Follow-up Points Research Articles

Retinal phakomatosis and Von Hippel-Lindau peripheral capillary hemangioblastoma: proposal for staged surgery.

Retinal capillary hemangioblastoma (RCH) is present in about half of the carriers of the VHL (von Hippel-Lindau) gene mutation and can lead to the evolution of blindness. Herewith is a proposal for surgical intraretinal feeder vessel ligature to induce ischemia the phakoma and to resolve the exudative secondary retinal detachment, with satisfying results at the 6 months follow-up end point. The patient underwent a chandelier-assisted 23 G pars plana vitrectomy with valved trocars. A bimanual transretinal ligature of the hemangioblastoma's feeder vessel was performed, followed by localized endolaser to ablate the surrounding retina and capillaries, and a Polydimethylsiloxane 1000 (PDMS 1000) final tamponade. After 3 months, exchange PDMS/air/balanced salt solution (BSS), phacoemulsification, and in-the-bag intraocular lens (IOL) implantation were performed. At sixth month, fundus fluorescein angiography (FFA) showed a significant reduction of blood flow in the phakoma. Final best-corrected visual acuity (BCVA) was 6/6 (9 lines gain obtained compared to the baseline time). This surgical technique seems to be effective and promising for the treatment of VHL retinal capillary hemangioblastomas and their related retinal complications.

Weight change following diagnosis with psychosis: a retrospective cohort study in Greater Manchester, UK

IntroductionWeight gain in the months/years after diagnosis/treatment of severe enduring mental illness (SMI) is a major predictor of future diabetes, dysmetabolic profile and increased risk of cardiometabolic diseases. There is limited data on the longer-term profile of weight change in people with a history of SMI and how this may differ between individuals. We here report a retrospective study on weight change over the 5 years following an SMI diagnosis in Greater Manchester UK, an ethnically and culturally diverse community, with particular focus on comparing non-affective psychosis (NAP) vs affective psychosis (AP) diagnoses.MethodsWe undertook an anonymised search in the Greater Manchester Care Record (GMCR). We reviewed the health records of anyone who had been diagnosed for the first time with first episode psychosis, schizophrenia, schizoaffective disorder, delusional disorder (non-affective psychosis = NAP) or affective psychosis (AP). We analysed body mass index (BMI) change in the 5-year period following the first prescription of antipsychotic medication. All individuals had taken an antipsychotic agent for at least 3 months. The 5-year follow-up point was anywhere between 2003 and 2023.ResultsWe identified 9125 people with the diagnoses above. NAP (n = 5618; 37.3% female) mean age 49.9 years; AP (n = 4131; 60.5% female) mean age 48.7 years. 27.0% of NAP were of non-White ethnicity vs 17.8% of AP individuals. A higher proportion of people diagnosed with NAP were in the highest quintile of social disadvantage 52.4% vs 39.5% for AP. There were no significant differences in baseline BMI profile. In a subsample with HbA1c data (n = 2103), mean HbA1c was higher in NAP at baseline (40.4 mmol/mol in NAP vs 36.7 mmol/mol for AP). At 5-year follow-up, there was similarity in both the overall % of individuals in the obese ≥ 30 kg/m2 category (39.8% NAP vs 39.7% AP), and % progressing from a normal healthy BMI transitioned to obese/overweight BMI (53.6% of NAP vs 55.6% with AP). 43.7% of those NAP with normal BMI remained at a healthy BMI vs 42.7% with AP. At 5-year follow-up for NAP, 83.1% of those with BMI ≥ 30 kg/m2 stayed in this category vs 81.5% of AP.ConclusionThe results of this real-world longitudinal cohort study suggest that the changes in BMI with treatment of non-affective psychosis vs bipolar disorder are not significantly different, while 43% maintain a healthy weight in the first 5 years following antipsychotic prescription.

