Connectivity based on glucose dynamics reveals exaggerated sensorimotor network coupling on subject-level in Parkinson's disease.

PURPOSE: While fMRI provides information on the temporal changes in blood oxygenation, 2- [18F]fluoro-2-deoxy-D-glucose ([18F]FDG)-PET has traditionally offered a static snapshot of brain glucose consumption. As a result, studies investigating metabolic brain networks as potential biomarkers for neurodegeneration have primarily been conducted at the group level. However, recent pioneering studies introduced time-resolved [18F]FDG-PET with constant infusion, which enables metabolic connectivity studies at the individual level. METHODS: In the current study, this technique was employed to explore Parkinson's disease (PD)-related alterations in individual metabolic connectivity, in comparison to inter-subject measures and hemodynamic connectivity. Fifteen PD patients and 14 healthy controls with comparable cognition underwent sequential resting-state dynamic PET with constant infusion and functional MRI. Intrinsic networks were identified by independent component analysis and interregional connectivity calculated for summed static PET images, PET time series and functional MRI. RESULTS: Our findings revealed an intrinsic sensorimotor network in PD patients that has not been previously observed to this extent. In PD, a significantly higher number of connections in cortical motor areas was observed compared to elderly control subjects, as indicated by both static PET and functional MRI (pBonferroni-Holm = 0.027), as well as constant infusion PET and functional MRI connectomes (pBonferroni-Holm = 0.012). This intensified coupling was associated with disease severity (ρ = 0.56, p = 0.036). CONCLUSION: Metabolic connectivity, as revealed by both static and dynamic PET, provides unique information on metabolic network activity. Subject-level metabolic connectivity based on constant infusion PET may serve as a potential marker for the metabolic network signature in neurodegeneration.

The effect of early skin-to-skin contact after cesarean section on breastfeeding duration and development of atopic-allergic diseases.

INTRODUCTION: Breastfeeding to strengthen the immune system suggests allergy prevention as a possible option. The connection between breastfeeding and the development of atopic-allergic diseases is being discussed. The primary aim of this work was to investigate an association of the first early skin-to-skin contact following cesarean section with the development of atopic diseases within the 1st year of life. METHODS: The present study was conducted as a bicentric prospective cohort study in central Germany with a 15-month recruitment period. Data collection was by telephone interviews with a follow-up of 12 months. The statistical evaluation procedure was based on a hierarchical test of the association of early skin-to-skin contact between mother and child with the two main outcome measures. The primary outcome is the duration of breastfeeding. The second outcome is the onset of atopic-allergic disease within the 1st year of life. RESULTS: Mothers breastfed longer if they had skin-to-skin contact within the first 30 minutes postpartum [χ²(df=5) = 19.020, p=0.002], if they breastfed their newborns early immediately after birth (p<0.001), and if the first skin-to-skin contact lasted more than one hour [χ²(df=4) = 19.617, p<0.001]. Regarding atopic-allergic diseases, no significant effects of skin-to-skin contact were found in relation to disease development. Regarding breastfeeding, no significant effects of atopic-allergic diseases could be detected either. CONCLUSIONS: The results of this study reflect the benefits of skin-to-skin contact in the context of breastfeeding and atopic disease. The current scientific knowledge regarding skin contact and the development of atopic-allergic diseases should be extended and deepened.

Reduced Gastric Contraction in Rapid-Eye-Movement Sleep Behavior Disorder and De Novo Parkinson's Disease.

BACKGROUND: Reduced gastric motility in Parkinson's disease (PD) has been reported, but hardly any study exists in subjects with isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD), a specific prodrome of α-synucleinopathies. OBJECTIVES: We compared the gastric motility of 17 iRBD subjects with that of 18 PD subjects (15 drug naive, 3 early treated in defined off) and 15 healthy controls (HC) with real-time magnetic resonance imaging (rtMRI). METHODS: After overnight fasting, participants consumed a standardized breakfast and underwent a 3-T rtMRI of the stomach. Amplitude and velocity of the peristaltic waves were analyzed under blinded conditions. Gastric motility index (GMI) was calculated. The procedure was repeated in 12 of 17 iRBD subjects ~2.5 years later. Nine of these 12 iRBD subjects were hyposmic. RESULTS: In iRBD and PD subjects the amplitude of the peristaltic waves was significantly reduced compared with HCs (iRBD vs. HC: 8.7 ± 3.7 vs. 11.9 ± 4.1 mm, P = 0.0097; PD vs. HC: 6.8 ± 2.2 vs. 11.9 ± 4.1 mm, P = 0.0001). The amplitude in iRBD and PD subjects was decreased to the same extent. The GMI was reduced in only PD subjects (PD vs. HC: P = 0.0027; PD vs. iRBD: P = 0.0203). After ~2.5 years the amplitude in iRBD subjects did not significantly decrease further. CONCLUSION: The amplitude of the peristaltic waves was markedly reduced in iRBD, a prodrome of α-synucleinopathies. This reduction was similar to the extent observed already in manifest early PD. This finding implies that the α-synuclein pathology affects the innervation of the stomach already in the prodromal stage. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Comparison of intraocular lens power calculation formulas with and without total keratometry and ray tracing in patients with previous myopic SMILE.

