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The optimization of the targeting of a defined cortical region is a challenge in the current practice of transcranial magnetic stimulation (TMS). The dorsolateral prefrontal cortex (DLPFC) and the primary motor cortex (M1) are among the most usual TMS targets, particularly in its “therapeutic” application. This study describes a practical algorithm to determine the anatomical location of the DLPFC and M1 using a three-dimensional (3D) brain reconstruction provided by a TMS-dedicated navigation system from individual magnetic resonance imaging (MRI) data. The coordinates of the right and left DLPFC and M1 were determined in 50 normal brains (100 hemispheres) by five different investigators using a standardized procedure. Inter-rater reliability was good, with 95% limits of agreement ranging between 7 and 16mm for the different coordinates. As expressed in the Talairach space and compared with anatomical or imaging data from the literature, the coordinates of the DLPFC defined by our algorithm corresponded to the junction between BA9 and BA46, while M1 coordinates corresponded to the posterior border of hand representation. Finally, we found an influence of gender and possibly of age on some coordinates on both rostrocaudal and dorsoventral axes. Our algorithm only requires a short training and can be used to provide a reliable targeting of DLPFC and M1 between various TMS investigators. This method, based on an image-guided navigation system using individual MRI data, should be helpful to a variety of TMS studies, especially to standardize the procedure of stimulation in multicenter “therapeutic” studies. •Correct targeting may increase the therapeutic impact of TMS.•We developed original algorithms to precisely target the DLPFC and M1.•We located these areas in 50 brain MRIs, using a TMS-dedicated navigation system.•We found high inter-rater reliability and anatomical accuracy of our procedure.•Our algorithms can be useful for DLPFC and M1 targeting in TMS practice.

Objectives To assess MRI-pathology concordance and factors influencing tumour size measurement in breast cancer. Materials and methods MRI tumour size (greatest diameter in anatomical planes (MRI-In-Plane) and greatest diameter along main tumour axis (MRI-MPR)) of 115 consecutive breast lesions (59 invasive lobular carcinoma, 46 invasive ductal carcinoma, and 10 ductal carcinoma in situ) was retrospectively compared to size measured at histopathology (pT size (Path-TNM) and greatest tumour diameter as relevant for excision (Path-Diameter; reference standard)). Histopathological tumour types, preoperative palpability, surgical management, additional high-risk lesions, and BI-RADS lesion type (mass versus non-mass enhancements) were assessed as possible influencing factors. Results Systematic errors were most pronounced between MRI-MPR and Path-TNM (7.1 mm, limits of agreement (LoA) [-21.7; 35.9]), and were lowest between MRI-In-Plane and Path-Diameter (0.2 mm, LoA [-19.7; 20.1]). Concordance rate of MRI-In-Plane with Path-Diameter was 86 % (97/113), overestimation 9 % (10/113) and underestimation 5 % (6/113); BI-RADS mass lesions were overestimated in 7 % (6/81) versus 41 % (13/32) for non-mass enhancements. On multivariate analysis only BI-RADS lesion type significantly influenced MRI-pathology concordance ( p  < 0.001). 2/59 (3 %) ILC did not enhance. Conclusion Concordance rate varies according to the execution of MRI and histopathological measurements. Beyond this only non-mass enhancement significantly predicted discordance. Key Points • Execution and scope of MRI and histopathological size measurements influence concordance rate. • Non-mass like enhancement predicts discordance. • Additional high-risk lesions in proximity of tumour do not cause measurement discordance. • Low percentage of ILC do not enhance at all.

