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KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC–dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application.Significance:KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.This article is highlighted in the In This Issue feature, p. 995

Studies of dense carbon materials formed by bolide impacts or produced by laboratory compression provide key information on the high-pressure behavior of carbon and for identifying and designing unique structures for technological applications. However, a major obstacle to studying and designing these materials is an incomplete understanding of their fundamental structures. Here, we report the remarkable structural diversity of cubic/hexagonally (

Minimally invasive hysterectomy is a commonly performed gynecologic procedure with associated postoperative pain managed with opioid medications. Uncontrolled postoperative pain leads to increased opioid use/abuse, longer hospital stays, increase in healthcare visits, and may negatively affect patient satisfaction. Current data suggests that reduced pneumoperitoneum insufflation pressure during laparoscopic surgery may impact postoperative pain. Given the current opioid epidemic, surgeons are proactively finding ways to reduce postoperative pain. It is unclear how reduced pneumoperitoneum pressure impacts the surgeon. We investigated the impact of reduced pneumoperitoneum insufflation pressure on surgeon satisfaction.This was a pilot, double-blinded, randomized controlled trial from March 2020 to July 2021 comparing pneumoperitoneum pressure of 15 mmHg to reduced pressures of 12 mmHg and 10 mmHg during laparoscopic hysterectomy.A total of 40 patients were randomized (13 - 15 mmHg, 13 - 12 mmHg, and 14 - 10 mmHg). The primary outcome was surgeon satisfaction. Secondary outcomes included patient satisfaction, operative time, blood loss, postoperative pain, opioid usage, and discharge timing. There were no differences in baseline demographics or perioperative characteristics. Surgeon satisfaction was negatively impacted with lower pneumoperitoneum pressures greatest with 10 mmHg, including overall satisfaction (p =.01), overall effect of the pneumoperitoneum (p =.04), and quality of visualization (p =.01). There was an apparent although not statistically significant difference in operative time (p =.06) and blood loss (p =.054). There was no difference in patient satisfaction, postoperative pain scores, opioid usage, or time to discharge.Reduced pneumoperitoneum insufflation pressure during laparoscopic hysterectomy negatively impacted surgeon satisfaction with a trend towards longer operative times and greater blood loss, and did not positively impact patient satisfaction, postoperative pain, opioid demand, or discharge timing.

Objective comparative evidence of the time to onset and duration of effect provided by local anaesthetic (LA) agents for perineural blocks in the horse is lacking. Clear knowledge of these properties is required to guide clinically appropriate agent selection and aid interpretation of response to diagnostic blocks for lameness examinations. An interventional study, with complete, randomised crossover design was used to compare time to onset and duration of skin desensitisation provided by four LA agents applied to palmar digital nerve blocks in 12 horses. Effect at each time point was determined using a pressure gauge to measure the mechanical nociceptive threshold (MNT) over the heel bulbs. Complete desensitisation was defined when MNT was greater than four times the pre-block baseline. Onset and duration of complete desensitisation were recorded and compared across agents using a mixed linear model. When significant (P ≤ 0.05), post-hoc paired comparisons between agents were performed against a Tukey's corrected P ≤ 0.05. Onset of complete skin desensitisation for each agent was

The purpose of this review is to summarize the current literature evaluating the effect of surgeon gender on patient outcomes and satisfaction, and the impact of gender bias on female surgeons.The proportion of female physicians has increased in recent years, especially in Obstetrics and Gynecology. Recent literature assessing this impact supports equivalent or superior medical and surgical outcomes for women surgeons and physicians. It also reveals superior counseling and communication styles as perceived by patients. However, women in medicine receive lower patient ratings in competence, medical knowledge, and technical skills despite the existing evidence. Additionally, female physicians experience pay inequality, limited advancement opportunities, higher prevalence of microaggressions, and higher rates of burnout.Recognition of gender bias is essential to correcting this issue and improving the negative impact it has on female physicians, our patients, and the field of women's health.

