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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.

IntroductionBalance is achieved through interactions between the vestibular, somatosensory, and visual systems. There are several clinical tests to measure postural stability. However, most of them do not assess postural stability with head movements, which is the main function of the vestibular system, and those that do, require the use of sizeable, expensive equipment. Therefore, an applicable, easy-to-perform test that challenges the function of the visual, somatosensory and vestibular systems, using head movements, is needed. The Zur Balance Scale (ZBS) contains ten conditions, which are a combination of surfaces (floor or Styrofoam with subject standing on its width in Romberg position or its length in tandem position), stances (Romberg or tandem), tasks (no head movement with eyes open or closed and horizontal or vertical head movements with eyes open). The purpose of this study was to determine the validity, inter- and intra-examiner reliability, and normal performance values of the ZBS among individuals 29–70-years of age and to introduce the modified version: the mZBS, using kinetic measurements.MethodsHealthy participants ages 29–70 years were evaluated for inter- and intra-tester reliability (n = 65), kinetic measurements on a force plate, and validity compared to the modified clinical test of sensory interaction and balance (mCTSIB) (n = 44) and characterization of normal values (n = 251).ResultsZur Balance Scale head movements, duration of each condition (up to 10 s) and the total ZBS score agreed across examiners (ICC > 0.8). Normal ZBS scores were negatively correlated with age (r = −0.34; P < 0.0001). Older subjects (60–70 years) had a median score of 95.5 compared with younger subjects, where medians ranged from 97.6 to 98.9. Kinetic parameters showed positive correlations between ZBS and the mCTSIB scores, with the highest correlation between the five Romberg tasks (modified ZBS).ConclusionZur Balance Scale is a valid and reliable test. Its advantages include using head movements and the ability to detect minimal differences in postural control, even in healthy populations. Kinetic evaluation of the ZBS enables the use of a modified, shorter version of the ZBS (mZBS).

Background:Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention.Methods:We chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran’s Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care.Results:SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARα-dependent mechanism in both alpha and delta variants. Analysis of 3233 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 non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period.Conclusions:Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials.Funding:Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003).Clinical trial number:NCT04661930.

The wicked nature of sustainability challenges facing food systems demands intentional and synergistic actions at multiple scales and sectors. The Southern Cone of Latin America, with its historical legacy of “feeding the world,” presents interesting opportunities for generating insights into potential trajectories and processes for food system transformation. To foster such changes would require the development of collective understanding and agency to effectively realize purposeful and well-informed action toward desirable and sustainable food futures. This in turn demands the transdisciplinary engagement of academia, the private sector, government/policy-makers, community groups, and other institutions, as well as the broader society as food consumers. While the need for contextualized knowledge, priorities and definitions of what sustainable food systems change means is recognized, there is limited literature reporting these differences and critically reflecting on the role of knowledge brokers in knowledge co-production processes. The political nature of these issues requires arenas for dialogue and learning that are cross-sectoral and transcend knowledge generation. This paper presents a case study developed by SARAS Institute, a bridging organization based in Uruguay. This international community of practice co-designed a 3-year multi-stakeholder transdisciplinary process entitled “Knowledges on the Table.” We describe how the process was designed, structured, and facilitated around three phases, two analytical levels and through principles of knowledge co-production. The case study and its insights offer a model that could be useful to inform similar processes led by transdisciplinary communities of practice or bridging institutions in the early stages of transformative work. In itself, it also represents a unique approach to generate a language of collaboration, dialogue, and imagination informed by design skills and methods. While this is part of a longer-term process toward capitalizing on still-unfolding insights and coalitions, we hope that this example helps inspire similar initiatives to imagine, support, and realize contextualized sustainable food system transformations.

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.

Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy [e.g., temozolomide (TMZ)], and targeted therapy [e.g., the antiangiogenic agent bevacizumab (BEV)]. Diffusing alpha-emitters radiation therapy (DaRT) is a new modality that employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown to be effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with standard-of-care therapies such as TMZ or BEV was investigated. In a viability assay, the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone in U87 cultured cells. A colony formation assay demonstrated that the surviving fraction of U87 cells treated by TMZ in combination with alpha irradiation was lower than was achieved by alpha- or x-ray irradiation as monotherapies, or by x-ray combined with TMZ. The treatment of U87-bearing mice with DaRT and TMZ delayed tumor development more than the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in large tumors relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of 224Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care chemotherapy or antiangiogenic therapy are promising approaches, which may improve the treatment of GBM patients.

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.

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.

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.

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

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.

