Secukinumab in patients with moderate to severe hidradenitis suppurativa based on prior biologic exposure: An efficacy and safety analysis from the SUNSHINE and SUNRISE phase III trials.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease associated with a substantial disease burden. Secukinumab has previously been reported to have sustained efficacy with a favourable safety profile in patients with moderate to severe HS. It is unknown if prior biologic exposure impacts the efficacy and safety of secukinumab. OBJECTIVES: To investigate the efficacy and safety of secukinumab in patients with moderate to severe HS based on prior exposure to biologics. METHODS: This was an analysis of the SUNSHINE and SUNRISE phase III trials of secukinumab in patients with moderate to severe HS. Patients were randomized at baseline to receive secukinumab every 2 (SECQ2W) or 4 weeks (SECQ4W), or placebo for 16 weeks. After week 16, patients receiving SECQ2W and SECQ4W remained on the same treatment regimen, while patients randomized to placebo were switched to either SECQ2W or SECQ4W up to week 52. Assessments based on prior exposure to biologics included HS clinical response (HiSCR), abscess and inflammatory nodule (AN) count, flare rates, HS-related pain (numeric rating scale [NRS]) 30], international HS severity scoring system (IHS4), dermatology life quality index, European quality of life five-dimension, and safety. RESULTS: Overall, 1084 patients were randomized in the SUNSHINE and SUNRISE trials and included in this analysis, with 255 (23.5%) patients being biologic experienced (SECQ2W [N=80]; SECQ4W [N=81]; placebo [N=94]) and 829 (76.5%) being biologic-naïve (SECQ2W [N=281]; SECQ4W [N=279]; placebo [N=269]). At week 16, responses were more efficacious for secukinumab compared with placebo for HiSCR in patients who were biologic-experienced (SECQ2W, 37.0% [odds ratio (OR): 1.60; 95% confidence interval (CI): 0.83, 3.08]; SECQ4W, 38.8% [OR: 1.67; 95% CI: 0.86, 3.22; placebo, 27.3%) and biologic-naive (SECQ2W, 45.6% [OR: 1.64; 95% CI: 1.15, 2.33]; SECQ4W, 45.4% [OR: 1.61; 95% CI: 1.13, 2.29]; placebo, 34.2%). Similar results were observed for AN count, NRS30, and IHS4-55. The higher response seen at week 16 with secukinumab was sustained, with a trend for improvement over time, through week 52 in both subgroups. Additional efficacy was observed for quality-of-life assessments, and no differences in safety between subgroups were observed. CONCLUSIONS: Regardless of prior biologic exposure, secukinumab was efficacious in improving signs and symptoms of HS. This finding positions secukinumab as the first option in patients who are biologic-naïve, as well as in patients who have previously been treated with other biologic therapy, based on individual patient needs. TRIAL REGISTRATION: SUNSHINE (NCT03713619) and SUNRISE (NCT03713632).

A Bayesian approach to clinical trial designs in dermatology with multiple simultaneous treatments per subject and multiple raters.

We consider the statistical analysis of clinical trial designs with multiple simultaneous treatments per subject and multiple raters. The work is motivated by a clinical research project in dermatology where different hair removal techniques were assessed based on a within-subject comparison. We assume that clinical outcomes are assessed by multiple raters as continuous or categorical scores, e.g. based on images, comparing two treatments on the subject-level in a pairwise manner. In this setting, a network of evidence on relative treatment effects is generated, which bears strong similarities to the data underlying a network meta-analysis of clinical trials. We therefore build on established methodology for complex evidence synthesis and propose a Bayesian approach to estimate relative treatment effects and to rank the treatments. The approach is, in principle, applicable to situations with any number of treatment arms and/or raters. As a major advantage, all available data is brought into a network and analyzed in one single model, which ensures consistent results among the treatment comparisons. We obtain operating characteristics via simulation and illustrate the method with a real clinical trial example.

Secukinumab in moderate-to-severe hidradenitis suppurativa (SUNSHINE and SUNRISE): week 16 and week 52 results of two identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials.