BackgroundAlthough the long-term efficacy, tolerability, and safety of methotrexate (MTX) in patients with rheumatoid arthritis (RA) are well documented, the clinical response and incidence of adverse events (AE) vary. Data on adherence to MTX in RA patients vary between retention rate of 35% to 80% in 5 years. In addition to aspects of safety, important determinants for continuing MTX therapy are patient-associated factors including individual treatment preferences and expectations.ObjectivesThis study investigated treatment expectations in RA patients who were about to start therapy with MTX, and aim to identify variables associated with discontinuation of MTX.MethodsConsecutive patients with RA who were about to start MTX were prospectively included after informed consent. Treatment expectations, medication-related beliefs and AE, treatment satisfaction and health–related quality of life were assessed using the generic rating scale for previous experiences, expectations and effects of treatment (G-EEE), the general assessment of side effects (GASE), the beliefs about medicines questionnaire (BMQ), the treatment satisfaction questionnaire for medication (TSQM) and the EuroQol-5 dimensions (EQ-5D) before treatment initiation (T0), and after 3 months (T1). Treatment adherence to MTX was checked at month 6 (T2). Associations treatment expectations and adherence to MTX were explored by regression analyses.ResultsA total of n=100 consecutive RA patients before starting MTX treatment were included (table 1). A history of inadequate response to sulfasalazine was determined in n=6 (6%) and to hydroxychloroquine in n=1 patient, respectively. At T0, patients perceived the need for treatment with MTX as high, and they were only moderately concerned regarding potential adverse events of this therapy. Treatment expectations regarding the decrease of pain levels and development of adverse events did not differ much between T0 and T1, when disease activity had significantly decreased and physical function increased. MTX was withdrawn in 3 out of 59 patients (5.0%) and in 13 out of 64 patients (20.3%) assessed at T1 and T2, respectively, with a mean of 16.0 (5.9) weeks after treatment initiation. The most frequent reason for discontinuation of MTX was the occurrence of adverse events (n=12) followed by infections or malignancies (both n=2). There was no significant relationship between patients’ treatment expectations reported at T0 and their adherence to MTX at T2.ConclusionIn this study, we found no evidence for the assumption that patients’ expectations before the start of MTX did substantially influence adherence to treatment.Table 1.Patients and disease characteristicsVariables*T0 Treatment initiation (n=100)T1 (n=59)Age, in years59.1 (11.5)Gender female, n (%)55 (55%)Education, university level, n (%)17 (17%)Employment, n (%)59 (59%)Time (months) since RA symptoms11.9 (25.3)BMI, kg/m2,25.6 (4.2)No. of patients using GC n (%)56 (56.6%)Prednisolone dosage, mg/d8.8 (10.1)ACPA positive (%)42CRP, mg/dl1.9 (2.2)0.5 (0.7)Pain, 0-106.4 (2.2)3.0 (2.1)Patient global assessment (PtGA), 0-106.3 (2.3)3.7 (2.3)DAS-28-CRP4.7 (0.8)3.0 (0.8)RADAI-55.6 (1.9)3.9 (1.9)FFbH, 0-10065.2 (21.1)83.5 (16.8)G-EEE, improvement8.6 (1.9)8.2 (2.1)G-EEE, adverse events2.1 (1.9)2.9 (2.7)GASE-P total0.5 (4.4)12.2 (10.2)BMQ necessity score, 5-2518.4 (3.6)19.1 (3.2)BMQ concern score, 5-2514.3 (3.8)15.8 (3.9)RAID6.1 (2.1)3.2 (1.8)given as mean (SD), otherwise indicatedREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Purpose Due to the demographic shift, the number of older people suffering from hearing loss and from cognitive impairment increases. Both are closely related and hard to differentiate as most standard cognitive test batteries are auditory-based and hearing-impaired individuals perform worse also in non-auditory test batteries. Therefore, reference data for hearing-impaired are mandatory. Methods The computer-based battery ALAcog assesses multiple cognitive domains, such as attention, (delayed) memory, working memory, inhibition, processing speed, mental flexibility and verbal fluency. A data set of 201 bilaterally hearing-impaired subjects aged ≥ 50 (mean 66.6 (SD 9.07)) was analysed. The LMS method, estimated curves for the 10th, 25th, 50th, 75th and 90th percentile were calculated, and classified according to age, starting from the age of 50. Results Cognitive function shows a decline in all subtests as people age, except for verbal fluency, which remains almost stable over age. The greatest declines were seen in recall and delayed recall and in mental flexibility. Age and hearing ability did not correlate ( p  = 0.68). However, as people age, inter-subject variability of cognitive test results increases. This was especially the case for inhibition. Cognitive function was not correlated with hearing ability (each p  ≥ 0.13). Conclusion The present results make an approach to establish reference data for a comprehensive non-auditory test battery in a large sample of elderly hearing-impaired people which can be used as a simple tool to better contextualise cognitive performance beyond mean and median scores.