The clinical outcome of emergency superficial temporal artery-to-middle cerebral artery bypass in acute ischemic stroke with large vessel occlusion

The role of superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass in acute ischemic stroke (AIS) is contentious, with no evidence in patients with AIS and large vessel occlusion (AIS-LVO). We conducted a cohort study to assess emergency STA-MCA outcomes in AIS-LVO and a meta-analysis to evaluate STA-MCA outcomes in early AIS treatment. From January 2018 to March 2021, we consecutively recruited newly diagnosed AIS-LVO patients, dividing them into STA-MCA and non-STA-MCA groups. To evaluate the neurological status and outcomes, we employed the National Institutes of Health Stroke Scale (NIHSS) during the acute phase and the modified Rankin Scale (mRS) during the follow-up period. Additionally, we conducted a meta-analysis encompassing all available clinical studies to assess the impact of STA-MCA on patients with AIS. In the cohort study (56 patients), we observed more significant neurological improvement in the STA-MCA group at two weeks (p = 0.030). However, there was no difference in the clinical outcomes between the two groups. Multivariable logistic regression identified the NIHSS at two weeks (OR: 0.840; 95% CI: 0.754–0.936, p = 0.002) as the most critical predictor of a good outcome. Our meta-analysis of seven studies indicated a 67% rate for achieving a good outcome (mRS < 3) at follow-up points (95% CI: 57%–77%, I2 = 44.1%). In summary, while the meta-analysis suggested the potential role of STA-MCA bypass in mild to moderate AIS, our single-center cohort study indicated that STA-MCA bypass does not seem to improve the prognosis of patients who suffer from AIS-LVO.

Effects of internal limiting membrane peeling versus non-internal limiting membrane peeling during vitrectomy for diabetic tractional retinal detachment on postoperative macular thickness, foveal contour, and formation of epiretinal membranes

Aim To investigate the impact of internal limiting membrane (ILM) peeling during vitrectomy for diabetic tractional retinal detachment (TRD) on postoperative central macular thickness, foveal contour, and creation or reformation of epiretinal membranes. Methods In a randomized trial, patients aged 40–65 years old with TRD were recruited from the outpatient clinic in Suez Canal University Hospital from August 2020 to February 2022. Patients were randomized into two groups: group 1 did vitrectomy with ILM peeling, while group 2 did vitrectomy without ILM peeling. At 1, 3, and 6 months after surgery, optical coherence tomography (OCT) was carried out to investigate the central macular thickness (CMT), foveal contour, and epiretinal membrane’s presence. For categorical variables, the Chi-squared test or Fisher’s exact test was performed, while the Student’s t-test was used to assess differences in continuous data. Results Thirty-two patients (16 in each group) completed the required follow-up. There was no significant difference between both groups concerning the affected eye (P=1.00). There was no statistically significant difference regarding the CMT recorded via optical coherence tomography at any point of follow-up in the two groups (P=0.289). Also, there was no statistically significant difference regarding the presence of foveal depression at any point of follow-up in the two groups (P=0.680). On the other hand, the percentage of patients who showed no presence of epiretinal membranes in the ILM peeling group was statistically significant when compared with the non-ILM peeling group (P&lt;0.001). Conclusions ILM peeling decreases the incidence of epiretinal membrane proliferation following diabetic vitrectomy.

Naturalistic Evaluation of HeadGear: A Smartphone App to Reduce Depressive Symptoms in Workers

Mobile health (mHealth) apps have the potential to expand access to evidence-based interventions for mental health conditions, including depression. HeadGear was developed to prevent depression and improve well-being among the working population and was associated with significant positive effects in an efficacy trial. This study presents the results from a naturalistic trial intended to evaluate real-world usage of the app. We examined the naturalistic use of HeadGear between March 2019 and March 2022, using app analytic data, in-app event data, and surveys assessing depressive symptoms, well-being, and work performance repeated at 30-day intervals over 5-month app usage. During the observation period, HeadGear was widely disseminated to the public, and downloaded 26,455 times. Of those who downloaded the app, 12,995 completed baseline. The mean age of users was 38.23 (SD = 12.39) and 60% were women. Approximately one in four met criteria for probable depression at baseline. Depressive symptoms showed consistent improvement at all time points (Cohen’s d ranging from 0.24 at 1 month to 0.13 at 5 months). A similar pattern emerged for well-being. Work performance showed improvement to 2-month follow-up only. The strongest change was found for those with greater symptom severity at baseline, and those with high app engagement. Attrition at follow-up points was high. Findings regarding the real-world use of HeadGear are promising and highlight the use of such apps among those with higher symptom severity (despite the intended use of the app as a prevention tool). Further work is required to tailor mHealth apps to reach their full potential through an enhanced understanding of the utility of individual features for effectiveness and engagement.

