2-week Period Research Articles

Drug retention after intradiscal administration.

Intradiscal drug delivery is a promising strategy for treating intervertebral disk degeneration (IVDD). Local degenerative processes and intrinsically low fluid exchange are likely to influence drug retention. Understanding their connection will enable the optimization of IVDD therapeutics. Release and retention of an inactive hydrophilic fluorine-19 labeled peptide (19F-P) as model for regenerative peptides was studied in a whole IVD culture model by measuring the 19F-NMR (nuclear magnetic resonance) signal in culture media and IVD tissue extracts. In another set-up, noninvasive near-infrared imaging was used to visualize IR-780, as hydrophobic small molecular drug model, retention upon injection into healthy and degenerative caudal IVDs in a rat model of disk degeneration. Furthermore, IR-780-loaded degradable polyester amide microspheres (PEAM) were injected into healthy and needle pricked degenerative IVDs, subcutaneously, and in knee joints with and without surgically-induced osteoarthritis (OA). Most 19F-P was released from the IVD after 7 days. IR-780 signal intensity declined over a 14-week period after bolus injection, without a difference between healthy and degenerative disks. IR-780 signal declined faster in the skin and knee joints compared to the IVDs. IR-780 delivery by PEAMs enhanced disk retention beyond 16 weeks. Moreover, in degenerated IVDs the IR-780 signal was higher over time than in healthy IVDs while no difference between OA and healthy joints was noted. We conclude that the clearance of peptides and hydrophobic small molecules from the IVD is relatively fast. These results illustrate that development of controlled release formulations should take into account the target anatomical location and local (patho)biology.

Effects of Two In-Season Short High-Intensity Interval Training Formats on Aerobic and Neuromuscular Performance in Young Soccer Players

Supplementary high-intensity interval training (HIIT) programs, focusing on different aspects of fitness, are commonly used in soccer practice. This study examined the impact of two different HIIT formats applied during the competitive season on aerobic and neuromuscular performance. Twenty-six young players from two youth amateur soccer teams (aged 18.1 ± 0.7 and 18.7 ± 1.1 years) participated. In a randomized design, Team A served as an experimental group, performing either a 10s/10s linear running HIIT or a 15s/15s HIIT with changes of direction, both at 100% of maximum aerobic speed, twice per week for six weeks. In that period, team B acted as a control group, maintaining their usual training soccer regimen. Following two weeks of lower volume and frequency training, team B added the two HIIT formats in their training for six weeks, while team A acted as control. Before and after each 6-weeks period, aerobic fitness and neuromuscular performance was evaluated by the countermovement jump (CMJ). The 3-way ANOVA showed that both HIIT formats significantly enhanced Yo-Yo Intermittent Recovery Test Level 1 (Yo-YO IR1) performance compared to the respective control periods. However, the main finding was that the 10s/10s compared with the 15s/15s HIIT format induced 45-50% greater improvements in Yo-YO IR1 (total distance: 18.5 ± 11.7% vs. 9.0 ± 8.5%, V̇O2max: 5.6 ± 3.2% vs. 3.0 ± 2.7%, and vV̇O2max: (3.3 ± 1.9% vs. 1.8 ± 1.7%, all p = 0.39, d = 0.85). Countermovement jump performance remained unchanged across both groups (p > 0.68). During HIIT rating of perceived exertion was higher in the 15s/15s vs. the 10s/10s format (6.4 ± 0.5 vs. 4.7 ± 1.2 a.u., p < 0.001). These findings suggest that while both HIIT formats effectively enhance aerobic performance during the season, the 10s/10s format offers superior benefits with less perceived exertion, while the 15s/15s format induces higher internal load.

Phase I Dose Volume Escalation of Rectally Administered PC-1005 to Assess Safety, Pharmacokinetics, and Antiviral Pharmacodynamics as a Multipurpose Prevention Technology (MTN-037)

Background: On demand, topical PrEP is desired by those preferring episodic, nonsystemic PrEP. PC-1005 gel (MIV-150, zinc, and carrageenan) exhibits in vitro antiviral HIV-1, human papillomavirus (HPV), and herpes simplex virus type 2 (HSV-2) activity, attractive for a multipurpose prevention technology candidate. We evaluated the safety, pharmacokinetics, and antiviral effect of rectally applied PC-1005. Methods: HIV-uninfected adults received a series of 3 rectal PC-1005 doses—4, 16, and 32 mL separated by 2-week washout periods. Following each dose, plasma, rectal fluid and tissue, and vaginal fluid were collected over 48 hours. Results: Thirteen adults enrolled; 12 completed all 3 doses. All 13 adverse events reported were grade 1 or 2; 5 were judged study drug related. Plasma MIV-150 peaked 1–2 h after dosing with a median peak concentrations range of 0.07–0.23 ng/mL and median half-life range of 4.9–7.4 hours across dose volumes; median concentrations were below assay quantitation limits (BLQ) 24 hours after dosing. Rectal tissue MIV-150 peaked 0.5–1 hours after dosing at 1.4 ng/g (ng/mL) (0.8, 1.9), 46.0 (30.7, 831.0), and 79.7 (11.9, 116.0), respectively, after each dose volume; median tissue concentrations were BLQ beyond 5 hours for all doses. All vaginal fluid samples were BLQ. Ex vivo antiviral assays showed 5 hours of antiviral HPV and HSV effects but no anti-HIV activity. Conclusions: MIV-150 rectal tissue concentrations were below the 100 ng/g target concentration and transient. Ex vivo assays demonstrated antiviral HSV and HPV effects but not against HIV. PC-1005 requires a more potent antiviral and longer-lasting formulation for further consideration as a multipurpose prevention technology candidate. Clinical Trials: NCT03408899.