PURPOSE: To evaluate the prediction error (PE) variance and absolute median PE of different intraocular lens (IOL) calculation formulas including last-generation formulas such as Barrett True-K with K, Okulix and total keratometry (TK)-based calculations with Haigis, and Barrett True-K in a simulation model in post-small-incision lenticule extraction (SMILE) eyes. SETTINGS: Department of Ophthalmology, University Hospital Marburg, Marburg, Germany. DESIGN: Prospective study. METHODS: Preoperative measurements included IOL power calculation before and after SMILE surgery. The target refraction was set to be the lowest myopic refractive error in pre-SMILE eyes. The IOL power targeting at the lowest myopic refractive error in pre-SMILE eyes was selected for the post-SMILE IOL calculation of the same eye. The difference between the predicted refraction of pre- and post-SMILE eyes with the same IOL power was defined as IOL difference. The refractive change induced by SMILE was defined as the difference between preoperative and postoperative manifest refraction. RESULTS: 98 eyes from 49 patients underwent bilateral myopic SMILE. The PE variance of Okulix was not significantly different compared with Barrett True-K with TK ( P = .471). The SDs of the mean PEs were ±0.413 D (Haigis-TK), ±0.453 D (Okulix), ±0.471 D (Barrett True-K with TK), ±0.556 D (Haigis-L), and ±0.576 D (Barrett True-K with K). The mean absolute PE was 0.340 D, 0.353 D, 0.404 D, 0.511 D, and 0.715 D for Haigis-TK, Okulix, Barrett True-K with TK, Barrett True-K with K, and Haigis-L, respectively. The highest percentage of eyes within ±0.50 D was achieved by Okulix, followed by Haigis-TK, Barrett True-K with TK, Barrett True-K with K, and Haigis-L. CONCLUSIONS: Results suggest that Haigis in combination with TK, Okulix, and Barrett True-K with and without TK offer good options for accurate IOL power calculation after SMILE. Haigis-L showed a tendency for myopic shift in eyes after previous SMILE.

Transdermal Nicotine Treatment and Progression of Early Parkinson's Disease.

BACKGROUND: Epidemiologic studies show that smokers have a lower incidence of Parkinson's disease. Nicotine has been hypothesized to slow progression in early Parkinson's disease. METHODS: In a double-blind, placebo-controlled multicenter trial, we randomly assigned patients with Parkinson's disease, diagnosed within 18 months, who were in Hoehn and Yahr disease stage less than or equal to 2 (range from 0 to 5; higher scores indicate greater impairment), who were therapy naïve (except for stable monoamine-oxidase-B inhibition), and not requiring dopaminergic therapy, to transdermal nicotine or placebo. The primary end point was change in Unified Parkinson's Disease Rating Scale parts I­III (Total UPDRS) score (range from 0 to 172; higher scores indicate greater impairment) between baseline and 60 weeks (52 weeks of trial therapy, 8 weeks of washout). The first secondary end point was change in Total UPDRS from baseline to 52 weeks. Differences between groups were estimated using the Hodges­Lehmann (HL) method and tested with the exact two-sided stratified Mann­Whitney­Wilcoxon test according to the intention-to-treat principle. RESULTS: Among 163 participants, 101 were assessed for the primary end point. Mean worsening of Total UPDRS was 3.5 in the placebo versus 6.0 in the nicotine group (HL-difference with 95% CI: ­3 [­6 to 0], P=0.06). For the first secondary end point, analysis of 138 participants showed a mean worsening of 5.4 in the placebo versus 9.1 in the nicotine group (HL-difference with 95% CI: ­4 [­7 to ­1]). Dropout was mainly because of early treatment discontinuation or adverse events. Cutaneous adverse effects at the patch application site were common. In all, 34.6% of participants initiated dopaminergic therapy during participation. CONCLUSIONS: One-year transdermal nicotine treatment did not slow progression in early Parkinson's disease. (Funded by the Michael J. Fox Foundation for Parkinson's Research and others; ClinicalTrials.gov number, NCT01560754; EudraCT number, 2010-020299-42.)

Pulmonary inflammatory response and immunomodulation to multiple trauma and hemorrhagic shock in pigs.

