Post Hoc Research Articles

Effect of Haemodiafiltration Versus Haemodialysis on Vascular Access Patency when Starting Haemodialysis.

Haemodiafiltration (HDF) therapy improves the prognosis by reducing inflammation and oxidative stress, and improving endothelial function. These factors contribute to vascular access (VA) stenosis, one of the most common complications in patients on haemodialysis (HD) or HDF. This study aimed to assess the efficacy of HDF on VA patency. This multicentre, prospective, observational study with post-hoc analysis included 612 patients among 643 who underwent VA procedures and started dialysis between April 2012 and March 2021. Five hundred and sixteen patients were on HD from starting dialysis, while 96 switched to HDF after starting dialysis. One-to-one propensity score matching was performed to compare the 24-month patency rates of VA between groups by Kaplan-Meier and log-rank tests, and a Cox proportional hazard regression analysis was used to identify factors affecting patency rates. There were 87 patients in each group. The 24-month primary patency rates were 74.2% for HDF and 47.7% for HD (P<0.001). A multivariate Cox proportional hazards analysis showed that a history of cardiovascular disease (hazard ratio [HR] 2.29; 95% confidence interval [CI] 1.21-4.34, P=0.01) and higher haemoglobin A1c values (HR 1.37; 95% CI 1.00-1.82, P=0.04) were associated with poor 24-month primary patency. However, HDF (HR 0.30; 95% CI 0.16-0.56, P<0.001) and use of statins (HR 0.50; 95% CI 0.27-0.94, P=0.03) were associated with better patency. A stratified analysis showed that HRs for loss of VA patency were lower in patients with HDF than in those with HD in the subgroups of≥65 years, male sex, radiocephalic arteriovenous fistula, a history of diabetes mellitus or cardiovascular disease, haemoglobin concentrations <10g/dL, and albumin concentrations<3.5g/dL. HDF potentially improves VA patency rates compared with HD, even in patients with cardiovascular disease or diabetes, commonly associated with poor patency.

Repeated transcranial magnetic stimulation on the bilateral cerebellum to improve symptoms of ataxia with multiple system atrophy: a prospective, randomized, sham-controlled pilot study.

Ataxia is a common symptom in patients with Cerebellar subtype of Multiple system atrophy (MSA-C), but effective treatments remain elusive. The present study aims to investigate whether repetitive transcranial magnetic stimulation (rTMS) over the bilateral cerebellum could relieve ataxia in patients with MSA-C. This is a single-center, randomized and double-blind trial. 26 patients with MSA-C were randomly divided into experimental group and control group. The experimental group underwent (rTMS) in both cerebellum for 10 consecutive days, while the control group was given sham rTMS. The participants underwent clinical assessments at baseline (T0), and three follow-up timepoints, that is, immediately after the tenth treatment session (T1), 2weeks (T2), and 4weeks (T3) after T1. The Scale for the Assessment and Rating of Ataxia scores (SARA) was used as the primary outcome measure, with the Fatigue Severity Scale-9 (FSS-9), the Hamilton Anxiety Scale (HAMA) and the Hamilton Depression Rating Scale-24 (HAMD-24) as secondary outcomes. Two-way repeated ANOVAs showed significant group × time interactions among SARA (p < 0.001), FSS-9 (p < 0.001), HAMA (p < 0.001) and HAMD-24 (p < 0.001). Post-hoc analyses showed that compared with T0, the activity group showed significant improvement in SARA, HAMA and HAMD-24 scores at T1, T2 and T3, and significant improvement in FSS-9 scores at T1 and T2, but no significant improvement in T3. rTMS over bilateral cerebellum could provide short-term improvements for alleviating ataxia and the symptoms of fatigue, depression anxiety, but the beneficial effects last no more than 4weeks.

Specific symptomatology profile associated with treatment resistant depression: A multicentric study from the Group for the Study of Resistant Depression with a focus on sex.

Clinical predictors of treatment-resistant depression could improve treatment strategies. Depressive symptom profiles at baseline are potential outcome predictors, but little evidence is available, and sex-specific profiles have been scarcely investigated. Baseline symptom scores of 1294 patients with major depressive disorder were assessed by the Montgomery-Åsberg depression rating scale (MADRS) as part of a multicenter study by the "Group for the Studies of Resistant Depression". Treatment outcomes were assessed according to the MADRS after ≥4 weeks of naturalistic treatment. We tested if individual MADRS item scores at baseline were associated with treatment outcome in the whole sample and in sex-stratified subgroups. A specific baseline symptom profile was associated with non-response in the whole sample. In particular, apparent and reported sadness, reduced sleep, lassitude, inability to feel, and pessimistic thoughts were the only MADRS items that scored higher at baseline in patients with subsequent lack of response. In the sex-stratified analysis, females showed a similar profile overall, however they showed higher baseline levels of inner tension, inability to feel, and pessimistic thoughts compared to males, and these symptoms were associated with lack of response in females but not in males. Neurovegetative symptoms were poorly predictive. Overall baseline severity related to poor response. This is a post-hoc analysis. The naturalistic design of the study with a retrospective assessment is potential limitations. A specific baseline symptom profile characterized by higher sadness, reduced sleep and anhedonic features may be indicative of poor treatment outcome. Females showed a distinctive baseline profile associated with poor response.