BACKGROUND: Few therapeutic options are available for patients with moderate-to-severe hidradenitis suppurativa. We aimed to assess the efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa in two randomised trials. METHODS: SUNSHINE and SUNRISE were identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials done in 219 primary sites in 40 countries. Patients aged 18 years old or older with the capacity to provide written informed consent and with moderate-to-severe hidradenitis suppurativa (defined as a total of ≥5 inflammatory lesions affecting ≥2 distinct anatomical areas) for at least 1 year were eligible for inclusion. Included patients also agreed to daily use of topical over-the-counter antiseptics on the areas affected by hidradenitis suppurativa lesions while on study treatment. Patients were excluded if they had 20 or more fistulae at baseline, had ongoing active conditions requiring treatment with prohibited medication (eg, systemic biological immunomodulating treatment, live vaccines, or other investigational treatments), or met other exclusion criteria. In both trials, patients were randomly assigned (1:1:1) by means of interactive response technology to receive subcutaneous secukinumab 300 mg every 2 weeks, subcutaneous secukinumab 300 mg every 4 weeks, or subcutaneous placebo all via a 2 mL prefilled syringe in a double-dummy method as per treatment assignment. The primary endpoint was the proportion of patients with a hidradenitis suppurativa clinical response, defined as a decrease in abscess and inflammatory nodule count by 50% or more with no increase in the number of abscesses or in the number of draining fistulae compared with baseline, at week 16, assessed in the overall population. Hidradenitis suppurativa clinical response was calculated based on the number of abscesses, inflammatory nodules, draining fistulae, total fistulae, and other lesions in the hidradenitis suppurativa affected areas. Safety was assessed by evaluating the presence of adverse events and serious adverse events according to common terminology criteria for adverse events, which were coded using Medical Dictionary for Regulatory Activities terminology. Both the SUNSHINE, NCT03713619, and SUNRISE, NCT03713632, trials are registered with ClinicalTrials.gov. FINDINGS: Between Jan 31, 2019, and June 7, 2021, 676 patients were screened for inclusion in the SUNSHINE trial, of whom 541 (80%; 304 [56%] women and 237 [44%] men; mean age 36·1 years [SD 11·7]) were included in the analysis (181 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 180 [33%] in the placebo group). Between the same recruitment dates, 687 patients were screened for inclusion in the SUNRISE trial, of whom 543 (79%; 306 [56%] women and 237 [44%] men; mean age 36·3 [11·4] years) were included in the analysis (180 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 183 [34%] in the placebo group). In the SUNSHINE trial, significantly more patients in the secukinumab every 2 weeks group had a hidradenitis suppurativa clinical response (rounded average number of patients with response in 100 imputations, 81·5 [45%] of 181 patients) compared with the placebo group (60·7 [34%] of 180 patients; odds ratio 1·8 [95% CI 1·1-2·7]; p=0·0070). However, there was no significant difference between the number of patients in the secukinumab every 4 weeks group (75·2 [42%] of 180 patients) and the placebo group (1·5 [1·0-2·3]; p=0·042). Compared with the placebo group (57·1 [31%] of 183 patients), significantly more patients in the secukinumab every 2 weeks group (76·2 [42%] of 180 patients; 1·6 [1·1-2·6]; p=0·015) and the secukinumab every 4 weeks group (83·1 [46%] of 180 patients; 1·9 [1·2-3·0]; p=0·0022) had a hidradenitis suppurativa clinical response in the SUNRISE trial. Patient responses were sustained up to the end of the trials at week 52. The most common adverse event by preferred term up to week 16 was headache in both the SUNSHINE (17 [9%] patients in the secukinumab every 2 weeks group, 20 [11%] in the secukinumab every 4 weeks group, and 14 [8%] in the placebo group) and SUNRISE (21 [12%] patients in the secukinumab every 2 weeks group, 17 [9%] in the secukinumab every 4 weeks group, and 15 [8%] in the placebo group) trials. No study-related deaths were reported up to week 16. The safety profile of secukinumab in both trials was consistent with that previously reported, with no new or unexpected safety findings detected. INTERPRETATION: When given every 2 weeks, secukinumab was clinically effective at rapidly improving signs and symptoms of hidradenitis suppurativa with a favourable safety profile and with sustained response up to 52 weeks of treatment. FUNDING: Novartis Pharma.

Hospital Admission and Discharge: Lessons Learned from a Large Programme in Southwest Germany.