BACKGROUND: Patients suffering from severe trauma experience substantial immunological stress. Lung injury is a known risk factor for the development of posttraumatic complications, but information on the long-term course of the pulmonary inflammatory response and treatment with mild hypothermia are scarce. AIM: To investigate the pulmonary inflammatory response to multiple trauma and hemorrhagic shock in a porcine model of combined trauma and to assess the immunomodulatory properties of mild hypothermia. METHODS: Following induction of trauma (blunt chest trauma, liver laceration, tibia fracture), two degrees of hemorrhagic shock (45 and 50%) over 90 (n = 30) and 120 min. (n = 20) were induced. Animals were randomized to hypothermia (33°C) or normothermia (38°C). We evaluated bronchoalveolar lavage (BAL) fluid and tissue levels of cytokines and investigated changes in microRNA- and gene-expression as well as tissue apoptosis. RESULTS: We observed a significant induction of Interleukin (IL) 1ß, IL-6, IL-8, and Cyclooxygenase-2 mRNA in lung tissue. Likewise, an increased IL-6 protein concentration could be detected in BAL-fluid, with a slight decrease of IL-6 protein in animals treated with hypothermia. Lower IL-10 protein levels in normothermia and higher IL-10 protein concentrations in hypothermia accompanied this trend. Tissue apoptosis increased after trauma. However, intervention with hypothermia did not result in a meaningful reduction of pro-inflammatory biomarkers or tissue apoptosis. CONCLUSION: We observed signs of a time-dependent pulmonary inflammation and apoptosis at the site of severe trauma, and to a lower extent in the trauma-distant lung. Intervention with mild hypothermia had no considerable effect during 48 hours following trauma.

Prognostic Significance of the Nodal Ratio and Number of Positive Nodes in Patients With Squamous Cell Carcinomas of the Head and Neck.

BACKGROUND/AIM: The lymph node status has high prognostic relevance in head and neck squamous cell carcinoma (HNSCC). This study aimed to address the hypothesis that the number of positive nodes and the nodal ratio have a prognostic impact on survival in HNSCC. PATIENTS AND METHODS: A retrospective analysis of 221 patients with HNSCC and clinical N+ status who underwent a neck dissection during primary surgery or after definitive radio(chemo)therapy was performed. The possible influence of age, sex, TNM stage, number of positive nodes and nodal ratio on survival was analyzed by univariate and multivariate Cox models and log-rank tests. RESULTS: On average, 30.1 lymph nodes were removed and 4.96 metastases were detected. The mean nodal ratio was 9.4%, the median nodal ratio was 5.3%. Multivariate analysis demonstrated a nodal ratio of ≥6-<12.5% [hazard ratio (HR)=2.33, 95% confidence interval (CI)=1.24-4.37; p=0.008] and of ≥12.5% (HR=2.86, 95% CI=1.40-5.84; p=0.004) compared to nodal ratio 0, number of positive nodes pN=1 compared to number of positive nodes=0 (HR=2.02, 95% CI=1.08-3.80. p=0.029), as well as N3 compared to N0 (HR=8.10, 95% CI=1.89-34.66; p=0.005), and Mx compared to M0 (HR of 2.76, 95% CI=1.59-4,79, p≤0.001) were of main importance for poor prognosis. Postoperative radio(chemo)therapy after surgery was associated with prolonged survival in multivariate analysis (HR=0.37, 95% CI=0.24-0.57; p≤0.001). CONCLUSION: The nodal ratio and number of positive nodes seem to have a high prognostic impact in patients with HNSCC and can be of value in identifying patients at high risk who warrant more aggressive therapy.

Calculating the individual probability of successful ocriplasmin treatment in eyes with vitreomacular traction-Validation and refinement of a multivariable prediction model.

PURPOSE: To evaluate a multivariable model predicting the individual probability of successful intravitreal ocriplasmin (IVO) treatment in eyes with vitreomacular traction (VMT). METHODS: Data from three prospective, multicenter IVO studies (OASIS, ORBIT, and INJECT) were pooled. Patients were included if they were treated for a symptomatic VMT without a full-thickness macular hole. A prediction model for VMT resolution using the factors 'age' and 'horizontal VMT diameter' was validated by receiver operating characteristic analysis and according to grouped prediction after calibration. Multivariable regression analysis was performed to check robustness and explore further improvements. RESULTS: Data from 591 eyes was included. In the univariate analysis all key factors (age, gender, VMT diameter, lens status, ERM) significantly correlated to treatment success. The prediction model was robust and clinically applicable to estimate the success rate of IVO treatment (AUC of ROC: 0.70). A refinement of the model was achieved through a calibration process. CONCLUSION: The developed multivariable model using 'horizontal VMT diameter' and 'age' is a valid tool for prediction of VMT resolution upon IVO treatment.

Intensive Care as an Independent Risk Factor for Infection after Reconstruction and Augmentation with Autologous Bone Grafts in Craniomaxillofacial Surgery: A Retrospective Cohort Study.