Ffects of Short Sprint Interval Training Frequency on Physical and Physiological Performance Adaptations in Male Soccer Players

The study aimed to evaluate the effects of varying frequencies (1 vs. 2 vs. 3) of short sprint interval training (sSIT) on young male soccer players' physical performance and physiological parameters. Forty young male soccer players were randomly assigned to four experimental groups engaging in 36 trials sSIT for a duration of 6 weeks as follows: once weekly (1sSIT = 4 sets of 9 × 5 sec all-out runs), twice weekly (2sSIT = 2 sets of 9 × 5 sec all-out runs), and three times weekly (3sSIT = 2 sets of 6 × 5 sec all-out runs), or an active control group which continued their soccer practice routines. Before and after the 6-week training period, physical performance (countermovement vertical jump, 20-m sprint, Illinois change of direction, Yo-Yo intermittent recovery level 1 [Yo-Yo IR 1] and kicking distance) and physiological parameters (cardiorespiratory fitness, peak and average power output) were evaluated. All sSIT groups demonstrated significant (p < 0.01) and small to very large training effects (i.e., effect size) on measured parameters. More importantly, a comparison of inter-individual variability in the adaptive changes revealed that the 3sSIT group results in lower residuals in changes in cardiorespiratory fitness and anaerobic power, coupled with lower coefficient of variations in the mean group changes and perceived exertion throughout the training period. The findings indicate that incorporating one, two, or three weekly sessions of sSIT into routine soccer training can lead to similar enhancements in soccer players' physiological and performance adaptations. More importantly, higher training frequencies result in more homogenized adaptations among team members by reducing inter-individual variability in the magnitude of the adaptive responses.

Hand-Arm Bimanual Intensive Therapy Including Lower Extremities in Infants With Unilateral Cerebral Palsy

ImportanceEarlier detection of cerebral palsy (CP) and the high neuroplastic potential during the first years of life have motivated a search for early interventions to improve children’s long-term motor abilities.ObjectiveTo determine the effectiveness of baby Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) to improve motor function in infants with unilateral CP (UCP).Design, Setting, and ParticipantsThis parallel group, 1:1, randomized clinical trial was conducted between December 1, 2020, and September 9, 2022, in infants recruited through centers specializing in CP treatment and parents’ spontaneous applications. Therapy took place in Brussels, Belgium, from March 8, 2021, through June 17, 2022. Infants were matched in pairs by age and lesion type and randomized to either the treatment or control group. Infants were assessed at baseline (T0) and 1 (T1) and 3 months (T2) follow-up. Inclusion criteria were aged 6 to 18 months at T0 (corrected age if preterm birth), a diagnosis or being at risk of UCP, and the ability to comply with the testing and training procedures. Exclusion criteria were uncontrolled seizures, botulinum toxin injections, orthopedic surgery, or specific intensive therapy within 6 months before and until the end of the study.InterventionInfants in the treatment group received 50 hours of baby HABIT-ILE over 2 weeks, while those in the control group continued their usual motor activities.Main Outcomes and MeasuresThe primary outcome was use of the more affected hand as measured using the Mini-Assisting Hand Assessment (Mini-AHA). Secondary outcomes included Canadian Occupational Performance Measure (COPM) performance and satisfaction scores, Gross Motor Function Measure-66 (GMFM-66) scores, and other motor and functional outcomes. Between-group comparisons were calculated using repeated-measures analysis of variance (2 groups × 3 assessment times). Effect sizes were reported as partial η squared (ηp2) (small, 0.01; medium, 0.06; large, 0.14).ResultsOf the 48 infants entering the study, 46 (mean [SD] age, 13.3 [4.1] months; 27 boys [58%]) were included in the final analyses, with 24 in the treatment group and 22 in the control group. Group × assessment time interactions showed significant improvements that favored the treatment group for the Mini-AHA (mean [SE] difference from T0 to T2, 7.4 [1.4] Mini-AHA units in the treatment group vs 1.9 [1.5] Mini-AHA units in the control group; P = .008; ƞp2 = 0.11) and for both parts of the COPM (mean [SE] difference from T0 to T2, 5.0 [0.4] in the treatment group vs 2.9 [0.4] in the control group; P < .001; ƞp2 = 0.35 for the performance score and 4.4 [0.4] in the treatment group vs 2.1 [0.4] in the control group; P < .001; ƞp2 = 0.33 for the satisfaction score). Although both groups improved in the GMFM-66 (mean [SE] difference from T0 to T2, 6.6% [0.7%] logits in the treatment group vs 5.5% [0.7%] logits in the control group; P < .001; ηp2 = 0.68), there was no significant interaction (P = .43; ηp2 = 0.02).Conclusions and RelevanceThis randomized clinical trial demonstrates the feasibility of delivering 50 hours of HABIT-ILE over a 2-week period in infants with UCP. These findings show that the intervention is effective in improving motor abilities, as revealed by an increase in the use of the more affected hand in bimanual tasks and in enhanced reported functional goal outcomes.Trial RegistrationClinicalTrials.gov Identifier: NCT04698395

