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Diffusing alpha-emitters Radiation Therapy (DaRT) releases alpha-emitting atoms into the tumor microenvironment. The treatment effectively ablates human and mice xenografts and shows 100% response rates in skin or head and neck squamous cell carcinoma patients. DaRT induces specific and systemic antitumor immune activation and synergizes with immune stimulation and modulation in mice. Here, the transcriptional profile activated by DaRT, and its potential to enhance responsiveness to immune checkpoint inhibition by programmed cell death protein 1 (PD-1) blockade were studied.Squamous cell carcinoma tumor- bearing BALB/C mice were treated with DaRT or inert seeds in combination with anti-PD-1 (aPD-1) or IgG control antibody. Sixteen days after seed insertion, tumors and spleens were subjected to immunophenotyping and immunohistochemical staining. Combination of DaRT and aPD-1 was tested for efficacy. Gene expression analysis was performed on mRNA extracted from tumors 7 days after DaRT or inert insertion using Nanostring PanCancer-IO-360 panel, and tumors and spleens were subjected to flow cytometry analysis.DaRT in combination with aPD-1 delayed tumor development, induced CD3 and CD8 lymphocytes infiltration more efficiently than either monotherapy. The combined treatment reduced splenic polymorphonuclear myeloid derived suppressor cells more than aPD-1 therapy or control. Granzyme B release in the tumor was increased only in the combinational treatment and was correlated with T-lymphocyte infiltration. Gene expression and gene set enrichment analysis of mRNA levels 7 days after DaRT insertion indicated that DaRT upregulated apoptosis, p53 signaling, G1/S-related arrest, interferon signaling and myeloid related transcription, while downregulating DNA repair, cell proliferation, and notch-related transcription. Flow cytometry showed that DaRT increased dendritic cells activation and led to changes in MDSCs distribution.DaRT promotes a "hot" tumor microenvironment and changes in immune suppression that lead to a potentiation of aPD-1 blockade induced effector T cell function and improved treatment efficacy. This study provides rationale for investigating DaRT and aPD-1 combination in patients with squamous cell carcinoma.

Theory of Change (ToC) has been promoted as a useful tool in sustainability research for visioning, planning, communication, monitoring, evaluation and learning. It involves a mapping of steps towards a desired long-term goal supplemented with continuous reflection on how and why change is expected to happen in a particular context. However, there is limited reported experience with the development and application of ToCs in inter- and transdisciplinary research contexts. While some previous publications have focused on ex-post application, there has been little discussion about the process of developing and using ToCs in strategic planning and monitoring in large inter- and transdisciplinary research programs. This article reports challenges and lessons learned from the experience of developing and using ToCs in the inter- and transdisciplinary research program Wings (Water and sanitation innovations for non-grid solutions). Challenges include (1) managing time constraints, (2) balancing between concrete and abstract discussions, (3) ensuring diversity in group composition, (4) fluctuating between reservations and appreciation, and (5) fulfilling both service and science roles while leading the ToC process. The experience highlights the importance of alternating formal and informal interaction formats throughout the process, ensuring heterogenous group formation, involving early career scientists, being responsive to emergent needs and making the added value of developing and using ToCs explicit and tangible for all participants. Although these lessons are mainly derived from developing ToCs within the interdisciplinary program team, they can support other programs in both their inter- and transdisciplinary research endeavors.

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was0.94 and the NPV99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

