternative to these toxic and historic chemotherapy agents, the efficacy of the anti-PD-L1 monoclonal antibody (avelumab) was assessed in the TROPHIMMUN phase II trial Cohort A. Avelumab yielded a 53% cure rate with an acceptable tolerance profile, including normal further pregnancy and delivery. Beyond the blockade of PD-1/PD-L1 interactions, avelumab effect could rely on the induction of antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by FcγR3A-expressing natural killer (NK) cells. ObjectiveThis translational study aimed at testing whether ADCC is involved in avelumab efficacy on GTN and if FcγR3A affinity polymorphism could help predicting the response to avelumab in GTN. Study DesignThe expression of PD-L1 by the tumor and the phenotype of NK cells infiltrating GTN were verified by performing transcriptomic and proteomic analyses. Then, JEG-3 choriocarcinoma cells were cocultured with human NK cells in presence and absence of avelumab. The impact of FcγR3A functional polymorphism was assessed on the activation status of NK cells and the viability of JEG-3 choriocarcinoma cells. Finally, the data from TROPHIMMUN trial were reanalyzed to determine the impact of the FcγR3A polymorphism of patients on their response to avelumab. ResultsWe confirmed that FcγR3A+ NK cells infiltrated PD-L1-expressing GTN. In vitro, avelumab-coated JEG-3 choriocarcinoma cells induced NK cell activation, which promoted the destruction of JEG-3 cells. NK cell activation was abolished when the Fc portion of avelumab was removed, demonstrating the importance of Fcγ receptor in this process. Using this model of ADCC, we demonstrated that high-affinity FcγR3A polymorphism on NK cells was associated with better in vitro response to avelumab. In line with this result, patients from the TROPHIMMUN trial homozygous for the high affinity FcγR3A polymorphism had better clinical response to avelumab. ConclusionsOur work demonstrates that ADCC contributes to the therapeutic effect of avelumab in GTN and that the individual patient response is impacted by the FcγR3A polymorphism. The FcγR3A polymorphism could be used as a biomarker to identify patients diagnosed with monochemoresistant GTN who are most likely to respond to avelumab.

Preliminary findings from a multicentre study evaluating acceptability and gastrointestinal tolerance of a high-energy, plant-based enteral tube feed

Preliminary findings from a multicentre study evaluating acceptability and gastrointestinal tolerance of a high-energy, plant-based enteral tube feed

Implementation of the Internet of Things in Centrifuge Calibrators

The implementation of Internet of Things (IoT) technology in centrifuge calibrators brings innovation by enhancing accuracy and efficiency in medical device calibration. This research develops an IoT-based centrifuge calibrator capable of storing calibration data digitally and providing real-time access, using the E18-D80NK sensor for rotational motion detection, which is more cost-effective than conventional laser modules. Measurement results demonstrate high accuracy across various RPM settings (1000, 1500, 2000, 2500, and 3000 RPM), with minimal error and stability within acceptable tolerance limits. The key advantage of IoT implementation lies in efficient calibration data management, enabling real-time access and integration with other systems for effective analysis and monitoring of calibration outcomes. Overall, IoT technology in centrifuge calibration not only enhances healthcare service quality with reliable results but also supports efficient and transparent equipment management in medical settings, offering long-term benefits to healthcare facilities and patients.

Neoadjuvant Immunotherapy and De-Escalation of Surgery in Locally Advanced Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL)

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of non-Hodgkin T cell lymphoma diagnosed in patients with a history of breast implants. Most patients develop a periprosthetic effusion at early stages of disease while less common presentations include a palpable mass, severe capsular contracture, lymphadenopathy, or cutaneous erythema. Due to the complex nature of this disease, a multidisciplinary approach is necessary for optimal management, particularly in locally advanced disease or inoperable patients. We present the successful use of neoadjuvant therapeutic protocols in two cases of locally advanced BIA-ALCL. The first case, a 52-year-old patient with a left breast mass-like stage III disease who underwent combined targeted immunotherapy and chemotherapy (BV-CHP). Following a complete radiological and metabolic response, the patient underwent bilateral implant removal, right total intact capsulectomy, left en bloc capsulectomy and skin resection from the left inframammary fold in continuity with the capsule. The second case, a 65-year-old patient with a right breast swelling and mass-like stage IIA disease who received targeted immunotherapy, Brentuximab vedotin (BV). Following a complete metabolic response, she underwent bilateral implant removal and en bloc capsulectomy. A literature review and the reported cases suggest the effectiveness of targeted immunotherapy as monotherapy or in combination with chemotherapy in locally advanced BIA-ALCL in disease downstaging, surgical de-escalation, reduction of significant post-operative complications and an acceptable tolerance profile. Although surgery is an essential part of treatment, timing and type of intervention should be carefully planned, especially when primary, radical resection is uncertain.