Anthropometric and laboratory parameter alterations following bimaxillary orthognathic surgery

The aim of this study was to investigate the impact of bimaxillary orthognathic surgery on patients’ anthropometric measures and laboratory parameters. This study was conducted on patients who underwent bimaxillary orthognathic surgery. Anthropometric measurements were collected before surgery (T0) and at intervals of one week (T1), two weeks (T2), one month (T3), and three months (T4) postoperatively, and laboratory parameters at T0 and T4. Data analysis included repeated-measures ANOVA for assessing weight changes, body mass index (BMI) and fat percentage changes, the Friedman test for muscle mass changes, and independent t tests to understand gender-based differences. Significant reductions were observed in weight (mean differences ranging from 2.26 kg to 3.84 kg, 95.00% CI: 1.29 to 4.62, p < 0.01) and BMI (mean differences ranging from 0.76 to 1.32, 95.00% CI: 0.38 to 1.58, p < 0.01) postoperatively at all follow-up points. Fat percentage changes were significant between T0 – T3 (MD = 1.17, 95.00% CI: 0.26 to 2.08, p < 0.05) and T0 - T4 (MD = 1.28, 95.00% CI: 0.14 to 2.43, p < 0.05). Changes in muscle mass were significant until T3 (MD ranging from 71.00 to 107.0, p < 0.01). Also, haemoglobin levels were significantly higher at T0 than T4 (MD = 0.35, 95% CI: 0 to 0.7). These changes showed no significant gender-based differences (p > 0.05). Our study showed that orthognathic surgery prompts temporary changes in body weight, Body Mass Index, and haemoglobin levels. Future research should explore interventions to mitigate these changes and enhance postoperative recovery.

Lanadelumab demonstrates high efficacy in reducing the frequency of angioedema attacks in patients with severe HAE in real-life settings

Introduction and objective: Evaluation of lanadelumab efficacy in preventing angioedema attacks in patients with severe hereditary angioedema due to C1-inhibitor deficiency in Poland and descriptive analysis of this group of patients. Materials and methods: Retrospective analysis of patients treated with lanadelumab in Poland. Data were acquired from the electronic database of the National Health Fund, compiled from 15 hereditary angioedema centres. Only patients with severe hereditary angioedema course (at least 12 severe – abdominal, pharyngeal or laryngeal – hereditary angioedema attacks per six months, requiring on-demand medications) initiated treatment. The patients received lanadelumab 300 mg every two weeks. The efficacy of the therapy was assessed after six months. Results: Lanadelumab was initiated in a total of 43 patients (group B). Twenty of them achieved the follow-up point after six months (group A). The mean age of the patients was 44 years. The majority (76.7%) were female and 79% had a family history of hereditary angioedema. Most patients (95.3%) had HAE-1 (absolute deficiency of C1-inhibitor). On average, within six months before treatment, group A patients experienced 19.7 (95% confidence interval, CI: 16.06–23.33) severe hereditary angioedema attacks. In the six months following treatment initiation, the number of attacks decreased to an average of 0.5 (95% CI: 0–1.0), with significant reductions in all types of hereditary angioedema attacks – abdominal (p &lt; 0.0001), pharyngeal (p &lt; 0.005), and laryngeal (p &lt; 0.05). Utilisation of on-demand medications dropped from an average of 23.5 (95% CI: 16.7–30.3) to 0.5 standard therapeutic dose (95% CI: 0–1.1). Conclusions: The study highlights the therapeutic potential of lanadelumab in managing hereditary angioedema, usually offering patients a complete resolution of severe hereditary angioedema attacks and release from dependence on rescue medication. Our results support the current paradigm shift in hereditary angioedema treatment.

Validation of schedules for optimal prostate-specific antigen monitoring after radical prostatectomy.