To evaluate the efficacy and safety of concurrent non-invasive stimulation of occipital and trigeminal nerves in acute treatment of migraine with or without aura.Non-invasive neuromodulation devices stimulating a single peripheral nerve or anatomic distribution are routinely used by patients with migraine refractory to the first-line drugs or those who opt out of pharmaceutical treatment. Concurrent occipital and trigeminal stimulation was described in an invasive setting, and its safety cost outweighed its efficacy gain. This study evaluated the efficacy and safety of an external concurrent occipital and trigeminal device in acute treatment of migraine.This was a randomized, sham-controlled, double-blind, multi-center trial. Patients 18 years of age or older who met the International Classification of Headache Disorders (2018) diagnostic criteria for migraine with or without aura, reported 1-6 migraine attacks per month, and other headaches no more than 6 days per month were enrolled. Of 131 intention-to-treat participants (67 and 64 in the active and sham groups, respectively), 109 (50 and 59 in the active and sham groups, respectively) treated at least one migraine episode. Reduction of migraine headache (pain relief) 2 h after treatment initiation was the primary efficacy endpoint. Pain relief at 1 h, and pain freedom and relief in most bothersome symptom at 2 h after treatment initiation were the secondary endpoints. Freedom from most bothersome symptom at 2 h and sustained pain freedom 24 h after treatment initiation were among the exploratory endpoints.Sixty percent of participants (30/50) in the active arm reported pain relief at 2 h after initiation of the first eligible treatment (primary outcome) compared to 37% (22/59) in the control arm (difference, 23%; 95% confidence interval [CI], 2%-41%; p = 0.018). Pain freedom at 2 h without rescue medication was reported by 46% (23/50) of participants in the active arm and by 12% (7/59) of participants in the sham arm (p 0.001). Pain freedom 2 h after the treatment and, subsequently, at 24 h, was reported by 4.25 times more participants in the active arm (36%; 18/50) than in the sham arm (8%; 5/59). The 28% difference was statistically significant (95% CI, 1%-43%; p 0.001). A 4.25-fold difference was also observed comparing the proportion of participants free from pain and most bothersome symptom 2 h after the stimulation (47% [17/36] and 11% [5/45] in the active and sham arms, respectively; 95% CI, 14%-54%; p 0.001). Adverse events were not serious or severe. All study-related events resolved without treatment.External concurrent occipital and trigeminal neurostimulation is a well-tolerated, safe, and effective migraine treatment that provided a fast and durable relief and freedom from migraine pain and associated symptoms in a randomized setting. The observed safety and performance suggest external concurrent occipital and trigeminal neurostimulation is a viable alternative to the currently available acute migraine treatments.clinicaltrials.gov identifier NCT03631550.

Background: Combined peripheral occipital and trigeminal neurostimulation is clinically proven to alleviate migraine symptoms, however, it was previously possible only via high-risk surgical procedures. Neuromodulation using currently available peripheral nerve stimulation devices stimulates only one nerve. The objective of this prospective, randomized, double-blind, sham-controlled trial was to evaluate the efficacy, safety and tolerability of a novel external concurrent occipital and trigeminal neurostimulation (eCOT-NS) device designed as a self-administered home treatment for migraine (Relivion® MG, Neurolief, Ltd; Netanya, Israel).Methods: Episodic and chronic migraine subjects (N=55) were randomized to receive active (n=27) or sham (n=28) treatment. Each subject received an eCOT-NS device and performed a 60 ±20-minute treatment at home within 45 minutes of migraine episode onset. The primary endpoint was the change in mean baseline pain intensity based on VAS pain scores 1 hour after treatment initiation, defined as relative (percent) change. Treatment outcomes assessed at 1, 2 and 24 hours post-treatment initiation were pain-reduction, and proportion of pain-free subjects and treatment responders, defined as ≥50% pain reduction. Categorical pain ratings (none, mild, moderate, and severe pain) were also analyzed.Results: Active stimulation was significantly more effective than sham stimulation for decreasing pain intensity at 1 hour (53% vs.10%), 2 hours (52% vs. 17%) and 24-hours (71% vs. 34%). Pain-free ratings were greater for the active treatment arm at 1 hour (29.2% vs. 16%), 2 hours (41.7% vs. 20%) and 24 hours (65.2% vs. 40%). Subjects with moderate or severe migraine baseline pain who were pain-free at 2 hours was significantly greater among subjects receiving active treatment (43% vs. 10.5%). The responder rate was significantly higher among the active treatment group at 1 hour (67% vs. 20%), 2 hours (66.7% vs. 32%,) and 24 hours (78.3% vs. 48%). Overall headache-relief was significantly higher in the active treatment group at 1 hour (67% vs. 26%) and 2 hours (76% vs. 31.6%). Mild adverse events, reported by a minority of subjects, resolved spontaneously. Conclusions: eCOT-NS provides superior clinically meaningful relief and freedom of migraine pain compared to sham, offering a highly effective and safe non-pharmacological treatment for acute migraine.Trial registration: ClinicalTrials.gov Identifier NCT03398668.