Acupuncture navigation method integrated with augmented reality.

Acupuncture and moxibustion are effective in alleviating symptoms, but the large number of acupoints can make accurate needle placement and training difficult. To address these challenges, this study aims to develop an augmented reality (AR) acupuncture navigation system designed to improve the accuracy and intuitiveness of acupoint localization. The proposed system employs a six-point registration and positioning technique, enabling the AR navigation model to adapt to the specific characteristics of each patient. In testing, discrepancies between virtual and actual acupuncture points ranged from 0.6mm to 3.9mm, which is within the acceptable tolerance range for acupuncture. This AR-based system shows promise in enhancing the precision of acupuncture point localization, potentially leading to improved treatment outcomes.

Base-Promoted One-Pot Strategy for Expeditious Assembly of Highly Functionalized Benzocoumarin Derivatives.

A versatile and atom-economic three-component reaction between 3-cyano-4-styrylcoumarins, 1,3-indandione, and aliphatic alcohols is described for synthesizing diversely multifunctionalized benzocoumarins. This strategy allows facile access to various benzocoumarins bearing an amine and a substituted benzoyl scaffold under simple heating conditions. Readily available precursors, operational simplicity, acceptable functional group tolerance, and excellent yields are some highlighted advantages of this transformation.

Effect of post weld heat treatment on the springback of dissimilar aluminium and steel tailor welded blanks fabricated using friction stir welding

ABSTRACT Springback is a common geometrical defect that occurs in the sheet metal forming process and depends on material properties. Different methods have been used to compensate or minimise the springback effect to date. One of the methods is post-weld heat treatment. However, not all materials are heat treatable. In this study, post-weld heat treatment effect on the springback of dissimilar materials AA6061 and SAE1020 fabricated by friction stir welding was investigated using free bending. Different artificial ageing times during the heat treatment process were explored to identify the optimum duration to minimise springback via experiment and finite element analysis. Punch stroke and punch offset tests were conducted to evaluate the effect of multiple parameter values on springback. It was found that an artificial ageing time of 6 hours results in the lowest springback. Springback is inversely proportional to punch stroke as higher punch strokes produce lower springback. For punch offset, the springback increases as the punch is offset towards AA6061 and decreases when offset towards SAE 1020. Interestingly, samples that went through post-weld heat treatment recorded lower springback on both sides even for non-treatable material. The experimental results show a similar pattern and acceptable tolerance compared to the simulation results.

Comprehensive commissioning of a cone beam CT imaging ring for treatment of HDR GYN patients

PurposeA new mobile cone beam computed tomography (CBCT) imaging ring (IRm, Elekta, v2.10.6, Veenendaal, Netherlands) has recently been proposed for brachytherapy to improve procedure efficiency. We describe the commissioning process and end-to-end tests for GYN HDR brachytherapy employing IRm CBCT imaging. Materials and MethodsCommissioning included imaging isocenter test, 3D image quality, 2D imaging quality, image dose, and tube characteristics. CIRS HDR GYN phantom and Venezia CT/MR gynecological applicator were used to perform end-to-end (E2E) tests and optimize workflow. Venezia applicator and four interstitial needles were inserted into the phantom and IRm CBCT images were acquired. Phantom and applicator were scanned with CT scanner (Siemens SOMATOM go.Open Pro) using department's pelvis imaging protocol. MR imaging was performed using 0.35T MR Linac TRUFI pulse sequence. CBCT images were registered to CT and MR using rigid registration to assess image quality and applicator geometry fidelity. ResultsAll physics tests passed within acceptance tolerances. Registration of CBCT images to MR and CT scans was acceptable for applicator placement. Applicator registration of CBCT images to CT demonstrated excellent agreement of most distal source dwell position (<1 mm). Slice thickness was also measured to be 1.25 mm, within 0.5 mm of its nominal value. ConclusionBased on E2E and commissioning results, IRm is an appropriate tool for brachytherapy treatment planning. This study demonstrated good image quality in GYN phantom and Venezia applicator using the IRm. Distal source dwell position agreement between CBCT and CT was acceptable for clinical use.