Autologous bone grafts for reconstruction and augmentation are routinely used for maintaining functionality and facial aesthetics. Associated complications, however, have a significant impact on patients and health care systems. This study aims to investigate the possible risk factors associated with the occurrence of complications in order to provide evidence for the outcome of autologous bone graft reconstructive procedures. Patients from 2008 to 2018 who underwent autologous (mostly mandibular) reconstruction were included in the observational study. Clinical, pathological, and therapeutic factors were examined in univariate and multivariate analysis for significance with occurring complications. A multivariate model was used to create a prognostic model predicting the occurrence of complications. Graft complications requiring revision were exhibited by 33/128 patients. Infections were most frequent, with 4/22 patients affected by multi-resistant germs. Multivariate analysis showed radiotherapy (OR = 5.714; 95% CI: 1.839-17.752; p = 0.003), obstructive pulmonary disease (OPD) (OR = 4.329; 95% CI: 1.040-18.021; p = 0.044) and length of defect (in mm) (OR = 1.016; 95% CI: 1.004-1.028; p = 0.009) as independent risk factors associated with graft complications with high accuracy of prediction (AUC = 0.815). Intensive care (OR = 4.419; 95% CI: 1.576-12.388; p = 0.005) with a coefficient between intensive care and OPD (0.214) being low was identified as the most relevant risk factor for infection. Although intensive care is not a classic risk factor, but rather a summation of factors not reaching significance in the individual case, a stay in ICU (intensive care unit) needs to be considered for graft complications. As a clinical consequence, we recommend using the best possible hygienic measures during procedures e.g., while performing dressing and drainage changes in ICU.

Trabeculectomy offers better intraocular pressure reduction in intrapatient comparison to transscleral cyclophotocoagulation.

PURPOSE: Both trabeculotomy (TE) as well as transscleral endodiode laser cyclophotocoagulation (CPC) are common approaches in glaucoma surgery. The purpose of this study was to perform an intraindividual comparison of these procedures carried out by the same surgeon in the same patient on the same day. METHODS: An observational monocentric retrospective cohort study was conducted. Patients with a bilateral refractory open-angle glaucoma who underwent trabeculectomy in one eye and transscleral endodiode laser cyclophotocoagulation in the fellow eye simultaneously were included and followed up with over the course of 1 year. RESULTS: Eighty-two eyes of 41 patients were included. Seventeen patients (41.5%) were men and 24 (58.5%) women. The mean age was 68.7 ± 9.5 years. The diagnosis comprised 33 (80.5%) patients with a primary open-angle glaucoma, five (12.2%) patients with pseudoexfoliation glaucoma, and three (7.3%) patients with pigment dispersion glaucoma. A reduction in intraocular pressure (IOP) was seen in both after TE (from 26.2 ± 13.2 to 10.6 ± 4.1 mmHg, 52 weeks post-treatment) as well as CPC (from 24.2 ± 9.9 to 15.0 ± 5.4 mmHg, 52 weeks post-treatment). In comparison to each other, TE was significantly more effective in lowering the IOP (10.6 ± 4.1 vs. 13.4 ± 5.0; p = 0.0030, 52 weeks post-treatment) and needed antiglaucomatous medications (0.45 ± 0.80 vs. 1.24 ± 1.13; p = 0.0009, 52 weeks post-treatment). Consistently, the achievement rate of an IOP ≤ 16 mmHg without antiglaucomatous medications was significantly higher in TE-treated eyes (65.8% vs. 31.6%; p = 0.0019). Re-interventions, including 10 secondary TEs, were commonly required in those eyes undergoing CPC, especially in younger patients. CONCLUSIONS: Trabeculectomy was demonstrated to be more effective in reducing IOP in comparison to fellow eyes receiving CPC. In particular, in younger patients, an additional TE in the CPC-treated eyes was necessary. The outcome of those secondary TEs however was comparable to the primarily performed TEs. Our study thus supports the use of CPC as tool to control IOP, especially in the context of bilateral refractive glaucoma.

Effect of iloprost inhalation on postoperative outcome in high-risk cardiac surgical patients: a prospective randomized-controlled multicentre trial (ILOCARD).