Viruses are efficient metabolic engineers that actively rewire host metabolic pathways to support their lifecycle, presenting attractive metabolic targets for intervention. Here we chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples. Bulk and single-cell analyses show that viral replication induces endoplasmic stress and lipid accumulation. Protein expression screen suggests a role for viral proteins in mediating this metabolic response even in the absence of replication. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication. Analysis of 3,233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective interventional open-label study was carried out in 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate (TriCor®) in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to control patients admitted during the same period and treated with the standard-of-care. Taken together, our data show that elevated lipid metabolism underlies critical aspects of COVID-19 pathogenesis, suggesting that pharmacological modulation of lipid metabolism should be strongly considered for the treatment of coronavirus infection.

Purpose: To compare an analog visual scale in grading anterior chamber cells (ACC) to a modified Standardization of Uveitis Nomenclature (SUN) ACC scale. Method: A graphical representation of anterior chamber cells as a reference and a test set was created and shown to two groups of experienced uveitis experts. Group 1 was given the analog scale in written format, while group two was given the reference images for comparison. Each test subject was asked to provide the best approximation for each grade. Results: Eleven graders participated in phase 1. Correct grading occurred in 87.4% of cases. Discrepancies were seen at all grades. Only 3 of 11 graders were able to achieve a perfect score. Seven graders participated in phase 2. Agreement was 95.2% with 4/7 graders achieving a perfect score. Discrepancies were seen at higher grades only. Conclusions: ACC grading is improved by a visual grading scale, and interobserver variability is reduced.

Several works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time.This phase II, prospective study was open to pediatric patients with TRE on stable antiepileptic drugs' (AEDs) doses, who experienced ≥4 seizures within four weeks of enrolment and with a history of ≥4 AEDs failing to provide seizure control. Following a 4-week observation period, patients began a 2-week dose-titration phase (up to ≤25mg/kg or 450mg, the lower of the two), followed by a 10-week maintenance treatment period. Caregivers recorded seizure frequency, type, and severity and ranked their global impressions after 7 and 12weeks of treatment. Responders were those showing a ≥50% reduction from baseline monthly seizure frequency. Safety assessments monitored vital signs, adverse effects, physical and neurological exams, and laboratory tests.Sixteen patients (age: 9.1±3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the end of the treatment period, 81.9% and 73.4±24.6% (p0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders' rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved.PTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE.

Intrathecal morphine provides excellent analgesia after cesarean delivery; however, respiratory events such as apnea, bradypnea, and hypoxemia have been reported. The primary study aim was to estimate the number of apneas per subject, termed "apnea alert events" (AAEs) defined by no breath for 30-120 seconds, using continuous capnography in women who underwent cesarean delivery.We performed a prospective, observational study with institutional review board approval of women who underwent cesarean delivery with spinal anesthesia containing 150-µg intrathecal morphine. A STOP-Bang obstructive sleep apnea assessment was administered to all women. Women were requested to use continuous capnography and pulse oximetry for 24 hours after cesarean delivery. Nasal sampling cannula measured end-tidal carbon dioxide (EtCO2) and respiratory rate (RR), and oxygen saturation (SpO2) as measured by pulse oximetry. Capnography data were defined as "valid" when EtCO210 mm Hg, RR5 breaths per minute (bpm), SpO270%, or during apnea (AAE) defined as "no breath" (EtCO2,5 mm Hg) for 30-120 seconds. Individual respiratory variable alerts were 10-second means of EtCO210 mm Hg, RR8 bpm, and SpO294%. Nurse observations of RR (hourly and blinded to capnography) are reported.We recruited 80 women, mean (standard deviation [SD]) 35 (5) years, 47% body mass index30 kg/m2/weight90 kg, and 11% with suspected obstructive sleep apnea (known or STOP-Bang score3). The duration of normal capnography and pulse oximetry data was mean (SD) (range) 8:28 (7:51) (0:00-22:32) and 15:08 (6:42) (1:31-23:07) hours:minutes, respectively; 6 women did not use the capnography. There were 198 AAEs, mean (SD) duration 57 (27) seconds experienced by 39/74 (53%) women, median (95% confidence interval for median) (range) 1 (0-1) (0-29) per subject. Observation of RR by nurses was ≥14 bpm at all time-points for all women, r = 0.05 between capnography and nurse RR (95% confidence interval, -0.04 to 0.14). There were no clinically relevant adverse events for any woman. Sixty-five women (82%) had complaints with the capnography device, including itchy nose, nausea, interference with nursing baby, and overall inconvenience.We report 198 AAEs detected by capnography among women who underwent cesarean delivery after receiving intrathecal morphine. These apneas were not confirmed by the intermittent hourly nursing observations. Absence of observer verification precludes distinction between real, albeit nonclinically significant alerts with capnography versus false apneas. Discomfort with the nasal sampling cannula and frequent alerts may impact capnography application after cesarean delivery. No clinically relevant adverse events occurred.