Proximal protection devices for carotid artery stenting - A benchtop assessment of flow reversal performance.

Proximal protection devices, such as TransCarotid Artery Revascularization (TCAR, SilkRoad Medical, Sunnyvale), aim to yield better outcomes in carotid artery stenting (CAS) than distal protection devices by preventing plaque embolization to the brain. However, transfemoral catheters may not fully reverse flow from the external carotid artery (ECA) to the internal carotid artery (ICA). We assess a new balloon-sheath device, Femoral Flow Reversal Access for Carotid Artery Stenting (FFRACAS), for this purpose. The FFRACAS prototype (ID = 0.117"; L=80cm) was compared to TCAR (ID=0.104", L=30cm) and MoMa (Medtronic, Minneapolis; ID=0.083", L=90cm) in a pulsatile flow model with blood simulant at 800mL/min. MoMa was used according to labeled instructions, with both CCA and ECA balloon inflation, without CCA-femoral vein shunt placement, and in an off-label fashion with single balloon occlusion in the CCA and shunt. Flow rates of the ICA, ECA, and shunt, when applicable, were monitored during CAS stages: CCA flow arrest, shunt activation, and stent delivery. Experiments were conducted under two ECA inflow conditions (-10 and -20 mL/min). Statistical comparison of ICA flow rates was conducted using ANOVA and Tukey's post-hoc tests. MoMa's on-label use maintained retrograde ICA flow (-0.3 mL/min) throughout CAS. Upon shunt activation, TCAR and FFRACAS reversed ICA flow similarly under low ECA inflow (ICA=-5.10 mL/min vs. -4.83 mL/min; p=0.349), but neither achieved ICA flow reversal under high ECA inflow or during stent delivery. MoMa off-label use failed to reverse ICA flow. FFRACAS presents a potential alternative to TCAR, achieving similar degrees of flow reversal from a transfemoral approach to that achieved with the transcarotid approach. The MoMa system reliably prevents anterograde flow in ICA during CAS. CAS = Carotid Artery Stenting; TCAR = Transcarotid Arterial Revascularization; CCA = Common Carotid Artery; ICA = Internal Carotid Artery; ECA = External Carotid Artery; VA = Vertebral Artery; FFRACAS = Femoral Flow Reversal Access for Carotid Artery Stenting; ID = Inner Diameter; OD = Outer Diameter.

Spleen stiffness in a healthy pediatric population undergoing liver magnetic resonance elastography.

Splenic stiffness is a potential imaging marker of portal hypertension. Normative spleen stiffness values are needed to define diagnostic thresholds. To report stiffness measurements of the spleen in healthy children undergoing liver magnetic resonance (MR) elastography across MRI vendors and field strengths. This was a post-hoc analysis of data collected under a prospective multicenter cross-sectional study. Volunteers aged 7-17.9years without a known history of liver or spleen disease were recruited for a research MRI between February 2018 and October 2019. Gradient recalled echo (GRE) or spin-echo-echo-planar imaging (SE-EPI) MR elastography was performed on a total of three vendor platforms and at two field strengths (1.5T (T) and 3T) with standard right upper quadrant passive driver placement (frequency of 60Hz). Two independent reviewers measured spleen stiffness, length, and volume. Descriptive statistics, independent sample t-tests or Mann-Whitney test, and Pearson's or Spearman's correlation were used. From 101 study volunteers, 72 (34 female) had measurable splenic stiffness. Median age was 12years (interquartile range [IQR], 9.9-14.9years). Mean (± SD) spleen stiffness was 4.7 ± 0.9kPa (IQR, 3.8-5.4kPa) with 6.1kPa reflecting the 95th percentile. Strong correlation was observed between reviewers (ICC = 0.89 [95%CI, 0.71-0.93; P < 0.001]). Male volunteers had slightly higher splenic stiffness compared to females: 4.9 ± 0.9 vs. 4.3 ± 0.8kPa (P = 0.014). There was significant correlation between spleen stiffness and body mass index (r = 0.33 [95%CI, 0.06-0.56; P = 0.024]) but no other measure of patient size (r = 0.15-0.29). No significant difference in spleen stiffness was observed across vendors (P = 0.089) or field strengths (P = 0.236). MR elastography-based spleen stiffness, measured as part of a liver MR elastography acquisition, is < 6.1kPa in a healthy pediatric population and does not vary with MRI vendor or field strength.

Implantable Cardioverter-Defibrillators and Cardiovascular Resynchronization Therapy with Left Ventricular Assist Devices: A MOMENTUM 3 Trial Analysis.

