Focused ultrasounds: What is their future in epileptology? A critical review.

High intensity focused ultrasounds (HIFU) are being increasingly advocated as a useful tool in the management of focal drug-resistant epilepsy. Our aim was to review current literature on the topic and perform an inventory of open trials assessing HIFU effectiveness and safety in epilepsy management. To do so, a review was conducted and yielded one prospective clinical trials, two case reports and one safety study were retrieved, indicating that HIFU is still in its infancy when it comes to focal drug-resistant epilepsy therapy. Efforts should be made to develop this technology using multicentric prospective data with larger cohorts and prolonged follow-up.

Search for Gamma-Ray Spectral Lines from Dark Matter Annihilation up to 100 TeV toward the Galactic Center with MAGIC.

Linelike features in TeV γ rays constitute a "smoking gun" for TeV-scale particle dark matter and new physics. Probing the Galactic Center region with ground-based Cherenkov telescopes enables the search for TeV spectral features in immediate association with a dense dark matter reservoir at a sensitivity out of reach for satellite γ-ray detectors, and direct detection and collider experiments. We report on 223 hours of observations of the Galactic Center region with the MAGIC stereoscopic telescope system reaching γ-ray energies up to 100 TeV. We improved the sensitivity to spectral lines at high energies using large-zenith-angle observations and a novel background modeling method within a maximum-likelihood analysis in the energy domain. No linelike spectral feature is found in our analysis. Therefore, we constrain the cross section for dark matter annihilation into two photons to ⟨σv⟩≲5×10^{-28} cm^{3} s^{-1} at 1 TeV and ⟨σv⟩≲1×10^{-25} cm^{3} s^{-1} at 100 TeV, achieving the best limits to date for a dark matter mass above 20 TeV and a cuspy dark matter profile at the Galactic Center. Finally, we use the derived limits for both cuspy and cored dark matter profiles to constrain supersymmetric wino models.

Research Note: In-feed Bacteriophage does not impact efficacy of live Salmonella vaccine.

Dietary bacteriophages potentially can serve as a step to reduce Salmonella contamination of feed through direct lysis of the bacteria. However, poultry producers commonly vaccinate with live Salmonella vaccines, which could potentially be lysed by dietary bacteriophages. The objective of this study was to evaluate if dietary bacteriophages impacted the colonization of a live Salmonella vaccine. A total of 210 day-of-hatch Ross male broiler chicks were divided into 3 treatments consisting of 2 replicate per treatment. Each replicate contained 35 birds. T1 was the challenge control, given no Salmonella vaccine, T2 was challenged and given Salmonella vaccine and T3 was challenged, given Salmonella vaccine as well as dietary bacteriophage. Salmonella vaccine was administered day of hatch. On d 3, four birds/pen were sampled for Salmonella vaccine colonization of ceca and liver/spleen. The remaining birds were challenged with 5 × 107 CFU of nalidixic acid- resistant Salmonella enteritidis (S.E.). On d 28, ten birds/replicate were sampled via cloaca swabs to culture for S.E. On d 42, the trial was terminated, birds were weighed, and performance was calculated. In addition, 15 birds/replicate were sampled for cecal cultures of S.E. On d 3, T1 had 0% vaccine strain isolated, and significantly lower (P = 0.009) cecal prevalence compared with T2 (75%) and T3 (38%) being intermediate. T1 (0%) had significantly lower liver/spleen vaccine strain prevalence (P = 0.002) compared with T3 (88%) and T2 (63%) being intermediate. No significant differences (P > 0.05) were observed among treatments in Salmonella prevalence in d 28 cloacal swabs. No significant differences (P > 0.05) were observed in d 42 cecal Salmonella prevalence between all treatments. No significant differences in bird weight were observed between treatments d 0 to 42 (P > 0.05). However, T2 and T3 had lower mortality and adjusted feed conversion ratio (FCR; P < 0.05) compared with T1. Therefore, the dietary bacteriophage did not interfere with colonization or protection afforded by the live Salmonella vaccine.

