12-month Time Points Research Articles

Pilsner Modification of Mesh Sacrohysterocolpopexy(PiMMS): An Initial Report on Safety and Efficacy.

It is reported that up to 60% of women would prefer to spare their uterus during pelvic organ prolapse (POP) repair surgery. A reliable hysteropexy technique is therefore crucial. We aimed to describe the safety profile and initial core patient-reported and clinical outcomes of the Pilsner modification of laparoscopic mesh sacrohysterocolpopexy (PiMMS) in comparison with the laparoscopic sacrohysterocolpopexy technique (standard laparoscopic sacrohysterocolpopexy [sLSH]) previously used in our unit. This was a retrospective cohort study conducted in a single tertiary referral urogynecological center. All patients who underwent laparoscopic mesh sacrohysterocolpopexy between 1 January 2015, and 31 January 2022 were included in the study. Follow-up clinical, patient-reported, and imaging outcomes at the 12-month follow-up time point are presented. A total of 87 patients were included. Of these, 49 (56.3%) and 38 (43.7%) underwent sLSH and PiMMS respectively. Low numbers of perioperative complications were found in both groups with no mesh-related complications reported following PiMMS up to 12months postoperatively. There were no apical compartment failures in either group. There were 8 (17.0%) vs 1 (2.7%) anterior compartment failures (Ba ≤ -1) in the sLSH and PiMMS groups respectively (p = 0.07) at 12months. At the 1-year follow-up, 42 (89.4%) patients reported a Patient Global Impression of Improvement score of ≤ 2 in the sLSH groups compared with 35 (94.6%) patients following PiMMS. The PiMMS technique seems to have comparable safety profile and patient-reported outcomes with the sLSH technique. However, there is a trend toward reduced anterior compartment failures with this modification. The findings of this preliminary report need to be re-evaluated in a well-powered prospective study.

Predicting Postoperative Speech Perception and Audiometric Thresholds Using Intracochlear Electrocochleography in Cochlear Implant Recipients.

Electrocochleography (ECochG) appears to offer the most accurate prediction of post-cochlear implant hearing outcomes. This may be related to its capacity to interrogate the health of underlying cochlear tissue. The four major components of ECochG (cochlear microphonic [CM], summating potential [SP], compound action potential [CAP], and auditory nerve neurophonic [ANN]) are generated by different cochlear tissue components. Analyzing characteristics of these components can reveal the state of hair and neural cell in a cochlea. There is limited evidence on the characteristics of intracochlear (IC) ECochG recordings measured across the array postinsertion but compared with extracochlear recordings has better signal to noise ratio and spatial specificity. The present study aimed to examine the relationship between ECochG components recorded from an IC approach and postoperative speech perception or audiometric thresholds. In 113 human subjects, responses to 500 Hz tone bursts were recorded at 11 IC electrodes across a 22-electrode cochlear implant array immediately following insertion. Responses to condensation and rarefaction stimuli were then subtracted from one another to emphasize the CM and added to one another to emphasize the SP, ANN, and CAP. Maximum amplitudes and extracochlear electrode locations were recorded for each of these ECochG components. These were added stepwise to a multi-factor generalized additive model to develop a best-fit model predictive model for pure-tone audiometric thresholds (PTA) and speech perception scores (speech recognition threshold [SRT] and consonant-vowel-consonant phoneme [CVC-P]) at 3- and 12-month postoperative timepoints. This best-fit model was tested against a generalized additive model using clinical factors alone (preoperative score, age, and gender) as a null model proxy. ECochG-factor models were superior to clinical factor models in predicting postoperative PTA, CVC-P, and SRT outcomes at both timepoints. Clinical factor models explained a moderate amount of PTA variance ( r2 = 45.9% at 3-month, 31.8% at 12-month, both p < 0.001) and smaller variances of CVC-P and SRT ( r2 range = 6 to 13.7%, p = 0.008 to 0.113). Age was not a significant predictive factor. ECochG models explained more variance at the 12-month timepoint ( r2 for PTA = 52.9%, CVC-P = 39.6%, SRT = 36.4%) compared with the 3-month one timepoint ( r2 for PTA = 49.4%, CVC-P = 26.5%, SRT = 22.3%). The ECochG model was based on three factors: maximum SP deflection amplitude, and electrode position of CM and SP peaks. Adding neural (ANN and/or CAP) factors to the model did not improve variance explanation. Large negative SP deflection was associated with poorer outcomes and a large positive SP deflection with better postoperative outcomes. Mid-array peaks of SP and CM were both associated with poorer outcomes. Postinsertion IC-ECochG recordings across the array can explain a moderate amount of postoperative speech perception and audiometric thresholds. Maximum SP deflection and its location across the array appear to have a significant predictive value which may reflect the underlying state of cochlear health.

EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical end point for multiple myeloma

AbstractEstimating progression-free survival (PFS) and overall survival superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier end point surrogates that are predictive of long-term clinical benefit. Minimal residual disease (MRD)-negativity is a common intermediate end point that has shown prognostic value for clinical benefit in MM. This meta-analysis was based on the US Food and Drug Administration guidance for considerations for a meta-analysis of MRD as a clinical end point and evaluates MRD-negativity as an early end point reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD-negativity as an end point in patients with MM, with follow-up of ≥6 months following an a priori–defined time point of 12 ± 3 months after randomization. Eight newly diagnosed MM studies evaluating 4907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv, 0.67 (95% confidence interval [CI], 0.43-0.91) and R2copula 0.84 (0.64 to >0.99) at the 12-month time point. The individual-level association between 12-month MRD-negativity and PFS resulted in a global odds ratio (OR) of 4.02 (95% CI, 2.57-5.46). For relapse/refractory MM, there were 4 studies included, and the individual-level association between 12-month MRD-negativity and PFS resulted in a global OR of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical end point reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby, expedite the availability of new drugs to patients with MM.

Endoscopic full-thickness plication along with argon plasma coagulation for treatment of proton pump inhibitor dependent gastroesophageal reflux disease

BACKGROUND Most endoscopic anti-reflux interventions for gastroesophageal reflux disease (GERD) management are technically challenging to practice with inadequate data to support it utility. Therefore, this study was carried to evaluate the effectiveness and safety newer endoscopic full-thickness fundoplication (EFTP) device along with Argon Plasma Coagulation to treat individuals with GERD. AIM To evaluate the effectiveness and safety newer EFTP device along with Argon Plasma Coagulation to treat individuals with GERD. METHODS This study was a single-center comparative analysis conducted on patients treated at a Noble Institute of Gastroenterology, Ahmedabad, hospital between 2020 and 2022. The research aimed to retrospectively analyze patient data on GERD symptoms and proton pump inhibitor (PPI) dependence who underwent EFTP using the GERD-X system along with argon plasma coagulation (APC). The primary endpoint was the mean change in the total gastroesophageal reflux disease health-related quality of life (GERD-HRQL) score compared to the baseline measurement at the 3-month follow-up. Secondary endpoints encompassed enhancements in the overall GERD-HRQL score, improvements in GERD symptom scores at the 3 and changes in PPI usage at the 3 and 12-month time points. RESULTS In this study, patients most were in Hill Class II, and over half had ineffective esophageal motility. Following the EFTP procedure, there were significant improvements in heartburn and regurgitation scores, as well as GERD-HRQL scores (P &lt; 0.001). PPI use significantly decreased, with 82.6% not needing PPIs or prokinetics at end of 1 year. No significant adverse events related to the procedures were observed in either group. CONCLUSION The EFTP along with APC procedure shows promise in addressing GERD symptoms and improving patients' quality of life, particularly for suitable candidates. Moreover, the application of a lone clip with APC yielded superior outcomes and exhibited greater cost-effectiveness.

Neural responses to reward, threat, and emotion regulation and transition to hazardous alcohol use.

Reward processing and regulation of emotions are thought to impact the development of addictive behaviors. In this study, we aimed to determine whether neural responses during reward anticipation, threat appraisal, emotion reactivity, and cognitive reappraisal predicted the transition from low-level to hazardous alcohol use over a 12-month period. Seventy-eight individuals aged 18-22 with low-level alcohol use [i.e. Alcohol Use Disorder Identification Test (AUDIT) score <7] at baseline were enrolled. They completed reward-based and emotion regulation tasks during magnetic resonance imaging to examine reward anticipation, emotional reactivity, cognitive reappraisal, and threat anticipation (in the nucleus accumbens, amygdala, superior frontal gyrus, and insula, respectively). Participants completed self-report measures at 3-, 6-, 9-, and 12-month follow-up time points to determine if they transitioned to hazardous use (as defined by AUDIT scores ≥8). Of the 57 participants who completed follow-up, 14 (24.6%) transitioned to hazardous alcohol use. Higher baseline AUDIT scores were associated with greater odds of transitioning to hazardous use (odds ratio = 1.73, 95% confidence interval 1.13-2.66, P = .005). Brain activation to reward, threat, and emotion regulation was not associated with alcohol use. Of the neural variables, the amygdala response to negative imagery was numerically larger in young adults who transitioned to hazardous use (g =0.31), but this effect was not significant. Baseline drinking levels were significantly associated with the transition to hazardous alcohol use. Studies with larger samples and longer follow-up should test whether the amygdala response to negative emotional imagery can be used to indicate a future transition to hazardous alcohol use.