The benefit of implantable cardioverter-defibrillators (ICD) and cardiovascular resynchronization therapy (CRT-D) in patients supported with a HeartMate 3 left ventricular assist device (LVAD) remains uncertain. An analysis of the MOMENTUM 3 randomized clinical trial and the first 1000 patients in the Continued Access Protocol trial. Patients were divided into three groups based on the presence of ICD and/or CRT-D: No device (n=153, 11%), ICD only (n=699, 50.4%), CRT-D (n=535, 38.6%). We assessed the association of ICD or CRT-D with overall mortality, ventricular arrhythmias (VA), rehospitalization rates, quality of life and six-minute walk test distance at 2-years of follow-up. Patients with ICD or CRT-D had similar survival to those without (HR 1.3, 95% CI 0.8-2.1, p=0.36) with no differences in rehospitalizations, quality-of-life or six-minute walk test distance. VA occurred more frequently in patients with ICD or CRT-D (HR 2.4, 95% CI 1.3-4.3, p=0.006). Compared to ICD alone, patients with CRT-D demonstrated similar survival (HR 1.1, 95% CI 0.9-1.5, p=0.36), however, had increased rates of VA (HR 1.3, 95% CI 1.0-1.7, p=0.03). There were no differences in rate of rehospitalization between those with ICD or CRT-D and those without (p=0.19) or between those with ICD and those with CRT-D (p=0.32). A propensity-matched sensitivity analysis confirmed these findings. In this post-hoc analysis of the MOMENTUM 3 trial, the presence of ICD or CRT-D at the time of HM3 LVAD implantation was associated with an increased incidence of VA but was not associated with survival, quality of life or functional capacity. Momentum 3 portfolio, NCT02224755 (Pivotal) and NCT02892955 (CAP).

Efficacy and safety of non-focused low-intensity ultrasound technology for subcutaneous lipolysis in the lower abdomen: a clinical study.

With rising demand for non-invasive body contouring, this study aimed to evaluate the efficacy and safety of non-focused, low-intensity ultrasound for lower abdominal lipolysis. The enrolled subjects prospectively received 6 weekly sessions of well-setting ultrasound treatment with frequency of 1MHz and an intensity of 2.2W/cm2, to target the subcutaneous fat of lower abdomen with three regions (left, middle, and right). Evaluations included ultrasound measurements and blood biochemical analyses at the baseline, pre-4th session, and at 1 and 2-month post-treatment points to confirm the efficacy and safety. A total of 17 subjects completed the whole treatment. Significant reductions in superficial abdominal fat layer thickness of all three regions were observed (all P-values of ANOVA <0.001), without severe adverse events reported. Post-hoc analysis showed the superficial fat layers of all the three regions at 1-month post-treatment significant reductions comparing the baseline (all adjusted P < 0.05). The reduction effects for superficial fat layers were still available at the 2-month post-treatment follow-up at the left and middle regions. Conversely, there was no significant improvements among the deep fat layers at the three regions. Non-focused, low-intensity ultrasound demonstrate its potential of efficacy and safety for reducing superficial abdominal fat, and may maintain the capability for at least two months. Further studies are needed to confirm long-term efficacy and optimize treatment parameters. What is already known on this topic? Non-focused ultrasound with low-intensity is recognized for its potential in non-invasive body contouring, but detailed efficacy and safety data were limited, especially for lower abdominal lipolysis. What this study adds? Our research demonstrated the efficacy and safety of non-focused ultrasound with low-intensity in reducing superficial abdominal fat, with sustained effects for at least two months. How this study might affect research, practice, or policy? This study could guide future researches toward long-term effects and optimization of ultrasound treatments, and influence clinical practice by providing a validated method for non-invasive fat reduction.

Long-Term Safety of Ixekizumab Treatment in Patients with Psoriasis, Psoriatic Arthritis, or Axial Spondyloarthritis: a PostHoc Analysis of Cerebro-Cardiovascular Events.