Purpose In contrast to adults, immune protection against SARS-CoV-2 in children and adolescents with natural or hybrid immunity is still poorly understood. The aim of this study was to analyze different immune compartments in different age groups and whether humoral immune reactions correlate with a cellular immune response. Methods 72 children and adolescents with a preceding SARS-CoV-2 infection were recruited. 37 were vaccinated with an RNA vaccine (BNT162b2). Humoral immunity was analyzed 3–26 months (median 10 months) after infection by measuring Spike protein (S), nucleocapsid (NCP), and neutralizing antibodies (nAB). Cellular immunity was analyzed using a SARS-CoV-2-specific interferon-γ release assay (IGRA). Results All children and adolescents had S antibodies; titers were higher in those with hybrid immunity (14,900 BAU/ml vs. 2118 BAU/ml). NCP antibodies were detectable in > 90%. Neutralizing antibodies (nAB) were more frequently detected (90%) with higher titers (1914 RLU) in adolescents with hybrid immunity than in children with natural immunity (62.5%, 476 RLU). Children with natural immunity were less likely to have reactive IGRAs (43.8%) than adolescents with hybrid immunity (85%). The amount of interferon-γ released by T cells was comparable in natural and hybrid immunity. Conclusion Spike antibodies are the most reliable markers to monitor an immune reaction against SARS-CoV-2. High antibody titers of spike antibodies and nAB correlated with cellular immunity, a phenomenon found only in adolescents with hybrid immunity. Hybrid immunity is associated with markedly higher antibody titers and a higher probability of a cellular immune response than a natural immunity.

Objective: The objective of this study was to investigate the effects of recorded lullabies and taped maternal voice in premature infants. Study design: Sixty-two preterm infants in a stable condition with 30<37 weeks of gestation and <10 days of postnatal age were randomly assigned to hear (A) recorded lullabies or (B) taped maternal voice for 30 min each evening during 14 consecutive days or (C) receive no standardized acoustic stimulation (control group). Heart rate and respiratory rate were recorded daily before, during and after the intervention (A and B) or a comparable period with no intervention (C), whereas activity was measured on days 1, 7 and 14 of the intervention using accelerometers. Results: Both interventions led to a significant decrease in heart rate and respiratory rate during and after the stimulation when compared with the control group. The changes were more pronounced in infants with higher gestational ages ( P =0.001). Lower activity was measured during the intervention when compared with the control group ( P <0.01). Conclusions: Standardized acoustic stimulation with recorded lullabies and taped maternal voice led to a decrease in heart rate and respiratory rate, and was associated with lower activity. Whether this indicates a reduced stress reaction needs to be investigated in further studies.

IntroductionMPFL reconstruction is widely and successfully used for treating patella instability, either as a standalone procedure or in combination. Although different techniques allow for MPFL reconstruction, the use of a free tendon graft is one of the most commonly used. The phenomenon of tunnel widening or tunnel enlargement is well described in ACL reconstruction, but so far only little effort has been put into evaluating this phenomenon after MPFL reconstruction.Materials and methodsPatients who received an MPFL reconstruction with a free gracilis tendon graft were identified by review of patient files. Additional clinical examination and magnetic resonance imaging were performed to assess tunnel enlargement and clinical outcome.ResultsFifty-one knees of 49 patients (34 female, 17 male) with a mean follow-up of 3.0 ± 1.4 years were included in this study. Mean age at the time of surgery was 22.6 ± 8.5 years. Mean Tegner score decreased from preoperative 5.3 ± 2.0 to 4.0 ± 1.4 postoperative. Postoperative IKDC and Kujala scores were 74 ± 16 and 80 ± 15, respectively. Twenty-three patients showed a tunnel enlargement at follow-up examination. Of these 23 patients, 20 showed a tunnel that was positioned too proximal, whereas only 13 of the 28 patients showing no enlargement had a tunnel that was positioned too proximal (p = 0.0033). Interestingly, patients showing a tunnel enlargement at follow-up examination also showed significantly better Kujala (84 ± 12 vs. 75 ± 16; p = 0.03) and IKDC scores (80 ± 7 vs. 70 ± 19; p = 0.02) when compared to the non-enlarged group.ConclusionTunnel enlargement after MPFL reconstruction with a free gracilis tendon graft seems to be connected to mechanical overload due to a proximal malposition of the femoral tunnel. Interestingly, this did not influence clinical outcome as patients with tunnel enlargement showed better Kujala and IKDC scores.