Introduction: In the context of a GP-based care programme, we implemented an admission, discharge and follow-up programme. Description: The VESPEERA programme consists of three sets of components: pre-admission interventions, in-hospital interventions and post-discharge interventions. It was aimed at all patients with a hospital stay participating in the GP-based care programme and was implemented in 7 hospitals and 72 general practices in southwest Germany using a range of strategies. Its' effectiveness was evaluated using readmissions within 90 days after discharge as primary outcome. Questionnaires with staff were used to explore the implementation process. Discussion: A statistically significant effect was not found, but the effect size was similar to other interventions. Intervention fidelity was low and contextual factors affecting the implementation, amongst others, were available resources, external requirements such as legal regulations and networking between care providers. Lessons learned were derived that can aid to inform future political or scientific initiatives. Conclusion: Structured information transfer at hospital admission and discharge makes sense but the added value in the context of a GP-based programme seems modest. Primary care teams should be involved in pre- and post-hospital care.

Predictive value of neutrophil-to-lymphocyte-ratio in neoadjuvant-treated patients with breast cancer.

PURPOSE: Breast cancer (BC) is the most common malignancy among women and prognosis is strongly influenced by tumor subtype. Neoadjuvant chemotherapy (NAC) is the standard treatment for both locally advanced- and early-stage triple-negative and Her2-positive BC. Pathologic complete response (pCR) to NAC is an important predictor of patient outcomes. Neutrophil-to-lymphocyte-ratio (NLR) in peripheral blood is associated with prognosis in various malignancies. Here, we investigated the value of the pretreatment NLR as a response predictor in neoadjuvant-treated patients with BC. METHODS: A retrospective chart analysis of 862 patients with invasive BC treated with NAC at the Heidelberg University Hospital during 2003-2015 was conducted. NLR was calculated as the ratio of the absolute neutrophil and lymphocyte counts in peripheral blood, and pCR was defined as absence of invasive or in situ carcinoma in breast and axillary lymph nodes. RESULTS: A total of 151 patients with invasive BC who underwent NAC were included in this study. NLR tended to be higher in the pCR group than the non-pCR group (p < 0.1). Analyses of BC subtypes demonstrated that NLR was significantly higher in the pCR- compared with the non-pCR group (3.304 vs. 2.379, respectively; p = 0.048) in patients with luminal B/Her2-negative tumors. Further, we found a significant difference in NLR according to remission status in postmenopausal patients (2.861 vs. 2.313, respectively; p = 0.043). CONCLUSION: NLR was significantly higher only for patients achieving pCR in the Luminal B/Her2-negative and postmenopausal subgroups. Hence, NLR is a candidate additional predictive factor in patients with Luminal B/Her2-negative BC.

UV Irradiation of Nevi: Impact on Performance of Electrical Impedance Spectroscopy and a Convolution Neural Network.

Introduction: UV irradiation of nevi induces transient melanocytic activation with dermoscopic and histological changes. Objectives: We investigated whether UV irradiation of nevi may influence electrical impedance spectroscopy (EIS) or convolution neural networks (CNN). Methods: Prospective, controlled trial in 50 patients undergoing phototherapy (selective UV phototherapy (SUP), UVA1, SUP/UVA1, or PUVA). EIS (Nevisense, SciBase AB) and CNN scores (Moleanalyzer-Pro, FotoFinder Systems) of nevi were assessed before (V1) and after UV irradiation (V2). One nevus (nevusirr) was exposed to UV light, another UV-shielded (nevusnon-irr). Results: There were no significant differences in EIS scores of nevusirr before (2.99 [2.51-3.47]) and after irradiation (3.32 [2.86-3.78]; P = 0.163), which was on average 13.28 (range 4-47) days later. Similarly, UV-shielded nevusnon-irr did not show significant changes of EIS scores (V1: 2.65 [2.19-3.11]), V2: 2.92 [2.50-3.34]; P = 0.094). Subgroup analysis by irradiation revealed a significant increase of EIS scores of nevusirr (V1: 2.69 [2.21-3.16], V2: 3.23 [2.72-3.73]; P = 0.044) and nevusnon-irr (V1: 2.57 [2.07-3.07], V2: 3.03 [2.48-3.57]; P = 0.033) for patients receiving SUP. In contrast, CNN scores of nevusirr (P = 0.995) and nevusnon-irr (P = 0.352) showed no significant differences before and after phototherapy. Conclusions: For the tested EIS system increased EIS scores were found in nevi exposed to SUP. In contrast, CNN results were more robust against UV exposure.

Impact of a synchronous prophylactic treatment of the anterior accessory saphenous vein on the recurrent varicose vein rate in patients undergoing thermal ablation of an insufficient great saphenous vein (SYNCHRONOUS-Study): study protocol for a prospective, multicentre, controlled observational study.