Abstract PO2-02-02: BREAst Cancer Personalized NuTrition (BREACPNT): dietary intervention in HR+ breast cancer patients treated with endocrine therapy

Abstract BACKGROUND Breast cancer patients treated with adjuvant endocrine therapy commonly experience weight gain, which has been associated with low adherence to therapy and worse breast cancer prognosis. Dietary interventions are the first-line treatment for weight management in breast cancer patients and have beneficial results. Yet, the ability to maintain these outcomes requires further research. Here, we aimed to assess whether a personalized postprandial glucose targeting (PPT) diet is beneficial for weight management and metabolic health as compared with the recommended Mediterranean (MED) diet in this population. DESIGN AND METHODS BREACPNT is a phase-2 randomized trial in HR+ patients with breast cancer, treated with adjuvant endocrine therapy. We randomly assigned participants to follow a MED diet or a PPT diet for a 6-month dietary intervention and additional 6-month follow-up. The PPT diet is based on a machine-learning algorithm that integrates clinical and microbiome features to predict personal postprandial glucose responses (PPGRs). During the intervention, participants were monthly followed by a registered dietitian, they were additionally connected to a 2-week continuous glucose monitoring (CGM) on 3-timepoints, provided stool and blood samples and self-reported dietary intake using a smartphone application. RESULTS Among 127 randomized patients (mean ± SD age 53 ± 10 years, BMI 28.6 ± 5 kg/m2), 103 (81%) completed the 6-month intervention period. A total of 94 participants provided 12-month follow-up data. Both interventions led to a significant weight loss. The PPT-diet showed numerically greater weight loss with median change of -1.45kg (IQR -3.75 – 0) compared to the MED-diet with median change of -1kg (IQR -3.2 - 0.1) , however this was not significant (p=0.9). Notably, at the 12-month time point , participants in the PPT arm were more likely to maintain the weight loss (median -1.2kg, IQR -4 - 0.1) compared to participants in the MED-arm (median -0.15kg , IQR -4.25 - 1.5), p=0.14) and had significantly improved waist circumference (median, IQR; -5 cm, -8-(-2) in the PPT arm, compared to -1cm, -6.5-3 in the MED arm, p=0.01). In terms of glucose metabolism the PPT-diet led to improved glycemic control as measured by CGM, with significant lower average postprandial glucose responses (PPGRs) and glucose coefficient of variation (CV) compared to the MED-diet arm (mean 6-month change in PPGR was 2.1 ± 7.5 mg/dL × h for MED and −3.4 ± 5.6 mg/dL × h for PPT, p&amp;lt; 0.001, and the 6-month mean change for CV was 0.15 ± 2.76 for MED and −1.37 ± 3.2 for PPT, p&amp;lt; 0.01). Within the entire cohort, participants who experienced the greatest weight loss (upper quartile) were more likely to be postmenopausal compared to participants in the lower quartile. Additionally, participants who did not achieve weight loss (lower quartile) were significantly more likely to be treated with tamoxifen than AI (p=0.015). CONCLUSIONS In this dietary intervention in HR+ breast cancer patients, both PPT diet and MED diet led to weight loss and improved food quality, with a slight advantage to PPT diet. PPT diet additionally improved glycemic features as compared to MED diet, which are linked to lower risk of obesity and disease recurrence, suggesting an advantage in a glucose targeting approach. Premenopausal and Tamoxifen treated patients were less likely to lose weight through the intervention. These findings may have implications for dietary advice in clinical practice. Citation Format: Michal Rein, Maya Dadiani, Anastasia Godneva, Michal Bakalenik-Gavry, Dana Morzaev-Sulzbach, Maya Lotan-Pompan, Adina Weinberger, Eran Segal, Einav Gal-Yam. BREAst Cancer Personalized NuTrition (BREACPNT): dietary intervention in HR+ breast cancer patients treated with endocrine therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-02-02.

Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer’s Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625.

P134 Developing a potential composite pharmacodynamic serum marker of skin severity in systemic sclerosis

Abstract Background/Aims Previously, through multilevel and high dimensional analysis, we derived a composite biomarker for modified Rodnan Skin Score (mRSS) in systemic sclerosis (SSc) patients using a derivation cohort (BIOPSY). This identified 4 blood proteins (COMP, COL4A1, TNC and SPON1) that independently correlated with mRSS and also with skin gene and dermal blister expression at a separate 12-month timepoint. These proteins likely reflect overlapping aspects of SSc skin pathobiology that are not overly influenced by other disease compartments. In the present study, we undertake technical and biological validation of this novel composite marker in well characterised SSc patients. Methods COMP (DCMP0, R&amp;D Systems), COL4A1 (CSB-EL005741HU, Cusabio), TNC (ab213831, Abcam) and SPON1 (CSB-EL022599HU, Cusabio) were examined in serum samples from diffuse cutaneous SSc (dcSSc) cases in two independent cohorts of patients, BIOPSY (n = 33) and MODERNISE (n = 37). The BIOPSY cohort was previously used to derive the composite marker and MODERNISE was a novel validation cohort. Later, early dcSSc patients from both cohorts were combined into a third analysis group (n = 36). Multiple regression analysis derived a formula for a composite biomarker score which predicted mRSS based on serum ELISA results. Results Serum concentration positively correlated with mRSS for COMP and TNC, particularly in early dcSSc patients (COMP, r = 0.10, p = 0.05; TNC, r = 0.13, p = 0.03). No significant correlation was observed for COL4A1 (r = 0.03, p = 0.34). Interpretable data could not be obtained for SPON1 due to technical limitations of the ELISA. Confirming previous results multiple regression analysis derived a formula for the prediction of mRSS using the three remaining serum proteins (r = 0.15, p = 0.009). mRSS = 9.896 + 0.01719(COMP) - 0.006481(COL4A1) - 0.002318(TNC). Patients receiving mycophenolate mofetil showed numerically lower serum concentrations of COMP (p = 0.16), COL4A1 (p = 0.32), TNC (p = 0.15) and a lower composite biomarker score (p = 0.22) with increasing treatment duration in early dcSSc cases (Table 1). Conclusion Our results confirm this novel three-protein composite serum marker predicts skin severity in SSc better than each individual analyte. After further validation, this blood-based approach may help evaluate treatment response to standard immunosuppression. Further work will establish utility of this composite measure as a predictive or prognostic biomarker. Disclosure E. Roblin: None. K.E.N. Clark: None. C. Beesley: None. V.H. Ong: None. C.P. Denton: Consultancies; C.P.D. has received consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring and Acceleron. Honoraria; C.P.D. has received honoraria from Janssen, Boehringer Ingelheim, and Corbus. Grants/research support; C.P.D. has received research grants to the institution from Servier, Horizon, Arxx Therapeutics and GlaxoSmithKline.