Background Posttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD. Methods Immediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers. Results Clinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024). Conclusions Both groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory–mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD.

BackgroundThe National Lung Screening Trial (NLST) demonstrated that annual screening with low dose CT in high-risk population was associated with reduction in lung cancer mortality. Nonetheless, the leading cause of mortality in the study was from cardiovascular diseases.PurposeTo determine whether the used machine learning automatic algorithms assessing coronary calcium score (CCS), level of liver steatosis and emphysema percentage in the lungs are good predictors of cardiovascular disease (CVD) mortality and incidence when applied on low dose CT scans.Materials and methodsThree fully automated machine learning algorithms were used to assess CCS, level of liver steatosis and emphysema percentage in the lung. The algorithms were used on low-dose computed tomography scans acquired from 12,332 participants in NLST.ResultsIn a multivariate analysis, association between the three algorithm scores and CVD mortality have shown an OR of 1.72 (p = 0.003), 2.62 (p < 0.0001) for CCS scores of 101-400 and above 400 respectively, and an OR of 1.12 (p = 0.044) for level of liver steatosis. Similar results were shown for the incidence of CVD, OR of 1.96 (p < 0.0001), 4.94 (p < 0.0001) for CCS scores of 101-400 and above 400 respectively. Also, emphysema percentage demonstrated an OR of 0.89 (p < 0.0001). Similar results are shown for univariate analyses of the algorithms.ConclusionThe three automated machine learning algorithms could help physicians to assess the incidence and risk of CVD mortality in this specific population. Application of these algorithms to existing LDCT scans can provide valuable health care information and assist in future research.

Cannabidiol (CBD) is the main nonpsychoactive component of the cannabis plant. It has been associated with antiseizure, antioxidant, neuroprotective, anxiolytic, anti-inflammatory, antidepressant, and antipsychotic effects. PTL101 is an oral gelatin matrix pellets technology-based formulation containing highly purified CBD embedded in seamless gelatin matrix beadlets. Study objectives were to evaluate the safety and tolerability of PTL101 containing 10 and 100 mg CBD, following single administrations to healthy volunteers and to compare the pharmacokinetic profiles and relative bioavailability of CBD with Sativex oromucosal spray (the reference product) in a randomized, crossover study design. Administration of PTL101 containing 10 CBD, led to a 1.7-fold higher Cmax and 1.3-fold higher AUC compared with the oromucosal spray. Tmax following both modes of delivery was 3-3.5 hours postdosing. CBD exhibited about a 1-hour lag in absorption when delivered via PTL101. A 10-fold increase in the dose resulted in an ∼15-fold increase in Cmax and AUC. Bioavailability of CBD in the 10-mg PTL101 dose was 134% relative to the reference spray. PTL101 is a pharmaceutical-grade, user-friendly oral formulation that demonstrated safe and efficient delivery of CBD and therefore could be an attractive candidate for therapeutic indications.

Sudden disruptions, or shocks, to food production can adversely impact access to and trade of food commodities. Seafood is the most traded food commodity and is globally important to human nutrition. The seafood production and trade system is exposed to a variety of disruptions including fishery collapses, natural disasters, oil spills, policy changes, and aquaculture disease outbreaks, aquafeed resource access and price spikes. The patterns and trends of these shocks to fisheries and aquaculture are poorly characterized and this limits the ability to generalize or predict responses to political, economic, and environmental changes. We applied a statistical shock detection approach to historic fisheries and aquaculture data to identify shocks over the period 1976–2011. A complementary case study approach was used to identify possible key social and political dynamics related to these shocks. The lack of a trend in the frequency or magnitude of the identified shocks and the range of identified causes suggest shocks are a common feature of these systems which occur due to a variety, and often multiple and simultaneous, causes. Shocks occurred most frequently in the Caribbean and Central America, the Middle East and North Africa, and South America, while the largest magnitude shocks occurred in Asia, Europe, and Africa. Shocks also occurred more frequently in aquaculture systems than in capture systems, particularly in recent years. In response to shocks, countries tend to increase imports and experience decreases in supply. The specific combination of changes in trade and supply are context specific, which is highlighted through four case studies. Historical examples of shocks considered in this study can inform policy for responding to shocks and identify potential risks and opportunities to build resilience in the global food system.

