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Characteristics of individuals with disruptive behavior disorders often include elevated externalizing behaviors such as impulsivity, defiance of authority and antagonism of social norms. Evidence shows that adolescents diagnosed with these types of disorders are particularly challenging to treat; however, therapies incorporating horses have shown some success. We examined the impact of an equine-assisted intervention compared to a non-manualized cognitive behavioral therapy in youth between 12- and 18-years old living in a residential childcare facility. Upon admittance, youth were administered three assessments: the Youth Self-Report, Adolescent Psychopathology Scale, and Basic Empathy Scale. Youth scoring in the clinical range for at least one externalizing subscale of the Youth Self-Report were assigned to equine-assisted intervention (EQI; N = 23) or non-manualized cognitive behavioral therapy (NM-CBT; N = 20) groups. Each group received a total of 7 h of treatment per week (three 2-hr group sessions and one 1-hr individual session) for 24 weeks. After 24 weeks of treatment, the same three assessments were administered a second time. There were no significant differences between the NM-CBT and EQI groups in the amount of change between assessments. A significant time effect was found for total externalizing behaviors in the Adolescent Psychopathology Scale and Youth Self-Report such that these measures were within the normal range after 24 weeks of treatment for participants in both groups.

High-entropy carbide ceramics (HECCs) possess promising properties for extreme high-temperature applications. Machine learning offers an effective pathway to accelerate the discovery of novel HECCs, but data imbalance poses challenges for predictive performance. Here, we integrate the Borderline-SMOTE with machine learning algorithms to address this issue. A dataset containing 251 samples was established from literature, experimental synthesis, and synthetic oversampling. Key features influencing phase formation were selected via a four-step feature selection strategy. Ten common machine learning models were trained and optimized, with the random forest (RF) model identified as the most suitable for predicting HECCs phase formation ability. Eight HECCs compositions with high uncertainty were experimentally validated, and the results were incorporated back into the dataset to iteratively improve model accuracy. This work provides an efficient strategy for predicting phase formation in HECCs, particularly for small or imbalanced datasets, facilitating the accelerated design and reliable prediction of new HECCs.

Our sense of hearing relies upon speedy synaptic transmission of sound information from cochlear inner hair cells (IHCs) to spiral ganglion neurons (SGNs). To accomplish this, IHCs employ a sophisticated presynaptic machinery including the multi-C2-domain protein otoferlin which is affected by human deafness mutations. Otoferlin is essential for IHC-exocytosis but how it binds Ca2+ and the target membrane to serve synaptic vesicle (SV) tethering, docking and fusion remained unclear. Here, we obtained cryo-electron-microscopy structures of Ca2+-bound otoferlin and employed molecular dynamics simulations of membrane binding. We show that membrane binding involves C2B-C2G-domains and repositions C2F- and C2G-domains. Progressive disruption of Ca2+-binding by the C2D-domain in mice increasingly altered synaptic sound encoding and eliminated the Ca2+-cooperativity of SV-exocytosis, indicating that this Ca2+-cooperativity reflects binding of several Ca2+-ions to otoferlin. Together, our findings elucidate molecular mechanisms underlying otoferlin-mediated SV-docking and support a role of otoferlin as Ca2+-sensor of SV-fusion in IHCs.

The Middle East respiratory syndrome coronavirus (MERS-CoV) has killed ∼50% of individuals known to be infected, making understanding its mechanisms of transmission and pathogenesis and identifying candidate treatments a high priority. Heinz Feldmann, Vincent J. Munster and Michael G. Katze and their colleagues now report that treating MERS-CoV-infected rhesus macaques with interferon-α2b and ribavirin reduced virus replication and infection severity, suggesting the potential use of this combination for the clinical treatment of infected humans. The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) is of global concern: the virus has caused severe respiratory illness, with 111 confirmed cases and 52 deaths 1 at the time of this article's publication. Therapeutic interventions have not been evaluated in vivo ; thus, patient management relies exclusively on supportive care, which, given the high case-fatality rate, is not highly effective. The rhesus macaque is the only known model organism for MERS-CoV infection, developing an acute localized to widespread pneumonia with transient clinical disease 2 , 3 that recapitulates mild to moderate human MERS-CoV cases 4 , 5 . The combination of interferon- α 2b and ribavirin was effective in reducing MERS-CoV replication in vitro 6 ; therefore, we initiated this treatment 8 h after inoculation of rhesus macaques. In contrast to untreated, infected macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Moreover, treated animals showed lower levels of systemic (serum) and local (lung) proinflammatory markers, in addition to fewer viral genome copies, distinct gene expression and less severe histopathological changes in the lungs. Taken together, these data suggest that treatment of MERS-CoV infected rhesus macaques with IFN- α 2b and ribavirin reduces virus replication, moderates the host response and improves clinical outcome. As these two drugs are already used in combination in the clinic for other infections, IFN- α 2b and ribavirin should be considered for the management of MERS-CoV cases.