This article examines media ownership transparency through the lens of European human rights policy and evaluates media ownership transparency in over 30 European countries based on data returned to the Media Pluralism Monitor. Using these data, we examine the existence and quality of two types of disclosure, ‘upwards’, to public bodies and ‘downwards’, directly to the public, enabling both the monitory and informational functions of ownership transparency to be fulfilled. We conclude that regulation is patchy and variable across Europe and that a coordinated, multi-actor approach is necessary to give effect to internationally recognized standards in the field.

Coastal ecosystems are exposed to multiple anthropogenic stressors. Effective management actions would be better informed from generalized predictions of the individual, combined and interactive effects of multiple stressors; however, few generalities are shared across different meta-analyses. Using an experimental study, we present an approach for analysing regression-based designs with generalized additive models that allowed us to capture nonlinear effects of exposure duration and stressor intensity and access interactions among stressors. We tested the approach on a globally distributed marine diatom, using 72 h photosynthesis and growth assays to quantify the individual and combined effects of three common water quality stressors; photosystem II-inhibiting herbicide exposure, dissolved inorganic nitrogen (DIN) enrichment and reduced light (due to excess suspended sediment). Exposure to DIN and reduced light generally resulted in additivity, while exposure to diuron and reduced light resulted in additive, antagonistic or synergistic interactions, depending on the stressor intensity, exposure period and biological response. We thus find the context of experimental studies to be a primary driver of interactions. The experimental and modelling approaches used here bridge the gap between two-way designs and regression-based studies, which provides a way forward to identify generalities in multiple stressor interactions.

A Late Iron Age farmstead was represented by an oval ditched enclosure, subsequently cut by another enclosure and together possibly forming a figure-of- eight plan, with contemporary features including a well, pits and post-holes. This was succeeded by a larger, early Roman enclosure in which lay a rectangular post-built structure and a sub-oval gully that may have been associated with a roundhouse, as well as hearths, pits, a well and a waterhole. The final mid–late Roman phase of settlement was characterised by a series of rectilinear enclosures. Although there is nothing of particular note amongst the finds and environmental assemblages, the significance of the site overall is that it provides a rare example of rural settlement of this date and duration on the Hampshire claylands, just to the south of Silchester and close to the Roman road that linked this with Chichester.

This chapter focuses on adapting structured clinical management (SCM) in order to improve care pathways and treatment for people diagnosed with borderline personality disorder (BPD). It describes and outlines two adaptations to SCM as a treatment model for BPD. The first describes a specialist SCM Case Management Service based on SCM principles for service users who present with complex and severe personality disorder and are high risk to themselves or others. The second adaptation focuses on the training of some mental health professionals as personality disorder linkworkers who provide individual SCM informed sessions in adapted form to the system of care surrounding the service user. Case management and linkwork are integrated in service provision when complexity, severity, and systemic risk are high.

Diamond is a material of immense technological importance and an ancient signifier for wealth and societal status. In geology, diamond forms as part of the deep carbon cycle and typically displays a highly ordered cubic crystal structure. Impact diamonds, however, often exhibit structural disorder in the form of complex combinations of cubic and hexagonal stacking motifs. The structural characterization of such diamonds remains a challenge. Here, impact diamonds from the Popigai crater were characterized with a range of techniques. Using the MCDIFFaX approach for analysing X-ray diffraction data, hexagonality indices up to 40% were found. The effects of increasing amounts of hexagonal stacking on the Raman spectra of diamond were investigated computationally and found to be in excellent agreement with trends in the experimental spectra. Electron microscopy revealed nanoscale twinning within the cubic diamond structure. Our analyses lead us to propose a systematic protocol for assigning specific hexagonality attributes to the mineral designated as lonsdaleite among natural and synthetic samples.