Psoriasis (PsO), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) may confer an increased risk for cardiovascular (CV) disease, including major adverse cerebro-cardiovascular events (MACE), deep vein thrombosis (DVT), and pulmonary embolism (PE). Patients with these conditions are often exposed for extended time periods to biologics, such as ixekizumab (IXE). Therefore, understanding the risk of CV events, especially MACE, in patients with PsO, PsA, and axSpA exposed to IXE is important. The incidence of MACE (i.e., adjudicated cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), DVT, and PE was assessed in adults who received ≥ 1 dose of IXE across 25 randomized clinical trials (17 PsO, 4 PsA, 4 axSpA). Rates of CV events were analyzed for pooled studies by indication and analyzed from treatment initiation up to the end of the study program. Exposure-adjusted incidence rates per 100 patient-years (IR/100PY) are reported. This integrated safety analysis included 6892 patients with PsO, 1401 with PsA, and 932 with axSpA. The median duration of IXE exposure was 478.5days (1.3years) for patients with PsO, 504.5days (1.4years) for patients with PsA, and 981.0days (2.7years) for patients with axSpA. The incidence of adjudicated MACE was low (IR/100PY: PsO = 0.5; PsA = 0.5; axSpA = 0.3) and stable over the treatment periods. The most common types of MACE reported were non-fatal myocardial infarction (IR/100PY: PsO = 0.3; PsA = 0.3; axSpA = 0.3), followed by non-fatal stroke (IR/100PY: PsO = 0.1; PsA = 0.2; axSpA = 0.0), and cardiovascular death (IR/100PY: PsO = 0.1; PsA = 0.1; axSpA = 0.0). The incidences of DVT (IR/100PY: PsO = 0.1; PsA = 0.1; axSpA = 0.1) and PE (IR/100PY: PsO = 0.1; PsA = 0.0; axSpA = 0.0) were low. This integrated safety analysis of 25 randomized clinical trials showed that the incidence of adjudicated MACE was low among adult patients with PsO, PsA, and axSpA and that the rates did not increase with increasing IXE exposure. The supplementary TableS1 provides a comprehensive list of clinical trials and their registration numbers.

Clinical Pharmacokinetics of N,N-Dimethyltryptamine (DMT): A Systematic Review and Post-hoc Analysis.

N,N-Dimethyltryptamine (DMT) is currently being studied for its therapeutic potential in various psychiatric disorders. An understanding of its pharmacokinetics (PK) is essential to determine appropriate dose ranges in future clinical studies. We conducted a systematic literature review on the PK of DMT. Clinical studies that administered known amounts of DMT and reported PK data and/or parameters in humans were included. Additionally, raw PK data were requested from authors and/or extracted from publications. In total, 219 references were retrieved, of which 13 publications were included, covering eight distinct datasets. All studies administered DMT intravenously in various infusion schemes, except for one intramuscular administration. High variability in dose-normalized exposure parameters and differences in exposure for bolus versus infusion administration were observed. DMT is extensively redistributed to other tissues, based on its biphasic elimination profile and high volume of distribution in the terminal elimination phase (range 123-1084 L). It is eliminated rapidly, with a half-life of 4.8-19.0 min and clearance of 8.1-46.8 L/min. This is a result of the rapid metabolization of DMT to indole-3-acetic acid (IAA), which is also reflected in the fact that the time of maximum concentration of IAA is similar to that of DMT. This review demonstrates that the PK of DMT in humans have been characterized to a limited extent, and publications lack details with regards to demographics, absolute doses, and PK parameters. Additional studies are necessary to investigate high intersubject variability and differences in exposure following bolus or prolonged infusion. Addressing these issues is essential for the development of DMT as a pharmacotherapeutic in neuropsychiatry.

DIGITAL THERAPEUTIC COMBINING HYPNOSIS AND DIAPHRAGMATIC BREATHING INTERVENTION FOR FUNCTIONAL ABDOMINAL BLOATING (FAB): A FEASIBILITY STUDY.

Abdominal bloating is a difficult symptom to treat. Hypnotherapy and diaphragmatic intervention have separately shown benefit on bloating in prior work but have not been united into a single intervention. We aimed to obtain data on the potential therapeutic impact of a novel audio-recorded bloating treatment for bloating integrating hypnosis and diaphragmatic breathing, with proposed synergistic effect. Patients with non-organic bowel disorders with predominant bloating symptoms completed a digitally delivered seven-session audio-recorded hypnotherapy program without clinician involvement. The intervention combined bloating-targeted hypnotic suggestions and guided diaphragmatic breathing delivered under hypnosis, supplemented with interval self-guided breathing exercises. Participants completed online REDCap assessments at baseline, mid-treatment, at end-of-treatment and at 3-month follow-up, evaluating symptom severity, GI symptom specific anxiety, overall anxiety/depression, and quality of life. Outcomes were assessed in an intention-to-treat manner with repeated measures ANOVAs with Bonferroni-adjusted pairwise post-hoc tests. Of 23 patients who started treatment, 22 (95.6%) completed follow-up. Bloating severity on IBS-SSS and PAGI-SYM showed reduction in bloating with large effect sizes (Cohen's d of ∼0.8) at the end of treatment, as did VSI bloating-related anxiety. At end of treatment, 16 patients (69.6 %) were IBS-SSS treatment responders (>30% symptom reduction) on bloating, and 17 (73.9%) on overall bowel symptom severity. Anxiety, depression, and quality of life scores were unchanged. Outcome measures were fully maintained at 3-month follow-up. Results suggest the therapeutic utility of a new cost-effective self-administered bloating intervention. A randomized controlled trial is planned to confirm these therapeutic effects.

Impact of motor features on non-motor symptoms in patients with de novo Parkinson's disease: Cognition, depression, anxiety, fatigue, and dysautonomia.