We studied community–environment relationships of lake macrophytes at two metacommunity scales using data from 16 regions across the world. More specifically, we examined (a) whether the lake macrophyte communities respond similar to key local environmental factors, major climate variables and lake spatial locations in each of the regions (i.e., within-region approach) and (b) how well can explained variability in the community–environment relationships across multiple lake macrophyte metacommunities be accounted for by elevation range, spatial extent, latitude, longitude, and age of the oldest lake within each metacommunity (i.e., across-region approach). In the within-region approach, we employed partial redundancy analyses together with variation partitioning to investigate the relative importance of local variables, climate variables, and spatial location on lake macrophytes among the study regions. In the across-region approach, we used adjusted R2 values of the variation partitioning to model the community–environment relationships across multiple metacommunities using linear regression and commonality analysis. We found that niche filtering related to local lake-level environmental conditions was the dominant force structuring macrophytes within metacommunities. However, our results also revealed that elevation range associated with climate (increasing temperature amplitude affecting macrophytes) and spatial location (likely due to dispersal limitation) was important for macrophytes based on the findings of the across-metacommunities analysis. These findings suggest that different determinants influence macrophyte metacommunities within different regions, thus showing context dependency. Moreover, our study emphasized that the use of a single metacommunity scale gives incomplete information on the environmental features explaining variation in macrophyte communities.

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) is of global concern: the virus has caused severe respiratory illness, with 111 confirmed cases and 52 deaths at the time of this article's publication. Therapeutic interventions have not been evaluated in vivo; thus, patient management relies exclusively on supportive care, which, given the high case-fatality rate, is not highly effective. The rhesus macaque is the only known model organism for MERS-CoV infection, developing an acute localized to widespread pneumonia with transient clinical disease that recapitulates mild to moderate human MERS-CoV cases. The combination of interferon- alpha 2b and ribavirin was effective in reducing MERS-CoV replication in vitro; therefore, we initiated this treatment 8 h after inoculation of rhesus macaques. In contrast to untreated, infected macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Moreover, treated animals showed lower levels of systemic (serum) and local (lung) proinflammatory markers, in addition to fewer viral genome copies, distinct gene expression and less severe histopathological changes in the lungs. Taken together, these data suggest that treatment of MERS-CoV infected rhesus macaques with IFN- alpha 2b and ribavirin reduces virus replication, moderates the host response and improves clinical outcome. As these two drugs are already used in combination in the clinic for other infections, IFN- alpha 2b and ribavirin should be considered for the management of MERS-CoV cases.

Ultrasound (US) has gained popularity as a guidance modality for percutaneous needle insertions because it is widely available and non-ionizing. However, coordinating scanning and needle insertion still requires significant experience. Current assistance solutions utilize optical or electromagnetic tracking (EMT) technology directly integrated into the US device or probe. This results in specialized devices or introduces additional hardware, limiting the ergonomics of both the scanning and insertion process. We developed the first ultrasound (US) navigation solution designed to be used as a non-permanent accessory for existing US devices while maintaining the ergonomics during the scanning process. A miniaturized EMT source is reversibly attached to the US probe, temporarily creating a combined modality that provides real-time anatomical imaging and instrument tracking at the same time. Studies performed with 11 clinical operators show that the proposed navigation solution can guide needle insertions with a targeting accuracy of about 5 mm, which is comparable to existing approaches and unaffected by repeated attachment and detachment of the miniaturized tracking solution. The assistance proved particularly helpful for non-expert users and needle insertions performed outside of the US plane. The small size and reversible attachability of the proposed navigation solution promises streamlined integration into the clinical workflow and widespread access to US navigated punctures.

In the paramyxovirus cell entry process, receptor binding triggers conformational changes in the fusion protein (F) leading to viral and cellular membrane fusion. Peptides derived from C-terminal heptad repeat (HRC) regions in F have been shown to inhibit fusion by preventing formation of the fusogenic six-helix bundle. We recently showed that the addition of a cholesterol group to HRC peptides active against Nipah virus targets these peptides to the membrane where fusion occurs, dramatically increasing their antiviral effect. In this work, we report that unlike the untagged HRC peptides, which bind to the postulated extended intermediate state bridging the viral and cell membranes, the cholesterol tagged HRC-derived peptides interact with F before the fusion peptide inserts into the target cell membrane, thus capturing an earlier stage in the F-activation process. Furthermore, we show that cholesterol tagging renders these peptides active in vivo: the cholesterol-tagged peptides cross the blood brain barrier, and effectively prevent and treat in an established animal model what would otherwise be fatal Nipah virus encephalitis. The in vivo efficacy of cholesterol-tagged peptides, and in particular their ability to penetrate the CNS, suggests that they are promising candidates for the prevention or therapy of infection by Nipah and other lethal paramyxoviruses.