Determinants of Long Waiting Time to Kidney Transplantation

BackgroundDisparity in waiting time to kidney transplantation led to new policy (KAS250). Our aims were to identify variables associated with long wait time (LWT); assess the impact of KAS250 on WT; and analyze modifiable transplant center behaviors correlated with WT. MethodsSRTR data for adult deceased donor kidney transplants were analyzed. Time-periods from 8/1/2018-7/31/2019 and 5/1/2021-4/30/2022 were chosen for pre- and post-KAS250 analyses. Transplant centers were categorized as LWT or SWT centers depending on whether pre-KAS250 median center waiting times were greater or less than the national pre-KAS250 median waiting time of 57.8 months. ResultsIn multivariate analysis, transplantation with HCV NAT negative kidneys was associated with an additional 21.3 months of WT (CI: 18.5-24.2, P < .0001), and transplantation with KDPI <85% kidneys was associated with an additional 10.8 months (CI: 8.2-13.3, P < .0001). Post-KAS250 national kidney transplant waiting time decreased from 61-58 months (P < .0001) and waiting time at LWT centers decreased from 74-69 months (P < .0001). Cold ischemic times (CIT) increased (20.2 hours vs 18.3 hours, P < .0001) and DGF rates also increased (32.7% vs 31.0%, P < .0001). Centers generally displayed more aggressive transplantation practices post-KAS250 however significant differences in DCD utilization, organ offer acceptance ratios and tolerance for long CIT persist between SWT and LWT centers. ConclusionKAS250 has reduced waiting time disparities between SWT and LWT centers at the cost of increased CIT and DGF and reduced allocation efficiency. Significant differences in transplant practice persist between SWT and LWT centers.

Beam profile characteristics of a Varian linear accelerator across different photon energy levels

Radiotherapy employs variety of energy radiation to destroy cancer cells. A linear accelerator(also called LINAC) is the machine used to delivered external beam radiation therapy.In order to confirm the treatment planning systems that deliver the best radiation to the tumors while sparing the surrounding normal tissues, extensive measurements of dosimetric parameters are part of the commissioning procedure of a LINAC for clinical usage. This work aimed to compare and assess photon beam profiles with respect to penumbra width, symmetry, and beam flatness. Beam profile measurements were performed for this study atTMSS Cancer Center, Bogura, Bangladesh, using a linear accelerator (Varian VitalBeam SN: 5199) with 6MV,10MV and 15MV photon energies for a set of field sizes (4 × 4, 10 × 10 and 20 × 20 cm2) and various reference depths keeping the same environmental conditions. A 3D water phantom, CC13 ionization chamber (SN:18635)as a reference chamber, CC04 ionization field chamber (SN:18616) as a and IBA myQA Accept software version 1.6 were used to measure the profiles of photon energies 6 MV, 10 MV 15 MV respectively. Utilizing the Eclipse (Version: 16.1) external treatment planning system, the profile calculation was carried out. According to the manufacturer's and IEC specifications, the photon beam profile data from the current investigation are compatible, and all of the tolerances fall within the ranges of clinically acceptable tolerance.

Outcomes of adjuvant lymph node field radiotherapy and immunotherapy for stage III melanoma

PurposeWith the promising results of immunotherapy in patients with stage III melanoma, the role of adjuvant radiotherapy after resection and complete lymph-node dissection must be reassessed. We evaluate the outcomes and safety of adjuvant radiotherapy and immunotherapy compared to immunotherapy only in patients with resected stage III melanoma. Patients and methodsThis retrospective and single institution study included patients treated for a stage III melanoma with complete lymph-node dissection and adjuvant immunotherapy from January 2019 to December 2022. The radiotherapy associated with immunotherapy group was defined by completion of immunotherapy and adjuvant radiotherapy in the lymph-node dissection area. The primary endpoint was disease-free survival. The secondary endpoints were locoregional progression, incidence of adverse events grade 3 or above and disease-free survival rate in patients with high risk of locoregional recurrence. ResultsThirty-three patients were included. Among them, twelve received adjuvant lymph-node field radiotherapy. The median duration of follow-up was 17months (range: 8–45months). Patients receiving radiotherapy and immunotherapy had a significantly higher disease stage and more frequent extracapsular extension. At 12months, the disease-free survival rate was 66.7% for the patients receiving immunotherapy alone (95% CI: 42.5–82.5%) and 83.3% for those receiving radiotherapy and immunotherapy (95% CI: 48.2–95.6%; P=0.131). The locoregional progression rate was 24% in patients receiving immunotherapy and 8% in patients receiving immunotherapy and radiotherapy (P=0.379). After adjuvant treatment, 6% of patients developed grade 3 or above immunotherapy-related events and none developed grade 3 or above radiation-related adverse events. ConclusionIn patients with stage III melanoma, adjuvant lymph-node field radiotherapy combined with immunotherapy seems to be associated with longer disease-free survival, with acceptable tolerance. However, these results need to be confirmed by long-term and prospective studies.