Investigate the relation between age, baseline neurological and functional status, and survival after out-of-hospital cardiac arrest (OHCA).Data analysis from the Jerusalem District Resuscitation Study. Patients80 years and those 18-80 years with OHCA from 4/2005-12/2010 were compared.survival at four time points; secondary outcomes: neurological and functional status at hospital discharge, and relationship between survival, age and pre-arrest activities of daily living (ADL) and Cerebral Performance Category (CPC) scores (higher scores indicate worse function in both).3,211 patients (1,25980 years, 1952 aged 18-80) with median follow-up 5.9 years (range 0.1-11.1 years) were included. Survival was better for younger patients at all four time points, including 7.8% versus 2.5% at hospital discharge, 4.6% versus 0.2% at late follow-up. Functional status at discharge was also better, 4.8 ± 5.4 versus 9.0 ± 4.7, p0.001, and more young patients had CPC1/2, 60.7% versus 32.2%, p = 0.004. Older patients who survived to emergency department admission had increased mortality per year of age (2.6%, hazard ratio [HR] 1.026, 95% confidence interval [CI] 1.006-1.048 versus 1.7%, HR 1.017, 95% CI 1.010-1.025), per point in pre-arrest ADL (3.0%, HR 1.030, 95% CI 1.007-1.054 versus 5.8%, HR 1.058, 95% CI 1.036-1.080), and per point in pre-arrest CPC (24%, HR 1.242, 95% CI 1.097-1.406 versus 37%, HR 1.370 95% CI 1.232-1.524).Patient independence before arrest may be a more crucial determinant of resuscitation outcome than older age alone. Discussion of end-of-life preferences is particularly important for older individuals with functional and cognitive decline.

Objective To compare the reported accuracy and sensitivity of the various modalities used to diagnose autism spectrum disorders (ASD) in efforts to help focus further biomarker research on the most promising methods for early diagnosis. Methods The Medline scientific literature database was searched to identify publications assessing potential clinical ASD biomarkers. Reports were categorized by the modality used to assess the putative markers, including protein, genetic, metabolic, or objective imaging methods. The reported sensitivity, specificity, area under the curve, and overall agreement were summarized and analyzed to determine weighted averages for each diagnostic modality. Heterogeneity was measured using the I2 test. Results Of the 71 papers included in this analysis, each belonging to one of five modalities, protein-based followed by metabolite-based markers provided the highest diagnostic accuracy, each with a pooled overall agreement of 83.3% and respective weighted area under the curve (AUC) of 89.5% and 88.3%. Sensitivity provided by protein markers was highest (85.5%), while metabolic (85.9%) and protein markers (84.7%) had the highest specificity. Other modalities showed degrees of sensitivity, specificity, and overall agreements in the range of 73%-80%. Conclusions Each modality provided for diagnostic accuracy and specificity similar or slightly higher than those reported for the gold-standard Autism Diagnostic Observation Schedule (ADOS) instrument. Further studies are required to identify the most predictive markers within each modality and to evaluate biological pathways or clustering with possible etiological relevance. Analyses will also be necessary to determine the potential of these novel biomarkers in diagnosing pediatric patients, thereby enabling early intervention.