Evolving the narrative for protecting a rapidly changing ocean, post-COVID-19.

The ocean is the linchpin supporting life on Earth, but it is in declining health due to an increasing footprint of human use and climate change. Despite notable successes in helping to protect the ocean, the scale of actions is simply not now meeting the overriding scale and nature of the ocean's problems that confront us.Moving into a post-COVID-19 world, new policy decisions will need to be made. Some, especially those developed prior to the pandemic, will require changes to their trajectories; others will emerge as a response to this global event. Reconnecting with nature, and specifically with the ocean, will take more than good intent and wishful thinking. Words, and how we express our connection to the ocean, clearly matter now more than ever before.The evolution of the ocean narrative, aimed at preserving and expanding options and opportunities for future generations and a healthier planet, is articulated around six themes: (1) all life is dependent on the ocean; (2) by harming the ocean, we harm ourselves; (3) by protecting the ocean, we protect ourselves; (4) humans, the ocean, biodiversity, and climate are inextricably linked; (5) ocean and climate action must be undertaken together; and (6) reversing ocean change needs action now.This narrative adopts a 'One Health' approach to protecting the ocean, addressing the whole Earth ocean system for better and more equitable social, cultural, economic, and environmental outcomes at its core. Speaking with one voice through a narrative that captures the latest science, concerns, and linkages to humanity is a precondition to action, by elevating humankind's understanding of our relationship with 'planet Ocean' and why it needs to become a central theme to everyone's lives. We have only one ocean, we must protect it, now. There is no 'Ocean B'.

Transmitted HIV-1 drug resistance in a large international cohort using next-generation sequencing: results from the Strategic Timing of Antiretroviral Treatment (START) study.

OBJECTIVES: The aim of this analysis was to characterize transmitted drug resistance (TDR) in Strategic Timing of Antiretroviral Treatment (START) study participants by next-generation sequencing (NGS), a sensitive assay capable of detecting low-frequency variants. METHODS: Stored plasma from participants with entry HIV RNA > 1000 copies/mL were analysed by NGS (Illumina MiSeq). TDR was based on the WHO 2009 surveillance definition with the addition of reverse transcriptase (RT) mutations T215N and E138K, and integrase strand transfer inhibitor (INSTI) surveillance mutations (Stanford HIVdb). Drug resistance mutations (DRMs) detected at three thresholds are reported: > 2%, 5% and 20% of the viral population. RESULTS: Between 2009 and 2013, START enrolled 4684 antiretroviral therapy (ART)-naïve individuals in 35 countries. Baseline NGS data at study entry were available for 2902 participants. Overall prevalence rates of TDR using a detection threshold of 2%/5%/20% were 9.2%/5.6%/3.2% for nucleoside reverse transcriptase inhibitors (NRTIs), 9.2%/6.6%/4.9% for non-NRTIs, 11.4%/5.5%/2.4% for protease inhibitors (PIs) and 3.5%/1.6%/0.1% for INSTI DRMs and varied by geographic region. Using the 2% detection threshold, individual DRMs with the highest prevalence were: PI M46IL (5.5%), RT K103NS (3.5%), RT G190ASE (3.1%), T215ISCDVEN (2.5%), RT M41L (2.2%), RT K219QENR (1.7%) and PI D30N (1.6%). INSTI DRMs were detected almost exclusively below the 20% detection threshold, most commonly Y143H (0.4%), Q148R (0.4%) and T66I (0.4%). CONCLUSIONS: Use of NGS in this study population resulted in the detection of a large proportion of low-level variants which would not have been detected by traditional Sanger sequencing. Global surveillance studies utilizing NGS should provide a more comprehensive assessment of TDR prevalence in different regions of the world.

Comparative effectiveness of antiretroviral drug classes for the treatment of HIV infection in patients with high viral loads: a multicentre retrospective cohort study.