Perioperative administration of sub-anesthetic ketamine/esketamine for preventing postpartum depression symptoms: A trial sequential meta-analysis

Objective Postpartum depression (PPD) is a major mental health issue affecting 10%–15% of women globally. This meta-analysis synthesized updated evidence on sub-anesthetic ketamine/esketamine’s efficacy in preventing PPD. Methods Randomized controlled trials (RCTs) comparing ketamine/esketamine to a placebo for PPD prevention were searched without language restriction. Primary outcomes were PPD risk at 1- and 4–6-week postpartum. Secondary outcomes included the difference in depression scores and risk of adverse events. Trial sequential analysis (TSA) was conducted to validate the reliability. Results A meta-analysis of 22 RCTs (n = 3,463) showed that ketamine/esketamine significantly decreased PPD risk at 1- (risk ratio [RR], 0.41; 95% confidence interval [CI], 0.3–0.57) and 4–6-week (RR, 0.47; 95%CI, 0.35–0.63) follow-ups. Consistently, participants receiving ketamine/esketamine had lower depression-related scores at 1- (standardized mean difference [SMD], −0.94; 95%CI, −1.26 to −0.62) and 4–6-week (SMD, −0.89; 95%CI, −1.25 to −0.53) follow-ups. Despite potential publication bias, TSA confirmed the evidence’s reliability. Subgroup analysis showed that ketamine/esketamine’s preventive effect on 1-week PPD was consistent, regardless of administration timing, type of agents, or total dosage (<0.5 vs. ≥0.5 mg/kg). For the 4–6-week period, PPD risk was favorably reduced only with postoperative administration or the use of esketamine, with the total dosage having no observed influence. Participants on ketamine/esketamine experienced more frequency of hallucinations (RR, 4.77; 95%CI, 1.39–16.44) and dizziness (RR, 1.36; 95%CI, 1.02–1.81). Conclusion Our findings advocate for the postoperative administration of low-dose ketamine/esketamine to avert PPD, which needed additional research for confirmation.

Comparative analysis of layered curriculum and project-based learning approaches in an oral radiological course.

This study aims to compare the effectiveness of the layered curriculum method (LCM) and project-based learning method (PBLM), on dental students in the evaluation of cysts and tumors affecting the jaws and surrounding tissues, which have an important place in dental practice. Forty-nine 3rd-year dental students who agreed to participate in the study voluntarily were randomly divided into two groups: LCM and PBLM. Pre-test was administered to all students. Students in the PBLM group were divided into five groups and each group was asked to complete a project within a 5-week period and present it to their groupmates at the end of the period. Students in the LCM group were asked to choose the activities most suitable for their learning styles at each layer and to progress by being evaluated by educators in brief interviews throughout the learning process. At the end of the 5-week training period, a post-test and a post-participation questionnaire were administered to students in both groups to obtain feedback. The pre-test and post-test results of the groups and their answers to the post-participation questionnaire were analyzed statistically. Post-test results were statistically higher than pre-test results in both LCM and PBLM groups (p<0.001). When the LCM and PBLM groups were compared, there was no statistically significant difference in terms of pre-test and post-test results (p>0.05). Both PBLM and LCM positively contributed to pre-graduate dental education by enhancing students' academic achievements. Students in both groups stated that their research skills, study habits, and learning motivation increased. Since both models adopt the theory of multiple intelligences, similar methods are recommended for inclusion in dental education.

Wear and use of prostheses in sport by adolescents with upper limb absence: A preliminary mixed-methods study

Background: There is minimal research on sports participation in adolescents with upper limb absence (ULA) and specifically on the impact of prosthesis provision. Objectives: This study explored using activity monitoring sensors and interviews to gain insight into levels of sport participation and associated prosthesis use in active adolescents with ULA. Study design: A mixed methods study using a convergent parallel design. Methods: Semi-structured interviews and activity diaries were used to investigate sports and related activities undertaken during a 2-week period. Prosthesis wear/use were determined via accelerometers worn on the anatomical and prosthetic wrists throughout; interview data added context. For comparison, accelerometer data and activity diaries were captured from similar aged anatomically intact (AI) participants. Results: Three adolescents with unilateral transradial ULA and 4 AI adolescents were recruited. Two ULA participants wore prostheses during sport (16.2% and 56.5% of the time). The third rarely wore their prosthesis. The ability to participate in sport has a powerful influence on participants' lives, and prostheses were used when participants felt they offered specific benefits. In contrast to AI participants, who showed similar reliance on each of their arms throughout, when wearing a prosthesis, users were heavily reliant on the anatomical arm, including during periods playing sports. Conclusions: Prosthesis use facilitated access to some sports, although they were only used by 2 out of 3 participants for short periods. The methods were acceptable to adolescent individuals with ULA.