Early detection of biochemical recurrence (BCR) after radical prostatectomy (RP) is crucial for early treatment and improving survival outcomes. The optimal prostate-specific antigen (PSA) monitoring remains unclear, and several models have been proposed. We aimed to externally validate four models for optimal PSA monitoring after RP and propose modifications to improve them. We reviewed the clinicopathological data of 896 patients who underwent robot-assisted RP between 2009 and 2022. We examined all PSA values and estimated the PSA value for four monitoring schedules at each time point in the virtual follow-up. We defined the ideal PSA for BCR detection between 0.2 and 0.4 ng/mL. During the median follow-up of 21.4 months, 128 (14.3%) patients presented BCR. The original and modified Keio models, National Cancer Center Hospital model, and American Urological Association/American Society for Radiation Oncology model detected BCR in 14 (10.9%), three (2.3%), 12 (9.4%), and 11 (8.6%) patients with PSA >0.4 ng/mL. Most patients experienced BCR detected with PSA >0.4 ng/mL during the first year postoperative. The modification of interval within 6 months postoperative avoided BCR detection with PSA >0.4 ng/mL within the first year postoperative in 8/9 (88.9%), 1/2 (50.0%), 5/6 (83.3%), and 4/4 (100%) for the original and modified Keio models, National Cancer Center Hospital model, and American Urological Association/American Society for Radiation Oncology model, respectively. We validated four models for PSA monitoring after RP to detect BCR and suggested modifications to avoid detections out of the desired range of PSA. These modifications could help to establish an optimal PSA monitoring schedule after RP.

Efficacy and safety of 308-nm Excimer lamp combined with Tacrolimus 0.1% ointment vs Tacrolimus 0.1% ointment as monotherapy in treating children with limited vitiligo: a randomized controlled trial

Objective This study aims to assess the efficacy and safety of combining the 308-nm Excimer lamp with Tacrolimus 0.1% ointment, compared to Tacrolimus 0.1% ointment monotherapy, for treating pediatric vitiligo involving less than 10% of the body surface area. Methods Fifty pediatric patients with vitiligo were randomly assigned to two groups. Group A received Tacrolimus 0.1% ointment twice daily and Excimer light at 308-nm twice weekly, while Group B received Tacrolimus 0.1% ointment alone, administered twice daily. Repigmentation percentages were evaluated after 30, 90, and 180 days using the rule of nine. Results Group A exhibited a significant improvement in repigmentation, increasing from 10% after one month to 65% after six months. In contrast, Group B observed an increase from 10% to 30% over the same timeframe. The efficacy of the treatment was significantly higher in Group A at both the 3-month and 6-month follow-up points (p-value < .001). Moreover, Group A achieved notably higher repigmentation rates in the face, trunk, and lower limbs. Conclusion The combination of Tacrolimus and the 308-nm excimer lamp yielded superior repigmentation results compared to Tacrolimus monotherapy in pediatric vitiligo patients. This combined approach may offer an effective new treatment protocol for pediatric vitiligo.

Pacemaker, organ or walking stick? Pre-op association with and post-op subjective perception of a deep brain stimulation device

This study was conducted in a pre-post design with a survey of patients who had undergone deep brain stimulation (DBS) as treatment for a neurological movement disorder. The aim of the study was to compare patients' expectations and beliefs before a DBS intervention with patients' subjective experience of this intervention. The longitudinal study of patients (n=132) with an indication for DBS therapy was based on a written survey at the time points of preoperative screening (pre-op) and one-year follow-up (post-op). Preoperatively, a clear majority of respondents believed DSB to be similar to a pacemaker intervention, but one year after the intervention less than one third did so, as they compared DBS to using a walking stick or glasses. The experience of DBS in the patient's own body seems to be comparable by means of individually different associations, whereby the comparison with non-invasive aids predominates postoperatively. The discussion of these descriptions in the educational interview can contribute to a realistic horizon of patients' expectations before DBS.

Effect of intelligent hypertension management system on blood pressure: protocol for a randomised controlled multicentre trial

IntroductionHypertension is one of the most serious global health problems, and its prevention and treatment mainly rely on lifestyle intervention and medication. However, the current situation of hypertension control in...

Genetic Variability in VEGFA Gene Influences the Effectiveness of Tennis Elbow Therapy with PRP: A Two-Year Prospective Cohort Study.