PURPOSE: Perioperative right ventricular (RV) failure due to pressure overload from pulmonary hypertension (PH) worsens postoperative outcomes after cardiac surgery. Inhaled iloprost is a potent pulmonary vasodilator improving RV performance, ameliorating myocardial and pulmonary ischemia-reperfusion injury and attenuating inflammation. We hypothesized that the prophylactic inhalation of iloprost would reduce postoperative ventilation times after cardiac surgery. METHODS: In this phase III, multicentre, randomized, double-blind, placebo-controlled trial, we randomly assigned 253 cardiac surgical patients at high risk of perioperative RV failure to the prophylactic inhalation of 20 µg iloprost or placebo before and during weaning from extracorporeal circulation. The primary endpoint was the duration of postoperative ventilation. Secondary endpoints included perioperative hemodynamics, intensive care unit and hospital length of stay, and 90-day mortality. Safety was assessed by the incidence of adverse events. RESULTS: Iloprost had no significant effect on the median [interquartile range] duration of postoperative ventilation compared with placebo (720 [470-1170] min vs 778 [541-1219] min, respectively; median decrease, 65 min; 95% confidence interval [CI], - 77 to 210; P = 0.37). While the nebulization of iloprost decreased RV afterload and improved cardiac index, major secondary endpoints were not significantly affected. Ninety-day mortality occurred in 14% of the iloprost patients compared with 14% of the placebo patients (hazard ratio, 0.97; 95% CI, 0.50 to 1.89; P = 0.93). The incidence of adverse events was comparable in both groups. CONCLUSIONS: The prophylactic inhalation of iloprost did not meaningfully improve the outcome in high-risk cardiac surgical patients. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00927654); registered 25 June, 2009.

RéSUMé: OBJECTIF: L'insuffisance cardiaque droite périopératoire due à une surcharge de pression provoquée par l'hypertension pulmonaire (HP) a un impact négatif sur le pronostic postopératoire après une chirurgie cardiaque. L'iloprost administré par inhalation est un vasodilatateur pulmonaire puissant qui améliore la performance du ventricule droit (VD), réduisant ainsi la lésion d'ischémie-reperfusion myocardique et pulmonaire et atténuant l'inflammation. Nous avons émis l'hypothèse qu'une inhalation prophylactique d'iloprost réduirait les temps de ventilation postopératoire après une chirurgie cardiaque. MéTHODE: Dans cette étude multicentrique de phase III, contrôlée par placebo, à double insu et randomisée, nous avons distribué aléatoirement 253 patients chirurgicaux courant un risque élevé d'insuffisance cardiaque droite périopératoire à une prophylaxie de 20 µg d'iloprost ou d'un placebo par inhalation avant et pendant le sevrage de la circulation extracorporelle. Le critère d'évaluation principal était la durée de ventilation postopératoire. Les critères d'évaluation secondaires étaient les données hémodynamiques périopératoires, la durée de séjour à l'unité de soins intensifs et à l'hôpital, et la mortalité à 90 jours. L'innocuité a été évaluée en fonction de l'incidence d'événements indésirables. RéSULTATS: L'iloprost n'a pas eu d'effet significatif sur la durée médiane [écart interquartile] de ventilation postopératoire par rapport au placebo (720 [470­1170] min vs 778 [541­1219] min, respectivement; réduction médiane, 65 min; intervalle de confiance [IC] 95 %, − 77 à 210; P = 0,37). Bien que la nébulisation d'iloprost ait réduit la post-charge du VD et amélioré l'index cardiaque, cette manœuvre n'a pas eu d'impact significatif sur les critères d'évaluation secondaires majeurs. Une mortalité à 90 jours a été observée chez 14 % des patients ayant reçu de l'iloprost, comparativement à 14 % des patients ayant reçu un placebo (rapport de risque, 0,97; IC 95 %, 0,50 à 1,89; P = 0,93). L'incidence d'événements indésirables était comparable dans les deux groupes. CONCLUSION: L'inhalation prophylactique d'iloprost n'a pas amélioré le pronostic des patients de chirurgie cardiaque à haut risque. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT00927654); enregistrée le 25 juin 2009.

Effect of bupivacaine and adjuvant drugs for regional anesthesia on nerve tissue oximetry and nerve blood flow.

BACKGROUND: Nerve blood flow has a critical role in acute and chronic pathologies in peripheral nerves. Influences of local anesthetics and adjuvants on tissue perfusion and oxygenation are deemed as relevant factors for nerve damage after peripheral regional anesthesia. The link between low tissue perfusion due to local anesthetics and resulting tissue oxygenation is unclear. METHODS: Combined tissue spectrophotometry and laser-Doppler flowmetry were used to assess nerve blood flow in 40 surgically exposed median nerves in pigs, as well as nerve tissue oximetry for 60 min. After baseline measurements, test solutions saline (S), bupivacaine (Bupi), bupivacaine with epinephrine (BupiEpi), and bupivacaine with clonidine (BupiCloni) were applied topically. RESULTS: Bupivacaine resulted in significant decrease in nerve blood flow, as well as tissue oximetry values, compared with saline control. Addition of epinephrine resulted in a rapid, but nonsignificant, reduction of nerve blood flow and extensive lowering of tissue oximetry levels. The use of clonidine resulted in a reduction of nerve blood flow, comparable to bupivacaine alone (relative blood flow at T60 min compared with baseline, S: 0.86 (0.67-1.18), median (25th-75th percentile); Bupi: 0.33 (0.25-0.60); BupiCloni: 0.43 (0.38-0.63); and BupiEpi: 0.41(0.30-0.54). The use of adjuvants did not result in any relevant impairment of tissue oximetry values (saturation values in percent at T60, S: 91.5 [84-95]; Bupi: 76 [61-86]; BupiCloni: 84.5 [76-91]; and BupiEpi: 91 [56-92]). CONCLUSION: The application of bupivacaine results in lower nerve blood flow, but does not induce relevant ischemia. Despite significant reductions in nerve blood flow, the addition of clonidine or epinephrine to bupivacaine had no significant impact on nerve tissue oximetry compared with bupivacaine alone. Nerve ischemia due to local anesthetics is not enhanced by the adjuvants clonidine or epinephrine.