Patients with Parkinson's disease (PD) present with both motor and non-motor symptoms, and understanding the interplay between these symptoms is crucial for individualized patient care. This study aims to investigate the relationship between motor features and non-motor symptoms in patients with de novo PD. A total of 105 patients were analyzed, focusing on motor subtypes or subscores and their impact on cognition, depression, anxiety, fatigue, and dysautonomia. We utilized the Unified Parkinson's Disease Rating Scale-part III (UPDRS-III) for motor assessment, and various validated scales for non-motor symptoms. Compared with tremor-dominant (TD) patients, non-TD patients showed severe scores in fatigue and dysautonomia, but no difference in other non-motor symptoms, including global cognition, depression, and anxiety. Linear regression analysis revealed that the total motor score of UPDRS-III was negatively related to global cognition (β = -0.4454, P = 0.0121). As a post-hoc analysis, partial correlation analysis showed that rigidity and bradykinesia subscores were associated with global cognition (r = -0.3527, P = 0.0004; r = -0.2206, P = 0.0299, respectively), whereas the postural instability/gait difficulty subscore was associated with depression, anxiety, fatigue, and dysautonomia (r = 0.2181, P = 0.0319; r = 0.2371, P = 0.0194; r = 0.3659, P = 0.0002; r = 0.3968, P = 0.0001, respectively) but not with global cognition. These results suggest that motor features in the early stages of PD can serve as important indicators of non-motor symptoms, potentially guiding more personalized therapeutic approaches. Geriatr Gerontol Int 2025; ••: ••-••.

Primary Dentin Conditioning with Methylene Blue Activated Photodynamic Therapy, Phytic Acid, and Er,Cr:YSGG to Resin-Modified Glass Ionomer Cement in Comparison to Conventional Polyacrylic Acid.

Aim: Impact of surface conditioner phytic acid (IP6) Er,Cr:YSGG laser (ECYL) methylene blue photodynamic therapy (MB-PDT) on the microleakage and shear bond strength (SBS) of resin-modified glass ionomer cement (RMGIC) to primary sound dentin. Material and method: Overall, 80 extracted sound primary molars were collected followed by their submergence in self-cure acrylic resin. The dentin surface was exposed and made flat and was assigned into four groups based on the surface conditioning. Group 1: polyacrylic acid (PAA), Group 2: 1% IP6, Group 3: ECYL, and Group 4: MB-PDT. RMGIC restorative material was bonded to primary dentin. Marginal leakage assessment was performed using silver nitrate. SBS and failure mode assessment were performed using a universal testing machine and stereomicroscope. Mean and standard deviations of SBS and marginal leakage were compared using analysis of variance and multiple comparisons of Tukey's post-hoc test (p < 0.05). Results: MB-PDT treated specimens displayed the highest values of marginal leakage (37.56 ± 1.25 nm) and lowest SBS (7.93 ± 1.03 MPa). However, samples in Group 2 conditioned with IP6 presented the lowest dye penetration score (11.23 ± 1.22 nm) and highest bond strength scores (11.12 ± 0.82 MPa). Conclusions: IP6 and ECYL have proved to be better alternatives in terms of low microleakage and improved SBS scores to PAA as a primary dentin surface conditioner for bonding RMGIC restoration. Conversely, MB-PDT, when employed as a dentin surface conditioner for RMGIC restorations, exhibited suboptimal results, characterized by elevated microleakage and compromised bond strength.

Three-dimensional scapular kinematics during commonly used rehabilitation exercises in patients 12 weeks after Reversed Shoulder Arthroplasty.

Reversed shoulder arthroplasty (rTSA) is often used to restore functionality in patients with joint arthropathy and dysfunctional rotator cuff. As rTSA changes the biomechanical properties of the shoulder, an altered movement pattern of arm and scapula is to be expected. Previous studies focused on changes of the scapulohumeral rhythm during functional elevation tasks. To our knowledge, no study exists examining scapular kinematics during rehabilitation exercises in a patient population with rTSA. Therefore, this study aimed to analyze 3-dimensional scapular kinematics during 3 commonly used rehabilitation exercises, 12 weeks after rTSA surgery. It was hypothesized that scapular kinematics would be different between the horizontal and the vertical plane. Secondly, differences in scapular kinematics in the vertical plane, between the open and closed chain were hypothesized. In this cross-sectional study, 48 patients (55 shoulders) aged 69 ± 7.4 years participated. Scapular kinematics in terms of anterior/posterior tilt, external/internal rotation and upward/downward rotation were registered during 3 rehabilitation exercises. Exercises varied based on the plane (horizontal or vertical) and the modality (closed or open chain). Data were analyzed using Statistical Parametric Mapping (SPM). Post-hoc pairwise analysis within SPM (SPM(t)) revealed no significant differences among the exercises regarding posterior tilt. During vertical plane exercises (Standing Wall Slide 120° (WS), Standing reach 120° (REACH)), the scapula was more upwardly rotated for most of the time (14.93% - 74.63%, p<0.001) than during the exercise in the horizontal plane (Seated Bench Slide (BS)). No statistically significant differences were found between the vertical open chain (REACH) and the vertical closed chain exercise (WS). For the internal /external rotation, significant differences were found between the horizontal (BS) and the vertical plane (WS, REACH) (0% - 100%, p<0.001), and between the open (REACH) and closed chain (WS) vertical exercises (3.0% - 91.5%, p<0.001), with more external rotation when performing the movement in the vertical plane, and in the closed chain compared to respectively the horizontal plane and the open chain. Scapular kinematics during rehabilitation exercises after rTSA differ, depending on the plane and modality of the exercise. Insight into the impact of changing the plane (horizontal /vertical), and training in open versus closed chain, may assist physical therapists in the choice of exercises.