Relating preoperative MCS-12 to microdiscectomy outcomes

PurposeTo determine the impact of poor mental health on patient-reported and surgical outcomes after microdiscectomy.MethodsPatients ≥ 18 years who underwent a single-level lumbar microdiscectomy from 2014 to 2021 at a single academic institution were retrospectively identified. Patient-reported outcomes (PROMs) were collected at preoperative, three-month, and one-year postoperative time points. PROMs included the Oswestry Disability Index (ODI), Visual Analog Scale Back and Leg (VAS Back and VAS Leg, respectively), and the mental and physical component of the short form-12 survey (MCS and PCS). The minimum clinically important differences (MCID) were employed to compare scores for each PROM. Patients were categorized as having worse mental health or better mental health based on a MCS threshold of 50.ResultsOf 210 patients identified, 128 (61%) patients had a preoperative MCS score ≤ 50. There was no difference in 90-day surgical readmissions or spine reoperations within one year. At 3- and 12-month time points, both groups demonstrated improvements in all PROMs (p < 0.05). At three months postoperatively, patients with worse mental health had significantly lower PCS (42.1 vs. 46.4, p = 0.004) and higher ODI (20.5 vs. 13.3, p = 0.006) scores. Lower mental health scores were associated with lower 12-month PCS scores (43.3 vs. 48.8, p < 0.001), but greater improvements in 12-month ODI (− 28.36 vs. − 18.55, p = 0.040).ConclusionWhile worse preoperative mental health was associated with lower baseline and postoperative PROMs, patients in both groups experienced similar improvements in PROMs. Rates of surgical readmissions and reoperations were similar among patients with varying preoperative mental health status.

Schema therapy versus treatment as usual for outpatients with difficult-to-treat depression: study protocol for a parallel group randomized clinical trial (DEPRE-ST)

BackgroundAbout one third of patients with depression are in a condition that can be termed as “difficult-to-treat”. Some evidence suggests that difficult-to-treat depression is associated with a higher frequency of childhood trauma and comorbid personality disorders or accentuated features. However, the condition is understudied, and the effects of psychotherapy for difficult-to-treat depression are currently uncertain. The aim of this trial is to investigate the beneficial and harmful effects of 30 sessions of individual schema therapy versus treatment as usual for difficult-to-treat depression in the Danish secondary, public mental health sector.MethodsIn this randomized, multi-centre, parallel-group, superiority clinical trial, 129 outpatients with difficult-to-treat depression will be randomized (1:1) to 30 sessions of individual schema therapy or treatment as usual; in this context mainly group-based, short-term cognitive behaviour or psychodynamic therapy. The primary outcome is the change from baseline in depressive symptoms 12 months after randomization, measured on the observer-rated 6-item Hamilton Rating Scale for Depression. The secondary outcomes are health-related quality of life assessed with the European Quality of Life 5 Dimensions 5 Level Version, functional impairment assessed with the Work and Social Adjustment Scale, psychological wellbeing assessed with the WHO-5 Well-being Index, and negative effects of treatment assessed with the Negative Effects Questionnaire. Exploratory outcomes are improvement on patient self-defined outcomes, personal recovery, anxiety symptoms, anger reactions, metacognitive beliefs about anger, and perseverative negative thinking. Outcomes will be assessed at 6, 12, and 24 months after randomization; the 12-month time-point being the primary time-point of interest. Outcome assessors performing the depression-rating, data managers, statisticians, the data safety and monitoring committee, and conclusion makers for the outcome article will be blinded to treatment allocation and results. To assess cost-effectiveness of the intervention, a health economic analysis will be performed.DiscussionThis trial will provide evidence on the beneficial and harmful effects, as well as the cost-effectiveness of schema therapy versus treatment as usual for outpatients with difficult-to-treat depression. The results can potentially improve treatment for a large and understudied patient group.Trial registrationClinicalTrials.gov NCT05833087. Registered on 15th April 2023 (approved without prompts for revision on 27th April 2023).