Vascular endothelial growth factor (VEGF) is implicated in both the etiology of tendinopathy and its healing process. Polymorphic variants of the VEGFA gene exhibit varied expression, which can influence the phenotype and treatment effectiveness. The aim of the present study was to analyze the influence of VEGFA gene variants on the effectiveness of tennis elbow therapy using platelet-rich plasma (PRP), measured through common patient-reported outcome measures (PROMs). A cohort of 107 patients (132 elbows) with tennis elbow was prospectively analyzed, with a two-year follow-up (at weeks 2, 4, 8, 12, 24, 52, and 104 after PRP injection). PROMs values were compared between variants of five VEGFA gene polymorphisms (rs699947 A>C, rs2010963 C>G, rs1413711 C>T, rs3024998 C>T and rs3025021 C>T) at each follow-up point. Patients with genotypes GG (rs2010963) and CC (rs3024998) had better response to PRP therapy (significantly fewer symptoms and limitations in the upper limb compared to carriers of alleles C and T, respectively). Polymorphisms influenced also selected hematological parameters. VEGFA gene polymorphisms (rs2010963 and rs3024998) appear to be significant treatment modifiers for tendinopathy, and their genotyping may serve as an effective tool for personalized patient selection for PRP therapy.

Improved range of motion after manipulation under anesthesia versus physiotherapy for stage two frozen shoulder: a randomized controlled trial

BackgroundFrozen shoulder (FS) is a common cause of shoulder pain and stiffness. Conservative treatment is sufficient for the majority of patients with recovery of shoulder function at long term. Manipulation under anesthesia (MUA) is known as a well-established treatment option if conservative treatment fails. It is unknown whether MUA does indeed shorten the duration of symptoms or leads to a superior outcome compared to conservative treatment. The objective of the current trial is to evaluate the effectiveness of MUA followed by a physiotherapy program (PT) compared to a PT program alone in patients with stage two FS. MethodsA prospective, single center randomized controlled trial was performed. Patients between 18 and 70 years old with a stage two FS were deemed eligible if an initial course of conservative treatment, consisting of physiotherapy and an intra-articular corticosteroid infiltration was considered unsatisfactory. Patients were randomized and data was collected with an online data management platform (CASTOR). MUA was performed by a single surgeon under interscalene block and an intensive physiotherapy treatment protocol was started within 4 hours after MUA. In the PT group patients were referred to instructed physiotherapist, and treatment was guided by tissue irritability. The primary outcome was the SPADI score. Secondary outcomes were pain, range of motion, OSS, quality of life and ability to work. ResultsIn total, 82 patients were included, 42 in the PT group and 40 in the MUA group. There was a significant improvement in SPADI, OSS, pain, range of motion and quality of life in both groups at 1 year follow-up. SPADI scores at three months were significantly improved in favor of MUA. MUA showed a significant bigger increase in anteflexion and abduction compared to PT at all points of follow-up. No significant differences between both groups were found for all other parameters. No fractures, dislocations or brachial plexus injuries occurred in this trial. ConclusionMUA in stage 2 FS can be considered safe and results in a faster recovery of range of motion and improved functional outcome, measured with SPADI scores, compared to PT alone at short term. After 1 year, except for slightly better range of motion scores for MUA, the result of MUA is equal to PT.

Integrative group psychotherapy for patients with somatic symptom disorder: A randomized controlled trial

The study aimed to determine whether specific integrative group psychotherapy (IGPT), based on CBT, combined with techniques of psychodynamic therapy and mindful body and emotional awareness is more effective than non-specific supportive group psychotherapy (SGPT) and treatment as usual (TAU) alone. A total of 120 SSD patients were randomly assigned to IGPT, SGPT or TAU groups. Both IGPT and SGPT showed significantly lower SSD-12 scores at the 4, 8, and 12-week follow-ups compared to TAU. No significant differences were observed between IGPT and SGPT at any follow-up point. These findings highlight the potential benefits of group psychotherapy in SSD treatment.

A Multi-Institutional Safety and Feasibility Study Exploring the Use of Hydrogel to Create Spatial Separation between the Pancreas and Duodenum in Patients with Pancreatic Cancer