CTIM-08. FIRST IN HUMAN STUDY OF THE MRNA-BASED CANCER VACCINE CVGBM IN PATIENTS (PTS) WITH NEWLY-DIAGNOSED AND SURGICALLY RESECTED MGMT-UNMETHYLATED GLIOBLASTOMA (GBM): FIRST RESULTS FROM THE DOSE ESCALATION PHASE

Abstract INTRODUCTION CVGBM is an investigational therapeutic mRNA-based vaccine encoding 8 epitopes derived from tumor associated antigens with potential relevance in GBM. This is an ongoing, first-in-human study evaluating the safety of CVGBM in pts with newly-diagnosed MGMT-unmethylated GBM. METHODS HLA-A*02:01-positive pts with newly-diagnosed MGMT-unmethylated GBM (CNS WHO Grade [Gr] 4) who had a gross total or partial resection and completed radiotherapy ± concomitant temozolomide received CVGBM on Days 1, 8, 15, 29, 43, 57 and 71 + 6 optional doses at 6-week intervals. Primary endpoints are safety, tolerability and dose-limiting toxicities (DLTs). Immunogenicity is an exploratory endpoint. RESULTS As of 29/2/2024, 16 pts were enrolled in the dose-escalation part (Part A); 3 each in DL 1 (12 µg), DL 2 (25 µg), and DL 3 (50 µg), and 7 in DL 4 (100 µg). For all cohorts, mean time on study from 1st dose to last visit was 4.5 months (min: 1.5; max: 8). 109 doses were administered (mean: 6.8 doses per pt). All pts completed the 2-week DLT evaluation period without DLTs. Of 156 treatment-emergent adverse events (TEAEs), the majority (73%) were CTCAE Gr 1 (21% Gr 2, 6% Gr 3). The most common related TEAEs were chills (n=13), pyrexia (n=12), headache (n=12), fatigue (n=11) and malaise (n=5), mostly of mild to moderate severity. 7 pts had 9 ≥ Gr 3 AEs assessed as potentially related to CVGBM by the investigators outside the DLT period (cerebral edema [n=2], leukoencephalopathy, pseudoprogression with cerebral edema, structural epilepsy, ataxia, hypertension, malaise and fever [1 of each]), evenly distributed across cohorts. First immunogenicity data are planned to be presented. CONCLUSIONS CVGBM was generally well tolerated with an acceptable safety profile. The highest tolerated dose was not reached. Based on all available safety data, the selected dose for trial expansion was 100 µg. Previously presented at ESMO 2024, “FPN (Final Publication Number): 4400, Ghazaleh Tabatabai et al. - Reused with permission.

Investigating feasibility of clinical validation of repeat homecare prescriptions by an accredited checking technician (ACT) at Sheffield Teaching Hospitals (STH)

Abstract Introduction The Hackett report (Hackett, 2011) recommended that all NHS homecare prescriptions are clinically validated by a pharmacist prior to transfer to homecare delivery providers. The recent RPS professional standards for homecare evolved this, such that the validation may be undertaken by any competent healthcare professional (Mulford, 2024). Other regional Trusts have standard operating procedures (SOP) facilitating repeat (defined as a continuation of previous treatment, dose, frequency and formulation) homecare prescription validation by Accredited Pharmacy Technicians (ACT). In 2023, of 4979 of 5790 (86%) dermatology and rheumatology homecare prescriptions were repeats. Validation of these represents a significant workload for pharmacists, whilst not optimising their clinical expertise. Aim We aimed to assess the clinical risk and patient safety concerns associated with validation of repeat homecare prescriptions by ACTs, as supported by new RPS standards. Methods (including an ethical approval statement) The ACT screened repeat prescriptions in accordance with the STH clinical validation SOP for a 6-week period, between April and May 2023. Anonymised data from all prescriptions was recorded by the ACT, including time taken, number and nature of errors identified. In this study, errors were defined as any omission or discrepancy relating to demographic, clinical or pharmaceutical information. The pharmacist undertook a blinded second validation of each repeat prescription checked by the ACT and findings were compared. The study did not require ethical approval as ACT validation was an additional step and all prescriptions were subsequently validated by the pharmacist before dispensing , meaning there was no deviation to standard practice. Results 613 prescriptions were screened, of which 529 (86.3%) were repeats. A total of 33 errors were identified on 33 prescriptions by both the ACT and the pharmacist. The same errors were flagged by both. These errors were categorised as clinical 27 (82%), demographic 3 (9%), and pharmaceutical 3 (9%). Discussion and Conclusion (including study limitations) There were no additional errors identified by the clinical pharmacist, showing there was no added benefit from a pharmacist check. The implication is for improved skill mix, more rational and effective use of staffing resources and further development of the ACT role. Freeing pharmacist time to focus on prescribing or other clinical duties could have additional benefits for patients. It should be noted that all homecare prescriptions are generated in Microsoft Word templates, meaning that the utilisation of an electronic prescribing system capable of pre-filling data into fields has the potential to reduce the instances of clerical errors. 15 of the 33 errors (45%) could be rectified by the ACT without seeking input from the prescriber. Limitations Not all prescriptions in the 6-week study period could be included due to staff availability; those flagged as clinically urgent were processed outside the project to avoid delay.