Silver iodide (AgI) is used for a wide range of applications from photocatalysis and antimicrobial coatings to photography and ice nucleation. By fitting powder X-ray diffraction patterns with DIFFaX, we show that AgI displays a strong tendency to form stacking-disordered materials. Its polytypism is determined by the silver cation to iodide molar ratio during precipitation. Under iodide-rich conditions, fully hexagonal -AgI is obtained whereas a maximal percentage of cubic stacking of 80% is obtained at a 1:2 molar ratio in the silver cation-rich regime. These findings are explained on the basis of a concentration-dependent competition between kinetically and thermodynamically-favored adsorption processes. Furthermore, the previously reported memory effects observed upon transforming hexagonal and cubic AgI to the high-temperature superionic phase and back are now followed quantitatively. We propose that the memory effects originate from excess ions at the surfaces of AgI crystals that stabilize the pyroelectricity of AgI associated with hexagonal stacking. The ability to ‘design’ the polytypism of AgI by tuning the precipitation conditions provides a first example where the stacking disorder of a material can be controlled in a continuous fashion. Future studies will clarify if this design principle can be applied to other materials as well.

The United Kingdom is currently examining far-reaching regulatory proposals designed to address the online transmission of various forms of harmful content, including disinformation. Of particular interest for the UK, given concerns over the transmission of false information prior to the 2016 referendum on European Union membership, is French Law no. 2018-1202 on the ‘fight against the manipulation of information’. The French Law establishes a fast track civil procedure to tackle the transmission of false information in the run up to key elections and referenda; introduces measures to address foreign state funded broadcast propaganda; and seeks to enhance transparency for users on the way in which online content is financed and distributed. Restrictions on the transmission of information, particularly in the run up to elections, are inherently suspect and the Conseil constitutionnel carefully reviewed the French proposals to ensure that any restriction on freedom of expression was both justified and necessary. French Law 2018-1202 thus offers an example of a rather ‘muscular’ form of intervention in the election field, but one which seeks to preserve democratic legitimacy without undermining the individual freedoms on which it rests.

Background/Aims: Pediatric stroke is a rare and serious occurrence with an estimated incidence of 1.2-13 cases per 100,000 annually. There is a high level of morbidity and mortality; survivors often suffer from long term neurological sequela. The pathophysiology of sickle cell disease (SCD) creates a prothrombotic state, thus SCD patients constitute a unique population of pediatric patients at high risk for cerebral vascular accidents. It has been estimated that by the age of 20, approximately 11% of SCD patients will have a clinically significant infarction. Most SCD infarctions …

Introduction Epilepsy is a debilitating neurological condition characterized by spontaneous seizures as well as significant comorbid behavioral abnormalities. In addition to seizures, epileptic patients exhibit interictal spikes far more frequently than seizures, often, but not always observed in the same brain areas. The exact relationship between spiking and seizures as well as their respective effects on behavior are not well understood. In fact, spiking without overt seizures is seen in various psychiatric conditions including attention-deficit hyperactivity disorder. Methods In order to study the effects of spiking and seizures on behavior in an epileptic animal model, we used long-term video-electroencephalography recordings at six cortical recording sites together with behavioral activity monitoring. Animals received unilateral injections of tetanus toxin into either the somatosensory or motor cortex. Results Somatosensory cortex-injected animals developed progressive spiking ipsilateral to the injection site, while those receiving the injection into the motor cortex developed mostly contralateral spiking and spontaneous seizures. Animals with spiking but no seizures displayed a hyperactive phenotype, while animals with both spiking and seizures displayed a hypoactive phenotype. Not all spikes were equivalent as spike location strongly correlated with distinct locomotor behaviors including ambulatory distance, vertical movements, and rotatory movement. Conclusions Together, our results demonstrate relationships between brain region-specific spiking, seizures, and behaviors in rodents that could translate into a better understanding for patients with epileptic behavioral comorbidities and other neuropsychiatric disorders.