Crestal Bone Remodeling in Polished Collar Implants

OBJECTIVE: This study aimed to evaluate the amount of crestal bone remodeling in polished collar implants. METHODOLOGY: Thirty patients with a missing maxillary or mandibular 1st or 2nd premolar tooth requiring simultaneous bone grafting were recruited and implant placed at the level of crest with polished collar placed 1mm apical to the level of bone and bone augmentation was performed to graft the buccal threads. Buccal bone thickness was measure at crestal level as well as 1mm apical to polished collar. The implants were uncovered at 6 months and restored and patients followed up for 12 months from the time of implant placement. Cone beam computed tomography scans were taken at two time points, immediately after implant placement and at 12-month time point. RESULTS: At clinical re-entry (6 months), there was significant difference in mean buccal bone thickness found between crestal level and 1mm apical to polished collar (p&lt;0.05). Radiographically (at 12 months), the mean buccal bone change was -1.82mm 0.57mm at crest and -0.94mm 0.31mm at 1mm apical to crest. CONCLUSION: Bone regenerative techniques were unable to prevent biologic bone remodeling around the implant platform; therefore, the outcomes of bone augmentation might be affected by the polished collar of implant. KEY WORDS: Dental implants, polished collar, bone augmentation, bone remodeling, cone beam computed tomography

Clinical and Imaging Biomarkers Associated with Outer Retinal Atrophy Onset in Exudative Age-Related Macular Degeneration: A Real-Word Prospective Study.

Macular neovascularization (MNV) secondary to age-related macular degeneration (AMD) is well managed by anti-vascular endothelial growth factor (anti-VEGF) intravitreal injections. However, outer retinal atrophy represents an unavoidable occurrence detected during follow-up. Several imaging metrics have been proposed as clinically relevant in stratifying the risk of onset of outer retinal atrophy. The main goal of this study is to evaluate the impact of noninvasive imaging metrics on the assessment of outer retinal atrophy onset in a large cohort of eyes with neovascular AMD managed in a real-world setting. This study was a prospective, observational, case series. We included patients affected by newly diagnosed neovascular AMD, requiring anti-VEGF intravitreal injections. We collected clinical and imaging data, with a planned follow-up of 24months. The multimodal imaging protocol included optical coherence tomography, optical coherence tomography angiography, and fundus autofluorescence. We collected noninvasive imaging metrics and we assessed the relationship with the morphological and functional outcome evaluated at 12-month and 24-month time points. We included 370 eyes of 370 patients with exudative AMD (210 male; mean age 79 ± 8years). MNV were classified as follows: type 1, 198 (54%); type 2, 89 (24%); polypoidal choroidal vasculopathy, 29 (7%); and type 3, 54 (15%). A total of 120 out of 370 eyes (33%) showed complete outer retinal atrophy at the end of the 2-year follow-up. The presence of intraretinal fluid, thinning of the Sattler choroidal layer, late anti-VEGF switch, the overall number of anti-VEGF injections, and the perfusion characteristics of the MNV were found to be the most relevant factors associated with the onset of outer retinal atrophy. The other collected metrics were found to be less clinically relevant, also showing no cumulative effect in the multivariate analysis (p > 0.05). We identified imaging metrics significantly associated with the 2-year risk onset of outer retinal atrophy. These metrics might pave the way for the development of future customized anti-VEGF treatment strategies.

Effects on Lung Tissue After Breast Cancer Radiation: Comparing Photon and Proton Therapies

PurposeIn breast cancer, improved treatment approaches that reduce injury to lung tissue and early diagnosis and intervention for lung toxicity are increasingly important in survivorship. The aims of this study are to (1) compare lung tissue radiographic changes in women treated with conventional photon radiation therapy and those treated with proton therapy (PT), (2) assess the volume of lung irradiated to 5 Gy (V5) and 20 Gy (V20) by treatment modality, and (3) quantify the effects of V5, V20, time, and smoking history on the severity of tissue radiographic changes. Patients and MethodsA prospective observational study of female breast cancer patients was conducted to monitor postradiation subclinical lung tissue radiographic changes. Repeated follow-up x-ray computed tomography scans were acquired through 2 years after treatment. In-house software was used to quantify an internally normalized measure of pulmonary tissue density change over time from the computed tomography scans, emphasizing the 6- and 12-month time points. ResultsCompared with photon therapy, PT was associated with significantly lower lung V5 and V20. Lung V20 (but not V5) correlated significantly with increased subclinical lung tissue radiographic changes 6 months after treatment, and neither correlated with lung effects at 12 months. Significant lung tissue density changes were present in photon therapy patients at 6 and 12 months but not in PT patients. Significant lung tissue density change persisted at 12 months in ever-smokers but not in never-smokers. ConclusionPatients treated with PT had significantly lower radiation exposure to the lungs and less statistically significant tissue density change, suggesting decreased injury and/or improved recovery compared to photon therapy. These findings motivate additional studies in larger, randomized, and more diverse cohorts to further investigate the contributions of treatment modality and smoking regarding the short- and long-term radiographic effects of radiation on lung tissue.

