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This document discusses a study on the use of erythropoiesis stimulating agents (ESAs) as a treatment for anemia in low-risk myelodysplastic neoplasms (LR-MDS). The study used flow cytometry to analyze erythroid subpopulations in LR-MDS patients treated with ESAs and found that the response to ESAs was associated with an increase in certain bone marrow cells. However, this correlation was not seen in cases with a specific gene mutation. The study suggests that a combination of scoring and cell fraction analysis could predict ESA response in certain MDS cases. [Extracted from the article]

Background: There are few molecular markers driving treatment selection in later lines of treatment for advanced colorectal cancer patients. The vast majority of patients who progress after first- and second-line therapy undergo chemotherapy regardless of molecular data. Objective: We aimed to assess the prognostic and predictive effects of specific RAS mutations on overall survival of patients receiving regorafenib (rego), trifluridine/tipiracil (TFD/TPI), or both. Patients and methods: This was a retrospective observational study based on data from a previous study of our research network, involving nine Italian institutions over a 10-year timeframe (2012–2022). Extended RAS analysis, involving KRAS exon 2–4 and NRAS exon 2–4, and BRAF were the main criteria for inclusion in this retrospective evaluation. Patients with BRAF mutation were excluded. Patients were classified according to treatment (rego- or TFD/TPI-treated) and RAS mutational status (wild-type [WT], KRAS codon 12 mutations, KRAS codon 13 mutations, KRAS rare mutations and NRAS mutations, KRAS G12C mutation and KRAS G12D mutation). Results: Overall, 582 patients were included in the present analysis. Overall survival did not significantly differ in rego-treated patients according to RAS extended analysis, although a trend toward a better median survival in patients carrying G12D mutation (12.0 months), Codon 13 mutation (8.0 months), and Codon 12 mutation (7.0 months) has been observed, when compared with WT patients (6.0 months). Overall survival did not significantly differ in TFD/TPI-treated patients according to RAS extended analysis, although a trend toward a better median survival in WT patients had been observed (9.0 months) in comparison with the entire population (7.0 months). Patients receiving both drugs displayed a longer survival when compared with the population of patients receiving rego alone (p = 0.005) as well as the population receiving TFD/TPI alone (p < 0.001), suggesting a group enriched for favorable prognostic factors. However, when each group was analyzed separately, the addition of TFD/TPI therapy to the rego-treated group improved survival only in all-RAS WT patients (p = 0.003). Differently, the addition of rego therapy to TFD/TPI-treated patients significantly improved OS in the Codon 12 group (p = 0.0004), G12D group (p = 0.003), and the rare mutations group (p = 0.02), in addition to all-RAS WT patients (p = 0.002). The rego-TFD/TPI sequence, compared with the reverse sequence, significantly improved OS only in the KRAS codon 12 group (p = 0.003). Conclusions: Our data demonstrate that RAS mutations do not affect outcome in rego-treated patients as well as TFD/TPI-treated patients. Nevertheless, a trend toward a higher efficacy of rego in RAS-mutated (in particular codon 12, rare RAS mutations, and G12D) patients has been recorded. The rego-TFD/TPI sequence seems to be superior to the reverse sequence in patients carrying an RAS codon 12 mutation, although the impact of other factors as disease burden or performance status cannot be excluded. [ABSTRACT FROM AUTHOR]

Infections that are unusually severe or caused by opportunistic pathogens are a hallmark of primary immunodeficiency (PID). Anti-cytokine autoantibodies (ACA) are an emerging cause of acquired immunodeficiency mimicking PID. Nocardia spp. are Gram-positive bacteria generally inducing disseminated infections in immunocompromised patients, but seldom also occurring in apparently immunocompetent hosts. Anti-GM-CSF autoantibodies are associated with autoimmune pulmonary alveolar proteinosis (PAP). In those patients, an increased incidence of disseminated nocardiosis and cryptococcosis has been observed. It is unclear whether the PAP or the autoantibodies predispose to the infection. We report an apparently immunocompetent woman presenting with disseminated nocardiosis without any evidence of PAP. Clinical data and radiological images were retrospectively collected. Lymphocyte populations were analyzed by flow cytometry. Anti-GM-CSF autoantibodies were measured by ELISA. A 55-year-old otherwise healthy woman presented with cerebral and pulmonary abscesses. Personal and familial history of infections or autoimmunity were negative. After extensive examinations, a final diagnosis of disseminated nocardiosis was made. Immunologic investigations including neutrophilic function and IFN-γ/IL-12 circuitry failed to identify a PID. Whole-exome sequencing did not find pathogenic variants associated with immunodeficiency. Serum anti-GM-CSF autoantibodies were positive. There were no clinical or instrumental signs of PAP. Trimethoprim-sulfamethoxazole and imipenem were administered, with progressive improvement and recovery of the infectious complication. We identified anti-GM-CSF autoantibodies as the cause of disseminated nocardiosis in a previously healthy and apparently immunocompetent adult. This case emphasizes the importance of including ACA in the differential diagnosis of PID, especially in previously healthy adults. Importantly, anti-GM-CSF autoantibodies can present with disseminated nocardiosis without PAP. [ABSTRACT FROM AUTHOR]

Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47–0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39–0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling. [ABSTRACT FROM AUTHOR]

The increasing emergence of drug-resistance among mycobacteria represents a serious global health threat, requiring novel and effective therapeutic strategies. The lack of innovation in the drug discovery approach and/or in the combination of the therapeutic cocktail makes inevitable the onset of resistance also for the newly marketed drugs such as bedaquiline and delamanid. Therefore, different therapeutic tools are urgently required. Adjuvant therapies (AT), that is those approaches aimed at boosting the existing treatment, rather than replacing it with another, have gained increasing consideration in the antibacterial landfill. Efflux Inhibitors (EIs) represent the most studied example of such an approach, as they can slow down the emergence of resistance and have positive effects on the duration of the treatment. Working toward this direction, we have recently reported the biological characterization of N-(3,5-dichlorophenyl)-4,5-dihydronaphtho[1,2-d]thiazol-2-amine (compound 1), a 2-aminothiazole derivative remarkably affecting Mycobacterium tuberculosis energetics. Despite the encouraging overall activity (MIC = 16 µg/mL, RFF = 3.29), this compound poses several medicinal chemistry challenges concerning its toxicity and drug-likeness. Here we present a Structure-Activity Relationships around compound 1, with the disclosure of some derivatives with balanced efflux inhibitory characteristics, tolerable toxicity and drug-like physicochemical features. [ABSTRACT FROM AUTHOR]