Persistence of Retinal Fluid after Anti-VEGF treatment for neovascular age-related macular degeneration: A Systematic Review and Meta-Analysis.

To evaluate the prognosis of retinal fluid resolution in neovascular age-related macular degeneration (nAMD) after initiating treatment in terms of the prevalence of eyes with retinal fluid, the proportion of eyes which never achieve a fluid-free retina throughout the course of treatment, and the relationship between retinal fluid and visual acuity outcome. Retinal fluid often persists or recurs after initiating treatment for nAMD. It is unclear what proportion never achieve fluid resolution throughout their treatment course. MEDLINE, Embase, and Web of Science were searched till May 2024 for randomized control trials (including post-hoc analyses) and prospective studies treating nAMD patients with intravitreal anti-VEGF injections (CRD42023437516). To investigate the prevalence of persistent fluid, a meta-analysis of proportions was conducted at key time-points. To estimate the proportion of poor-responding patients, iterative algorithms were used to simulate individual-patient-data from time-to-fluid fluid-resolution Kaplan-Meier curves. Cure fractions from Weibull non-mixture cure models were meta-analysed. Finally, the weighted mean BCVA difference (WMD) between patients with and without any fluid, SRF or IRF was calculated. Fifty articles were included across the meta-analysed outcomes. The pooled prevalence of retinal fluid was 41.4% (95%CI:35.0%-48.0%) at 1 year, and 47.4% (95%CI:38.5%-56.5%) at 2 years. The pooled median time-to-first fluid-resolution was 10.2 weeks (95%CI:7.66-14.59 weeks). Cure modelling suggests that 17.6% (95%CI: 11.9%-25.3%) of patients may never achieve a fluid-free finding in the long run despite prolonged treatment. Eyes with SRF had significantly higher BCVA compared to eyes without SRF at 12m (WMD 2.39 letters; 95%CI, 0.27-4.52; p<0.05). Eyes with IRF had significantly poorer BCVA compared to eyes without IRF at 12m (WMD -5.38 letters; 95% CI, -8.65 - -2.11; p<0.05). At long follow-up (>60m), eyes with SRF had significantly higher BCVA compared to eyes without SRF (WMD 7.69 letters; 95%CI, 2.79-12.59; p<0.05). Notwithstanding the heterogeneity in studies included, our analysis estimates that nearly half of all treated patients have persistent retinal fluid after initiating treatment and a substantial 18% of patients may never attain complete fluid resolution. We confirm that SRF is associated with better visual outcomes, while IRF is associated with worse visual outcomes.

Association between glymphatic system function and cognitive impairment in elderly patients with late-onset epilepsy.

Recent studies have shown that late-onset epilepsy (LOE) is accompanied with cognitive decline and increased risk of dementia, particularly Alzheimer's disease (AD). However, the pathophysiological mechanism underlying the cognitive decline in LOE remains unclear. The aim of current study was to evaluate the relationship between glymphatic system (GS) function and cognitive decline in LOE patients using the diffusion tensor imaging (DTI) analysis along the perivascular space (DTI-ALPS). Medical records and neuro-imaging data were obtained from 21 LOE patients with cognitive decline, 14 LOE patients without cognitive decline, and 20 age- and sex-matched healthy controls (HCs). Plasma biomarkers including Aβ42 and Aβ40 were examined using single-molecule array (Simoa) assays. The DTI-ALPS parameter was calculated and correlated with the clinical characteristics of LOE, including age, seizure frequency, duration of epilepsy, Mini-Mental State Examination (MMSE), and Aβ42/40. Regression models were used to evaluate the influencing factors of DTI-ALPS index. LOE patients exhibited a decreased ALPS index and Aβ42/40 compared with the HCs. Post-hoc analysis indicated that the DTI-ALPS index and Aβ42/40 in LOE patients with cognitive decline was significantly lower in relative to LOE patients without cognitive decline and HCs. Spearman correlations showed a negative correlation between DTI-ALPS index and age, seizure frequency and disease duration while a positive correlations between the DTI-ALPS index and Aβ42/40 and MMSE scores in LOE patients. Linear regression analysis suggested that the DTI-ALPS index was independently related to age, Aβ42/40 and MMSE score after correcting for gender, education, and vascular risk factors. Our findings using DTI-ALPS method found a positive correlation between cognitive decline and GS dysfunction in LOE patients, and may indicate a potential internal link between age-related LOEU and dementia formation. Therefore, the DTI-ALPS index may serve as a potential imaging marker for diagnosing and monitoring the GS function in LOE patients.