IntroductionThe administration of dose-escalated radiation for pancreatic adenocarcinoma remains challenging due to the proximity of dose-limiting stomach and bowel, particularly the duodenum for pancreatic head tumors. We explore whether endoscopic injection of a temporary, absorbable hydrogel into the pancreatico-duodenal (PD) groove is safe and feasible for the purpose of increasing spatial separation between pancreatic head tumors and the duodenum. MethodsSix patients with localized pancreatic adenocarcinoma underwent endoscopic injection of hydrogel into the PD groove. Safety was assessed based on the incidence of procedure-related adverse events resulting in a delay of radiation therapy initiation. Feasibility was defined as the ability to create spatial separation between the pancreas and duodenum, as assessed on simulation CT. ResultsAll six patients were able to undergo endoscopic injection of hydrogel into the PD groove. No device-related events were experienced at any point in follow-up. Presence of hydrogel in the PD groove was apparent on simulation CT in all six patients. Mean space created by the hydrogel was 7.7 mm +/- 2.4 mm. In three patients who underwent Whipple resection, presence of hydrogel in the PD groove was pathologically confirmed with no evidence of damage to the duodenum. ConclusionsEndoscopic injection of hydrogel into the PD groove is safe and feasible. Characterization of the dosimetric benefit that this technique may offer in the setting of dose-escalated radiation should also be pursued, as should the ability of such dosimetric benefit to translate into clinically improved tumor control.

Human umbilical cord-derived mesenchymal stem cells for the treatment of decompensated cirrhosis (MSC-DLC-1): a dose-escalation, phase I trial protocol

IntroductionThere are limited therapeutic options to efficiently treat patients with decompensated liver cirrhosis. This trial aims to explore the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs)...

Neutrophil PNH Type II Cells Are Associated with Thrombosis and Bone Marrow Failure without Hemolysis: Evidence from Analysis of the 5-Year French Nation-Wide Multicenter Observational Study

Introduction Flow cytometry (FCM) is the gold standard test to diagnose a PNH clone, type II and III cells being defined by a partial or a complete deficiency, respectively, in GPI-linked proteins. The relevance of classifying type II and type III PNH cells on WBC, unlike their counterparts among red blood cells, remains unknown. Nevertheless, exploring this distinction could hold potential significance for clinical decision-making and patient management. We aimed to assess the distribution of type II and type III cells on WBC in patients displaying a major PNH clone (defined as GPI-deficient neutrophils above 50%) and to investigate their association to clinical presentations. Methods The 5-year French nation-wide multicenter observatory (2016-2021) gathered all patients with a diagnosed PNH clone or GPI-deficient cells ≥0.01% on neutrophils, detected in France by FCM. Only patients with a major PNH clone &amp;gt;50% were included in this study. For each patient, the baseline assessment was considered as the initial PNH clone detection, which facilitated long-term follow-up. A referent cytometrist at each center provided clinical and biological information as well as FCM raw data files. This study was approved by the national research ethics board. Fisher, chi-square and ANOVA tests were performed to compare the median values and frequencies. Results As of February 28 th, 2021, 41 participating FCM laboratories across France had enrolled 637 patients with a PNH clone or GPI-deficient cells ≥ 0.01%. Among 109 patients displaying a major PNH clone (i.e., ≥ 50%) on neutrophils, 100 patients with distribution of type II and type III cells on neutrophils were validated by the two principal investigators(Figure 1). We performed an AUROC test based on the presence or absence of hemolysis and determined a 3.9% threshold of type II neutrophils. This enabled the distinction of two groups at baseline: 14 patients with high type II cells (7.76%; IQR, 5.63-13.63) and 86 patients with low type II cells (0.05%; IQR, 0.00-0.71; p&amp;lt;0.0001). Besides, type II monocytes were higher in the “high type II” group (6.62%; IQR, 5.30-22.45) compared to the “low type II” group (0.00%; IQR, 0.00-0.71; p&amp;lt;0.0001). However, the total clone size was similar for both groups on WBC (median size on neutrophils: 91.51% (IQR, 80.47-96.90) vs 90.85% (IQR, 79.55-98.20); p=0.79, on monocytes: 89.88% (IQR, 80.27-92.24) vs 91.24% (IQR, 80.59-96.73); p=0.98). The patient median age at diagnosis was 51 years [24-79] for “high type II” group and 40 years [18-85] for “low type II” group and a M/F sex ratio of 1.0 vs 1.3. Diagnoses were confirmed between 2004 and 2021 with clinical information available in 96% of cases. Hemolysis was more frequent in “low type II” group: 96.0% (72/75) compared to “high type II” group: 50.0% (7/14) (p&amp;lt;0.0001) for the 89 patients with available data on hemolysis status, with a trend to more elevated LDH (1289 UI/L; IQR, 553-1931 vs 735 UI/L, IQR: 459-1037; p=0,052) and a reduced clone size on red blood cells (3.26%; IQR, 1.20-32.46 vs 30.48%; IQR, 16.47-45.02; p=0.097). Interestingly, thrombosis appears to be more frequent in “high type II” group: 35.7% (5/14) vs 7.3% (6/82) in the “low type II” group (p&amp;lt;0.01). Bone marrow failure (BMF) without hemolysis (aplastic anemia or MDS) appears to be also more frequent in “high type II” group: 42.9% (6/14) vs 2.7% (=2/75) in the “low type II group” (p=0.0001). All complete blood count parameters, including hemoglobin levels, were not significantly different between the 2 groups. Among the 62 out of 100 patients who displayed at least one follow-up point, 57 have been treated with anti-C5. Long-term follow-up up to 10.5 years showed that 22 patients displayed an increase in the total clone size (mean: +18.3%, Figure 2), 27 remained stable (+0.3%) and 8 decreased (-29.6%). Interestingly, we did not observe any major modification of type II neutrophil percentages regardless of the total clone size evolution (+0.2%; -0.1%, +0.2%). Conclusion This multicenter study based on robust FCM analysis showed for the first time the value of accurate quantification of neutrophil PNH type II cells as patients with high type II cells above 3.9% displayed less hemolysis, more thrombosis and more BMF without hemolysis, which suggests a closer follow-up may be warranted for these patients.