Safety and efficacy of immunotherapy with the recombinant B-cell epitope-based grass pollen vaccine BM32.

BACKGROUND: BM32 is a grass pollen allergy vaccine based on recombinant fusion proteins consisting of nonallergenic peptides from the IgE-binding sites of the 4 major grass pollen allergens and the hepatitis B preS protein. OBJECTIVE: We sought to study the safety and clinical efficacy of immunotherapy (allergen immunotherapy) with BM32 in patients with grass pollen-induced rhinitis and controlled asthma. METHODS: A double-blind, placebo-controlled, multicenter allergen immunotherapy field study was conducted for 2 grass pollen seasons. After a baseline season, subjects (n = 181) were randomized and received 3 preseasonal injections of either placebo (n = 58) or a low dose (80 µg, n = 60) or high dose (160 µg, n = 63) of BM32 in year 1, respectively, followed by a booster injection in autumn. In the second year, all actively treated subjects received 3 preseasonal injections of the BM32 low dose, and placebo-treated subjects continued with placebo. Clinical efficacy was assessed by using combined symptom medication scores, visual analog scales, Rhinoconjunctivitis Quality of Life Questionnaires, and asthma symptom scores. Adverse events were graded according to the European Academy of Allergy and Clinical Immunology. Allergen-specific antibodies were determined by using ELISA, ImmunoCAP, and ImmunoCAP ISAC. RESULTS: Although statistical significance regarding the primary end point was not reached, BM32-treated subjects, when compared with placebo-treated subjects, showed an improvement regarding symptom medication, visual analog scale, Rhinoconjunctivitis Quality of Life Questionnaire, and asthma symptom scores in both treatment years. This was accompanied by an induction of allergen-specific IgG without induction of allergen-specific IgE and a reduction in the seasonally induced increase in allergen-specific IgE levels in year 2. In the first year, more grade 2 reactions were observed in the active (n = 6) versus placebo (n = 1) groups, whereas there was almost no difference in the second year. CONCLUSIONS: Injections of BM32 induced allergen-specific IgG, improved clinical symptoms of seasonal grass pollen allergy, and were well tolerated.

Acetylcholine Receptor Antibody Titers and Clinical Course after Influenza Vaccination in Patients with Myasthenia Gravis: A Double-Blind Randomized Controlled Trial (ProPATIent-Trial).

BACKGROUND: It is a continuous matter of discussion whether immune activation by vaccination in general and Influenza vaccination in particular increases the risk for clinical deterioration of autoimmune diseases. This prospective study investigated the serological and clinical course of autoimmune Myasthenia gravis (MG) after a seasonal influenza vaccination. METHODS: This randomized, placebo-controlled, double-blind study enrolled MG patients with antibodies against acetylcholine-receptors (AChR-ab). They were allocated to receive seasonal influenza vaccine or placebo. The primary endpoint was the relative change of AChR-ab-titer over 12weeks. A relative increase of 20% was set as non-inferiority margin. Secondary endpoints were clinical changes in the modified Quantitative Myasthenia Gravis Score (QMG), increase of anti-influenza-ELISA-antibodies, and changes of treatment. The study is registered with Clinicaltrialsregister.eu, EudraCT number 2006-004374-27. FINDINGS: 62 patients were included. Mean±standard deviation (median) in the vaccine and placebo group were AChR-ab-titer changes of -6.0%±23.3% (-4.0%) and -2.8%±22.0% (-0.5%) and QMG score changes of -0.08±0.27 (0.17) and 0.11±0.31 (0.00), respectively. The difference between groups (Hodges-Lehmann estimate with 95% CI) was - for the AChR-ab-titer change 4·0% [-13.3%, 4.5%] (p=0.28 for testing a difference, p<0.0001 for testing non-inferiority) and for the QMG change 0·00 [-0.17, 0.00] (p=0.79 for testing a difference). The occurrence of 74 adverse events (AE) was comparable between groups. The most common AE was flu-like symptoms. One serious AE (hospitalisation following gastrointestinal haemorrhage) in the verum group was not related to the vaccine. INTERPRETATION: Influenza vaccination in MG is safe. Uprating the potential risk of a severe course of MG exacerbation during influenza infection compared to the 95% CI differences for the endpoints, vaccination is principally indicated in this patient population.