In 2012 a novel coronavirus, MERS-CoV, associated with severe respiratory disease emerged in the Arabian Peninsula. To date, 55 human cases have been reported, including 31 fatal cases. Several of the cases were likely a result of human-to-human transmission. The emergence of this novel coronavirus prompts the need for a small animal model to study the pathogenesis of this virus and to test the efficacy of potential intervention strategies. In this study we explored the use of Syrian hamsters as a small animal disease model, using intratracheal inoculation and inoculation via aerosol. Clinical signs of disease, virus replication, histological lesions, cytokine upregulation nor seroconversion were observed in any of the inoculated animals, indicating that MERS-CoV does not replicate in Syrian hamsters.

Results from a phase 2 trial of the TPEx chemotherapy regimen (docetaxel–platinum–cetuximab) showed promising results, with a median overall survival of 14·0 months in first-line recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). We therefore aimed to compare the efficacy and safety of the TPEx regimen with the standard of care EXTREME regimen (platinum–fluorouracil–cetuximab) in this setting. This was a multicentre, open-label, randomised, phase 2 trial, done in 68 centres (cancer centres, university and general hospitals, and private clinics) in France, Spain, and Germany. Eligible patients were aged 18–70 years with histologically confirmed recurrent or metastatic HNSCC unsuitable for curative treatment; had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less. Participants were randomly assigned (1:1) using the TenAlea website by investigators or delegated clinical research associates to the TPEx regimen or the EXTREME regimen, with minimisation by ECOG performance status, type of disease evolution, previous cetuximab treatment, and country. The TPEx regimen consisted of docetaxel 75 mg/m2 and cisplatin 75 mg/m2, both intravenously on day 1, and cetuximab on days 1, 8, and 15 (intravenously 400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly subsequently). Four cycles were repeated every 21 days with systematic granulocyte colony-stimulating factor (G-CSF) support at each cycle. In case of disease control after four cycles, intravenous cetuximab 500 mg/m2 was continued every 2 weeks as maintenance therapy until progression or unacceptable toxicity. The EXTREME regimen consisted of fluorouracil 4000 mg/m2 on day 1–4, cisplatin 100 mg/m2 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly subsequently) all delivered intravenously. Six cycles were delivered every 21 days followed by weekly 250 mg/m2 cetuximab as maintenance therapy in case of disease control. G-CSF support was not mandatory per the protocol in the EXTREME regimen. The primary endpoint was overall survival in the intention-to-treat population; safety was analysed in all patients who received at least one dose of chemotherapy or cetuximab. Enrolment is closed and this is the final analysis. This study is registered at ClinicalTrials.gov, NCT02268695. Between Oct 10, 2014, and Nov 29, 2017, 541 patients were enrolled and randomly assigned to the two treatment regimens (271 to TPEx, 270 to EXTREME). Two patients in the TPEx group had major deviations in consent forms and were not included in the final analysis. Median follow-up was 34·4 months (IQR 26·6–44·8) in the TPEx group and 30·2 months (25·5–45·3) in the EXTREME group. At data cutoff, 209 patients had died in the TPEx group and 218 had died in the EXTREME group. Overall survival did not differ significantly between the groups (median 14·5 months [95% CI 12·5–15·7] in the TPEx group and 13·4 months [12·2–15·4] in the EXTREME group; hazard ratio 0·89 [95% CI 0·74–1·08]; p=0·23). 214 (81%) of 263 patients in the TPEx group versus 246 (93%) of 265 patients in the EXTREME group had grade 3 or worse adverse events during chemotherapy (p<0·0001). In the TPEx group, 118 (45%) of 263 patients had at least one serious adverse event versus 143 (54%) of 265 patients in the EXTREME group. 16 patients in the TPEx group and 21 in the EXTREME group died in association with adverse events, including seven patients in each group who had fatal infections (including febrile neutropenia). Eight deaths in the TPEx group and 11 deaths in the EXTREME group were assessed as treatment related, most frequently sepsis or septic shock (four in each treatment group). Although the trial did not meet its primary endpoint, with no significant improvement in overall survival with TPEx versus EXTREME, the TPEx regimen had a favourable safety profile. The TPEx regimen could provide an alternative to standard of care with the EXTREME regimen in the first-line treatment of patients with recurrent or metastatic HNSCC, especially for those who might not be good candidates for up-front pembrolizumab treatment. Merck Santé and Chugai Pharma.