INTRODUCTION: To date, there are no prospective studies evaluating the prevention of recurrent veins by the simultaneous treatment of a sufficient anterior accessory saphenous vein (AASV) in patients undergoing endovenous laser ablation (EVLA) of an insufficient great saphenous vein (GSV). This study will provide important information about the impact of the AASV on the development of recurrent veins after EVLA of the GSV. Additionally, it will be clarified whether patients benefit from a preventive ablation of a sufficient AASV. METHODS AND ANALYSIS: This is a multicentre, prospective, controlled, exploratory clinical study in 1150 patients with a medical indication for EVLA of a refluxing great saphenous vein. Patients will be enrolled into two study groups: in half of the patients EVLA will be performed on the insufficient GSV only. In the other half of the patients EVLA will be performed on the insufficient GSV and additionally on the sufficient AASV. Within seven study visits, patients will be followed-up over a time period of 5 years. Primary study endpoint is the recurrence rate; secondary endpoints include inter alia, complication rate, postoperative pain intensity, quality of life and patient satisfaction. ETHICS AND DISSEMINATION: Before initiation of the study, the protocol was presented and approved by the independent ethics committee of the medical faculty of the University of Heidelberg (Ethics approval number S-596/2018). This study was prospectively registered at the German Clinical Trial Register (https://www.germanctr.de/). Research findings will be disseminated in a peer-reviewed journal and at relevant conferences. TRIAL REGISTRATION NUMBER: German Clinical Trial Registry (DRKS00015486).

Near-Adult Heights and Adult Height Predictions Using Automated and Conventional Greulich-Pyle Bone Age Determinations in Children with Chronic Endocrine Diseases.

OBJECTIVES: To validate adult height predictions (BX) using automated and Greulich-Pyle bone age determinations in children with chronic endocrine diseases. METHODS: Heights and near-adult heights were measured in 82 patients (48 females) with chronic endocrinopathies at the age of 10.45 ± 2.12 y and at time of transition to adult care (17.98 ± 3.02 y). Further, bone age (BA) was assessed using the conventional Greulich-Pyle (GP) method by three experts, and by BoneXpert™. PAH were calculated using conventional BP tables and BoneXpert™. RESULTS: The conventional and the automated BA determinations revealed a mean difference of 0.25 ± 0.72 y (p = 0.0027). The automated PAH by BoneXpert™ were 156.26 ± 0.86 cm (SDS - 2.01 ± 1.07) in females and 171.75 ± 1.6 cm (SDS - 1.29 ± 1.06) in males, compared to 153.95 ± 1.12 cm (SDS - 2.56 ± 1.5) in females and 169.31 ± 1.6 cm (SDS - 1.66 ± 1.56) in males by conventional BP, respectively and in comparison to near-adult heights 156.38 ± 5.84 cm (SDS - 1.91 ± 1.15) in females and 168.94 ± 8.18 cm (SDS - 1.72 ± 1.22) in males, respectively. CONCLUSION: BA ratings and adult height predictions by BoneXpert™ in children with chronic endocrinopathies abolish rater-dependent variability and enhance reproducibility of estimates thereby refining care in growth disorders. Conventional methods may outperform automated analyses in specific cases.

Pre-Post Effects of the Psychoeducational, Autism-Specific Parent Training FAUT-E.

Objective: Psychoeducational parent training is an economic way to provide care for parents of children newly diagnosed with an autism spectrum disorder (ASD). This study explores pre-post effect sizes of the manualized autism-specific parent training FAUT-E (Frankfurter Autismus-Elterntraining). Method: Two behaviorally trained therapists worked with 6-10 parents in eight group sessions. Twenty-four parents of 24 children with ASD participated in the study. Outcomes were child- and parent-related measures obtained at T0 (first measurement), T1 (second measurement), T2 (postintervention), and T3 (3 months after intervention). Results: Children showed improved behavior in the parent-rated Aberrant Behavior Checklist (ABC) total score after therapy (p = .001; ES T1T2 = .73) and at T3 (p = .018; ES T1-T3 = -.51), and a lower intensity of parent-rated problem behavior at T3 (p = .031; ES T1-T3 = -.46). Parental measures did not change. Conclusions: This study found medium pre-post effects on the child's behavior by FAUT-E between T1 and T2/T3; these were not observed between the measurements T0-T1. FAUT-E was easy to implement and did not increase parental stress. This is in line with results of studies on other training programs to teach parents to use effective behavioral strategies with ASD.