Application of stem cells alone and in combination with low-level laser therapy for sciatic nerve repair in rats

This study evaluated the efficacy of tubular constructs containing stem cells and Type I collagen, both independently and in conjunction with low-level laser therapy (LLLT), in repairing the sciatic nerve in a rat model. In this animal study, the right sciatic nerve of 30 male Wistar rats, each weighing 250–300 g, was surgically excised to a length of 8 mm. The rats were then randomly allocated to three groups (n = 10 per group). In Group 1, the excised nerve segment was utilized as an autograft and sutured at the defect site. In Group 2, a tubular construct containing stem cells and Type I collagen was used to bridge the proximal and distal ends of the nerve. Group 3 received the same intervention as group 2, supplemented with 5 weeks of LLLT. After 5 and 12 weeks, rats underwent histological, behavioral, and electrophysiological assessments. Data were statistically analyzed using analysis of variance (ANOVA), Bonferroni post-hoc test, and Kruskal–Wallis test. At both 5 and 12 weeks, axonal count and nerve repair scores showed no significant differences among the three groups (P > 0.05). Notably, the Sciatic Functional Index (SFI) was the most favorable (lowest) in the autograft group, whereas the stem cell-only group exhibited the least favorable (highest) SFI at 5 weeks (P < 0.001). Additionally, distal latency was highest in the stem cell group and lowest in the stem cell combined with LLLT group at 5 weeks (P < 0.001). A significant difference was observed between the autograft and stem cell plus LLLT groups (P < 0.05). In conclusion, the application of stem cell-laden tubular constructs in conjunction with LLLT demonstrated efficacy for sciatic nerve repair in rats.

Cost-effectiveness of an additional hysterectomy after initially conservative treatment for cervical adenocarcinoma in situ.

Several European and American guidelines recommend to perform an additional hysterectomy in patients with cervical adenocarcinoma in situ (AIS), who initially received conservative treatment and who completed childbearing during follow-up. This study aimed to evaluate cost-effectiveness of performing an additional hysterectomy in comparison to expectative management. This post-hoc analysis was based on a retrospective cohort of patients diagnosed with AIS, who were conservatively treated by a radical (i.e., negative surgical margins) large loop excision of the transformation zone (LLETZ) or cold-knife conisation (CKC) in the Netherlands between 1990 and 2021. Based on these data, we estimated and compared the harms, benefits, and costs in 1000 simulated patients, both with and without an additional hysterectomy five years after conservative treatment for AIS. In the sensitivity analyses, we varied the timing of the additional hysterectomy, the risk of recurrent high-grade cervical dysplasia and cervical cancer risk after AIS treatment, and the utility loss for hysterectomy. Less than 2% of the patients who did not receive an additional hysterectomy after AIS developed cervical cancer. When an additional hysterectomy was performed, no quality adjusted life-years (QALYs) were gained and costs were 863% higher (€6203,485 versus €644,238). Only when assuming no utility loss for a hysterectomy, QALYs were gained resulting in a cost-effectiveness ratio of €144,273, which is far above the cost-effectiveness threshold of €20,000. It is not cost-effective to perform an additional hysterectomy after completion of childbearing in patients who were primarily treated by a radical LLETZ or CKC.

Comparison of Clazosentan and Nimodipine on Vasospasm and Vasospasm-Related Outcomes after Aneurysmal Subarachnoid Hemorrhage : A Post-hoc Propensity Score-Matched Analysis of Six Randomized Clinical Trials.

Clazosentan is a recently approved endothelin receptor antagonist indicated for the prevention of vasospasm and related complications following aneurysmal subarachnoid hemorrhage (aSAH). To date, no direct, head-to-head comparison between clazosentan and nimodipine has been conducted. In this study, we indirectly assessed the efficacy and safety of these two drugs in preventing vasospasm and its associated outcomes after aSAH. Participants from six randomized clinical trials of clazosentan were reclassified into three subgroups based on their concomitant use of oral nimodipine: (1) a clazosentan subgroup (without nimodipine), (2) a nimodipine subgroup (without clazosentan), and (3) a placebo subgroup (receiving neither clazosentan nor nimodipine). Data from participants who received the approved dose of clazosentan 10 mg/h was analyzed. To account for heterogeneities among the analyzed studies, we performed within-study comparisons of subgroups and pooled data from the same subgroup. To further balance the three groups, we conducted a propensity score-matching and compared the outcomes among subgroups. The outcomes measured were angiographic vasospasm within 14 days after aSAH and vasospasm-related morbidity and all-cause mortality (MM) within 6 weeks, defined as death, vasospasm-related new cerebral infarcts, delayed ischemic neurological deficits, or initiation of rescue therapy. Incidence and relative risk reduction (RRR) were analyzed across subgroups, and overall safety was reviewed. The pooled data from within-study comparisons demonstrated that clazosentan significantly reduced the risk of vasospasm (RRR 0.48 [95 % CI: 0.35, 0.58]) and MM (RRR 0.47 [95 % CI: 0.30, 0.60]) compared to placebo, whereas nimodipine did not. In the propensity score-matched analysis, clazosentan demonstrated a significant risk reduction in outcomes when compared to nimodipine (RRR 0.63 [95% CI: 0.46, 0.75] for vasospasm; RRR 0.29 [95% CI: 0.04, 0.48] for MM) and placebo (RRR 0.59 [95% CI: 0.40, 0.72] for vasospasm; RRR 0.41 [95% CI: 0.21, 0.56] for MM).The overall safety results were comparable across the three subgroups and consistent with the expected range for endothelin receptor antagonists. Clazosentan at 10 mg/h significantly reduced the incidence of cerebral vasospasm and MM following aSAH, compared to both placebo and nimodipine. Further clinical studies are warranted to compare the efficacy of clazosentan and nimodipine to optimize treatment strategies for aSAH.