Calculating the individual probability of successful ocriplasmin treatment in eyes with VMT syndrome: a multivariable prediction model from the EXPORT study.

BACKGROUND/AIMS: To evaluate predictive factors for the treatment success of ocriplasmin and to use these factors to generate a multivariate model to calculate the individual probability of successful treatment. METHODS: Data were collected in a retrospective, multicentre cohort study. Patients with vitreomacular traction (VMT) syndrome without a full-thickness macular hole were included if they received an intravitreal injection (IVI) of ocriplasmin. Five factors (age, gender, lens status, presence of epiretinal membrane (ERM) formation and horizontal diameter of VMT) were assessed on their association with VMT resolution. A multivariable logistic regression model was employed to further analyse these factors and calculate the individual probability of successful treatment. RESULTS: 167 eyes of 167 patients were included. Univariate analysis revealed a significant correlation to VMT resolution for all analysed factors: age (years) (OR 0.9208; 95% CI 0.8845 to 0.9586; p<0.0001), gender (male) (OR 0.480; 95% CI 0.241 to 0.957; p=0.0371), lens status (phakic) (OR 2.042; 95% CI 1.054 to 3.958; p=0.0344), ERM formation (present) (OR 0.384; 95% CI 0.179 to 0.821; p=0.0136) and horizontal VMT diameter (µm) (OR 0.99812; 95% CI 0.99684 to 0.99941, p=0.0042). A significant multivariable logistic regression model was established with age and VMT diameter. CONCLUSION: Known predictive factors for VMT resolution after ocriplasmin IVI were confirmed in our study. We were able to combine them into a formula, ultimately allowing the calculation of an individual probability of treatment success with ocriplasmin in patients with VMT syndrome without FTHM.

Protocol for a prospective interventional trial to develop a diagnostic index test for stroke as a cause of vertigo, dizziness and imbalance in the emergency room (EMVERT study).

INTRODUCTION: Identifying stroke as a cause of acute vertigo, dizziness and imbalance in the emergency room is still a clinical challenge. Many patients are admitted to stroke units, but only a minority will have strokes. This imposes a heavy financial burden on the healthcare system. The aim of this study is to develop a diagnostic index test to identify patients with a high risk of having a stroke as the cause of acute vertigo and imbalance. METHODS AND ANALYSIS: Patients with acute onset of vertigo, dizziness, postural imbalance or double vision within the last 24 hours lasting for at least 10 min are eligible to be included in the study. Patients with clinically proven peripheral or central aetiology will be excluded. In the emergency room, all enrolled patients will undergo standardised neuro-ophthalmological/physiological testing (including video-oculography, mobile posturography, measurement of subjective visual vertical) (EMVERT block 1). Within 10 days, standardised MRI will be performed as a reference test to identify stroke (EMVERT block 2). Data from EMVERT block 2 will be compared with results from block 1 in order to devise a diagnostic index test with a high specificity and sensitivity to predict the risk of stroke in the emergency room. ETHICS AND DISSEMINATION: The study was approved by the ethics committee of the University of Munich and will be conducted according to the Guideline for Good Clinical Practice, the Federal Data Protecting Act and the Helsinki Declaration of the World Medical Association in its recent version. Study results are expected to be published in international peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: German Clinical Trial Register: DRKS00008992; Universal trial number: U1111-1172-8719); pre-results.

Effects of acetyl-DL-leucine on cerebellar ataxia (ALCAT trial): study protocol for a multicenter, multinational, randomized, double-blind, placebo-controlled, crossover phase III trial.