GO-8: Stable Expression of Factor VIII over 5 Years Following Adeno-Associated Gene Transfer in Subjects with Hemophilia a Using a Novel Human Factor VIII Variant

Background: GO-8 (ClinicalTrials.gov: NCT03001830) is a study of liver-directed adeno-associated virus (AAV) gene therapy for haemophilia A (HA) that uses a factor VIII (FVIII) variant containing a 17 amino-acid peptide comprising six N-linked glycosylation motifs from the human FVIII B-domain (AAV-HLP-hFVIII-V3). In preclinical studies, AAV-HLP-hFVIII-V3 mediated a 3-fold higher FVIII expression when compared to an identical AAV construct encoding the hFVIII-SQ variant used in most HA gene therapy trials. Methods: In a multi-centre, open-label, non-randomised, phase I/II clinical trial, we assessed the safety and efficacy of escalating doses of AAV-HLP-hFVIII-V3 pseudotyped with an AAV8 capsid in adults with severe haemophilia A (FVIII activity ≤1%). All participants received prophylactic glucocorticoids, with or without tacrolimus, with the aim of reducing the risk of vector-related transaminase elevation. The primary endpoints were safety and efficacy. Efficacy was assessed by measuring FVIII activity (FVIII: C) using both chromogenic and one-stage clotting assays and factor consumption pre and post-gene therapy. Results: As of May 31 2023, 12 participants were enrolled sequentially into one of four vector doses: 6×1011 vector genomes (vg)/kg body weight (n=1), 2×1012 vg/kg (n=3), 4×1012 vg/kg (n=3), or 6×1012 vg/kg (n=5). All participants were on FVIII prophylaxis prior to gene therapy. The most common vector-related adverse event was an elevation in liver aminotransferase levels, which occurred in 10 of 12 participants. In 7 of the 8 participants treated at doses ≥4×1012 vg/kg, recurrent elevation in aminotransferase levels was observed during the first 12 months, often associated with tapering of immunosuppression. This resulted in a reduction in transgene expression from peak levels in all participants, with a complete loss of transgenic protein in one participant. Vector-related elevation in aminotransferase was not observed after the 12-month time point in long-term follow-up. Mean chromogenic FVIII: C levels at 12 months after gene therapy were 3 IU/dL in the 6×1011 vg/kg cohort, 13±9IU/dL (range: 2-19 IU/dl) in the 2×1012 vg/kg cohort, 8±1IU/dl in the 4×1012 vg/kg cohort (range: 7-9 IU/dl) and 22±34 IU/dl in the 6×1012 vg/kg cohort (range 1-82 IU/dl). Transgene expression was then stably maintained over a median follow-up of 3 years (range: 0.2-5 years) from the level achieved 1-year post-infusion, best illustrated by the data from the 2×1012 and 4×1012 vg/kg cohorts shown in Figure 1. FVIII: C was, on average 2-fold higher when measured using a one-stage clotting assay compared to the chromogenic method. Nine of the 12 participants remained off prophylaxis after gene therapy for the duration of the follow-up period. Baseline mean and median annualised factor VIII use was 4097 and 4657 IU/kg per year before gene therapy. Following gene therapy, the mean and median annualised factor VIII concentrate use reduced across all participants to 1186 and 61 IU/kg (One sample t-test p=0.0009), respectively. No FVIII inhibitors or thrombotic events were reported for the duration of the study. Conclusion: A single infusion of AAV-HLP-hFVIII-V3 resulted in stable FVIII expression over a follow-up period of up to 5 years in participants with severe haemophilia A. A high rate of liver aminotransferase elevation following gene transfer impacted transgene expression. However, 9 of the 12 participants were able to discontinue FVIII prophylaxis over the duration of the study, resulting in a significant reduction in FVIII concentrate usage.