Fil: Rocha, Juan C. Stockholm University. Stockholm Resilience Centre. Stockholm, Suecia. Fil: Baraibar, Matilda M. Stockholm University. Department of Economic History and International Relations. Stockholm, Suecia. Fil: Deutsch, Lisa. Stockholm University. Stockholm Resilience Centre. Stockholm, Suecia. Fil: Bremond, Ariane de. University of Bern. Centre for Development and Environment. Bern, Suiza. Fil: Oestreicher, Jordan S. Universidade de Brasília. Centro de Desenvolvimento Sustentável. Distrito Federal, Brasil. Fil: Rositano, Florencia. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Producción Vegetal. Cátedra de Cerealicultura. Buenos Aires, Argentina. Fil: Gelabert, Cecilia Corina. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Economía, Desarrollo y Planeamiento Agrícola. Cátedra de Sistemas Agroalimentarios. Buenos Aires, Argentina. Climate change, financial shocks, and fluctuations in international trade are some of the reasons why resilience is increasingly invoked in discussions about land-use policy. However, resilience assessments come with the challenge of operationalization, upscaling their conclusions while considering the context-specific nature of land-use dynamics and the common lack of long-term data. We revisit the approach of system archetypes for identifying resilience surrogates and apply it to land-use systems using seven case studies spread across Latin America. The approach relies on expert knowledge and literature-based characterizations of key processes and patterns of land-use change synthesized in a data template. These narrative accounts are then used to guide development of causal networks, from which potential surrogates for resilience are identified. This initial test of the method shows that deforestation, international trade, technological improvements, and conservation initiatives are key drivers of land-use change, and that rural migration, leasing and land pricing, conflicts in property rights, and international spillovers are common causal pathways that underlie land-use transitions. Our study demonstrates how archetypes can help to differentiate what is generic from context dependant. They help identify common causal pathways and leverage points across cases to further elucidate how policies work and where, as well as what policy lessons might transfer across heterogeneous settings. tbls., grafs., mapas

OBJECTIVE:Complex Regional Pain Syndrome (CRPS), a chronic pain condition, develops mainly after limb trauma and severely inhibits function. While early diagnosis is essential, factors for CRPS onset are elusive. Therefore, identifying those at risk is crucial. Sensory modulation dysfunction (SMD), affects the capacity to regulate responses to sensory input in a graded and adaptive manner and was found associated with hyperalgesia in otherwise healthy individuals, suggestive of altered pain processing. AIM:To test SMD as a potential risk factor for CRPS. METHODS:In this cross-sectional study, forty-four individuals with CRPS (29.9±11 years, 27 men) and 204 healthy controls (27.4±3.7 years, 105 men) completed the Sensory Responsiveness Questionnaire-Intensity Scale (SRQ-IS). A physician conducted the CRPS Severity Score (CSS), testing individuals with CRPS. RESULTS:Thirty-four percent of the individuals with CRPS and twelve percent of the healthy individuals were identified to have SMD (χ2 (1) = 11.95; p

Sensory Modulation Disorder (SMD) interferes with the daily life participation of otherwise healthy individuals and is characterized by over-, under- or seeking responsiveness to naturally occurring sensory stimuli. Previous laboratory findings indicate pain hyper-sensitivity in SMD individuals suggesting CNS alteration in pain processing and modulation. However, laboratory studies lack ecological validity, and warrant clinical completion in order to elicit a sound understanding of the phenomenon studied. Thus, this study explored the association between sensory modulation and pain in a daily life context in a general population sample.Daily life context of pain and sensations were measured in 250 adults (aged 23-40 years; 49.6% males) using 4 self-report questionnaires: Pain Sensitivity Questionnaire (PSQ) and Pain Catastrophizing Scale (PCS) to evaluate the sensory and cognitive aspects of pain; the Sensory Responsiveness Questionnaire (SRQ) to appraise SMD; and the Short Form - 36 Health Survey, version 2 (SF36) to assess health related Quality of Life (QoL).Thirty two individuals (12.8%) were found with over-responsiveness type of SMD, forming the SOR-SMD group. While no group differences (SOR-SMD vs. Non-SMD) were found, low-to-moderate total sample correlations were demonstrated between the SRQ-Aversive sub-scale and i) PSQ total (r=0.31, p0.01) and sub-scales scores (r=0.27-0.28, p0.01), as well as ii) PCS total and the sub-scales of Rumination and Helplessness scores (r=0.15, p0.05). PSQ total and sub-scale scores were more highly correlated with SRQ-Aversive in the SOR-SMD group (r=0.57-0.68, p=0.03-0.01) compared to Non-SMD group. The Physical Health - Total score (but not the Mental Health - Total) of the SF36 was lower for the SOR-SMD group (p=0.03), mainly due to the difference in the Body pain sub-scale (p=0.04).Results suggest that SOR-SMD is strongly associated with the sensory aspect of pain but weakly associated with the cognitive aspect. This indicates that SMD co-occurs with daily pain sensitivity, thus reducing QoL, but less with the cognitive-catastrophizing manifestation of pain perception.