The role of Healthy Life Centres in delivering weight management: A retrospective study

IntroductionHealthy Life Centres (HLCs) in Turkey were established as primary health services to promote healthier lifestyle behaviours, aiming to reduce obesity and diseases linked to physical inactivity. This study aimed to investigate the weight management programme delivered by one HLC and to track the participants’ progress in terms of weight loss and adherence to the program. MethodsThis was a retrospective study. Participants consisted of adults aged ≥18 who attended the HLC for weight management from Sept 2017-June 2020. Data including attendance, age, gender, height and body weight were collected and analysed at 3, 6, 12-month time-points. Missing data were interpreted using last observed weight carried forward analysis (LOCF). ResultsOver a two-year period 2652 adults (88% female) consulted the nutrition counselling service, of whom 43% attended once. Mean age of those attending once was 40.2 (12.35) years and age increased significantly with adherence. Baseline body mass index (BMI) was 31.4 (6.32) kg/m2. For those attending at the different time-points, weight loss was 4.4 % of initial body weight at 3-months (n = 841), 8.6 % of initial body weight at 6-month (n = 237), and 11.8 % initial body weight at 12-month follow-up (n = 56). LOCF analysis revealed a significant time effect for change in percentage body weight for the data collected at 6 and 12 months. ConclusionThis programme was successful in reaching clinically meaningful weight loss at 3, 6, 12-month for the participants who committed to the weight management programme. However, there was a substantial decline in participant engagement, with only a 2 % attendance rate at 12 months. Furthermore, it is noteworthy that nearly half of the clients attended only one session during the study period. The findings of the current study can be used to inform policy makers about the strengths and weaknesses of HLCs.

Objective Outcomes to Evaluate Voretigene Neparvovec Treatment Effects in Clinical Practice

AimTo assess the efficacy of Voretigene Neparvovec (VN) treatment by objective fixation stability and chromatic pupillometry testing in clinical practice. DesignRetrospective cohort study with longitudinal follow-up. SubjectsTwelve patients (aged 7 to 34 years) with RPE65-related inherited retinal dystrophies were treated at the same center with VN in both eyes. MethodsPatients treated at the same center with VN were evaluated over a 12-month post-treatment follow-up by subjective and objective tests. Furthermore, patients treated with VN who developed atrophy were compared to those who did not. Main outcome measuresBest corrected visual acuity (BCVA), full field stimulus threshold test (FST), semi-automated kinetic visual field (SKVF), microperimetry, and chromatic pupillometry over a 12-month follow-up ResultsSignificant improvements of BCVA (p<0.001), SKVF (p<0.05) and FST (p<0.001) were already observed 45 days after treatment and were maintained at the 12-month timepoint. Fixation stability, assessed by microperimetry, improved significantly (p<0.05) after treatment. Chromatic pupillometry showed significant improvements (p<0.05) at the 6- and 12-month timepoints. The increase in maximum pupillary constriction significantly (p<0.001) correlated with higher retinal sensitivity in FST. Four patients developed multifocal retinal atrophy in both eyes, detected at the 6-month timepoint, but this atrophy was not generally associated with worse visual function outcomes. ConclusionsThis study is the first attempt to demonstrate the efficacy of VN treatment in real life using objective tests in addition to those normally performed in clinical practice. Our findings show a significant improvement of retinal function both in subjective assessments, such as BCVA, SKVF and FST, and in objective measurements of fixation stability and maximum pupillary constriction. Moreover, the significant correlation between maximum pupillary constriction and light sensitivity thresholds corroborates the introduction of chromatic pupillometry as an objective test to better assess treatment outcomes in patients with inherited retinal dystrophies.

Analysis of the incidence and symptomatology of low anterior resection syndrome after laparoscopic anterior resection for rectal cancer