Historical records with recent events reveal that tsunamis are threatening the western coast of Turkey due to the intensely active seismicity of the Eastern Mediterranean Sea. The most recent tsunami events in the region (30 October 2020 Izmir-Samos and 20 July 2017 Bodrum-Kos) restated that the cities located near the Eastern Mediterranean and connected seas should also consider tsunami events in their disaster mitigation plans. Bodrum is one of the most critical coastal districts vulnerable to marine hazards, with popular hotels, numerous coastal facilities, long and famous beaches, cultural, historical and touristic places. Tsunami evacuation planning is required for Bodrum district to mitigate the damage caused by destructive tsunami waves inundating on land. This study calculates the geospatial distribution of pedestrian evacuation time, based on selected credible worst-case scenarios. A widely used anisotropic least-cost distance model is applied via the Pedestrian Evacuation Analyst Tool to calculate the required time for a pedestrian to evacuate the region under tsunami threat based on the selected scenarios. The model includes landscape properties that affect the walking pace of pedestrians during an evacuation, such as elevation, slope, land cover, and land use types (beach, road, bushes, water bodies, and barriers). The resultant pedestrian evacuation time maps show that the maximum time needed for a pedestrian is 8, 6, 5, 4, and 3 min for highly populated coastal settlements of Bodrum, which are Central Bodrum, Yahsi, Akyarlar-Karaincir-Aspat Bays, Bitez, and Gumbet Bays, respectively. [ABSTRACT FROM AUTHOR]

Purpose: To develop a tool allowing to classify the magnitude of structural tissue damage occurring in ACL injured knees. The proposed ACL Injury Severity Scale (ACLISS) would provide an easy description and categorization of the wide spectrum of injuries in patients undergoing primary ACL reconstruction, reaching from isolated ACL tears to ACL injuries with a complex association of combined structural damage. Methods: A stepwise approach was used to develop the ACLISS. The eligibility of each item was based on a literature search and a consensus between the authors after considering the diagnostic modalities and clinical importance of associated injuries to the menisci, subchondral bone, articular cartilage or collateral ligaments. Then, a retrospective analysis of associated injuries was performed in 100 patients who underwent a primary ACL reconstruction (ACLR) by a single surgeon. This was based on acute preoperative MRI (within 8 weeks after injury) as well as intraoperative arthroscopic findings. Depending on their prevalence, the number of selected items was reduced. Finally, an analysis of the overall scale distribution was performed to classify the patients according to different injury profiles. Results: A final scoring system of 12 points was developed (12 = highest severity). Six points were attributed to the medial and lateral tibiofemoral compartment respectively. The amount of associated injuries increased with ACLISS grading. The median scale value was 4.5 (lower quartile 3.0; higher quartile 7.0). Based on these quartiles, a score < 4 was considered to be an injury of mild severity (grade I), a score between ≥ 4 and ≤ 7 was defined as moderately severe (grade II) and a score > 7 displayed the most severe cases of ACL injuries (grade III). The knees were graded ACLISS I in 35%, ACLISS II in 49% and ACLISS III in 16% of patients. Overall, damage to the lateral tibiofemoral compartment was predominant (p < 0.01), but a proportional increase of tissue damage could be observed in the medial tibiofemoral compartment with the severity of ACLISS grading (p < 0.01). Conclusions: The ACLISS allowed to easily and rapidly identify different injury severity profiles in patients who underwent primary ACLR. Injury severity was associated with an increased involvement of the medial tibiofemoral compartment. The ACLISS is convenient to use in daily clinical practice and represents a feasible grading and documentation tool for a reproducible comparison of clinical data in ACL injured patients. Level of evidence: Level III. [ABSTRACT FROM AUTHOR]

The high frequency of homologous recombination deficiency (HRD) is the main rationale of testing platinum-based chemotherapy in triple-negative breast cancer (TNBC), however, the existing methods to identify HRD are controversial and there is a medical need for predictive biomarkers. We assess the in vivo response to platinum agents in 55 patient-derived xenografts (PDX) of TNBC to identify determinants of response. The HRD status, determined from whole genome sequencing, is highly predictive of platinum response. BRCA1 promoter methylation is not associated with response, in part due to residual BRCA1 gene expression and homologous recombination proficiency in different tumours showing mono-allelic methylation. Finally, in 2 cisplatin sensitive tumours we identify mutations in XRCC3 and ORC1 genes that are functionally validated in vitro. In conclusion, our results demonstrate that the genomic HRD is predictive of platinum response in a large cohort of TNBC PDX and identify alterations in XRCC3 and ORC1 genes driving cisplatin response. Homologous recombination deficiency is linked with platinum-based chemotherapy response in triple-negative breast cancer (TNBC) but methods to clinically identify these patients are lacking. Here, using patient-derived xenografts of TNBC the authors demonstrate that shallow HRD is predictive of response to platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

Cajal-Retzius cells (CRs) are transient neurons, disappearing almost completely in the postnatal neocortex by programmed cell death (PCD), with a percentage surviving up to adulthood in the hippocampus. Here, we evaluate CR's role in the establishment of adult neuronal and cognitive function using a mouse model preventing Bax-dependent PCD. CRs abnormal survival resulted in impairment of hippocampus-dependent memory, associated in vivo with attenuated theta oscillations and enhanced gamma activity in the dorsal CA1. At the cellular level, we observed transient changes in the number of NPY+ cells and altered CA1 pyramidal cell spine density. At the synaptic level, these changes translated into enhanced inhibitory currents in hippocampal pyramidal cells. Finally, adult mutants displayed an increased susceptibility to lethal tonic-clonic seizures in a kainate model of epilepsy. Our data reveal that aberrant survival of a small proportion of postnatal hippocampal CRs results in cognitive deficits and epilepsy-prone phenotypes in adulthood. Cajal-Retzius neurons number drastically decreases during postnatal life. Here, authors show that their programmed death is required for the construction of functional hippocampal circuits and memory with aberrant survival leading to gamma rhythmopathies and susceptibility to seizures. [ABSTRACT FROM AUTHOR]