Potential of phosphodiesterase 4B inhibitors in the treatment of interstitial lung disease associated with autoimmune diseases.

Patients with autoimmune disease-related interstitial lung disease may develop pulmonary fibrosis, which may become progressive. Progressive pulmonary fibrosis (PPF) is associated with poor outcomes. Antifibrotic therapies have shown efficacy as treatments for PPF in patients with autoimmune diseases, but new treatments are needed to slow or halt disease progression. Phosphodiesterases (PDEs) are enzymes that mediate the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Pre-clinical data suggest that preferential inhibition of PDE4B has the potential to slow the progression of pulmonary fibrosis by inhibiting inflammatory and fibrotic pathways, with a lower risk of gastrointestinal adverse events than associated with pan-PDE4 inhibitors. Nerandomilast (BI 1015550) is a preferential PDE4 inhibitor that has demonstrated anti-inflammatory and antifibrotic effects in pre-clinical studies. In a phase II trial in patients with idiopathic pulmonary fibrosis, nerandomilast (given alone or on top of background antifibrotic therapy) prevented a decrease in lung function over 12 weeks with an acceptable safety and tolerability profile. The phase III FIBRONEER-ILD trial is evaluating the efficacy and safety of nerandomilast, given alone or on top of nintedanib, in patients with PPF, including PPF associated with autoimmune diseases. In this article, we review the potential of PDE4B inhibition in the treatment of ILD associated with autoimmune diseases, including the pre-clinical and early clinical data available to date.

Characterization of probiotics isolated from dietary supplements and evaluation of metabiotic-antibiotic combinations as promising therapeutic options against antibiotic-resistant pathogens using time-kill assay

BackgroundThe global probiotics dietary supplements market size is continuously growing. To overcome probiotics’ health concerns, metabiotics are recognized as a safer alternative. Aiming to deal with the escalating antimicrobial resistance, the current work demonstrates synergistic metabiotic-antibiotic combinations against antibiotic-resistant pathogens.MethodsThe probiotic properties of lactic acid bacteria (LAB) strains isolated from 3 commercial dietary supplements were characterized in vitro. The combinations of the cell-free supernatants (CFS) of selected probiotic strains and conventional antibiotics against Staphylococcus aureus and Escherichia coli clinical isolates were evaluated using the time-kill assay. To our knowledge, the current literature lacks sufficient time-kill assay studies revealing the kinetics of such metabiotic-antibiotic combinations against S. aureus and E. coli.ResultsFour LAB strains isolated from dietary supplements as well as two reference strains were included in this study. The isolated LAB strains were identified by MALDI-TOF mass spectrometry as follows: P2: Lactobacillus acidophilus, P3: Lactiplantibacillus plantarum, P4: Lacticaseibacillus rhamnosus, and P5: Pediococcus acidilactici. The identification matched with that annotated by the manufacturers, except for P3. The tested strains could resist the acidic environment at pH 3. Excluding P2, the examined strains showed less than 1 log reduction in survivors upon the addition of reconstituted skimmed milk to pepsin at pH 2 and displayed an acceptable tolerance to 0.3% ox-bile. All the strains tolerated pancreatin. The hydrophobicity and autoaggregation capacities ranged between 7–92% and 36–66%, respectively. P2 was excluded owing to its inferior probiotic potential. Although the remaining strains showed excellent growth at 0.2% phenol, their growth was reduced at higher concentrations. L. plantarum and P. acidilactici strains possessed bile salt hydrolysis activity. The time-kill assay revealed promising synergistic activities of the combinations of CFS of L. rhamnosus P4 with either ceftazidime or gentamicin against E. coli and with only ceftazidime against S. aureus, as well as CFS of P. acidilactici P5 and ceftazidime against S. aureus.ConclusionsStrict identification and evaluation of the probiotic strains incorporated in dietary supplements is crucial to ensure their safety and efficacy. The CFS of probiotics could be utilized to formulate novel biotherapeutics targeting problematic pathogens. However, future in vivo studies are required to evaluate the appropriate treatment regimen.

Safety, pharmacokinetics, and pharmacodynamics of efzimfotase alfa, a second-generation enzyme replacement therapy: phase 1, dose-escalation study in adults with hypophosphatasia.

Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated efzimfotase alfa safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. Fifteen adults (5/cohort) with HPP received efzimfotase alfa in doses of 15mg (cohort 1), 45mg (cohort 2), or 90mg (cohort 3) as one intravenous (i.v.) dose followed by 3 weekly subcutaneous (s.c.) doses. The primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics of ALP substrates known to be biomarkers of disease (inorganic pyrophosphate [PPi] and pyridoxal 5'-phosphate [PLP]) and immunogenicity. Treatment-emergent adverse events (TEAEs) occurred in 12 (80%) participants. Eight (53%) participants had injection site reactions (ISRs), observed after 10 of 41 (24%) s.c. injections. Most ISR TEAEs were mild and resolved within 1-2d. Peak and total exposures of efzimfotase alfa increased in a greater-than-dose proportional manner over the range of 15-90mg after i.v. and s.c. dosing. The arithmetic mean elimination half-life was approximately 6d; absolute bioavailability was 28.6%-36.8% over the s.c. dose range of 15-90mg. Dose-dependent reductions in plasma concentrations of PPi and PLP relative to baseline reached nadir in the first week after i.v. dosing and were sustained for 3-4wk after the last s.c. dose. Four (27%) participants tested positive for antidrug antibodies (ADAs), 3 of whom were ADA positive before the first dose of efzimfotase alfa. ADAs had no apparent effect on efzimfotase alfa pharmacokinetics/pharmacodynamics. No participants had neutralizing antibodies. Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients. Registration: ClinicalTrials.gov NCT04980248 (https://clinicaltrials.gov/study/NCT04980248).

Sustainability of athletic field turf comparing organic and synthetic practices under two heights of cut

AbstractLong‐term comparisons over several years between organic and synthetic management are lacking in sports turf research. Our objective was to investigate playing surface qualities and soil properties over an 8‐year period. For this trial, Kentucky bluegrass (KBG, Poa pratensis L.) sod was established and annually inter‐seeded with perennial ryegrass (Lolium perenne L.) and KBG. Factors included height of cut (3.2 and 6.4 cm) and management systems (MSs; synthetic and organic) with three replicates. Synthetic practices included chemical fertilizers and pesticides, while the organic system used hand‐weeding and biological fertilizers (leaf compost and naturally derived organics) with biological controls. In all years, wear was simulated in the fall using a slip‐wear machine and evaluated for playing qualities including visual wear tolerance, ball bounce (BB), surface hardness, and traction. Soil properties were evaluated in some years including pH, soil organic matter (SOM), soil bulk density, soil aggregate stability (SAG), and soil available P. Both MS received the same total N of 196 kg ha−1 year−1 but P applied varied with the MS (synthetic, 7.6 kg ha−1 year−1; organic, 23.2 kg ha−1 year−1). Synthetic practices provided acceptable visual wear tolerance (1–9, ≥6 acceptable) in 4 of 8 years compared to only 1 year for organic practices. Shorter cut grass (3.2 cm) consistently provided better visual wear tolerance (average = 5.6), harder surfaces (average = 51 g), and higher BB (average = 35.8%) consistent with accepted player standards. Synthetic practices afforded better tolerance to wear compared to organic practices in 5 of 8 years but little difference was observed in the other surface properties. Organic practices were consistently above 6.0 in soil pH (higher by 12%), 20% higher in soil available P, 25% higher in SOM, and with lower soil bulk density. SAG was higher following 8 years of simulated traffic by the last year of the test under organic practices. Results suggest competing benefits with synthetic practices affording better wear tolerance while organic practices promote better soil health.

Implementation of a soft grading system for chemistry in a Moodle plugin: reaction handling

Here, we present a new method for evaluating questions on chemical reactions in the context of remote education. This method can be used when binary grading is not sufficient as some tolerance may be acceptable. In order to determine a grade, the developed workflow uses the pairwise similarity assessment of two considered reactions, each encoded by a single molecular graph with the help of the Condensed Graph of Reaction (CGR) approach. This workflow is part of the ChemMoodle project and is implemented as a Moodle Plugin. It uses the Chemdoodle engine for reaction drawing and visualization and communicates with a REST server calculating the similarity score using ISIDA fragment descriptors. The plugin is open-source, accessible in GitHub (https://github.com/Laboratoire-de-Chemoinformatique/moodle-qtype_reacsimilarity) and on the Moodle plugin store (https://moodle.org/plugins/qtype_reacsimilarity?lang=en). Both similarity measures and fragmentation can be configured.Scientific contribution This work introduces an open-source method for evaluating chemical reaction questions within Moodle using the CGR approach. Our contribution provides a nuanced grading mechanism that accommodates acceptable tolerances in reaction assessments, enhancing the accuracy and flexibility of the grading process.