Urinalysis and perceived effects following 2-week use of a commercial broad-spectrum cannabidiol product.

A growing number of hemp-derived cannabidiol (CBD) products are available with negligible amounts (< 100 ppm) of delta-9-tetrahydrocannabinol (THC) due in part to consumer concerns regarding the risk of positive drug screens. There are, however, no published studies that report whether repeated use of these products may lead to positive urine drug tests for THC. There is also scant research on the effects of these products on physical and mental well-being. Twenty healthy adults consumed a hemp-derived broad-spectrum CBD product every day for 2 weeks. Participants attended study visits at the beginning and end of the 2-week period. At each visit, participants underwent urinalysis testing for CBD, THC, and metabolites (analyzed via liquid chromatography with tandem mass spectrometry) and completed a validated assessment of physical and mental well-being. Participants reported using an average of 1.09 ± 0.51 ml (34.20 ± 16.00 mg CBD) of study product per day. Neither tetrahydrocannabinol nor its metabolites were detectable in urine following the 2-week period of use. Ingestion of the broad-spectrum product was associated with a significant reduction in sleep disturbance and pain intensity symptoms (p < .05), which remained significant after correcting for possible confounds (i.e., age, sex, dosage). No adverse events were reported. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation.

Mitochondrial disease is a group of rare conditions, with no approved treatment to date, except for Leber hereditary optic neuropathy. Therapeutic options to alleviate the symptoms of mitochondrial disease are urgently needed. Sonlicromanol is a promising candidate, as it positively alters the key metabolic and inflammatory pathways associated with mitochondrial disease. Sonlicromanol is a reductive and oxidative distress modulator, selectively inhibiting microsomal prostaglandin E1 synthase activity. This Phase 2b program, aiming at evaluating sonlicromanol in adults with m.3243A>G mutation and primary mitochondrial disease, consisted of a randomized controlled (RCT) study (dose-selection) followed by a 52-week open-label extension study (EXT, long-term tolerability, safety, and efficacy of sonlicromanol). Patients were randomized (1:1:1) to receive 100- or 50-mg sonlicromanol, or placebo twice daily (bid) for 28 days with ≥2-week wash-out period between treatments. Patients who completed the RCT study entered the EXT study wherein they received 100-mg sonlicromanol bid. Overall, 27 patients were randomized (24 RCT patients completed all periods). 15 patients entered the EXT, and 12 patients were included in the EXT analysis set. All patients reported good tolerability and favourable safety, with pharmacokinetic results comparable to the earlier Phase 2a study. The RCT primary endpoint (change from placebo in the attentional domain of cognition score [IDN: visual identification, Cogstate]) did not reach statistical significance. Using a categorisation of the subject's period baseline a treatment effect over placebo was observed if their baseline was more affected (p=0.0338). Using this approach, there were signals of improvements over placebo in at least one dose in the Beck Depression Inventory (BDI, p=0.0143), Cognitive Failure Questionnaire (CFQ, p=0.0113), and the Depression subscale of the Hospital Anxiety and Depression Scale (p=0.0256). Statistically and/or clinically meaningful improvements were observed in the patient- and clinician-reported outcome measures at the end of the EXT study (Test of attentional performance [TAP] with alarm, p=0.0102; TAP without alarm, p=0.0047; BDI somatic, p=0.0261; BDI Total, p=0.0563; SF12 physical component score, p=0.0008). Seven of nine domains of RAND-Short form-36 like SF-36 pain improved (p=0.0105). Other promising results were observed in Neuro QoL-Fatigue-SF (p=0.0036), MiniBESTest (p=0.0009), McGill Pain Questionnaire (p=0.0105), EQ-5D-5L-VAS (p=0.0213) and EQ-5D-5L-index (p=0.0173). Most patients showed improvement in the 5× sit-to-stand test. Sonlicromanol was well-tolerated and demonstrated a favourable benefit/risk ratio for up to one year. Sonlicromanol was efficacious in patients when affected at baseline, as seen across a variety of clinically relevant domains. Long-term treatment showed more pronounced changes from baseline.