BACKGROUND: Cerebellar ataxia (CA) is a frequent and often disabling condition that impairs motor functioning and impacts on quality of life (QoL). No medication has yet been proven effective for the symptomatic or even causative treatment of hereditary or non-hereditary, non-acquired CA. So far, the only treatment recommendation is physiotherapy. Therefore, new therapeutic options are needed. Based on three observational studies, the primary objective of the acetyl-DL-leucine on ataxia (ALCAT) trial is to examine the efficacy and tolerability of a symptomatic therapy with acetyl-DL-leucine compared to placebo on motor function measured by the Scale for the Assessment and Rating of Ataxia (SARA) in patients with CA. METHODS/DESIGN: An investigator-initiated, multicenter, European, randomized, double-blind, placebo-controlled, 2-treatment 2-period crossover phase III trial will be carried out. In total, 108 adult patients who meet the clinical criteria of CA of different etiologies (hereditary or non-hereditary, non-acquired) presenting with a SARA total score of at least 3 points will be randomly assigned in a 1:1 ratio to one of two different treatment sequences, either acetyl-DL-leucine (up to 5 g per day) followed by placebo or vice versa. Each sequence consists of two 6-week treatment periods, separated by a 4-week wash-out period. A follow-up examination is scheduled 4 weeks after the end of treatment. The primary efficacy outcome is the absolute change in the SARA total score. Secondary objectives are to demonstrate that acetyl-DL-leucine is effective in improving (1) motor function measured by the Spinocerebellar Ataxia Functional Index (SCAFI) and SARA subscore items and (2) QoL (EuroQoL 5 dimensions and 5 level version, EQ-5D-5 L), depression (Beck Depression Inventory, BDI-II) and fatigue (Fatigue Severity Score, FSS). Furthermore, the incidence of adverse events will be investigated. DISCUSSION: The results of this trial will inform whether symptomatic treatment with the modified amino-acid acetyl-DL-leucine is a worthy candidate for a new drug therapy to relieve ataxia symptoms and to improve patient care. If superiority of the experimental drug to placebo can be established it will also be re-purposing of an agent that has been previously used for the symptomatic treatment of dizziness. TRIAL REGISTRATION: The trial was prospectively registered at www.clinicaltrialsregister.eu (EudraCT no. 2015-000460-34) and at https://www.germanctr.de (DRKS-ID: DRKS00009733 ).

Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival.

BACKGROUND: Somatostatin analogs have been shown to control the growth of well-differentiated metastatic neuroendocrine tumors. Their effect on overall survival is a matter of debate. We analyzed the prognostic significance of early treatment with octreotide LAR and of hepatic tumor load in the PROMID trial cohort. PATIENTS AND METHODS: Between 2001 and 2008, 85 treatment-naïve patients were randomly assigned to monthly octreotide LAR 30 mg or placebo until tumor progression or death. Post-study treatment was at the discretion of the investigator. Upon disease progression, 38 out of 43 placebo patients (88.4%) received octreotide LAR. For survival, patients were followed until May 2014. RESULTS: Forty-eight out of 85 patients (56.5%) died. In 38 patients (79.2%), death was tumor related. The median overall survival (84.7 and 83.7 months) was only slightly different in patients assigned to octreotide and placebo [HR = 0.83 (95% CI: 0.47-1.46); p = 0.51]. The median overall survival was 84.7 months for all 85 patients, 107.6 months in the low-tumor-load (n = 64) and 57.5 months in the high-tumor-load (n = 21) subgroups [HR = 2.49 (95% CI: 1.36-4.55); p = 0.002]. There was a trend towards improved overall survival in patients with a low hepatic tumor load receiving octreotide compared to placebo ['median not reached' and 87.2 months; HR = 0.59 (95% CI: 0.29-1.2); p = 0.142]. CONCLUSION: The extent of tumor burden is a predictor for shorter survival. Overall survival was similar in patients receiving octreotide LAR or placebo treatment at randomization. Crossover of the majority of placebo patients to octreotide LAR may have confounded the data on overall survival.

Salvage Treatment of Adrenocortical Carcinoma with Trofosfamide.

Adrenocortical carcinoma (ACC) has a dismal prognosis in advanced stages. Despite treatment with the adrenal toxicant mitotane and/or aggressive chemotherapy, tumor control is often short-lived. Here, we examine trofosfamide as a salvage treatment of ACC in an observational cohort study within the German ACC registry. Response defined as progression-free survival (PFS) at first tumor evaluation was assessed by RECIST 1.1 or clinically, and PFS and overall survival (OS) were estimated by the Kaplan-Meier method. Twenty-seven patients (11 males; median age 46.9 years) progressing after mitotane and three (median, range 0-5) other systemic treatments were evaluated for safety. Trofosfamide (150 mg/day) was administered as monotherapy (n = 13) or in combination with mitotane (n = 14). Overall tolerability was good with only mild adverse events. Six patients did not meet criteria for response assessment. Of the 21 patients, 8 patients had clinically progressive disease (3 deaths from ACC); among the 13 patients evaluable by RECIST 1.1, best response to treatment was stable disease (SD, n = 3) or progressive disease (n = 10). Hence, predefined response criteria were met in 3/21 patients (14 %). Median PFS was 84 days (95 % confidence interval 74-95) and median OS survival 198 days (95 % CI 89-307). One prolonged disease stabilization (best response by RECIST 1.1 -26 %) was observed for 479 days. In conclusion, trofosfamide is overall well tolerated but disease stabilization is rather rare. Accordingly, it may be used in selected cases of ACC not amenable to other treatment options such as clinical trials.