OBJECTIVES: We aimed to compare the effectiveness of antiretroviral therapy (ART) classes for achieving HIV RNA suppression to < 50 HIV-1 RNA copies/mL within 6 months of initiation with high viral loads (VLs). Secondary objectives were to compare viral suppression (VS) at 12 weeks and 12 months, partial HIV RNA suppression to < 200 copies/mL, time to VS, time to rebound, and change in CD4 cell count. METHODS: This was a multicentre, retrospective, observational study. Adult patients were included if they initiated ART between January 2005 and December 2016 with a VL ≥ 100 000 copies/mL. RESULTS: There were 220 patients included in the study. The median VL was 252 919 [interquartile range (IQR) 149 472-500 000] copies/mL. Nonnucleoside reverse transcriptase inhibitor (NNRTI) recipients were more likely to achieve VS by 6 months compared to those initiating ART containing protease inhibitors (PIs) [75.4% vs. 44.1%, respectively; odds ratio (OR) 3.34; 95% confidence interval (CI) 1.62-6.90] or integrase strand transfer inhibitors (INSTIs) (75.4% vs. 55.8%, respectively; OR 2.40; 95% CI 1.03-5.58). VS at 12 weeks was more frequent with INSTI-containing regimens than with PIs (28.9% vs. 9.0%, respectively; OR 4.10; 95% CI 1.69-9.92). VS at 12 months did not significantly differ between treatment regimens. Median time to complete VS for INSTI, PI and NNRTI recipients was 22.3 (95% CI 13.4-33), 30.1 (95% CI 25-36) and 19.9 (95% CI 16-22.3) weeks, respectively. There were no significant differences in time to viral rebound or change in CD4 cell counts. CONCLUSIONS: Patients with high VLs initiated on NNRTIs were more likely to achieve VS by 6 months on ART compared to INSTI and PI recipients.

Large-area electrode design for vertical electrical impedance scanning of concrete bridge decks.

Vertical electrical impedance (VEI) testing is a method that was developed specifically for quantifying the level of protection against chloride ingress in concrete bridge decks. A significant operational difficulty associated with VEI testing has been establishing the required rebar tap as a ground reference. As described in this work, the use of a large-area electrode (LAE) can potentially remove the need for a rebar tap and therefore significantly simplify and accelerate the VEI testing process. The specific objective of the research was to develop both theoretical and practical guidance for the design of an LAE for VEI testing. To investigate several variables that can affect the accuracy of VEI measurements obtained using an LAE connection, including various combinations of deck cover and water resistivity values, electrode separation distance, counter electrode (CE) effective area, and area ratio between the LAE and the CE, an analytical model (AM) and a finite-element model (FEM) were developed and validated with laboratory and field experiments. From the results of the AM and FEM simulations and the results of the laboratory and field experiments, LAE design considerations were developed for each of these variables that should allow proper implementation of a VEI measurement system using an LAE connection.

Effects of vitamin supplementation on inflammatory markers and psychological wellbeing among distressed women: a randomized controlled trial.

BACKGROUND: Multivitamins are a popular supplement taken to promote physical and mental health. During periods of stress, they may have a protective role for health and wellbeing, although the current evidence of their efficacy is mixed. OBJECTIVE: To determine whether multivitamin supplementation impacts psychological and inflammatory markers of women who are experiencing psychological distress. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: An 8-week randomized controlled trial was conducted to assess changes in both psychological state and pro-inflammatory markers of patients receiving multivitamins or placebo. The sample comprised women who reported elevated psychological distress in the previous 4 weeks. MAIN OUTCOME MEASURES: Psychological state was assessed using Spielberger's State-Trait Personality Inventory to assess anxiety, curiosity, depression and anger. Pro-inflammatory markers comprised interleukin (IL)-1ß, IL-5, IL-6, tumour necrosis factor (TNF)-α and TNF-ß. RESULTS: Improvements across time were observed for all psychological measures and cytokines, except IL-5, but were independent of the active intervention. Only TNF-ß demonstrated a significant differential change between groups over the course of the intervention, in favour of multivitamin supplementation (active group mean rank decreased from 11.1 to 7.1; placebo group mean rank decreased from 8.9 to 7.8). CONCLUSION: The results suggest that administration of multivitamins was not effective in improving psychological state. However, some evidence supported the positive impact of multivitamin supplementation on pro-inflammatory cytokine profiles of women currently experiencing stress.