Surgical resection is one of the most relevant practices in neurosurgery. Finding the correct surgical extent of the tumor is a key question and so far several techniques have been employed to assist the neurosurgeon in preserving the maximum amount of healthy tissue. Some of these methods are invasive for patients, not always allowing high precision in the detection of the tumor area. The aim of this study is to overcome these limitations, developing machine learning based models, relying on features obtained from a contactless and non-invasive technique, the thermal infrared (IR) imaging. The thermal IR videos of thirteen patients with heterogeneous tumors were recorded in the intraoperative context. Time (TD)- and frequency (FD)-domain features were extracted and fed different machine learning models. Models relying on FD features have proven to be the best solutions for the optimal detection of the tumor area (Average Accuracy = 90.45%; Average Sensitivity = 84.64%; Average Specificity = 93,74%). The obtained results highlight the possibility to accurately detect the tumor lesion boundary with a completely non-invasive, contactless, and portable technology, revealing thermal IR imaging as a very promising tool for the neurosurgeon. [ABSTRACT FROM AUTHOR]

The limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling. MYC-mediated suppression of inflammatory signalling induced by BRCA1/2 inactivation is confirmed in human TNBC cell lines. Moreover, MYC overexpression prevents the recruitment and activation of lymphocytes in both human and mouse TNBC co-culture models. Chromatin-immunoprecipitation-sequencing reveals that MYC, together with its co-repressor MIZ1, directly binds promoters of multiple interferon-signalling genes, resulting in their downregulation. MYC overexpression thus counters tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist via suppressing induction of interferon signalling. Together, our data reveal that MYC suppresses innate immunity and facilitates tumor immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs. Tripe-negative breast cancers poorly respond to immune checkpoint inhibition therapy, due to their immune-hostile tumour microenvironment. Authors here show that the oncogene MYC plays a pivotal role in suppressing anti-tumour immunity via directly regulating the transcription of interferon signalling genes. [ABSTRACT FROM AUTHOR]

On October 30th, 2020, a magnitude 7.0 earthquake offshore off the northern coast of Samos, Greece, generated a tsunami that impacted the nearshore Greek islands and the Aegean coastline of Turkey. Here, we describe detailed results from several post-event field surveys, and report first wave arrival timing and polarity information as well as tsunami height/runup measurements, from five islands. In Chios, wave runup reached 1.38 m, in Samos ~ 3 m, in Fourni 1.57 m, in Thimena 1.46 m, and in Ikaria 1.18 m. This event marks two milestones. One, the General Secretariat for Civil Protection of Greece, disseminated a message through Greece's 1–1-2 Emergency Communications Service to all cell phones in the eastern Aegean geographical region, warning recipients to stay away from coastal areas. According to eyewitnesses, the message was received ~ 3–5 min prior to the second and largest flood in Vathi, as the first flood had not sufficiently alarmed the local authorities to evacuate residents. Two, we were able to infer complete tsunami hydrographs from measurements for the first two floods in Vathi, which suggests that the water level rose to about one meter overland flow depth in one minute. [ABSTRACT FROM AUTHOR]

Purpose: SARS-CoV-2 infection in immunocompromised hosts is challenging, and prolonged viral shedding can be a common complication in these patients. We describe the clinical, immunological, and virological course of a patient with eosinophilic granulomatosis with polyangiitis, who developed the status of long-term asymptomatic SARS-CoV-2 carrier for more than 7 months. Methods: Over the study period, the patient underwent 20 RT-PCR tests for SARS-CoV-2 detection on nasopharyngeal swabs. In addition, viral cultures and genetic investigation of SARS-CoV-2 were performed. As for immunological assessment, serological and specific T-cell testing was provided at different time points. Results: Despite the patient showing a deep drug-induced B and T adaptive immunity impairment, he did not experience COVID-19 progression to severe complications, and the infection remained asymptomatic during the follow-up period, but he was not able to achieve viral clearance for more than 7 months. The infection was finally cleared by SARS-CoV-2-specific monoclonal antibody treatment, after that remdesivir and convalescent plasma failed in this scope. The genetic investigations evidenced that the infection was sustained by multiple viral subpopulations that had apparently evolved intra-host during the infection. Conclusion: Our case suggests that people with highly impaired B- and T-cell adaptive immunity can prevent COVID-19 progression to severe complications, but they may not be able to clear SARS-CoV-2 infection. Immunocompromised hosts with a long-term infection may play a role in the emergence of viral variants. [ABSTRACT FROM AUTHOR]

Endovascular treatment has emerged as the predominant approach in intracranial aneurysms. However, surgical clipping is still considered the best treatment for middle cerebral artery (MCA) aneurysms in referral centers. Here we compared short- and long-term clinical and neuroradiological outcomes in patients with MCA aneurysms undergoing clipping or coiling in 5 Italian referral centers for cerebrovascular surgery. We retrospectively reviewed 411 consecutive patients admitted between 2015 and 2019 for ruptured and unruptured MCA aneurysm. Univariate and multivariate analyses of the association between demographic, clinical, and radiological parameters and ruptured status, type of surgical treatment, and clinical outcome at discharge and follow-up were performed. Clipping was performed in 340 (83%) cases, coiling in 71 (17%). Clipping was preferred in unruptured aneurysms and in those showing collateral branches originating from neck/dome. Surgery achieved a higher rate of complete occlusion at discharge and follow-up. Clipping and coiling showed no difference in clinical outcome in both ruptured and unruptured cases. In ruptured aneurysms age, presenting clinical status, intracerebral hematoma at onset, and treatment-related complications were significantly associated with outcome at both short- and long-term follow-up. The presence of collaterals/perforators originating from dome/neck of the aneurysms also worsened the short-term clinical outcome. In unruptured cases, only treatment-related complications such as ischemia and hydrocephalus were associated with poor outcome. Clipping still seems superior to coiling in providing better short- and long-term occlusion rates in MCA aneurysms, and at the same time, it appears as safe as coiling in terms of clinical outcome. [ABSTRACT FROM AUTHOR]

Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1–9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1–E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.Truncation of exon 18 of FGFR2 (FGFR2ΔE18) is a potent driver mutation in mice and humans, and FGFR-targeted therapy should be considered for patients with cancer expressing stable FGFR2ΔE18 variants. [ABSTRACT FROM AUTHOR]

Spontaneous intracerebral hemorrhage (ICH) has an increasing incidence and a worse outcome in elderly patients. The ability to predict the functional outcome in these patients can be helpful in supporting treatment decisions and establishing prognostic expectations. We evaluated the performance of a machine learning (ML) model to predict the 6-month functional status in elderly patients with ICH leveraging the predictive value of the clinical characteristics at hospital admission. Data were extracted by a retrospective multicentric database of patients ≥ 70 years of age consecutively admitted for the management of spontaneous ICH between January 1, 2014 and December 31, 2019. Relevant demographic, clinical, and radiological variables were selected by a feature selection algorithm (Boruta) and used to build a ML model. Outcome was determined according to the Glasgow Outcome Scale (GOS) at 6 months from ICH: dead (GOS 1), poor outcome (GOS 2–3: vegetative status/severe disability), and good outcome (GOS 4–5: moderate disability/good recovery). Ten features were selected by Boruta with the following relative importance order in the ML model: Glasgow Coma Scale, Charlson Comorbidity Index, ICH score, ICH volume, pupillary status, brainstem location, age, anticoagulant/antiplatelet agents, intraventricular hemorrhage, and cerebellar location. Random forest prediction model, evaluated on the hold-out test set, achieved an AUC of 0.96 (0.94–0.98), 0.89 (0.86–0.93), and 0.93 (0.90–0.95) for dead, poor, and good outcome classes, respectively, demonstrating high discriminative ability. A random forest classifier was successfully trained and internally validated to stratify elderly patients with spontaneous ICH into prognostic subclasses. The predictive value is enhanced by the ability of ML model to identify synergy among variables. [ABSTRACT FROM AUTHOR]

The Hippo/YAP pathway controls cell proliferation through sensing physical and spatial organization of cells. How cell-cell contact is sensed by Hippo signaling is poorly understood. Here, we identified the cell adhesion molecule KIRREL1 as an upstream positive regulator of the mammalian Hippo pathway. KIRREL1 physically interacts with SAV1 and recruits SAV1 to cell-cell contact sites. Consistent with the hypothesis that KIRREL1-mediated cell adhesion suppresses YAP activity, knockout of KIRREL1 increases YAP activity in neighboring cells. Analyzing pan-cancer CRISPR proliferation screen data reveals KIRREL1 as the top plasma membrane protein showing strong correlation with known Hippo regulators, highlighting a critical role of KIRREL1 in regulating Hippo signaling and cell proliferation. During liver regeneration in mice, KIRREL1 is upregulated, and its genetic ablation enhances hepatic YAP activity, hepatocyte reprogramming and biliary epithelial cell proliferation. Our data suggest that KIRREL1 functions as a feedback regulator of the mammalian Hippo pathway through sensing cell-cell interaction and recruiting SAV1 to cell-cell contact sites. How cell-cell contact is sensed by Hippo pathway is poorly understood. Here, the authors show that KIRREL1 functions as a feedback regulator of the mammalian Hippo pathway by sensing cell-cell interaction and recruiting SAV1 to cell-cell contacts. [ABSTRACT FROM AUTHOR]

Objective: In a previous work, we found that an Intracranial Elastance Index (IEI) ≥0.3 at ventricular infusion test had a high accuracy in predicting shunt response at 6 and 12 months in idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to verify the accuracy of IEI to predict response to shunt at both short- and long-term follow-up. Methods: Retrospective evaluation of 64 patients undergoing ventriculo-peritoneal shunting for iNPH between 2006 and 2015 based on a positive ventricular infusion test (IEI≥0.3). Patients were classified according to Krauss scale and mRS preoperatively, at 1-year and at last follow-up. An improvement of at least one point at Krauss score or at mRS was considered as a good outcome; unchanged or worsened patients were grouped as poor outcome. Results: Mean follow-up was 6.6 years. Improvement at Krauss scale was seen in 62.5% and 64.3% of patients at 1-year and last follow-up, respectively. Patients in good functional status (mRS≤2) increased from 25 in the preoperative period to 57% at both 1-year and last follow-up. IEI was significantly associated with Krauss (p=0.041) and mRS (p=0.036) outcome at last follow-up. Patients with worse preoperative Krauss and mRS had higher chance to improve but higher overall scores after treatment. At ROC curves, IEI showed a good long-term prediction of change in mRS from first year to last follow-up. Conclusions: IEI≥0.3 predicts outcomes at both short- and long-term, with more than 50% of patients being able to look after themselves after 6 years from treatment. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system" published in Nature Communications. The correction addresses an error in Figure 6b of the original article, where an image was inadvertently duplicated. The correct image has been replaced in both the PDF and HTML versions of the article. The authors of the article are Laura Rinaldi, Rossella Delle Donne, Bruno Catalanotti, Omar Torres-Quesada, Florian Enzler, Federica Moraca, Robert Nisticò, Francesco Chiuso, Sonia Piccinin, Verena Bachmann, Herbert H. Lindner, Corrado Garbi, Antonella Scorziello, Nicola Antonino Russo, Matthis Synofzik, Ulrich Stelzl, Lucio Annunziato, Eduard Stefan, and Antonio Feliciello. [Extracted from the article]