Nearly 40% of seafood is traded internationally and an even bigger proportion is affected by international trade, yet scholarship on marine fisheries has focused on global trends in stocks and catches, or on dynamics of individual fisheries, with limited attention to the link between individual fisheries, global trade and distant consumers. This paper examines the usefulness of fish price as a feedback signal to consumers about the state of fisheries and marine ecosystems. We suggest that the current nature of fisheries systems and global markets prevent transmission of such price signals from source fisheries to consumers. We propose several mechanisms that combine to weaken price signals, and present one example – the North Sea cod – to show how these mechanisms can be tested. The lack of a reliable price feedback to consumers represents a challenge for sustainable fisheries governance. We therefore propose three complimentary approaches to address the missing feedback: (i) strengthening information flow through improved traceability and visibility of individual fishers to consumers, (ii) capitalizing on the changing seafood trade structures and (iii) bypassing and complementing market mechanisms by directly targeting citizens and political actors regarding marine environmental issues through publicity and information campaigns. These strategies each have limitations and thus need to be pursued together to address the challenge of sustainability in global marine fisheries.

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22–68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p+0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p+0.013; remission: 32.6 vs. 14.6%, p+0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.

The ‘Great Acceleration’ graphs, originally published in 2004 to show socio-economic and Earth System trends from 1750 to 2000, have now been updated to 2010. In the graphs of socio-economic trends, where the data permit, the activity of the wealthy (OECD) countries, those countries with emerging economies, and the rest of the world have now been differentiated. The dominant feature of the socio-economic trends is that the economic activity of the human enterprise continues to grow at a rapid rate. However, the differentiated graphs clearly show that strong equity issues are masked by considering global aggregates only. Most of the population growth since 1950 has been in the non-OECD world but the world’s economy (GDP), and hence consumption, is still strongly dominated by the OECD world. The Earth System indicators, in general, continued their long-term, post-industrial rise, although a few, such as atmospheric methane concentration and stratospheric ozone loss, showed a slowing or apparent stabilisation over the past decade. The post-1950 acceleration in the Earth System indicators remains clear. Only beyond the mid-20th century is there clear evidence for fundamental shifts in the state and functioning of the Earth System that are beyond the range of variability of the Holocene and driven by human activities. Thus, of all the candidates for a start date for the Anthropocene, the beginning of the Great Acceleration is by far the most convincing from an Earth System science perspective.

There is a growing clinical interest in developing and commercializing pharmaceutical-grade cannabinoid products, containing primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive "first-pass" metabolism. A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the "first-pass" effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed reference oromucosal spray (Sativex ® ). Fourteen healthy male volunteers received, on separate treatment days, either a single dose of PTL401 or an equivalent dose of the oromucosal spray. Blood samples for pharmacokinetic analyses were collected, and safety and tolerability were assessed. PTL401 yielded 1.6-fold higher plasma C max than the equivalent dose of the oromucosal spray, for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, respectively). Values of T max were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray). The pharmacokinetic profiles of the active 11-OH-THC metabolite followed the same pattern as THC for both routes of delivery. No outstanding safety concerns were noted following either administration. We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clinical studies with this formulation.

GOALS To investigate the effect of implementing full-spectrum endoscopy (Fuse) on adenoma detection rate (ADR) at an ambulatory surgical center (ASC). BACKGROUND Traditional forward viewing (TFV) endoscopes have 1 camera and provide an angle of view of 140 to 170 degrees, whereas Fuse provides a 330 degrees view through the addition of 2 side cameras. Although randomized studies have shown that Fuse decreases adenoma miss rates, its impact on ADR in a screening population is currently unknown. STUDY We conducted a retrospective analysis of data from average risk screening colonoscopies at a 5-room ASC. This ASC transitioned from TFV to Fuse in April 2014. The primary outcome was ADR defined as the percentage of patients who underwent screening colonoscopy and were found to have at least 1 adenomatous polyp. RESULTS A total of 1696 screening colonoscopies were performed with TFV and 2302 with Fuse. Overall ADR was 23.7% with TFV and 29.0% with Fuse (P