Long-term satellite tracking reveals variable seasonal migration strategies of basking sharks in the north-east Atlantic.

Animal migration is ubiquitous in nature with individuals within a population often exhibiting varying movement strategies. The basking shark (Cetorhinus maximus) is the world's second largest fish species, however, a comprehensive understanding of their long-term wider-ranging movements in the north-east Atlantic is currently lacking. Seventy satellite tags were deployed on basking sharks over four years (2012-2015) off the west coast of Scotland and the Isle of Man. Data from 28 satellite tags with attachment durations of over 165 days reveal post-summer ranging behaviours. Tagged sharks moved a median minimum straight-line distance of 3,633 km; achieving median displacement of 1,057 km from tagging locations. Tagged individuals exhibited one of three migration behaviours: remaining in waters of UK, Ireland and the Faroe Islands; migrating south to the Bay of Biscay or moving further south to waters off the Iberian Peninsula, and North Africa. Sharks used both continental shelf areas and oceanic habitats, primarily in the upper 50-200 m of the water column, spanning nine geo-political zones and the High Seas, demonstrating the need for multi-national cooperation in the management of this species across its range.

Urinary Tract Infection Caused by Citrobacter koseri in a Patient With Spina Bifida, an Ileal Conduit and Renal Caluli Progressing to Peri-nephric Abscess and Empyema.

Urological problems are common in spina bifida and are often treated with urinary diversions. Spina bifida and ileal conduits put patients at increased risk for ascending urinary tract infections. Here we present a novel case of a Citrobacter koseri urinary tract infection complicated by a perinephric abscess with pleural extension. To our knowledge, no case of an ascending C. koseri UTI progressing to peri-nephric abscess and empyema by direct extension exists in the literature.

Determining patient preferences in the management of neovascular age-related macular degeneration: a conjoint analysis.

PurposeTo determine the opinions from a patient perspective on relevant variables in the delivery of treatment for neovascular age-related macular degeneration (nAMD).MethodsPilot interviews with patients and doctors were conducted to identify what variables in the provision of a nAMD service were important. This led to the generation of two sets of scenario options. Subsequently 100 patients undergoing active treatment for nAMD in the National Health Service University Hospital, United Kingdom underwent interview assessment. They were asked to rank their preferences for provision of their care with reference to these two sets of scenario options. Using conjoint analysis, percentage preferences, and utility scores for each variable in each scenario design were calculated.ResultsNinety-five patients completed the preference ranking for both scenarios. Eight patients ranked worse vision as preferable to better vision and were excluded on the basis that they had not understood the task. The results of the remaining 87 patients are presented. The most important factor to patients was having good vision, followed by a one-stop service and less frequent follow up. The least important factors were label status of the drug, cost to the health service, and grade of the injector.ConclusionPatients regard good vision and minimal visits to the hospital above the status of injector, label status of drug, or cost to the NHS.

OCEANOGRAPHY. Contrasting futures for ocean and society from different anthropogenic CO2 emissions scenarios.

The ocean moderates anthropogenic climate change at the cost of profound alterations of its physics, chemistry, ecology, and services. Here, we evaluate and compare the risks of impacts on marine and coastal ecosystems­and the goods and services they provide­for growing cumulative carbon emissions under two contrasting emissions scenarios. The current emissions trajectory would rapidly and significantly alter many ecosystems and the associated services on which humans heavily depend. A reduced emissions scenario­consistent with the Copenhagen Accord's goal of a global temperature increase of less than 2°C­is much more favorable to the ocean but still substantially alters important marine ecosystems and associated goods and services. The management options to address ocean impacts narrow as the ocean warms and acidifies. Consequently, any new climate regime that fails to minimize ocean impacts would be incomplete and inadequate.