Preparing physiotherapists for the future: the development and evaluation of an innovative curriculum

BackgroundEducational innovation in health professional education is needed to keep up with rapidly changing healthcare systems and societal needs. This study evaluates the implementation of PACE, an innovative curriculum designed by the physiotherapy department of the HAN University of Applied Sciences in The Netherlands. The PACE concept features an integrated approach to learning and assessment based on pre-set learning outcomes, personalized learning goals, flexible learning routes, and programmatic assessment. PACE distinguishes itself from traditional education because of the flexible learning routes, vertical organization in learning communities, absence of pre-defined learning activities and class schedules, and a culture of continuous learning and development. PACE is based on three guiding principles: 1) flexible and varied, 2) self-directed and collaborative, 3) future-oriented. PACE was implemented in 2021 for first-year students. This study evaluates the implementation to inform future curriculum development.MethodsA sequential explanatory mixed methods design was used to evaluate the implementation of PACE using a questionnaire, focus groups, in-depth interviews, and a national progress test allowing for benchmarking results. Participants were undergraduate physiotherapy students of cohort 2021–2022, the first group who experienced PACE and teachers involved with this cohort. Questionnaire data were analyzed using descriptive statistics. To compare mean total scores of the national progress test between four different universities a one-way ANOVA was conducted including a post-hoc analysis. Reflexive thematic analysis guidelines were applied to analyze the interview data.ResultsIn total 82 first year students (44,6%) of cohort 2021–2022 and 36 teachers (60%) completed the questionnaire. Results show that the guiding principles were implemented as intended. Results of the national progress test on knowledge and clinical reasoning showed that students of the HAN University performed well compared to other universities. Thematic analysis of interviews and focus groups resulted in three themes and nine subthemes: 1) navigating a personalized curriculum, 2) caring and sharing, and 3) shaping professional identity. PACE contributed positively to students' intrinsic motivation, learning joy, identity development, and life-long learning skills. Areas for improvement were self-directed learning support, and teaching strategies to prompt deep learning.ConclusionThe evaluation showed that the guiding principles of PACE were implemented as intended and that the innovation positively contributed to student learning,

Mild acute biliary pancreatitis: still a surgical disease. A post-hoc analysis of the MANCTRA-1 international study

BackgroundThe current standard of care for mild acute biliary pancreatitis (MABP) involves early laparoscopic cholecystectomy (ELC) to reduce the risk of recurrence. The MANCTRA-1 project revealed a knowledge-to-action gap and higher recurrence rates in patients admitted to medical wards, attributable to fewer ELCs being performed. The project estimated a 35% to 70% probability of narrowing this gap by 2025. This study evaluates the safety of suboptimal ELC implementation and identifies risk factors for recurrent acute biliary pancreatitis (RAP) in patients not undergoing ELC after an MABP episode.MethodsWe conducted a post-hoc analysis of the MANCTRA-1 registry, including MABP patients who did not undergo ELC during the index hospitalization, excluding those with related complications. The primary outcome was the 30-day hospital readmission rate due to RAP. We performed multivariable logistic regression to find risk factors associated with the primary outcome.ResultsBetween January 2019 and December 2020, 1920, MABP patients from 150 centers were included in the study. The 30-day readmission rate due to RAP was 6%. Multivariable logistic regression found the admission to a medical ward (internal medicine or gastroenterology) (OR = 1.95, p = 0.001) and a positive COVID-19 test (OR = 3.08, p = 0.029) as independent risk factors for RAP.ConclusionOur analysis offers valuable insights into the management of MABP, particularly in centers where ELC cannot be fully implemented due to logistical and clinical constraints, worsened by the COVID-19 pandemic. Regardless of the admitting ward, prompt access to surgical care is crucial in reducing the risk of early recurrence, highlighting the need to implement surgical consultation pathways within MABP care bundles.