Aim: Young-people with psychosis have higher rates of obesity, premature cardiovascular disease and death compared to non-psychotic peers in the general population due to changes in metabolic regulation linked to antipsychotic medication and adverse health risk behaviors. The aim of this paper is to outline the development, implementation, and evaluation of a combined 12-week exercise and health behavior intervention delivered as part of an Early Intervention in Psychosis (EIP) routine service, within the UK. Methods: Participants (n=27) completed a 12-week combined intervention program, engaging in weekly, 90-minute sessions comprising a healthy behavior education session (45 minutes), followed by a facilitated exercise session (45 minutes). Anthropometric data from participants (n=26) were collected at baseline, 12 weeks, and 12 months post-intervention. Health behaviors and clinical measurements were assessed at baseline and 12 months. Results: Mean baseline data suggests participants were at an increased health risk on entry to the program, with elevated values in mean body mass index (BMI; 70% overweight/obese), waist circumference, resting heart rate, and triglycerides. Fifty percent reported smoking daily, 64% ate < 5 fruits/vegetables per day, and 52% of participants were prescribed highly obesogenic antipsychotic medications (i.e., Olanzapine). At 12 weeks and 12 months, no changes were observed in mean BMI, waist circumference or any other clinical variable (p > 0.05). At 12 months, participants reported a positive impact on health behaviors including improved diet, increased physical activity levels, and cessation of substance use (n=2), alcohol use (n=2), and smoking (n=4). Focus groups captured participant experiences, engagement with and satisfaction with the program, including challenges/barriers to program adherence. Conclusions: The 12-week exercise and health behaviors program supported participants to attenuate their physical health risk which was sustained at 12 months follow up. Self-reported positive health behavior changes are likely to have contributed to the prevention of excessive weight gain in this high-risk period. The evaluation was designed to have validity for a ’real world EIP setting’ and reflect the complexity of delivery amongst this participant group. Evaluation findings influenced subsequent commissioning of the physical health intervention as an ongoing element of routine EIP care within the participant site.

The purpose of this review is to summarize the most recent evidence-based interventions for perioperative pain management in minimally invasive gynecologic surgery.With particular emphasis on preemptive interventions in recent studies, we found preoperative counseling, nutrition, exercise, psychological interventions, and a combination of acetaminophen, celecoxib, and gabapentin are highly important and effective measures to reduce postoperative pain and opioid demand. Intraoperative local anesthetics may help at incision sites, as a paracervical block, and a transversus abdominus plane block. Postoperatively, an effort should be made to utilize non-narcotic interventions such as abdominal binders, ice packs, simethicone, bowel regimens, gabapentin, and scheduled NSAIDs and acetaminophen. When prescribing narcotics, providers should be aware of recommended amounts of opioids required per procedure so as to avoid overprescribing.Our findings emphasize the evolving importance of preemptive interventions, including prehabilitation and pharmacologic agents, to improve postoperative pain after minimally invasive gynecologic surgery. Additionally, a multimodal approach to nonnarcotic intraoperative and postoperative interventions decreases narcotic requirement and improves opioid stewardship.

The search for new nanostructural topologies composed of elemental carbon is driven by technological opportunities as well as the need to understand the structure and evolution of carbon materials formed by planetary shock impact events and in laboratory syntheses. We describe two new families of diamond-graphene (diaphite) phases constructed from layered and bonded sp3 and sp2 nanostructural units and provide a framework for classifying the members of this new class of materials. The nanocomposite structures are identified within both natural impact diamonds and laboratory-shocked samples and possess diffraction features that have previously been assigned to lonsdaleite and postgraphite phases. The diaphite nanocomposites represent a new class of high-performance carbon materials that are predicted to combine the superhard qualities of diamond with high fracture toughness and ductility enabled by the graphitic units and the atomically defined interfaces between the sp3- and sp2-bonded nanodomains.