Towards Real-Time Integrated Water Vapor Estimates with Triple-Frequency Galileo Observations and CNES Products

Integrated water vapor (IWV) is a crucial parameter for tropospheric sounding and weather prediction applications. IWV is essentially calculated using observations from global navigation satellite systems (GNSS). Presently, the Galileo satellite system is further developed, including more visible satellites that transmit multi-frequency signals. This study aims to evaluate the accuracy of real-time IWV estimated from a triple-frequency Galileo-only precise point positioning (PPP) processing model utilizing E1, E5a, E5b, and E5 observations, which is not addressed by the previous studies. For this purpose, Galileo datasets from 10 global reference stations spanning various 4-week periods in the winter, spring, summer, and fall seasons are acquired. To process the acquired datasets, dual- and triple-frequency ionosphere-free PPP solutions are used, including E1E5a PPP, E1E5aE5b PPP, and E1E5E5b PPP solutions. The publicly available real-time products from the Centre National d’Etudes Spatiales (CNES) are utilized. The real-time IWV values are computed and then validated with the European Centre for Medium-Range Weather Forecasting (ECMWF) reanalysis products (ERA5) counterparts. The findings demonstrate that the root mean square error (RMSE) of the estimated IWV is less than 3.15 kg/m2 with respect to the ECMWF ERA5 counterparts. Furthermore, the E1E5aE5b PPP and E1E5E5b PPP models enhance the IWV’s accuracy by about 11% and 16%, respectively, compared with the E1E5a PPP model.

Impact of a Clinical Decision Support System on the Change over Time in the Anticholinergic Load in Geriatric Patients: The SADP-Antichol Study

Purpose: Anticholinergic drugs can cause adverse events (AEs) in older adults. Clinical decision support systems (CDSSs) can detect prescriptions with a high anticholinergic load. Our starting hypothesis was that the anticholinergic load could be reduced by combining a CDSS with a strategy for generating pharmacist interventions. The objective of the present study was to assess the impact of this combination on the change over time in the anticholinergic load in hospitalized older adults. Methods: This prospective, single-centre study was divided into two 6-week periods. During the interventional period, a pharmacist analyzed the alerts generated by the CDSS for 30 targeted anticholinergic drugs and decided whether to issue a pharmacist intervention. A control period corresponds to standard care. The primary endpoint of the study is the delta of the anticholinergic load between the alert and hospital discharge; the secondary endpoint is the incidence of anticholinergic adverse events (AEs). Results: Of the 144 alerts generated, 87 were considered to be relevant (36 in the interventional period and 51 in the control period). A significant difference was observed between the delta anticholinergic load between the experimental and control periods (1.61 vs. 0.67, p-value = 0.0115). For the targeted drugs (n = 94) over the 87 alerts, 46.8% were for antihistamines and 21.3% were for desloratadine. Of the 36 pharmacist interventions sent by the pharmacist, 19 (52.8%) were accepted. The most deprescribed drug class was the antihistamine class (n = 7), and the most deprescribed drug was amitriptyline (n = 5). Among these 87 patients with alerts, the correlation between the anticholinergic load and the number of AEs was not statistically significant (p = 0.887). The most common AE affecting the peripheral nervous system was constipation (28.6%), and the most common AE affecting the central nervous system was confusion (29.9%). Conclusions: Our results showed that the combination of specific CDSS rules with pharmacist-mediated risk management procedures could further reduce the anticholinergic load in hospitalized older adults, relative to routine care. It remains to be determined whether this reduction in the anticholinergic load has an impact on the incidence of peripheral and central anticholinergic AEs, and thus the health of these patients.

CARD-SARC: mixed-method study to develop a disease-specific health-related quality of life tool for cardiac sarcoidosis

Abstract Introduction Sarcoidosis is a rare inflammatory condition caused by the formation of lumps (granulomas) of abnormal tissue in any organ, and can affect physical, functional, mental, social and economic aspects of life. People living with cardiac sarcoidosis (CS) are likely to have worse clinical outcomes and greater impairment on health-related quality of life (HRQoL) than other sarcoidosis manifestations. HRQoL is the main concern for people living with sarcoidosis. However, measuring HRQoL in people with CS is difficult as existing tools focus on other forms of sarcoidosis (for example, lung, eye or skin involvement) or for specific cardiac symptoms (for example, atrial fibrillation, angina or heart failure), but not specifically for CS. Purpose To develop a disease-specific patient-reported outcome measure (CARD-SARC) to assess the impact of CS on HRQoL. Methods A sequential exploratory mixed-method, multicentre observational cohort study using a clinimetric approach was conducted. The McMaster Framework for evaluative instruments involved three steps (item selection, item scaling and item reduction) which were complemented with recommendations from the consensus-based standards for the selection of health measurement instruments (COSMIN). The item-generation process connected data from quantitative (theory, research findings and systematic review) and qualitative components (qualitative semistructured interviews, clinical observations and experts’ opinion). A simultaneous triangulation (QUAN+qual) method was followed to ensure a comprehensive list of preliminary items. The formatting of items was guided by patient and public involvement (PPI) with a 2-weeks recall period. The item reduction strategy was led by PPI and an international multidisciplinary clinical CS-experts. Results 740 potential items were generated by converging all the different sources and techniques. After removal of duplicates and simultaneous triangulation, a preliminary list with 111 items was reviewed by the CS-expert panel with 26 members (including 11 pulmonologists, 7 cardiologists, 5 CS-patients and 3 specialist-nurses). After a consensus meeting, the CARD-SARC included 61 relevant items in six sections for pilot-testing: "functioning", "social, leisure and occupation", "emotional", psychological", "physical" and "healthcare/self-care". Conclusions This study combined a robust methodology with active PPI engagement to develop the first disease-specific HRQoL tool for CS. Each data source was planned independently, however the input from PPI members was critical during the simultaneous triangulation for item-generation. The contributions of CS-experts (members of the PPI group and clinical multidisciplinary experts) enhanced the content validity of the CARD-SARC. The CARD-SARC has the potential to influence clinical management and treatment options, future research and health-economic stakeholders’ decisions for CS.