Freshwater use for food production is projected to increase substantially in the coming decades with population growth, changing demographics, and shifting diets. Ensuring joint food-water security has prompted efforts to quantify freshwater use for different food products and production methods. However, few analyses quantify freshwater use for seafood production, and those that do use inconsistent water accounting. This inhibits water use comparisons among seafood products or between seafood and agricultural/livestock products. This ‘seafood gap’ in the food-water nexus literature will become increasingly problematic as seafood consumption is growing globally and aquaculture is one of the fastest growing animal food sectors in the world. Therefore, the present study 1) reviews freshwater use concepts as they relate to seafood production; 2) provides three cases to highlight the particular water use concerns for aquaculture, and; 3) outlines future directions to integrate seafood into the broader food-water nexus discussion. By revisiting water use concepts through a focus on seafood production systems, we highlight the key water use processes that should be considered for seafood production and offer a fresh perspective on the analysis of freshwater use in food systems more broadly.

Negative symptoms and cognitive deficits are considered core symptoms of schizophrenia, yet treatment for them remains inadequate. Deep-transcranial magnetic stimulation (TMS) is a novel technology that enables non-invasive stimulation of deep layers of the prefrontal cortex. Preliminary evidence suggests that deep-TMS could be effective in the treatment of negative symptoms and cognitive deficits. The current study is the first double-blind, randomized sham-controlled study to examine the feasibility of deep-TMS add-on treatment for negative symptoms and cognitive deficits in schizophrenia. Twenty daily H1 deep-TMS treatments (20Hz, 120% MT) were delivered, in a double-blind, randomized sham-controlled design ( n=30). Extensive clinical and cognitive assessments were carried out throughout the study and for an additional one month follow-up period. The results indicate that at the end of the treatment period, negative symptoms (as indicated by the Scale for the Assessment of Negative Symptoms (SANS)) significantly reduced in the TMS group (–7.7), but not in the sham group (–1.9). Differences between the groups were not statistically significant.

Most people live in cities, but most food system studies and food security issues focus on the rural poor. Urban populations differ from rural populations in their food consumption by being generally wealthier, requiring food trade for their food security, defined as the extent to which people have adequate diets. Cities rarely have the self-provisioning capacity to satisfy their own food supply, understood as the extent to which the food consumed by the city's population is produced from the city's local agro-ecosystems. Almost inevitably, a city's food security is augmented by production from remote landscapes, both internal and external in terms of a state's jurisdiction. We reveal the internal and external food flows necessary for the food security of three wealthy capital cities (Canberra, Australia; Copenhagen, Denmark; Tokyo, Japan). These cities cover two orders of magnitude in population size and three orders of magnitude in population density. From traded volumes of food and their sources into the cities, we calculate the productivity of the city's regional and non-regional ecosystems that provide food for these cities and estimate the overall utilised land area. The three cities exhibit differing degrees of food self-provisioning capacity and exhibit large differences in the areas on which they depend to provide their food. We show that, since 1965, global land area effectively imported to produce food for these cities has increased with their expanding populations, with large reductions in the percentage of demand met by local agro-ecosystems. The physical trading of food commodities embodies ecosystem services, such as water, soil fertility and pollination that are required for land-based food production. This means that the trade in these embodied ecosystem services has become as important for food security as traditional economic mechanisms such as market access and trade. A future policy question, raised by our study, is the degree to which governments will remain committed to open food trade policies in the face of national political unrest caused by food shortages. Our study demonstrates the need to determine the food security and self-provisioning capacity of a wide range of rich and poor cities, taking into account the global location of the ecosystems that are provisioning them.

Livestock production is one of the fastest growing agricultural subsector globally. Expansion and intensification of animal production increase demand for natural resources. Sustainable intensification approaches are needed that limit pressure on often already scarce land and water resources. This paper quantifies water requirements in three Uruguayan beef production systems - extensive, mixed and intensive - and explores impacts on water-related ecosystem services. Mixed beef production systems were found to make most effective use of water. However, the shift from pastures in crop rotation towards continuous feed-crop cultivation decreases soil organic-matter contents, reducing soil water-holding capacity; this may result in lower agricultural yields and reduced resilience to droughts.