A standardised computed tomography measurement method for distal fibular rotation.

PURPOSE: The aim of the study is to identify an ideal location to measure fibular rotation in the ankle joint using axial computed tomography (CT) scans. Another objective was to detect the average fibular rotation in the uninjured ankle joint in a large cohort. METHODS: Standardised axial CT with coronal/sagittal reconstructions was performed in healthy ankle joints. Three investigators performed the measurements. In the axial view, each investigator appointed the ideal location to measure the angle of fibular rotation with the use of reference lines either 4, 6, 8 or 10 mm distal from the talar joint line. Inter- and intraobserver reliability, as well as the intraclass correlation coefficient, were determined. RESULTS: CT scans of one hundred individuals-78 males and 22 females-were analysed. The most common locations for measuring the fibular rotation were in 31% of cases 4 mm and in 51% of cases 6 mm distal the talar joint line. The external rotation of the fibula averaged 8.42° ± 4.86° (range 0°-26°). The intraclass coefficient correlations (ICC) for interrater and intrarater reliability were 0.75. CONCLUSIONS: The results of the study demonstrate a reproducible location to measure the fibular rotation in the ankle joint. The most convenient location to measure fibular rotation with a high reliability was 6 mm distal to the talar joint line.

The onset of active disease in systemic lupus erythematosus patients is characterised by excessive regulatory CD4+-T-cell differentiation.

OBJECTIVES: An imbalance between CD4+-regulatory T-cells (Tregs) and CD4+-responder T-cells (Tresps) correlates with active disease flares in systemic lupus erythematosus (SLE) patients. Both cell subsets consist of highly proliferating Tregs/Tresps expressing inducible T-cell co-stimulatory molecule (ICOS) and less proliferating ICOS--Tregs/Tresps. METHODS: Six-colour-flow-cytometric analysis was used to examine the effect of ICOS+- and ICOS--Treg/Tresp cell differentiation on the composition of the total CD4+-T-helper cell pool with ICOS+- and ICOS--Tregs/Tresps. Functionality of Tregs was examined using suppression assays. RESULTS: In 83 healthy volunteers, the ratio of ICOS+-Tregs/ICOS+-Tresps increased significantly with age, while that of ICOS--Tregs/ICOS--Tresps did not change. In 86 SLE patients (SLEDAI <7), disease activity was associated with an age-independently increased ratio of both ICOS+-Tregs/ICOS+-Tresps and ICOS--Tregs/ICOS--Tresps. In these patients, the functional activity of ICOS+-Tregs, but not of ICOS--Tregs, was preserved. In 13 markedly active disease patients (SLEDAI >7), the percentage of both ICOS+-Tregs and ICOS+-Tresps, was strongly increased within total CD4+-T-helper cells. However, the increased ratio of ICOS+-Tregs/ICOS+-Tresps was not maintained in these patients, due to terminal differentiation and accumulation of naïve cells within total ICOS+-Tregs. Despite increased differentiation of both ICOS--Tregs and ICOS--Tresps, the percentage of ICOS--Tregs increased within CD4+-T-helper cells, while that of ICOS--Tresps decreased, resulting in a significantly increased ratio of ICOS--Tregs/ICOS--Tresps independent of age. CONCLUSIONS: Our data reveal a crucial role of Treg immune senescence for the occurrence of disease flares in SLE patients, with ICOS+-Treg cells being most affected.

Development and internal validation of prognostic models to predict negative health outcomes in older patients with multimorbidity and polypharmacy in general practice.