Effects of puerarin on gait disturbance in a 6-hydroxydopamine mouse model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder caused by dopamine (DA) neuronal dysfunction. Although DA agonists and N-methyl-D-aspartate receptor (NMDAR) antagonists are used to treat PD, chronic use causes severe side effects. Puerarin (PUE) is a natural bioactive compound that affects the DA system; however, its effect on PD-associated motor functions is unknown. Therefore, we investigated whether PUE treatment in a 6-hydroxydopamine (6-OHDA) PD mouse model affects motor dysfunction. Adult male ICR mice received unilateral 6-OHDA microinfusion into the right medial forebrain bundle. After a 2-week recovery period, PUE (20 or 50mg/kg) or the vehicle (saline, VEH) was administered intraperitoneally once daily for 21 days. Motor dysfunction was assessed using the locomotion, gait cycle, and rotation tests. Local field potentials (LFPs) were measured in the substantia nigra compacta (SNc), striatum (STR), subthalamic nucleus (STN), and primary motor cortex. 6-OHDA-lesioned PD mice showed increased gait cycle disturbance and unidirectional rotation. PUE treatment ameliorated the gait cycle disturbance, but not unidirectional rotation of PD mice. These effects differed with DA agonist treatment (which improved PD symptoms) and NMDAR antagonist treatment (which aggravated PD symptoms). Moreover, locomotion was increased only in NMDAR antagonist treatment. PUE treatment induced no changes in the attenuated LFP of the beta wave in the STR and STN, and SNc-STN delta-wave coherence was shown in PD animals. This study suggests that PUE is a beneficial co-therapeutic agent for alleviating gait cycle disturbance in PD symptoms.

Short-term effects on sacubitril/valsartan therapy on right ventricle work and mechanics in patients with heart failure and reduced ejection fraction

Abstract Introduction In previous studies, sacubitril/valsartan (ARNI) therapy has been shown to have a positive effect on right ventricle (RV) function and on systolic pulmonary artery pressure in addition to improvement of left ventricle (LV) function in patients with heart failure and reduced ejection fraction (HFrEF). Recently, it was shown that a short-term ARNI therapy compared to valsartan-only therapy led to reduced systemic blood pressure and LV mechanical work, contributing to reduced LV myocardial perfusion and oxygen consumption. Purpose This paper aimed to study the effect of short-term ARNI therapy on RV mechanics and work and pulmonary and LV filling pressures compared to valsartan-only therapy in patients with HFrEF. Methods The study was a phase IV, prospective, randomized, double-blind, parallel-group study in patients with NYHA class II–III heart failure and LV ejection fraction (LVEF) &amp;lt;= 35 %. During a 6-week run-in period, all patients received valsartan therapy, which was up-titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, and cardiac and systemic hemodynamics were quantified using echocardiography and 11C-acetate PET before and after 6 weeks of therapy (on stable dose) in 55 patients. The analyses were done with ANCOVA adjusting for pre-randomization values. Results The RV myocardial resting perfusion (mean difference of 0.056 (95% CI, 0.02 to 0.109) ml/g/min, p = 0.041) and RV myocardial oxygen consumption (0.005 (0.001 to 0.010) 1/min, p = 0.015) were significantly lower in the ARNI group compared with the valsartan-only group. The left atrial end-diastolic volume indexed to body surface area (geometric mean difference of 1.071 (95% CI, 0 to 1.148) ml/m2, p = 0.048) and the ratio of early mitral inflow velocity to medial mitral annular early diastolic velocity (mean difference of 2.467 (95% CI, 0.096 to 4.838), p = 0.042) were also significantly lower in the ARNI group compared with the control group. There was no difference between the groups in peak systolic right ventricle to right atrial pressure gradient. Still, the tricuspid annular plane systolic excursion was significantly higher in the valsartan-only group compared with the ARNI group (0.221 (0.039 to 0.404) cm, p = 0.018). There was no difference in RV free wall strain, fractional area change or systolic excursion velocity between the treatment arms (p&amp;gt; 0.262). Conclusions In addition to our earlier findings, sacubitril when added to valsartan appears to reduce also right ventricle myocardial perfusion and oxygen consumption. There was also a reduction in left atrial end-diastolic volume and in early mitral inflow to medial mitral annular early diastolic velocity in the sacubitril/valsartan group as compared to the valsartan-only group, which suggest decreased LV filling pressure.