Evaluating adaptive co-management as conservation conflict resolution: Learning from seals and salmon.

By linking iterative learning and knowledge generation with power-sharing, adaptive co-management (ACM) provides a potential solution to resolving complex social-ecological problems. In this paper we evaluate ACM as a mechanism for resolving conservation conflict using a case study in Scotland, where seal and salmon fishery stakeholders have opposing and entrenched objectives. ACM emerged in 2002, successfully resolving this long-standing conflict. Applying evaluation approaches from the literature, in 2011 we interviewed stakeholders to characterise the evolution of ACM, and factors associated with its success over 10 years. In common with other ACM cases, triggers for the process were shifts in slow variables controlling the system (seal and salmon abundance, public perceptions of seal shooting), and exogenous shocks (changes in legal mandates, a seal disease outbreak). Also typical of ACM, three phases of evolution were evident: emerging local leadership preparing the system for change, a policy window of opportunity, and stakeholder partnerships building the resilience of the system. Parameters maintaining ACM were legal mechanisms and structures, legal power held by government, and the willingness of all stakeholders to reach a compromise and experiment with an alternative governance approach. Results highlighted the critical role of government power and support in resolving conservation conflict, which may constrain the extent of local stakeholder-driven ACM. The evaluation also demonstrated how, following perceived success, the trajectory of ACM has shifted to a 'stakeholder apathy' phase, with declining leadership, knowledge exchange, stakeholder engagement, and system resilience. We discuss remedial actions required to revive the process, and the importance of long term government resourcing and alternative financing schemes for successful conflict resolution. Based on the results we present a generic indicator framework and participatory method for the longitudinal evaluation of ACM applied to conservation conflict resolution.

Global HIV-1 transmitted drug resistance in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: HIV-1 transmitted drug resistance (TDR) in treatment-naïve individuals is a well-described phenomenon. Baseline genotypic resistance testing is considered standard of care in most developed areas of the world. The aim of this analysis was to characterize HIV-1 TDR and the use of resistance testing in START trial participants. METHODS: In the Strategic Timing of AntiRetroviral Treatment (START) trial, baseline genotypic resistance testing results were collected at study entry and analysed centrally to determine the prevalence of TDR in the study population. Resistance was based on a modified 2009 World Health Organization definition to reflect newer resistance mutations. RESULTS: Baseline resistance testing was available in 1946 study participants. Higher rates of testing occurred in Europe (86.7%), the USA (81.3%) and Australia (89.9%) as compared with Asia (22.2%), South America (1.8%) and Africa (0.1%). The overall prevalence of TDR was 10.1%, more commonly to nonnucleoside reverse transcriptase inhibitors (4.5%) and nucleoside reverse transcriptase inhibitors (4%) compared with protease inhibitors (2.8%). The most frequent TDR mutations observed were M41L, D67N/G/E, T215F/Y/I/S/C/D/E/V/N, 219Q/E/N/R, K103N/S, and G190A/S/E in reverse transcriptase, and M46I/L and L90M in protease. By country, the prevalence of TDR was highest in Australia (17.5%), France (16.7%), the USA (12.6%) and Spain (12.6%). No participant characteristics were identified as predictors of the presence of TDR. CONCLUSIONS: START participants enrolled in resource-rich areas of the world were more likely to have baseline resistance testing. In Europe, the USA and Australia, TDR prevalence rates varied by country.

Reflux composition influences the level of NF-κB activation and upstream kinase preference in oesophageal adenocarcinoma cells.