Objective: This study aims to explore the temporal trend of Low Anterior Resection Syndrome (LARS) and its symptoms after laparoscopic anterior resection for rectal cancer. Methods: A retrospective cohort study design was employed. The study included primary rectal (adenocarcinoma) cancer patients who underwent laparoscopic anterior resection at Tongji Hospital, Huazhong University of Science and Technology, between January 1, 2010, and December 31, 2020. Complete medical records and follow-up data at 3, 6, 9, 12, and 18 months postoperatively were available for all patients. A total of 1454 patients were included, of whom 1094 (75.2%) were aged ≤65 years, and 597 (41.1%) were females. Among them, 1040 cases (71.5%) had an anastomosis-to-anus distance of 0-5cm, and 86 cases (5.9%) received neoadjuvant treatment. All patients completed the Chinese version of the LARS questionnaire and their LARS occurrence and specific symptom information were recorded at 3, 6, 9, 12, and 18 months postoperatively. Considering past literature and clinical experience, further subgroup analyses were performed to explore the potential impact factors on severe LARS, including anastomosis level, preoperative neoadjuvant therapy, postoperative adjuvant therapy, and the presence of preventive stoma. Results: The occurrence rates of LARS at 3, 6, 9, 12, and 18 months postoperatively were 78.5% (1142/1454), 71.4% (1038/1454), 55.0% (799/1454), 45.7% (664/1454), and 45.7% (664/1454), respectively (χ2=546.180, P<0.001). No statistically significant difference was observed between the 12-month and 18-month time points (P>0.05). When compared with the symptoms at 3 months, the occurrence rates of gas incontinence [1.7% (24/1454) vs. 33.9% (493/1454)], liquid stool incontinence [3.9% (56/1454) vs. 41.9% (609/1454)], increased stool frequency [79.6% (1158/1454) vs. 95.9% (1395/1454)], stool clustering [74.3% (1081/1454) vs. 92.9% (1351/1454)], and stool urgency [46.5% (676/1454) vs. 78.7% (1144/1454)] in the LARS symptom spectrum were significantly alleviated at 12 months (all P<0.05) and remained stable beyond 12 months (all P>0.05). With the extension of postoperative time, the incidence rates of severe LARS exhibited a decreasing trend in different subgroups, of anastomosis level, preoperative neoadjuvant therapy, postoperative adjuvant therapy, and the presence of preventive stoma, and reached stability at 12 months postoperatively (all P>0.05). Conclusion: LARS and its specific symptom profile showed a trend of gradual improvement over time up to 1 year postoperatively, and stabilized after more than 1 year. Increased stool frequency and stool clustering are the most common features of abnormal bowel dys function, which improve slowly after surgery.

Expression of the Pro-Fibrotic Marker Periostin in a Mouse Model of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is characterised by fibrotic tissue deposition in skeletal muscle. We assessed the role of periostin in fibrosis using mdx mice, an established DMD murine model, for which we conducted a thorough examination of periostin expression over a year. RNA and protein levels in diaphragm (DIA) muscles were assessed and complemented by a detailed histological analysis at 5 months of age. In dystrophic DIAs, periostin (Postn) mRNA expression significantly exceeded that seen in wildtype controls at all timepoints analysed, with the highest expression at 5 months of age (p < 0.05). We found Postn to be more consistently highly expressed at the earlier timepoints compared to established markers of fibrosis like transforming growth factor-beta 1 (Tgf-β1) and connective tissue growth factor (Ctgf). Immunohistochemistry confirmed a significantly higher periostin protein expression in 5-month-old mdx mice compared to age-matched healthy controls (p < 0.01), coinciding with a significant fibrotic area percentage (p < 0.0001). RT-qPCR also indicated an elevated expression of Tgf-β1, Col1α1 (collagen type 1 alpha 1) and Ctgf in mdx DIAs compared to wild type controls (p < 0.05) at 8- and 12-month timepoints. Accordingly, immunoblot quantification demonstrated elevated periostin (3, 5 and 8 months, p < 0.01) and Tgf-β1 (8 and 12 months, p < 0.001) proteins in the mdx muscle. These findings collectively suggest that periostin expression is a valuable marker of fibrosis in this relevant model of DMD. They also suggest periostin as a potential contributor to fibrosis development, with an early onset of expression, thereby offering the potential for timely therapeutic intervention and its use as a biomarker in muscular dystrophies.

What have we learned from the real-world efficacy of FFA in DS and LGS? A post-marketing study in clinical practice

ObjectiveTo evaluate the effectiveness and tolerability of fenfluramine (FFA) in routine clinical practice treating real-world populations with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). MethodsThis was a retrospective analysis of patients with DS or LGS who initiated FFA treatment from 2018 to 2022 at a single center. Patient demographics, medical history, seizure characteristics, and treatment outcomes were collected from electronic medical records. Duration of FFA treatment, dosage regimens, seizure frequency, seizure severity, improvements in cognitive, social, and motor outcomes, and adverse events were extracted and analyzed. Effectiveness was assessed using ≥50 % sustained reduction in monthly seizure frequency vs baseline for ≥2 consecutive months at 12 months; seizure freedom was a secondary measure. ResultsSeizure frequency data was available for 56 of 68 patients included in the study. At 12 months, 50 patients (89.3 %) remained on FFA treatment; 58 % of these patients achieved a ≥50 % sustained response and 10 % experienced seizure freedom. Cognitive, motor, and social improvement were noted in 70.7 %, 36.2 %, and 27.6 % of patients, respectively. The total number of concomitant antiseizure medications was reduced by ≥1 in 29.4 % of patients. No differences were found between DS and LGS patients in these outcomes; age at start of FFA and age at the 12-month timepoint did not have an effect.At least one AE was experienced by 59.7% of patients; in 86.5% of the cases, AEs were plausibly related to treatment. While 70.3% of AEs were self-resolving and 81.8% of the remaining patients experienced mild AEs, 1 patient experienced a serious AE unrelated to FFA which resulted in the patient’s death. There were no cases of pulmonary arterial hypertension or ventricular heart disease. SignificanceThe effectiveness and tolerability of FFA treatment in patients with DS or LGS in this retrospective analysis of real-world data were consistent with those seen in randomized clinical trials.