Efficacy of hypertonic dextrose (prolotherapy) in early knee osteoarthritis: a short term outcome

Background: Knee osteoarthritis (OA) is a prevalent, painful, and progressive condition significantly affecting patients' quality of life and imposing a social and economic burden. Traditionally managed through symptom relief and joint function improvement, research is increasingly focusing on disease-modifying treatments. Dextrose prolotherapy, a low-cost alternative involving the injection of a hypertonic solution, has shown promise despite limited acceptance in current guidelines. Methods: This prospective cohort study, approved by the Institutional Ethical Board of Jamia Hamdard University, assessed the effects of 12.5% hypertonic dextrose prolotherapy in 92 patients with knee OA. Patients received injections at multiple sites over a 6-week period. Outcomes were evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and visual analog scale (VAS) scores at baseline, 4, 8, 16, and 24 weeks. Results: Significant improvements were observed in both WOMAC and VAS scores. WOMAC scores decreased from 53.83 to 26.70 (p&lt;0.0001), and VAS scores dropped from 7.12 to 3.06 (p&lt;0.0001) at the 24-week follow-up. No major complications were noted, with minimal adverse effects reported. Improvement was consistent across all OA grades. Conclusions: Dextrose prolotherapy demonstrated substantial, sustained improvements in pain and function in knee OA patients. Given its safety, low cost, and efficacy, it represents a viable therapeutic option, especially in resource-constrained settings. Further high-quality randomized controlled trials are needed to confirm these findings and optimize treatment protocols.

Insights into physiological roles of flavonoids in plant coldacclimation.

Flavonoids represent a diverse group of plant specialised metabolites which are also discussed in the context of dietary health and inflammatory response. Numerous studies have revealed that flavonoids play a central role in plant acclimation to abiotic factors like low temperature or high light, but their structural and functional diversity frequently prevents a detailed mechanistic understanding. Further complexity in analysing flavonoid metabolism arises from the different subcellular compartments which are involved in biosynthesis and storage. In the present study, non-aqueous fractionation of Arabidopsis leaf tissue was combined with metabolomics and proteomics analysis to reveal the effects of flavonoid deficiencies on subcellular metabolism during cold acclimation. During the first 3 days of a 2-week cold acclimation period, flavonoid deficiency was observed to affect pyruvate, citrate and glutamate metabolism which indicated a role in stabilising C/N metabolism and photosynthesis. Also, tetrahydrofolate metabolism was found to be affected, which had significant effects on the proteome of the photorespiratory pathway. In the late stage of cold acclimation, flavonoid deficiency was found to affect protein stability, folding and proteasomal degradation, which resulted in a significant decrease in total protein amounts in both mutants. In summary, these findings suggest that flavonoid metabolism plays different roles in the early and late stages of plant cold acclimation and significantly contributes to establishing a new protein homeostasis in a changing environment.

Healthy Dietary Pattern Cycling Affects Gut Microbiota and Cardiovascular Disease Risk Factors: Results from a Randomized Controlled Feeding Trial with Young, Healthy Adults.

Previous research demonstrates that adopting, abandoning, and re-adopting (i.e., cycling) a healthy dietary pattern (HDP) improved, reverted, and re-improved cardiovascular disease (CVD) risk factors. In addition, changes in CVD risk factors are associated with dietary modifications of gut microbiota. We sought to assess the effects of cycling an HDP on gut microbiota and CVD risk factors. Retrospectively, we used data from a randomized controlled, crossover trial with three 3-week controlled dietary interventions, each separated by a 5-week period of participant-chosen, uncontrolled food intake. Seventeen participants (10 males, 7 females, age 26 ± 4 years old, BMI 23 ± 3 kg/m2) all consumed intervention diets that followed healthy U.S.-style dietary patterns. Gut microbiota composition and cardiovascular risk factors were measured before and after each HDP. Repeatedly adopting and abandoning an HDP led to a cycling pattern of changes in the gut microbial community and taxonomic composition. During the HDP cycles, relative abundances of several bacterial taxa (e.g., Collinsella, Mediterraneibacter, Romboutsia, and Dorea) decreased and returned to baseline repeatedly. Similar HDP cycling occurred for multiple CVD risk factors (i.e., serum total cholesterol and LDL-C concentrations). Consistent negative associations were observed between changes in Mediterraneibacter or Collinsella and serum total cholesterol/HDL-C ratio. These results support previous findings that HDP cycling affected multiple CVD risk factors and expand the HDP cycling phenomenon to include several bacterial taxa. Young adults are encouraged to adopt and sustain a healthy dietary pattern to improve cardiovascular health, potentially through modifying gut microbiota composition.