BACKGROUND: Polypharmacy interventions are resource-intensive and should be targeted to those at risk of negative health outcomes. Our aim was to develop and internally validate prognostic models to predict health-related quality of life (HRQoL) and the combined outcome of falls, hospitalisation, institutionalisation and nursing care needs, in older patients with multimorbidity and polypharmacy in general practices. METHODS: Design: two independent data sets, one comprising health insurance claims data (n=592 456), the other data from the PRIoritising MUltimedication in Multimorbidity (PRIMUM) cluster randomised controlled trial (n=502). Population: ≥60 years, ≥5 drugs, ≥3 chronic diseases, excluding dementia. Outcomes: combined outcome of falls, hospitalisation, institutionalisation and nursing care needs (after 6, 9 and 24 months) (claims data); and HRQoL (after 6 and 9 months) (trial data). Predictor variables in both data sets: age, sex, morbidity-related variables (disease count), medication-related variables (European Union-Potentially Inappropriate Medication list (EU-PIM list)) and health service utilisation. Predictor variables exclusively in trial data: additional socio-demographics, morbidity-related variables (Cumulative Illness Rating Scale, depression), Medication Appropriateness Index (MAI), lifestyle, functional status and HRQoL (EuroQol EQ-5D-3L). Analysis: mixed regression models, combined with stepwise variable selection, 10-fold cross validation and sensitivity analyses. RESULTS: Most important predictors of EQ-5D-3L at 6 months in best model (Nagelkerke's R² 0.507) were depressive symptoms (-2.73 (95% CI: -3.56 to -1.91)), MAI (-0.39 (95% CI: -0.7 to -0.08)), baseline EQ-5D-3L (0.55 (95% CI: 0.47 to 0.64)). Models based on claims data and those predicting long-term outcomes based on both data sets produced low R² values. In claims data-based model with highest explanatory power (R²=0.16), previous falls/fall-related injuries, previous hospitalisations, age, number of involved physicians and disease count were most important predictor variables. CONCLUSIONS: Best trial data-based model predicted HRQoL after 6 months well and included parameters of well-being not found in claims. Performance of claims data-based models and models predicting long-term outcomes was relatively weak. For generalisability, future studies should refit models by considering parameters representing well-being and functional status.

Consideration of eyeball length and prismatic side-effects of spectacle lenses in strabismus surgery-a randomised, double-blind interventional study.

PURPOSE: Potential sources of error in dosage planning in strabismus surgery are (a) prismatic side-effects of spectacle lenses when measuring the preoperative angle with the alternating prism cover test and (b) a potential influence of eye ball axial length on dose response. As both errors take effect in opposite directions, many strabismus surgeons set aside their consideration. This study investigates whether considering both factors for dosage planning yields better operative results. METHODS: In this prospective, randomised, double-blind, interventional pilot study, we included patients scheduled for purely horizontal strabismus surgery and determined each patient's surgical dose (total amount of recession/plication) either with (study group) or without (control) consideration of the two factors. The deviation of the resulting angle from the target angle 3 months postoperatively was the primary endpoint. RESULTS: One hundred one patients were included, 51 of which in the intervention group and 50 in the control group. The primary endpoint showed a median deviation from the target of 3.0° in the intervention group and 4.8° in the control group. We observed a group difference of 1.8° in favour of the intervention group (p = 0.053). Subgroup analysis showed a difference between groups of 2.2° for esotropic patients and of 5.1° for patients with hyperopia > + 2 D. CONCLUSION: Taking prismatic side-effects of spectacle lenses and eye ball length into account when calculating strabismus surgery doses showed a trend towards more accurate results. Esotropic patients and patients with hyperopia > + 2 D seemed to benefit most. TRIAL REGISTRATION: International Clinical Trials Registry Platform: DRKS00011121.

Prediction of pathological complete response in breast cancer patients during neoadjuvant chemotherapy: Is shear wave elastography a useful tool in clinical routine?

OBJECTIVE: To compare the validity of Shear Wave Elastography (SWE) for the preoperative assessment of pathological complete response (pCR) to standard clinical assessment in breast cancer patients undergoing neoadjuvant chemotherapy (NACT). MATERIALS AND METHODS: This prospective, consecutive clinical trial was conducted under routine clinical practice. Analysis included 134 patients. SWE served as index test, final pathology from surgical specimen as reference standard. PCR (ypT0) was defined as primary endpoint. Elasticity changes were compared for the pCR- vs. non-pCR group. To determine the validity of shear wave velocity (Vs), ROC analyses and diagnostic accuracy parameters were calculated and compared to the final standard clinical assessment by physical examination, mammography and B-mode ultrasound (ycT + vs. ycT0). RESULTS: Vs was significantly reduced in pCR and non-pCR groups during NACT (pCR: ΔVs(abs) = 3.90 m/s, p < 0.001; non-pCR: ΔVs(abs) = 3.10 m/s, p < 0.001). The pCR-group showed significant lower Vs for all control visits (t1,2,END: p < 0.001). ROC analysis of Vs yielded moderate AUCs for the total population (t0: 0.613, t1: 0.745, t2: 0.685, tEND: 0.718). Compared to standard clinical assessment, Vs(tEND) (cut-off: ≤3.35 m/s) was superior in sensitivity (79.6 % vs. 54.5 %), NPV (86.4 % vs. 77.5 %), FNR (20.4 % vs. 45.5 %), inferior in specificity (58.6 % vs. 77.5 %), PPV (46.3 % vs. 54.5 %), FPR (41.4 % vs. 22.5 %). CONCLUSION: SWE measures significant differences in tumour elasticity changes in pCR vs. non-pCR cases. SWE shows improved sensitivity compared to standard clinical assessment, high NPV and low FNR, but failed in specificity in order to predict pCR under routine conditions.