Excavations on the south-eastern slopes of King Barrow Ridge, 1.5 km east of Stonehenge, revealed five pits, a grave and other features of Middle Neolithic date. Analysis of the pit assemblages and the partial inhumation interred in the grave has provided insights into lifeways in this landscape in the late fourth millennium cal BC. Evidence suggests that the area was visited by a pastoralist, mobile community on a semi-regular basis for a significant period, in late autumn or winter. Selected remnants of craft-working and consumption were deposited in pits, before deliberate infilling. These depositions repeatedly memorialised activity on the hillside at a time of contemporary activity elsewhere on King Barrow Ridge and at the future site of Stonehenge. Middle Neolithic pits are present in significant numbers across King Barrow Ridge, and alongside pits in the Durrington area, form one of the densest concentrations of such activity in the region. Long distance mobility is suggested by the possible Irish origins of the inhumation, the first Middle Neolithic individual excavated in the environs of Stonehenge. Whilst of significance for understanding the Middle Neolithic in the WHS and the region, this research also hints at the roots of Late Neolithic monumentalisation of this landscape.

Background : Decreased volume and disrupted function in neural structures essential for memory formation (e.g. medial temporal lobe and prefrontal cortex) are common among individuals with depression. Hypothalamic-pituitary-axis function, as reflected by measurement of cortisol levels, is linked to neural activity during memory encoding in healthy people. However, it is not as well understood whether cortisol is associated with alterations in fronto-temporal recruitment during memory encoding in depression. Methods : In this pilot study, we evaluated associations between cortisol and neural activation during memory encoding in 62 adults (18–65 years) with mood disorders (MD; n = 39, 66.7% female), including major depression (n = 28) and bipolar I disorder (n = 11), and healthy controls (HC; n = 23, 43.5% female). Participants provided salivary cortisol samples before and after completing a semantically-cued list-learning task during 3-Tesla fMRI. Links between pre-scan cortisol (and cortisol change) and activation during encoding were evaluated using block and event-related models. Results : Overall, pre-scan cortisol level was positively associated with greater engagement of fronto-limbic activation during the encoding block. However, in MD, pre-scan cortisol was associated with attenuated activation during encoding in medial frontal, superior and middle temporal gyri, insula, lingual gyrus, and claustrum relative to HCs. Cortisol-related attenuation of activation in MD was also observed during encoding of words subsequently recalled in the ventral anterior cingulate, hypothalamus, and middle temporal gyrus. By and large, cortisol change (pre/post scan) predicted the same pattern of findings in both block and event-related contrasts. Limitations : Although analyses accounted for variations in scanner time of day, circadian alterations in cortisol may have introduced variability into the results. Conclusions : Pre-scan cortisol may selectively interfere with recruitment of important fronto-temporal memory circuitry in mood disorders. The inverted associations between cortisol and neural function in MD relative to HC also elucidate potentially unique pathophysiological markers of mood disorders.

Nanodiamonds (ND) with 1-5 nm dimensions found in meteorites or produced by chemical vapour deposition (CVD) and detonation synthesis are typically described in terms of an sp3-bonded carbon network. However, ultra-high-resolution transmission electron microscopy (uHRTEM) combined with density functional theory (DFT) modelling leads to a different structural interpretation. uHRTEM imaging and nanodiffraction studies of many NDs show six-fold symmetry features whose identity has long been controversial. We also observe diffraction patterns with twelve equally-spaced and symmetrically but unequally arranged reflections, indicating structures with crystallographically-forbidden ideal and distorted twelve-fold symmetry. Structural models based on our DFT calculations lead to an interpretation of these unusual features found throughout the meteoritic and CVD samples in terms of sp3 domains arranged around and coherently bonded to graphitic domains embedded within the diamond matrix. The bonding at the sp2-sp3 interface can explain the unusual features observed in electron energy-loss spectra (EELS) below the onset of the main diamond C1s core-loss edge leading to predictions of low-dimensional conductivity behaviour. The presence of sp2- as well as sp3-bonded regions allows us to interpret previously unexplained features of the Raman spectra and EELS data of ND materials.