Oesophageal adenocarcinoma (OA) incidence is rising and prognosis is poor. Understanding the molecular basis of this malignancy is key to finding new prevention and treatment strategies. Gastroesophageal reflux disease is the primary cause of OA, usually managed with acid suppression therapy. However, this often does little to control carcinogenic bile acid reflux. The transcription factor nuclear factor kappa B (NF-κB) plays a key role in the pathogenesis of OA and its activity is associated with a poor response to chemotherapy, making it an attractive therapeutic target. We sought to decipher the role of different bile acids in NF-κB activation in oesophageal cell lines using short, physiologically relevant exposure times. The effect of an acidic or neutral extracellular pH was investigated concurrently, to mimic in vivo conditions associated with or without acid suppression. We found that some bile acids activated NF-κB to a greater extent when combined with acid, whereas others did so in its absence, at neutral pH. The precise composition of an individual's reflux, coupled with whether they are taking acid suppressants may therefore dictate the extent of NF-κB activation in the oesophagus, and hence the likelihood of histological progression and chemotherapy success. Regardless of pH, the kinase inhibitor of κB kinase was pivotal in mediating reflux induced NF-κB activation. Its importance was confirmed further as its increased activation was associated with histological progression in patient samples. We identified further kinases important in acid or bile induced NF-κB signalling in oesophageal cells, which may provide suitable targets for therapeutic intervention.

Changes in markers of oxidative stress and DNA damage in human visceral adipose tissue from subjects with obesity and type 2 diabetes.

AIMS: In the past 30 years, prevalence of obesity has almost trebled resulting in an increased incidence of type 2 diabetes mellitus and other co-morbidities. Visceral adipose tissue is believed to play a vital role, but underlying mechanisms remain unclear. Our aim was to investigate changes in markers of oxidative damage in human visceral adipose tissue to determine levels of oxidative burden that may be attributed to obesity and/or diabetes. METHODS: Visceral adipose tissue samples from 61 subjects undergoing abdominal surgery grouped as lean, obese and obese with type 2 diabetes mellitus, were examined using 3 different markers of oxidative stress. Malondialdehyde (MDA) concentration was measured as a marker of lipid peroxidation, telomere length and Comet assay as markers of oxidative DNA damage. RESULTS: No significant difference in MDA concentration, telomere length and DNA damage was observed between groups, although longer telomere lengths were seen in the obese with diabetes group compared to the obese group (P<0.05). Lower MDA concentration and longer telomere length were seen in subjects with diabetes compared to those without (P<0.05). DNA damage, analysed via Comet assay, was significantly lower in subjects with diabetes compared to those without (P<0.05). CONCLUSION: A paradoxical decrease in oxidative stress and DNA damage was observed in samples from subjects with type 2 diabetes mellitus. Further work is required to investigate this further, however this phenomenon may be due to an up regulation of antioxidant defences in adipose tissue.

The prognosis of incurable cachectic cancer patients on home parenteral nutrition: a multi-centre observational study with prospective follow-up of 414 patients.

BACKGROUND: The role of home parenteral nutrition (HPN) in incurable cachectic cancer patients unable to eat is extremely controversial. The aim of this study is to analyse which factors can influence the outcome. PATIENTS AND METHODS: We studied prospectively 414 incurable cachectic (sub)obstructed cancer patients receiving HPN and analysed the association between patient or clinical characteristics and surviving status. RESULTS: Median weight loss, versus pre-disease and last 6-month period, was 24% and 16%, respectively. Median body mass index was 19.5, median KPS was 60, median life expectancy was 3 months. Mean/median survival was 4.7/3.0 months; 50.0% and 22.9% of patients survived 3 and 6 months, respectively. At the multivariable analysis, the variables significantly associated with 3- and 6-month survival were Glasgow Prognostic Score (GPS) and KPS, and GPS, KPS and tumour spread, respectively. By the aggregation of the significant variables, it was possible to dissect several classes of patients with different survival probabilities. CONCLUSIONS: The outcome of cachectic incurable cancer patients on HPN is not homogeneous. It is possible to identify groups of patients with a ≥6-month survival (possibly longer than that allowed in starvation). The indications for HPN can be modulated on these clinical/biochemical indices.