Purpose: To evaluate the feasibility and sensitivity of multimodality PET/CT and MRI imaging for non-invasive characterization of brain microglial/macrophage activation occurring during the acute phase in a mouse model of relapsing remitting multiple sclerosis (RR-MS) using [18F]DPA-714, a selective radioligand for the 18-kDa translocator protein (TSPO), superparamagnetic iron oxide particles (SPIO), and ex vivo immunohistochemistry. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice by immunization with PLP139–151. Seven symptomatic EAE mice and five controls underwent both PET/CT and MRI studies between 11 and 14 days post-immunization. SPIO was injected i.v. in the same animals immediately after [18F]DPA-714 and MRI acquisition was performed after 24 h. Regional brain volumes were defined according to a mouse brain atlas on co-registered PET and SPIO-MRI images. [18F]DPA-714 standardized uptake value (SUV) ratios (SUVR), with unaffected neocortex as reference, and SPIO fractional volumes (SPIO-Vol) were generated. Both SUVR and SPIO-Vol values were correlated with the clinical score (CS) and among them. Five EAE and four control mice underwent immunohistochemical analysis with the aim of identifying activated microglia/macrophage and TSPO expressions. Results: SUVR and SPIO-Vol values were significantly increased in EAE compared with controls in the hippocampus (p < 0.01; p < 0.02, respectively), thalamus (p < 0.02; p < 0.05, respectively), and cerebellum and brainstem (p < 0.02), while only SPIO-Vol was significantly increased in the caudate/putamen (p < 0.05). Both SUVR and SPIO-Vol values were positively significantly correlated with CS and among them in the same regions. TSPO/Iba1 and F4/80/Prussian blue staining immunohistochemistry suggests that increased activated microglia/macrophages underlay TSPO expression and SPIO uptake in symptomatic EAE mice. Conclusions: These preliminary results suggest that both activated microglia and infiltrated macrophages are present in vulnerable brain regions during the acute phase of PLP-EAE and contribute to disease severity. Both [18F]DPA-714-PET and SPIO-MRI appear suitable modalities for preclinical study of neuroinflammation in MS mice models. [ABSTRACT FROM AUTHOR]

On December 22, 2018, a destructive tsunami related to the phenomena caused by the volcanic eruption of Gunung Anak Krakatau (GAK) was generated following a partial collapse of the volcano that caused serious damage and killed more than 400 people. This recent event challenged the traditional understanding of tsunami hazard, warning and response mechanisms and raised the topic of volcanic tsunami hazard. The complex mechanism of this tsunamigenic volcano collapse still needs further investigation as Anak Krakatau is one of the potentially tsunamigenic volcanoes in the world. This study investigates the possible source mechanisms of this phenomenon and their contribution to explaining the observed sea level disturbances by considering the impacts of this destructive event. We configured a flank collapse scenario with a volume of 0.25 km3 as a combination of submarine and subaerial mass movement as the possible source scenarios to the December 22, 2018 Sunda Strait tsunami. A two-layer model is applied to simulate the tsunami generation by these landslides up to 420 s. The tsunami propagation and inundation are then simulated by NAMI DANCE model in GPU environment. The simulation results suggest that this scenario seems capable of generating such a tsunami observed along the coast of Sunda Strait. However, the contribution of the possible submarine mass movements in the close area between GAK and the surrounding islands either to this event or potential tsunami threat in the region is still questionable. We employed a bathymetric dataset through pre- and post-event analyses, which demonstrate submarine slope failures in the southwestern proximity of GAK. Hence, additional two scenarios of elliptical landslide sources on the slopes of bathymetry change area (could be triggered by seismic motion/volcanic eruption) are considered, searching for the possible effects of the tsunami that might be generated by these submarine landslides. The study may also provide some perspective for potential tsunami generation by combined sources and help to elucidate the extent of volcanic tsunami hazard in the region due to potential future eruptions of Gunung Anak Krakatau. [ABSTRACT FROM AUTHOR]

Intraoperative ultrasonography (iUS) is considered an accurate, safe, and cost-effective tool to estimate the extent of resection of both high-grade (HGG) and low-grade (DLGG) diffuse gliomas (DGs). However, it is currently missing an evidence-based assessment of iUS diagnostic accuracy in DGs surgery. The objective of review is to perform a systematic review and meta-analysis of the diagnostic performance of iUS in detecting tumor residue after DGs resection. A comprehensive literature search for studies published through October 2018 was performed according to PRISMA-DTA and STARD 2015 guidelines, using the following algorithm: ("ultrasound" OR "ultrasonography" OR "ultra-so*" OR "echo*" OR "eco*") AND ("brain" OR "nervous") AND ("tumor" OR "tumour" OR "lesion" OR "mass" OR "glio*" OR "GBM") AND ("surgery" OR "surgical" OR "microsurg*" OR "neurosurg*"). Pooled sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR−), and diagnostic odds ratio (DOR) of iUS in DGs were calculated. A subgroup analysis for HGGs and DLGGs was also conducted. Thirteen studies were included in the systematic review (665 DGs). Ten articles (409 DGs) were selected for the meta-analysis with the following results: sensitivity 72.2%, specificity 93.5%, LR− 0.29, LR+ 3, and DOR 9.67. Heterogeneity among studies was non-significant. Subgroup analysis demonstrates a better diagnostic performance of iUS for DLGGs compared with HGGs. iUS is an effective technique in assessing DGs resection. No significant differences are seen regarding iUS modality and transducer characteristics. Its diagnostic performance is higher in DLGGs than HGGs and could be worsened by previous treatments, surgical artifacts, and small tumor residue volumes. [ABSTRACT FROM AUTHOR]

The transition from childhood and adolescence to adulthood is often tumultuous. For individuals with a chronic medical condition, this progression also includes a gradual transition to independence in healthcare management as well as a transfer in care location at some set point. As adolescents navigate these sometimes challenging processes, there is a significant risk for a decline in adequate health behaviors, which can have dire consequences. One of the most vital components of the transfer to adult care is medication adherence. Poor medication adherence puts patients at risk for worse outcomes, with the most profound being increased mortality for many conditions. In recent years, acknowledgment of the need to create evidence-based methods to aid patients during the transition period has been growing. This paper seeks to provide an overview of current research and recommendations for interventions to increase adherence to medication regimens during this period. [ABSTRACT FROM AUTHOR]