Item does not contain fulltext BACKGROUND: Data on myocardial deformation during the internationally widely used second-trimester screening are scarce and confusing. Reference values of time to peak strain are missing. The aims of this study were to assess reference values derived from two-dimensional speckle-tracking echocardiography for global and regional longitudinal right ventricular (RV) and left ventricular (LV) strain, strain rate, and time to peak global strain and to determine the influence of heart rate and gender on these strain parameters. METHODS: Seventy-five healthy fetuses were enrolled during second-trimester ultrasound (20-24 weeks). Clips with high frame rates (mean, 132 frames/sec) and two-dimensional (B-mode) grayscale images of apical or basal four-chamber views of both ventricles were used for offline analyses. RESULTS: There were no statistically significant differences in global strain and strain rate between both ventricles (P = .679 and P = .734, respectively) or among the RV, septal, and LV free walls. Regional measurements, modeled also as an interaction of wall and segment (basal mid and apical), showed only a small, statistically significant difference between the basal RV and LV free walls. Strain and strain rate values were independent of heart rate. The mean time to peak LV global strain adjusted for heart rate was statistically significantly shorter than the RV value (P < .0001]). Strain, strain rate, and time to peak global strain were not found to be associated with gender. CONCLUSIONS: The establishment of second-trimester two-dimensional speckle-tracking echocardiographic reference values for global and regional strain, strain rate, and time to peak global strain in a healthy fetal cohort is a mandatory prerequisite for its use in evaluating (pathologic) changes in both ventricular functions during pregnancy.

Cities are rapidly increasing in importance as a major factor shaping the Earth system, and therefore, must take corresponding responsibility. With currently over half the world's population, cities are supported by resources originating from primarily rural regions often located around the world far distant from the urban loci of use. The sustainability of a city can no longer be considered in isolation from the sustainability of human and natural resources it uses from proximal or distant regions, or the combined resource use and impacts of cities globally. The world's multiple and complex environmental and social challenges require interconnected solutions and coordinated governance approaches to planetary stewardship. We suggest that a key component of planetary stewardship is a global system of cities that develop sustainable processes and policies in concert with its non-urban areas. The potential for cities to cooperate as a system and with rural connectivity could increase their capacity to effect change and foster stewardship at the planetary scale and also increase their resource security. © Royal Swedish Academy of Sciences 2012.

Evidence has shown that repetitive transcranial magnetic stimulation (rTMS) can be effective as an acute treatment for major depressive disorder (MDD). However, few studies have examined the safety and feasibility of rTMS as a long-term\continuation treatment. Deep-TMS is a novel tool enabling deeper stimulation than standard coils. The current study examined the safety and feasibility of repetitive deep-TMS continuation treatment for MDD over the course of 18 weeks, following 4 weeks of acute treatment.A total of 29 MDD patients were enrolled in the study. rTMS sessions (20 Hz) were given for a total of 22 weeks, divided into: 4 weeks of acute daily treatments, followed by 18 weeks of continuation treatments. Clinical evaluations were performed weekly throughout the study.A significant decrease from baseline in Hamilton Depression Rating Scale (HDRS) score was found at the end of the acute phase, and maintained throughout the study (P0.0001). The Kaplan-Meier estimated probability of response was 46.15% (SE = 9.78%) at the end of the acute phase, and 81.12% (SE = 9.32%) at the end of the study (22 weeks). probability of remission at the end of the acute phase was 26.92% (SE = 8.70%) and 71.45% (SE = 10.99%) at the end of the study. Response in the acute phase was indicative of response in the continuation phases. The procedure was generally well tolerated and no adverse events were reported.The results suggest that H-coil deep-TMS administered continuation treatment can help maintain an antidepressant effect for 18 weeks, following 4 weeks of acute treatment.

Individuals with sensory modulation disorder (SMD) demonstrate abnormal responses to naturally occurring stimuli in a manner that interferes with daily life activities. This study is the first study applying quantitative sensory testing to characterize the somatosensory sensitivity of adults with SMD.One hundred and fifty one adults (68 males and 83 females) were tested comparing 91 SMD to 60 SMD-free, control individuals. Group placement (SMD vs. SMD-free) was determined using the Sensory Responsiveness Questionnaire (SRQ). Sensory detection thresholds for skin warming, cooling, punctate dynamic tactile sensation, vibration and thermal pain thresholds for heat and cold stimuli were determined at several body sites. Pinprick pain and prickliness were also assessed, as well as the duration and intensity of the after-sensations of prickliness and pain evoked by the prickly stimuli.Compared to control adults, individuals with SMD showed significantly higher pain intensity to prickle stimuli, marginally higher pain intensity to pinprick and hypoesthesia to punctate dynamic tactile sensation at one of two sites tested.These results are in line with our previous study that investigated children with SMD using the same stimuli, and found similar results. We suggest a CNS involvement as the underlying mechanisms in SMD.