IntroductionWeight restoration is a primary goal in anorexia nervosa (AN) treatment. Recent studies suggest that addressing physical activity urges in patients with AN is a promising target to facilitate weight restoration. This trial will evaluate the feasibility of a virtual reality (VR)-based intervention as an add-on treatment to psychotherapy to improve activity urges and, consequently, initial treatment responses on core outcomes as targeted per AN treatment guidelines.Methods and analysisThis single-centre feasibility trial adopts the single-blind, two-arm design and outcome measures of an intended full-scale randomised controlled trial (RCT) in order to establish that all necessary trial components work together as intended. It will evaluate feasibility as the primary endpoint and compare changes in ratings of the urge to be active between patients with AN randomly assigned to receiving VR intervention sessions and patients with AN in a control procedure. The feasibility of the full-scale RCT will depend on whether patients (1) will evaluate the experience as acceptable, (2) tolerate VR side effects and (3) will adhere to the intended intervention schedule. We define a set of three-tiered, formal progression criteria and employ a ‘traffic light system’ demarcating go (green), amend (amber) and stop (red) signals for advancing to the full-scale RCT.Ethics and disseminationThe study was approved by the ethics committee of the Ruhr University Bochum’s Medical Faculty at Campus East-Westphalia (AZ 2024-1296, 9 December 2024). Patients have to provide written consent before taking part in the study. The findings will be published with open access.Trial registration numberDRKS00035681, German Clinical Trials Register.

Due to their sub-normally low fat mass, leptin levels in patients with acute anorexia nervosa (AN) are well below reference levels for age and sex-matched controls. This hypoleptinemia entails endocrinological and behavioral characteristics observed in AN patients during starvation. We aimed to study the appropriateness of hypoleptinemia as a diagnostic marker for AN by assessing sensitivity, specificity and likelihood ratios for different referral serum leptin levels for predicting anorexia nervosa and healthy leanness. For prediction, we additionally generated a score based on a multivariate logistic model including body mass index (BMI; kg/m²) and leptin level. For this purpose, we measured leptin levels in 74 female patients with acute AN upon admission for inpatient or outpatient treatment. Adolescent and adult patients were recruited according to DSM-IV criteria from two multi-center studies. Additionally, leptin levels were measured in 65 female healthy, lean students. Mean serum leptin level was significantly decreased in patients with AN compared to underweight controls (0.87 ± 0.90 vs. 6.43 ± 3.55 μg/L, p < 0.001). Leptin predicted AN independently of BMI; we confirmed a cutoff value in the range of 2 μg/L as having both high specificity and sensitivity. Hypoleptinemia represents a state marker of acute AN and is useful for a laboratory-based diagnostic screening.

In-patient treatment (IP) is the treatment setting of choice for moderately-to-severely ill adolescents with anorexia nervosa, but it is costly, and the risks of relapse and readmissions are high. Day patient treatment (DP) is less expensive and might avoid problems of relapse and readmission by easing the transition from hospital to home. We investigated the safety and efficacy of DP after short inpatient care compared with continued IP. For this multicentre, randomised, open-label, non-inferiority trial, we enrolled female patients (aged 11–18 years) with anorexia nervosa from six centres in Germany. Patients were eligible if they had a body-mass index (BMI) below the tenth percentile and it was their first admission to hospital for anorexia nervosa. We used a computer-generated randomisation sequence to randomly assign patients to continued IP or DP after 3 weeks of inpatient care (1:1; stratified for age and BMI at admission). The treatment programme and treatment intensity in both study groups were identical. The primary outcome was the increase in BMI between the time of admission and a 12-month follow-up adjusted for age and duration of illness (non-inferiority margin of 0·75 kg/m2). Analysis was done by modified intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number Register, number ISRCTN67783402, and the Deutsches Register Klinischer Studien, number DRKS00000101. Between Feb 2, 2007, to April 27, 2010, we screened 660 patients for eligibility, 172 of whom we randomly allocated to treatment: 85 to IP and 87 to DP. DP was non-inferior to IP with respect to the primary outcome, BMI at the 12-month follow-up (mean difference 0·46 kg/m2 in favour of DP (95% CI, −0·11 to 1·02; pnon-inferiority<0·0001). The number of treatment-related serious adverse events was similar in both study groups (eight in the IP group, seven in the DP group). Three serious adverse events in the IP group and two in the DP group were related to suicidal ideation; one patient in the DP attempted suicide 3 months after she was discharged. DP after short inpatient care in adolescent patients with non-chronic anorexia nervosa seems no less effective than IP for weight restoration and maintenance during the first year after admission. Thus, DP might be a safe and less costly alternative to IP. Our results justify the broad implementation of this approach. German Ministry for Education and Research.