Effects of Extracorporeal Shock Wave Therapy in Patients with Mild-to-Moderate Carpal Tunnel Syndrome: An Updated Systematic Review with Meta-Analysis

Background: Carpal tunnel syndrome (CTS) is the most common entrapment syndrome, primarily affecting women between the ages of 40 and 70, and conservative treatments are the first option for mild-to-moderate CTS. However, the comparisons between extracorporeal shock wave therapy (ESWT) and other non-surgical methods in the treatment of mild-to-moderate CTS remain controversial, and an updated systematic review is needed. Methods: An electronic search was performed, and all available articles until August 2023 were included in the analysis. The overall quality of evidence was assessed by the GRADE approach. Meta-analyses were conducted using Manager V.5.3.3. Pooled effect sizes were expressed as the weighted mean difference (WMD) with 95% confidence intervals (CIs). Results: A total of 19 RCTs were included. Low-level quality evidence showed that ESWT outperformed the control intervention in terms of functional improvements, pain relief, electrodiagnostic parameters, and cross-sectional area of the median nerve at any time point of follow-up. Compared to local corticosteroid injection (LCI), there were statistically better improvements in functional improvements, pain relief, and electrodiagnostic parameters at 3 and 6 months of follow-up. Conclusions: There is low-level quality evidence to show that both fESWT and rESWT are more clinically effective than controls in symptom relief, functional enhancement, and electrophysiologic parameters’ improvement for patients with mild-to-moderate CTS at any time point of follow-up. Compared with LCI, ESWT yielded similar short-term (&lt;1 month) but better medium- (1–6 months) and long-term (&gt;6 months) improvements in pain relief and functional recovery with fewer potential complications.

Natural history and impact of irritable bowel syndrome-type symptoms in inflammatory bowel disease during 12 months of longitudinal follow-up.

Little is known about the natural history and impact of irritable bowel syndrome (IBS)-type symptoms on psychological health and quality of life in inflammatory bowel disease (IBD). We aimed to address this in a 12-month longitudinal follow-up study of secondary care patients. We collected demographic, Rome III IBS-type symptom, psychological, and quality of life data, with questionnaires at 3-month intervals, over 12 months of follow-up in patients with IBD in clinical remission at baseline. We assessed the natural history of Rome III IBS-type symptoms over the 12 months of the study and compared psychological and quality of life data between those reporting Rome III IBS-type symptoms at each of the points of follow-up with those not reporting such symptoms. Among 206 patients with IBD in clinical remission at baseline (104 [50.5%] women, mean age 56.9 years [range 18-83 years], 79 [38.3%] Crohn's disease), 33 (16.0%) reported Rome III IBS-type symptoms at baseline and 72 (35.0%) reported Rome III IBS-type symptoms at one or more time points. Among the 33 patients with Rome III IBS-type symptoms at baseline, symptoms resolved in 6 (18.2%) patients, were present throughout in 6 (18.2%) patients, and fluctuated in the remaining 21 (63.6%) patients. Among the 39 patients with new onset of Rome III IBS-type symptoms after baseline, 24 (65.1%) had symptoms at one point in time only, 10 (25.6%) at two points, four (10.3%) at three points, and one (2.6%) at four points. At each point in time, reporting IBS-type symptoms was associated with significantly higher anxiety, depression, or somatoform symptom-reporting scores, and/or lower quality of life scores. In this 12-month follow-up study, one-third of patients with IBD reported presence of Rome III IBS-type symptoms at any point in time. Reporting such symptoms was associated with significant impacts on psychological health and/or quality of life.