Objective To establish and compare the onset and duration of action of 2 local anesthetics based on objective lameness and skin sensitivity assessment. Study design Interventional crossover experimental trial with balanced randomization. Animals Eight horses. Methods Reversible forelimb lameness was induced in 8 horses. A palmar digital nerve block (PDNB) was applied with mepivacaine or lidocaine (both 2%). Quantitative lameness and skin sensitivity data were collected with an inertial sensor system and a force gauge, respectively. The times to lameness resolution/skin desensitization (T1), consistent lameness detection/partial return of skin sensitivity (T2), and complete return of lameness/skin sensitivity (T3) were determined and compared between treatments and assessment methods. Results Mepivacaine blocks resolved lameness in 8/8 horses, compared to 3/8 horses with lidocaine blocks. Both agents led to skin desensitization in 8/8 horses. Skin desensitization occurred sooner than lameness resolution after mepivacaine (P = .047). Duration of action was longer with mepivacaine than lidocaine (mean T3_lameness mepivacaine 366 minutes, lidocaine 113 minutes (P = .038); T3_skin mepivacaine 195 minutes, lidocaine 63 minutes [P ≤ .001]). Skin sensitivity returned sooner than lameness after lidocaine block at T3 (P = .015). Conclusion The use of lidocaine in PDNBs for the purpose of lameness diagnosis should be reassessed, as it may not resolve lameness despite loss of skin sensation. Mepivacaine is superior, with a reliable onset and longer duration of action. Skin desensitization as an indicator for the onset of action or effectiveness of PDNBs for mepivacaine and lidocaine, or as a measure of the duration of action of lidocaine PDNBs should be interpreted with caution.

European and International Media Law explores the role of international human rights and economic law in shaping a transnational media law order. It focuses on the impact on European law, in partic...

The rotor of a horizontal-axis floating offshore wind turbine is more frequently misaligned with the oncoming wind than that of a fixed offshore or onshore wind turbine due to the pitch and yaw motions of the floating support structure. This can lead to increased unsteady loading and fatigue on the components beyond those considered in the standard load cases. In this work, the Simulator fOr Wind Farm Applications (SOWFA) tool within the CFD toolbox OpenFOAM is used to perform simulations of a wind turbine at different stationary angles to the oncoming wind flow that a floating wind turbine may experience, so that the impact of misaligned flow on power production and blade loading can be studied. The turbine is modelled using an actuator line method which is coupled with NREL’s aeroelastic code FAST to compute the structural response. The results of this study will be used in future work to optimise the rotor geometry of a floating offshore wind turbine.

Gavin Millar and Andrew Scott characterise the law relating to newsgathering as the ‘Cinderella’ of media law in that lawyers have tended to be concerned with whether what was about to be, or had b...

Silver iodide (AgI) is used for a wide range of applications from photocatalysis and antimicrobial coatings to photography and ice nucleation. By fitting powder X-ray diffraction patterns with DIFFaX, we show that AgI displays a strong tendency to form stacking-disordered materials. Its polytypism is determined by the silver cation to iodide molar ratio during precipitation. Under iodide-rich conditions, fully hexagonal b-AgI is obtained whereas a maximal percentage of cubic stacking of 80% is obtained at a 1:2 molar ratio in the silver cation-rich regime. These findings are explained on the basis of a concentration-dependent competition between kinetically and thermodynamically-favored adsorption processes. Furthermore, the previously reported memory effects observed upon transforming hexagonal and cubic AgI to the high-temperature superionic phase and back are now followed quantitatively. We propose that the memory effects originate from excess ions at the surfaces of AgI crystals that stabilize the pyroelectricity of AgI associated with hexagonal stacking. The ability to ‘design’ the polytypism of AgI by tuning the precipitation conditions provides a first example where the stacking disorder of a material can be controlled in a continuous fashion. Future studies will clarify if this design principle can be applied to other materials as well.