Blood Pressure Thresholds and Neurologic Outcomes After Endovascular Therapy for Acute Ischemic Stroke: An Analysis of Individual Patient Data From 3 Randomized Clinical Trials.

Importance: The optimal blood pressure targets during endovascular therapy (EVT) for acute ischemic stroke (AIS) are unknown. Objective: To study whether procedural blood pressure parameters, including specific blood pressure thresholds, are associated with neurologic outcomes after EVT. Design, Setting, and Participants: This retrospective cohort study included adults with anterior-circulation AIS who were enrolled in randomized clinical trials assessing anesthetic strategy for EVT between February 2014 and February 2017. The trials had comparable blood pressure protocols, and patients were followed up for 90 days. A total of 3630 patients were initially approached, and 3265 patients were excluded. Exposure: Endovascular therapy. Main Outcomes and Measures: The primary efficacy variable was functional outcome as defined by the modified Rankin Scale (mRS) score at 90 days. Associations of blood pressure parameters and time less than and greater than mean arterial blood pressure (MABP) thresholds with outcome were analyzed. Results: Of the 365 patients included in the analysis, the mean (SD) age was 71.4 (13.0) years, 163 were women (44.6%), and the median National Institutes of Health Stroke Scale score was 17 (interquartile range [IQR], 14-21). For the entire cohort, 182 (49.9%) received general anesthesia and 183 (50.1%) received procedural sedation. A cumulated period of minimum 10 minutes with less than 70 mm Hg MABP (adjusted OR, 1.51; 95% CI, 1.02-2.22) and a continuous episode of minimum 20 minutes with less than 70 mm Hg MABP (adjusted OR, 2.30; 95% CI, 1.11-4.75) were associated with a shift toward higher 90-day mRS scores, corresponding to a number needed to harm of 10 and 4, respectively. A cumulated period of minimum 45 minutes with greater than 90 mm Hg MABP (adjusted OR, 1.49; 95% CI, 1.11-2.02) and a continuous episode of minimum 115 minutes with greater than 90 mm Hg MABP (adjusted OR, 1.89; 95% CI, 1.01-3.54) were associated with a shift toward higher 90-day mRS scores, corresponding to a number needed to harm of 10 and 6, respectively. Conclusions and Relevance: Critical MABP thresholds and durations for poor outcome were found to be MABP less than 70 mm Hg for more than 10 minutes and MABP greater than 90 mm Hg for more than 45 minutes, both durations with a number needed to harm of 10 patients. Mean arterial blood pressure may be a modifiable therapeutic target to prevent or reduce poor functional outcome after EVT.

Relative Efficacy of Spironolactone, Eplerenone, and cAnRenone in patients with Chronic Heart failure (RESEARCH): a systematic review and network meta-analysis of randomized controlled trials.

This study aims to assess the comparative benefit and risk profile of treatment with mineralocorticoid receptor antagonists (MRAs) with regard to all-cause mortality (primary endpoint), cardiovascular mortality, or heart failure (HF)-related hospitalization (secondary endpoints) and the safety endpoints hyperkalemia, acute renal failure, and gynecomastia in patients with chronic HF. We conducted a systematic review and network meta-analysis following PRISMA-P and PRISMA-NMA guidelines. From 16 different sources, 14 randomized controlled trials totaling 12,213 patients testing an active treatment of either spironolactone, eplerenone, or canrenone/potassium-canreonate in adults with symptomatic HF due to systolic dysfunction reporting any of the above endpoints were retained. Efficacy in comparison to placebo/standard medical care with respect to all-cause mortality was confirmed for spironolactone and eplerenone while no conclusion could be drawn for canrenone (HR 0.69 (0.62; 0.77), 0.82 (0.75; 0.91), and 0.50 (0.17; 1.45), respectively). Indirect comparisons hint a potential (non-significant) preference of spironolactone over eplerenone (HR 0.84 (0.68; 1.03)). The overall risk of bias was low to intermediate. Results for secondary endpoints as well as sensitivity analyses essentially mirrored these findings. The beta-blocker adjusted meta-analysis for the primary endpoint showed the same tendency as the unadjusted one (HR 0.39 (0.07; 2.03)). Results need to be interpreted with caution, though, as the resultant mix of patient- and study-level covariates produced unstable statistical modeling. We found no significant and systematic superiority of either MRA regarding efficacy toward all endpoints considered in both direct and indirect comparisons.