The Na+/Ca2+ exchanger 1 (NCX1) participates in the maintenance of neuronal Na+ and Ca2+ homeostasis, and it is highly expressed at synapse level of some brain areas involved in learning and memory processes, including the hippocampus, cortex, and amygdala. Furthermore, NCX1 increases Akt1 phosphorylation and enhances glutamate-mediated Ca2+ influx during depolarization in hippocampal and cortical neurons, two processes involved in learning and memory mechanisms. We investigated whether the modulation of NCX1 expression/activity might influence learning and memory processes. To this aim, we used a knock-in mouse overexpressing NCX1 in hippocampal, cortical, and amygdala neurons (ncx1.4over) and a newly synthesized selective NCX1 stimulating compound, named CN-PYB2. Both ncx1.4over and CN-PYB2-treated mice showed an amelioration in spatial learning performance in Barnes maze task, and in context-dependent memory consolidation after trace fear conditioning. On the other hand, these mice showed no improvement in novel object recognition task which is mainly dependent on non-spatial memory and displayed an increase in the active phosphorylated CaMKIIα levels in the hippocampus. Interestingly, both of these mice showed an increased level of context-dependent anxiety. Altogether, these results demonstrate that neuronal NCX1 participates in spatial-dependent hippocampal learning and memory processes. [ABSTRACT FROM AUTHOR]

The July 20, 2017 Bodrum–Kos Earthquake caused tsunami wave motions and damage in the south of Bodrum Peninsula, Turkey, and on Kos Island, Greece. Immediately after the earthquake, we conducted several post-tsunami field surveys including interviews in coastal zones impacted by the tsunami, i.e., the coastlines of Bodrum Peninsula, Karaada Islet and Akyaka Town in Gökova Bay, Turkey, and eastern Kos Island, Greece. We present observations and measurements to document the variation of the tsunami effects along the coast. The largest tsunami runup was about 1.9 m and observed at the mouth of a small dry streambed at Gumbet Bay, Bodrum. No significant water motions were reported at the northern and western coasts of Bodrum Peninsula. The tsunami runup distribution along the coast of eastern Kos was overall regular, with runup not exceeding 1 m except in the Port of Kos where a 1.5 m tsunami runup was measured. [ABSTRACT FROM AUTHOR]

On September 28th, 2018, a powerful earthquake (Mw 7.5) struck the Island of Sulawesi in Indonesia. The earthquake was followed by a destructive and deadly tsunami that hit the Bay of Palu. A UNESCO international tsunami survey team responded to the disaster and surveyed 125 km of coastline along the Palu Bay up to the earthquake epicentre region. The team performed 78 tsunami runup and inundation height measurements throughout the surveyed coastline. Measured values reached 9.1 m for the runup height and 8.7 m for the inundation height, both at Benteng village. The survey team also identified ten large coastal sectors that collapsed into the sea of Palu Bay after the earthquake. The distribution of the measured tsunami data within Palu Bay exhibits a clear localised impact suggesting the contribution of secondary non-seismic local sources to the generation of the tsunami. Findings of the field reconnaissance are discussed to provide an insight into the remaining debated source of the Palu tsunami. [ABSTRACT FROM AUTHOR]

Purpose: The current study compares the Patient Reported Outcomes Information System Physical Function Computer Adaptive Test (PROMIS PF CAT) to traditional knee PRO instruments in a healthy population undergoing surgery for ACL injuries with the following objectives: (1) identify and determine the strength of any correlations between the scores of PROMIS PF CAT and current knee PROs or their subscales that measure physical function; (2) evaluate PROMIS PF CAT's test burden; and (3) determine if PROMIS PF CAT has any floor or ceiling effects in this population.Methods: Patients indicated for ACL surgery completed the Short Form-36 Physical Function (SF-36 PF), Knee Injury and Osteoarthritis Outcome Score (KOOS), Marx Knee Activity Rating Scale (Marx), the EuroQol 5-dimensions Questionnaire (EQ-5D), and PROMIS PF CAT. Correlations between PROs were defined as follows: High (≥ 0.7); high-moderate (0.61-0.69); moderate (0.4-0.6); moderate-weak (0.31-0.39); and weak (≤ 0.3). Floor or ceiling effects were considered significant if 15% or more patients reported the lowest or highest possible total score, respectively.Results: 100 patients participated with a mean age of 26 years (range 11-57). The PROMIS PF CAT demonstrated high correlations with SF-36 PF (r = 0.82, p < 0.01), EQ-5D (r = - 0.70, p < 0.01) KOOS ADL (r = 0.74, p < 0.01), and KOOS Sport (r = 0.70, p < 0.01). There were no ceiling or floor effects for PROMIS PF CAT (0%). The mean number of items completed for the PROMIS PF CAT was 4.2 (median 4; range 4-11).Conclusions: The PROMIS PF CAT shows a high correlation with commonly employed PROs that also measure physical function with low test burden and without ceiling effects in this relatively young and healthy population. [ABSTRACT FROM AUTHOR]

Purpose: To perform a systematic review aimed to determine (1) if the postural stability deficit represents a risk factor for ankle sprains; (2) the most effective postural stability evaluation to predict ankle sprains and (3) eventual confounding factors that could influence postural stability and ankle sprain risk.Methods: A systematic electronic search was performed in MEDLINE, EMBASE and CINAHL using the search terms (balance) OR (postural stability) matched with (lower limb) OR (ankle) OR (foot) and (sprain) OR (injury) on October 2 2017. All prospective studies that evaluated postural stability as risk factor for ankle sprains were included. The PRISMA Checklist guided the reporting and data abstraction. Methodological quality of all included papers was carefully assessed.Results: Fifteen studies were included, evaluating 2860 individuals. Various assessment tools or instruments were used to assess postural stability. The injury incidence ranged from 10 to 34%. Postural stability deficit was recognized as risk factor for ankle sprain (OR = 1.22-10.2) in 9 cases [3 out of 3 with Star Excursion Balance Test (SEBT)]. Among the six studies that measured the center-of-gravity sway, five were able to detect worse postural stability in athletes that sustained an ankle sprain. In nine cases, the measurement of postural stability did not show any statistical relationship with ankle sprains (four out of five with examiner evaluation). In the studies that excluded patients with history of ankle sprain, postural stability was reported to be a significant risk factor in five out of six studies.Conclusions: The ultimate role of postural stability as risk factor for ankle sprains was not defined, due to the high heterogeneity of results, patient's populations, sports and methods of postural stability evaluation. Regarding assessment instruments, measurement of center-of-gravity sway could detect athletes at risk, however, standardized tools and protocols are needed to confirm this finding. The SEBT could be considered a promising tool that needs further investigation in wider samples. History of ankle sprains is an important confounding factor, since it was itself a source of postural stability impairment and a risk factor for ankle sprains. These information could guide clinicians in developing screening programs and design further prospective cohort studies comparing different evaluation tools.Level Of Evidence: I (systematic review of prospective prognostic studies). [ABSTRACT FROM AUTHOR]