Aggregation of α-synuclein, the hallmark of α-synucleinopathies such as Parkinson´s disease, occurs in various glycosphingolipidoses. Although α-synuclein aggregation correlates with deficiencies in the lysosomal degradation of glycosphingolipids (GSL), the mechanism(s) involved in this aggregation remains unclear. We previously described the aggregation of α-synuclein in Krabbe´s disease (KD), a neurodegenerative glycosphingolipidosis caused by lysosomal deficiency of galactosyl-ceramidase (GALC) and the accumulation of the GSL psychosine. Here, we used a multi-pronged approach including genetic, biophysical and biochemical techniques to determine the pathogenic contribution, reversibility, and molecular mechanism of aggregation of α-synuclein in KD. While genetic knock-out of α-synuclein reduces, but does not completely prevent, neurological signs in a mouse model of KD, genetic correction of GALC deficiency completely prevents α-synuclein aggregation. We show that psychosine forms hydrophilic clusters and binds the C-terminus of α-synuclein through its amino group and sugar moiety, suggesting that psychosine promotes an open/aggregation-prone conformation of α-synuclein. Dopamine and carbidopa reverse the structural changes of psychosine by mediating a closed/aggregation-resistant conformation of α-synuclein. Our results underscore the therapeutic potential of lysosomal correction and small molecules to reduce neuronal burden in α-synucleinopathies, and provide a mechanistic understanding of α-synuclein aggregation in glycosphingolipidoses. Fil: Abdelkarim, Hazem. University of Illinois; Estados Unidos Fil: Marshall, Michael S.. University of Illinois; Estados Unidos Fil: Scesa, Giuseppe. University of Illinois; Estados Unidos Fil: Smith, Rachael A.. University of Illinois; Estados Unidos Fil: Rue, Emily. University of Illinois; Estados Unidos Fil: Marshall, Jeffrey. University of Illinois; Estados Unidos Fil: Elackattu, Vince. University Of Illinois Chicago; Estados Unidos Fil: Stoskute, Monika. University Of Illinois Chicago; Estados Unidos Fil: Issa, Yazan. University Of Illinois Chicago; Estados Unidos Fil: Santos, Marta. University Of Illinois Chicago; Estados Unidos Fil: Nguyen, Duc. University Of Illinois Chicago; Estados Unidos Fil: Hauck, Zane. University Of Illinois Chicago; Estados Unidos Fil: Van Breemen, Richard B.. University Of Illinois Chicago; Estados Unidos Fil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina Fil: Gaponenko, Vadim. University Of Illinois Chicago; Estados Unidos Fil: Bongarzone, Ernesto R.. University Of Illinois Chicago; Estados Unidos

This randomized controlled trial evaluated the effect of treatment intensity (high intensity vs. lower intensity) on the feasibility and efficacy of a comprehensive psychosocial treatment for 47 high-functioning children, ages 7–12 years with ASD (HFASD). All participants received the comprehensive 5-week summer treatment (summerMAX), with half receiving the previously validated high-intensity (HI) program (2:1 child-to-staff ratio) and half receiving a lower intensity (LI) version of the same program (4:1 child-to-staff ratio). Results of the primary analyses indicated significant improvements on non-literal language and emotion recognition (decoding) child testing and parent ratings of targeted and broad social skills, ASD-related symptoms, withdrawal, and behavioral symptoms for the overall group (HI and LI combined) and no significant difference between the conditions (HI vs. LI). Secondary staff clinician ratings corroborated parent ratings. No significant cross-condition differences were observed in fidelity of implementation or in parent, child, or staff clinician satisfaction ratings indicating no reduction in feasibility for the LI group. Overall, results suggested that similar positive outcomes can be achieved when the summerMAX program is administered at a lower intensity level.

The Routledge Handbook of Media Law brings together leading authors from the communications field with the particular aim to provide comparative and socio-legal perspectives on current media policy...