Physicians' level of hindrance by body hair in dermatoscopy and clinical benefit of an automated hair removal algorithm.

BACKGROUND AND OBJECTIVES: Dermatoscopy may be hindered by body hair, and the development of an automated hair removal algorithm (AuHRA) might improve the diagnostic accuracy. However, the physicians' exact level of hindrance and the clinical benefit attained by AuHRA has not been assessed. The objectives of this study are to quantify the physicians' level of hindrance by body hair and the level of improvement in the visibility of underlying dermatoscopic patterns after application of AuHRA to digital images of hair-covered nevi. PATIENTS AND METHODS: A cross-sectional reader study including 59 sets of dermatoscopic images of benign nevi that were presented to six dermatologists. Each set included three images of one individual nevus (unshaved/physically shaved/digitally shaved with AuHRA), which were compared to each other within each set to assess the level of improvement caused by hair removal. RESULTS: In comparison to unshaved lesions, dermatologists attributed the highest mean level of improvement to a physical shave (+1.36, p < 0.001) followed by AuHRA's digital shave (+0.79, p < 0.001). The majority of dermatologists considered the application of AuHRA as helpful and confirmed a medical need. CONCLUSIONS: The dermatologists in our study confirmed a substantial impairment of the dermatoscopic examination by body hair. We demonstrated a clinical benefit attained by AuHRA in comparison to unshaved or physically shaved lesions.

Improving continuity of patient care across sectors: study protocol of the process evaluation of a quasi-experimental multi-centre study regarding an admission and discharge model in Germany (VESPEERA).

INTRODUCTION: Hospital stays are critical events as they often disrupt continuity of care. This process evaluation aims to describe and explore the implementation of the VESPEERA programme (Improving continuity of patient care across sectors: An admission and discharge model in general practices and hospitals, Versorgungskontinuitaet sichern: Patientenorientiertes Einweisungs- und Entlassmanagement in Hausarztpraxen und Krankenhauesern). The evaluation concerns the intervention fidelity, reach in targeted populations, perceived effects, working mechanisms, feasibility, determinants for implementation, including contextual factors, and associations with the outcomes evaluation. The aim of the VESPEERA programme is the development, implementation and evaluation of a structured admission and discharge programme in general practices and hospitals. METHODS AND ANALYSIS: The process evaluation is linked to the VESPEERA outcomes evaluation, which has a quasi-experimental multi-centre design with four study arms and is conducted in hospitals and general practices in Germany. The VESPEERA programme comprises several components: an assessment before admission, an admission letter, a telephonic discharge conversation between hospital and general practice before discharge, discharge information for patients, structured planning of follow-up care after discharge in the general practice and a telephone monitoring for patients with a risk of rehospitalisation. The process evaluation has a mixed-methods design, incorporating interviews (patients, both care providers who do and do not participate in the VESPEERA programme, total n=75), questionnaires (patients and care providers who participate in the VESPEERA programme, total n=475), implementation plans of hospitals, data documented in general practices, claims-based data and hospital process data. Data analysis is descriptive and explorative. Qualitative data will be transcribed and analysed using framework analysis based on the Consolidated Framework for Implementation Research. Associations between the outcomes of the program and measures in the process evaluation will be explored in regression models. ETHICS AND DISSEMINATION: Ethics approval has been obtained by the ethics committee of the Medical Faculty Heidelberg prior to the start of the study (S-352/2018). Results will be disseminated through a final report to the funding agency, articles in peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: http://www.drks.de/DRKS00015183. TRIAL STATUS: The study protocol on hand is the protocol V.1.1 from 18 June 2018. Recruitment for interviews started on 3 September 2018 and will approximately be completed by the end of May 2019.