Benralizumab Reduces Respiratory Exacerbations and Oral Glucocorticosteroid Dose in Patients with Severe Asthma and Eosinophilic Granulomatosis with Polyangiitis.

Benralizumab reduces exacerbations and long-term oral glucocorticosteroid (OCS) exposure in patients with severe eosinophilic asthma. In patients with eosinophilic granulomatosis with polyangiitis (EGPA), uncontrolled symptoms and exacerbations of asthma and chronic rhinosinusitis (CRS) are important reasons for continued OCS therapies. We aimed to describe outcomes of patients with severe asthma and EGPA treated with benralizumab in real-life. We retrospectively analyzed adult patients from the Severe Asthma Unit at LMU Munich diagnosed with severe asthma and EGPA treated with benralizumab, differentiating two groups: Group A, patients with a stable daily OCS dose and diagnosis of EGPA >6 months ago; and Group B, patients treated with high-dose daily OCS due to recent diagnosis of EGPA <6 months ago. We compared outcome parameters at baseline and 12 months after initiation of benralizumab, including respiratory exacerbations, daily OCS dose, and lung function. Group A included 17 patients, all receiving OCS therapy and additional immunosuppressants; 15 patients (88%) continued benralizumab for more than 12 months, demonstrating a significant reduction in daily OCS dose and exacerbations while FEV1 increased. Group B included 9 patients, all with high-dose daily OCS and some receiving cyclophosphamide pulse therapy for life-threatening disease. Benralizumab addition during induction was well tolerated. A total of 7/9 (78%) continued benralizumab for more than 12 months and preserved EGPA remission at the 12-month timepoint. In this real-life cohort of patients with severe asthma and EGPA, benralizumab initiation during remission maintenance reduced respiratory exacerbations and daily OCS dose. Benralizumab initiation during remission induction was associated with a high rate of clinical EGPA remission.

Influential factors of non-motor symptoms prognosis in Parkinson's disease patients undergoing deep brain stimulation

Objective: To investigate the effects of electrode activated contact location, volume of tissue activated (VTA) and age on non-motor symptoms, such as emotional symptoms and cognitive function, in Parkinson's disease (PD) patients with deep brain stimulation (DBS). Methods: PD patients who underwent DBS of subthalamic nucleus (STN) at the Department of Functional Neurosurgery of Beijing Tiantan Hospital from September 1, 2020 to August 31, 2022 were retrospectively enrolled. The International Parkinson and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Montreal Cognitive Assessment (MoCA), and Mini-Mental State Examination Scales (MMSE) were used at the preoperative, 1-month and 12-month postoperative time points. In this study, patients were divided into middle-aged (age<60 years,n=39) and elderly (age≥60 years,n=62) groups to investigate the effect of age factor on the clinical outcome of surgery. Lead-DBS software was used to convert the patients' electrode reconstruction results into Montreal standard space, and the patients were divided into sensorimotor(n=43) and combined groups(n=53) according to the distribution of activation contact locations in the subzones of the STN. In addition, the patients were divided into a cognitive improvement group(n=57)and a cognitive deterioration group(n=44) based on the results of MoCA at 12 months. The positional information of the electrode activation contacts was collected and the VTA was calculated to analyze the effects on electrode activation electroshock location and activated tissue volume on patients' non-motor symptoms. Results: A total of 101 patients with PD were enrolled, including 46 males and 55 females, aged (62.6±8.4) years. Middle-aged patients had significantly higher MoCA scores, delayed recall scores, attention scores, and naming scores than older patients at 12 months postoperatively (all P<0.05). At 12-month follow-up, the improvement rate of MoCA score, HAMA score and HAMD score were -1.77%±20.36%, 39.65%±42.91% and 36.23%±45.45% respectively in sensorimotor group. At 12-month follow-up, the improvement rate of MoCA score, HAMA score and HAMD score was 11.69%±22.24%, 16.62%±68.10% and 2.30%±95.04% respectively in the combined group, and the difference between the two groups was statistically significant (MoCA: P=0.002; HAMA: P=0.040; HAMD: P=0.033) The distribution of VTA in the sensory motor area and marginal area of the left hemisphere STN in patients with improved cognitive function was significantly smaller than that in the deterioration group [(60.53±52.04)mm³vs (84.55±61.00)mm³, P=0.035; (41.81±33.36)mm³vs (59.05±45.46)mm³, P=0.030]. Conclusion: The effect of STN-DBS on emotional symptoms and cognitive function in PD patients is influenced by various factors and is closely related to the patient's age, electrode activation contact location and VTA.