Aims Assessing the quality of wall motion (WM) on echocardiograms remains a challenge. Previously, we validated an automated application used by experienced echocardiographers for WM classification based on longitudinal two-dimensional (2D) strain. The aim of this study was to show that the use of this automatic application was independent of the user's experience. Methods and results We compared the WM classifications obtained by the application when used by 12 highly experienced readers (Exp-R) vs. 11 inexperienced readers (InExp-R). Both classifications were compared with expert consensus classifications using the standard visual method. Digitized clips of cardiac cycles from three apical views in 105 patients were used for these analyses. Reproducibility of both groups was high (overall intra-class correlation coefficient: InExp-R = 0.89, Exp-R = 0.83); the lowest was noted for hypokinetic segments (InExp-R = 0.79, Exp-R = 0.72). InExp-R scores were concordant with Exp-R mode scores in 88.8% of segments; they were overestimated in 5.8% and underestimated in 3.2%. The sensitivity, specificity, and accuracy of InExp-R vs. Exp-R for classifying segments as normal/abnormal were identical (87, 85, and 86%, respectively). Conclusion Classification of WM from apical views with an automatic application based on longitudinal 2D strain by InExp-R vs. Exp-R was similar to visual classification by Exp-R. This application may be useful for inexperienced echocardiographers/technicians and may serve as an automated ‘second opinion’ for experienced echocardiographers.

Over the past century, the total material wealth of humanity has been enhanced. However, in the twenty-first century, we face scarcity in critical resources, the degradation of ecosystem services, and the erosion of the planet’s capability to absorb our wastes. Equity issues remain stubbornly difficult to solve. This situation is novel in its speed, its global scale and its threat to the resilience of the Earth System. The advent of the Anthropence, the time interval in which human activities now rival global geophysical processes, suggests that we need to fundamentally alter our relationship with the planet we inhabit. Many approaches could be adopted, ranging from geo-engineering solutions that purposefully manipulate parts of the Earth System to becoming active stewards of our own life support system. The Anthropocene is a reminder that the Holocene, during which complex human societies have developed, has been a stable, accommodating environment and is the only state of the Earth System that we know for sure can support contemporary society. The need to achieve effective planetary stewardship is urgent. As we go further into the Anthropocene, we risk driving the Earth System onto a trajectory toward more hostile states from which we cannot easily return.

Feeding aquaculture growth through globalization: exploitation of marine ecosystems for fishmeal

Analysis of food consumption and agricultural production trends in Sweden has focused on domestic food production levels and yields, over looking human dependence on ecosystem support. We estimate ...

This paper develops a methodology for identifying that natural capital-called critical natural capital (CNC)-the maintenance of which is essential for environmental sustainability. By consideration of the characteristics of natural capital, of the environmental functions that these characteristics enable natural capital to perform and of the importance of these functions to humans and the biosphere, it shows how sustainability standards in respect of these environmental functions may be derived. The difference between the current situation and these standards is termed the sustainability gap. The methodology that emerges from bringing these ideas together into a single analytical framework enables policy makers to identify the extent of current unsustainability, the principal causes of it, the elements and processes of natural capital (the CNC) which need to be maintained or restored to close the sustainability gap and the costs of so doing. The framework should therefore be of use in identifying priorities and policies for moving towards environmental sustainability. (C) 2002 Published by Elsevier Science B.V.

Complex dynamic ecosystems are important natural capital assets. We investigate how Swedish national policy has approached these assets in its work on environmental indicators. In particular, we are interested in whether or not the indicators address ecosystem performance. We discuss our inventory of Swedish indicators in the context of ecosystem services, such as source and sink functions, and the capacity of ecosystems to sustain these functions for human well-being. We find that effective indicators have been developed to reflect energy and material flows within society and how human activities put pressure on the environment. The part of natural capital that concerns living systems is reflected in several of the Swedish indicators in a progressive fashion, but indicators that capture the dynamic capacity of ecosystems in sustaining the flow of source and sink functions need to be further developed. We provide examples of recent developments that have started to address such indicators in the context of ecosystem resilience and environmental change, and discuss directions for their further development. We stress the importance of monitoring ecosystem resilience and performance to avoid undesirable state shifts and building ecological knowledge and understanding of this capacity into environmental indicators and their associated management institutions.