Sphingosine 1-phosphate (S1P) has a role in many cellular processes. S1P is involved in cell growth and apoptosis, regulation of cell trafficking, production of cytokines and chemokines. The kinases SphK1 and SphK2 (SphKs) phosphorilate Sphingosine (Sph) to S1P and several phosphatases revert S1P to sphingosine, thus assuring a balanced pool that can be depleted by a Sphingosine lyase in hexadecenal compounds and aldehydes. There are evidences that SphK1 and 2 may per se control cellular processes. Here, we report that Sph kinases regulate IL-17 expression in human T cells. SphKs inhibition impairs the production of IL-17, while their overexpression up-regulates expression of the cytokine through acetylation of IL-17 promoter. SphKs were up-regulated also in PBMCs of patients affected by IL-17 related diseases. Thus, S1P/S1P kinases axis is a mechanism likely to promote IL-17 expression in human T cells, representing a possible therapeutic target in human inflammatory diseases. [ABSTRACT FROM AUTHOR]

53BP1 is a chromatin-binding protein that regulates the repair of DNA double-strand breaks by suppressing the nucleolytic resection of DNA termini [1], [2]. This function of 53BP1 requires interactions with PTIP [3] and RIF1 [4]- [9], the latter of which recruits REV7 (also known as MAD2L2) to break sites [10], [11]. How 53BP1-pathway proteins shield DNA ends is currently unknown, but there are two models that provide the best potential explanation of their action. In one model the 53BP1 complex strengthens the nucleosomal barrier to end-resection nucleases [12], [13], and in the other 53BP1 recruits effector proteins with end-protection activity. Here we identify a 53BP1 effector complex, shieldin, that includes C20orf196 (also known as SHLD1), FAM35A (SHLD2), CTC-534A2.2 (SHLD3) and REV7. Shieldin localizes to double-strand-break sites in a 53BP1- and RIF1-dependent manner, and its SHLD2 subunit binds to single-stranded DNA via OB-fold domains that are analogous to those of RPA1 and POT1. Loss of shieldin impairs non-homologous end-joining, leads to defective immunoglobulin class switching and causes hyper-resection. Mutations in genes that encode shieldin subunits also cause resistance to poly(ADP-ribose) polymerase inhibition in BRCA1-deficient cells and tumours, owing to restoration of homologous recombination. Finally, we show that binding of single-stranded DNA by SHLD2 is critical for shieldin function, consistent with a model in which shieldin protects DNA ends to mediate 53BP1-dependent DNA repair. The 53BP1 effector complex shieldin is involved in non-homologous end-joining and immunoglobulin class switching, and acts to protect DNA ends to facilitate the repair of DNA by 53BP1. [ABSTRACT FROM AUTHOR]

Purpose of Review: The goal of this review is to provide an overview of current surgical treatment options for tibial tubercle osteotomies as a treatment for recurrent patellofemoral instability. As such we sought to provide the reader with the most current answers to why treatment practices have changed and how this has affected the outcome of surgical treatment for patellar instability.Recent Findings: As our understanding of patellofemoral biomechanics have grown, appropriate surgical and non-surgical treatment options have followed suit to address these findings.Summary: A clear understanding of the pathomechanics causing the patient’s patellar instability is germane to choosing the most appropriate surgical intervention to address this instability. Likewise, understanding the goal of the intervention chosen—e.g., unloading, realignment—is paramount. These surgical techniques may be technically challenging and surgical specialists with experience in these techniques are recommended for optimal outcomes. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is considered largely reversible based on the capacity of surviving tubular cells to dedifferentiate and replace lost cells via cell division. Here we show by tracking individual tubular cells in conditional Pax8/Confetti mice that kidney function is recovered after AKI despite substantial tubular cell loss. Cell cycle and ploidy analysis upon AKI in conditional Pax8/FUCCI2aR mice and human biopsies identify endocycle-mediated hypertrophy of tubular cells. By contrast, a small subset of Pax2+ tubular progenitors enriches via higher stress resistance and clonal expansion and regenerates necrotic tubule segments, a process that can be enhanced by suitable drugs. Thus, renal functional recovery upon AKI involves remnant tubular cell hypertrophy via endocycle and limited progenitordriven regeneration that can be pharmacologically enhanced. [ABSTRACT FROM AUTHOR]

The modeling and optimal control of a class of random walks (RWs) is investigated in the framework of the Chapman-Kolmogorov (CK) and Fokker-Planck (FP) equations. This class of RWs includes jumps driven by a compound Poisson process and are subject to different barriers. A control mechanism is investigated that is included in the CK stochastic transition matrix and the purpose of the control is to track a desired discrete probability density function and attain a desired terminal density configuration. Existence and characterization of optimal controls are discussed. The proposed approach allows the derivation of a new FP model that accommodates the presence of the jumps and guarantees conservation of total probability in the case of reflecting barriers, which are modelled by appropriate operators. Results of numerical experiments are presented that successfully validate the proposed control framework. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to investigate the incidence of complete and partial peroneal nerve injuries in patients with posterolateral corner (PLC) knee injuries; additionally, to compare patient-reported outcomes among patients with and without peroneal nerve injury and to examine the factors that predict the recovery of nerve function.Methods: A retrospective chart review was performed to identify patients who underwent PLC reconstruction or repair from 2000 to 2012 with a minimum 6-month clinical follow-up. Peroneal nerve injuries were identified, and treatments and outcomes were analyzed. IKDC and KOOS outcome scores at the final follow-up were reported.Results: There were 61 PLC injuries in 60 patients. Sixteen of the 61 knees (26.2%) had a peroneal nerve injury at initial presentation; there were 13 complete and 3 partial nerve injuries. The median age was 31 years (15 men and 1 woman) and 31 years (33 men and 12 women) in the nerve and non-nerve injury cohorts, respectively. The median follow-up in the nerve injury group was 26 months (interquartile range (IQR): 12-48), and in the non-nerve injury cohort (n.s.) 61 months (IQR 22-85). All 13 complete injuries were treated with neurolysis: 3 were complete transections and 10 were stretch injuries. Of the ten stretch injuries, five (50%) spontaneously recovered full nerve function at the final follow-up. The remaining six patients chose definitive treatment with ankle-foot orthoses. Two of the three transected nerve patients underwent successful posterior tibialis transfer, and one chose ankle-foot orthoses. All three partial nerve injuries underwent neurolysis and had complete nerve recovery at the final follow-up. The median IKDC scores in the nerve injury group and the non-nerve injury group were 64.4 (IQR 47.8-73.3) and 72.8 (IQR 59.3-87.9) (n.s.), respectively, and the median Lysholm scores were 85 (IQR 83-92) and 86.5 (IQR 79-90) (n.s.), respectively. There were no significant differences in the rates of complications, secondary surgeries, mechanism of injury, KDIII injuries, or other injuries.Conclusion: This study demonstrated comparable rates of peroneal nerve injuries in PLC injuries (26.2%) to that in the literature. The rates of nerve recovery for complete disrupted injury, complete stretched injury, and partial injury were 0, 50, and 100% with an overall rate of recovery of 50%. The outcome scores were similar between patients with and without nerve injuries; however, a small cohort size led to limitations in statistical analysis. Thus, a prolonged trial of non-operative treatment is recommended for peroneal nerve injuries to allow for assessment of nerve recovery and patient outcome before entertaining surgical treatments.Level Of Evidence: Level IV. [ABSTRACT FROM AUTHOR]