The paper considers the role of Scottish culture and history, real or imagined, in the commercialisation of iconic Scottish creations such as tartan and Scotch whisky. It notes that many of the forms of legal protection available to the producers of such products were developed to encourage individual innovation, not designed to address communal interests in the preservation of national or group identities and heritage. This may be one reason why, as is illustrated by the case of tartan, these rights offer patchy and incomplete protection to ‘authentic’ Scottish products. Over time, however, the UK has developed various forms of collective protection for cultural products such as Harris Tweed, the effectiveness of which is explored in this article. The final part of the paper considers the importance, in a globalising world, of European Union and international protection for valuable cultural ‘products’. But protection, whether at the national or international level, necessitates a difficult balance to be drawn between the interest in cultural innovation and development, on the one hand, and cultural preservation and the protection of the commercial interests of specific communities, on the other. The article concludes by exploring some of the practical and conceptual challenges associated with determining whether a product should be considered part of the cultural patrimony of the world or, rather, the property of a specific nation or cultural group. ‘…cultural diversity is strengthened by the free flow of ideas, and…is nurtured by constant exchanges and interaction between cultures…’ (Preamble to the 2005 UNESCO Convention on the Protection and Promotion of the Diversity of Cultural Expressions)

The Report by Lord Justice Leveson into the Culture, Practices and Ethics of the British Press (HMSO, November 2012) provides, at just under 2,000 pages, a rich resource for anyone wishing to under...

Retinoblastoma is the most common malignant tumour of the eye in children and accounts for 3% of all childhood cancers. It can occur either unilaterally or bilaterally and generally develops before the first five years of life. A red reflex test must be performed if a child presents with any of the following: a white reflex (leukocoria) or an abnormal reflex in flash photographs; a recently onset squint (strabismus); a change in colour to the iris; deterioration in vision; a red, sore or swollen eye without infection. The presentation of any of these signs or symptoms in isolation can indicate retinoblastoma. However, it is vital to note that a child with retinoblastoma may appear well, apart from one or more of these signs. This article gives detailed instruction on how to carry out a red reflex test and appropriate referral information for suspected cases. A swift referral pathway is vital to reduce loss of vision and the risk of mortality.

This study evaluated the effect of a comprehensive psychosocial intervention on supplemental measures of facial emotion encoding for children with high-functioning autism spectrum disorder (HFASD) who were enrolled in prior randomized trials. A total of 60 children, ages 7 to 12 years were randomly assigned to treatment or wait-list control groups. Photographs of six posed facial expressions (happy, sad, angry, scared, surprised, and disgusted) taken at pretest and posttest were rated for encoding accuracy by naive raters. Ratings consisted of a) the extent to which the facial expression reflected each of the six possible emotions (extent rating) and b) a selection of the one emotion the raters identified as being portrayed (forced-choice). Results indicated significantly better encoding of sad at posttest for the treatment group on the extent (d = .58) and forced-choice (d = .56) ratings. Between-groups differences in encoding of the other emotions at posttest were non-significant. Implications for intervention and future research are presented.

This community effectiveness trial examined the feasibility and efficacy of a comprehensive psychosocial treatment for 28 children, aged 7 to 10 years with high-functioning autism spectrum disorders (HFASDs). Treatment included instruction and therapeutic activities targeting social skills, face-emotion recognition skills, interest expansion, and interpretation of non-literal language skills. A behavioral program was instituted to foster skills acquisition and reduce ASD symptoms and problem behaviors. Feasibility was supported in high levels of fidelity and satisfaction. Significant improvements were found for the children’s non-literal language skills and parent ratings of target social and communicative skills, broader social performance, and ASD symptoms. Secondary staff ratings corroborated parent ratings. Results suggest that the treatment, when administered by a community agency, was feasible and yielded positive outcomes similar to prior randomized clinical trials (RCTs).