A Fokker–Planck control strategy for collective motion is investigated. This strategy is formulated as the minimisation of an expectation objective with a bilinear optimal control problem governed by the Fokker–Planck equation modelling the evolution of the probability density function of the stochastic motion. Theoretical results on existence and regularity of optimal controls are provided. The resulting optimality system is discretized using an alternate-direction implicit Chang–Cooper scheme that guarantees conservativeness, positivity, L1 stability, and second-order accuracy of the forward solution. A projected non-linear conjugate gradient scheme is used to solve the optimality system. Results of numerical experiments validate the theoretical accuracy estimates and demonstrate the efficiency of the proposed control framework. [ABSTRACT FROM AUTHOR]

Purpose of Review: The adaptive immune response orchestrated by type 2 T helper (Th2) lymphocytes, strictly cooperates with the innate response of group 2 innate lymphoid cells (ILC2), in the protection from helminths infection, as well as in the pathogenesis of allergic disease. The aim of this review is to explore the pathogenic role of ILC2 in different type 2-mediated disorders. Recent Findings: Recent studies have shown that epithelial cell-derived cytokines and their responding cells, ILC2, play a pathogenic role in bronchial asthma, chronic rhinosinusitis, and atopic dermatitis. Summary: The growing evidences of the contribution of ILC2 in the induction and maintenance of allergic inflammation in such disease suggest the possibility to target them in therapy. Biological therapies blocking ILC2 activation or neutralizing their effector cytokines are currently under evaluation to be used in patients with type 2-dominated diseases. [ABSTRACT FROM AUTHOR]

Purpose: The goal of the study was to evaluate the repair of chondral lesions treated with combined autologous adult/allogenic juvenile cartilage fragments, compared with isolated adult and isolated juvenile cartilage fragments.Methods: Fifty-eight adult (>16 week old) and five juvenile (<6 week old) New Zealand White female rabbits were used. A large osteochondral defect was created in the center of the femoral trochlea of adult rabbits. The rabbits were divided in four groups: Group 1 = untreated defects (controls); Group 2 = adult cartilage fragments; Group 3 = juvenile cartilage fragments; and Group 4 = adult + juvenile cartilage fragments. Killings were performed at 3 and 6 months. The defects were evaluated with ICRS macroscopic score, modified O'Driscoll score, and Collagen type II immunostaining.Results: At 3 months, Group 4 performed better than Group 1, in terms of modified O'Driscoll score (p = 0.001) and Collagen type II immunostaining (p = 0.015). At 6 months, Group 4 showed higher modified O'Driscoll score (p = 0.003) and Collagen type II immunostaining score (p < 0.001) than Group 1. Histologically, also Group 3 performed better than Group 1 (p = 0.03), and Group 4 performed better than Group 2 (p = 0.004).Conclusions: Mixing adult and juvenile cartilage fragments improved cartilage repair in a rabbit model. In the clinical setting, a new "one-stage" procedure combining the two cartilage sources can be hypothesized, with the advantages of improved chondral repair and large defect coverage, because of the use of an off-the-shelf juvenile allograft. Further studies on larger animals and clinical trials are required to confirm these results. [ABSTRACT FROM AUTHOR]

Storm surges are an important coastal hazard component and it is unknown how they will evolve along Europe's coastline in view of climate change. In the present contribution, the hydrodynamic model Delft3D-Flow was forced by surface wind and atmospheric pressure fields from a 8-member climate model ensemble in order to evaluate dynamics in storm surge levels (SSL) along the European coastline (1) for the baseline period 1970-2000; and (2) during this century under the Representative Concentration Pathways RCP4.5 and RCP8.5. Validation simulations, spanning from 2008 to 2014 and driven by ERA-Interim atmospheric forcing, indicated good predictive skill (0.06 m < RMSE < 0.29 m and 10 % < RMSE < 29 % for 110 tidal gauge stations across Europe). Peak-over-threshold extreme value analysis was applied to estimate SSL values for different return periods, and changes of future SSL were obtained from all models to obtain the final ensemble. Values for most scenarios and return periods indicate a projected increase in SSL at several locations along the North European coastline, which is more prominent for RCP8.5 and shows an increasing tendency towards the end of the century for both RCP4.5 and RCP8.5. Projected SSL changes along the European coastal areas south of 50°N show minimal change or even a small decrease, with the exception of RCP8.5 under which a moderate increase is projected towards the end of the century. The present findings indicate that the anticipated increase in extreme total water levels due to relative sea level rise (RSLR), can be further enforced by an increase of the extreme SSL, which can exceed 30 % of the RSLR, especially for the high return periods and pathway RCP8.5. This implies that the combined effect could increase even further anticipated impacts of climate change for certain European areas and highlights the necessity for timely coastal adaptation and protection measures. The dataset is publicly available under this link: . [ABSTRACT FROM AUTHOR]