To determine the prevalence and characteristics of copy number variations (CNVs) in children with cerebral palsy (CP) of unknown etiology, comprising approximately 20% of the CP population.Fifty-two participants (age 10.5 ± 7.8 years; Gross Motor Function Classification System scale 2.8 ± 1.3) with nonprogressive pyramidal and/or extrapyramidal signs since infancy and no identified etiology were enrolled. Individuals with evidence of acquired causes were excluded. Participants underwent neurologic and clinical genetic examinations before the genomic testing. Chromosomal microarray analysis to detect CNVs was performed using the Affymetrix platform. CNVs identified were classified as pathogenic, likely pathogenic, likely benign, or benign. Only pathogenic and likely pathogenic CNVs were defined as clinically significant.Thirty-nine CNVs were found in 25 of 52 participants (48%). Sixteen participants (31%) had clinically significant CNVs: 10 pathogenic and 6 likely pathogenic, of which 7 were not previously associated with motor disability. Nine participants had likely benign CNVs. Clinically significant CNVs were more frequently de novo (12/16; p0.001) including in 5 of 8 individuals who had a first- or second-degree relative with a major neurologic disorder. Dysmorphic features and nonmotor comorbidities were more prevalent in individuals with clinically significant CNVs (p0.05 for both).CNVs, most frequently de novo, are common in individuals with cryptogenic CP. We recommend CNV testing in individuals with CP of unknown etiology.

Modern food production is a complex, globalized system in which what we eat and how it is produced are increasingly disconnected. This thesis examines some of the ways in which global trade has changed the mix of inputs to food and feed, and how this affects food security and our perceptions of sustainability. One useful indicator of the ecological impact of trade in food and feed products is the Appropriated Ecosystem Areas (ArEAs), which estimates the terrestrial and aquatic areas needed to produce all the inputs to particular products.The method is introduced in Paper I and used to calculate and track changes in imported subsidies to Swedish agriculture over the period 1962-1994. In 1994, Swedish consumers needed agricultural areas outside their national borders to satisfy more than a third of their food consumption needs. The method is then applied to Swedish meat production in Paper II to show that the term “Made in Sweden” is often a misnomer. In 1999, almost 80% of manufactured feed for Swedish pigs, cattle and chickens was dependent on imported inputs, mainly from Europe, Southeast Asia and South America. Paper III examines ecosystem subsidies to intensive aquaculture in two nations: shrimp production in Thailand and salmon production in Norway. In both countries, aquaculture was shown to rely increasingly on imported subsidies. The rapid expansion of aquaculture turned these countries from fishmeal net exporters to fishmeal net importers, increasingly using inputs from the Southeastern Pacific Ocean.As the examined agricultural and aquacultural production systems became globalized, levels of dependence on other nations’ ecosystems, the number of external supply sources, and the distance to these sources steadily increased. Dependence on other nations is not problematic, as long as we are able to acknowledge these links and sustainably manage resources both at home and abroad. However, ecosystem subsidies are seldom recognized or made explicit in national policy or economic accounts. Economic systems are generally not designed to receive feedbacks when the status of remote ecosystems changes, much less to respond in an ecologically sensitive manner. Papers IV and V discuss the problem of “masking” of the true environmental costs of production for trade. One of our conclusions is that, while the ArEAs approach is a useful tool for illuminating environmentally-based subsidies in the policy arena, it does not reflect all of the costs. Current agricultural and aquacultural production methods have generated substantial increases in production levels, but if policy continues to support the focus on yield and production increases alone, taking the work of ecosystems for granted, vulnerability can result. Thus, a challenge is to develop a set of complementary tools that can be used in economic accounting at national and international scales that address ecosystem support and performance.We conclude that future resilience in food production systems will require more explicit links between consumers and the work of supporting ecosystems, locally and in other regions of the world, and that food security planning will require active management of the capacity of all involved ecosystems to sustain food production.

We applied computer modeling as a consensus building tool as part of the development of the Patagonia Coastal Zone Management Plan (PCZMP). The objective was to build a ‘scoping model’ to assess some of the important ecological and economic interlinkages of the coastal zone of Patagonia. The main purposes were to build consensus, integrate across several parts of the system. and to educate stakeholders about other sectors, not to create a detailed research model. Nevertheless, the model provides some interesting preliminary conclusions. This model indicates that the total net present value (NPV) of the fisheries sector over a period of 40 years may be increased by 13% compared with current income, with a decrease in hake fishing levels by ≈50%. The natural capital on which the fishery sector depends would be used in a more sustainable way, both ecologically and economically. The model also simulates possible impacts of oil spills and dumping of tanker ballast water on the penguin population. which can have a significant negative impact on tourist industry incomes. The model implies that the importance of the tourist sector in Patagonia could in the future greatly exceed the value of the fishing industry (by 29%). The results argue for more emphasis on integrating the currently disparate components of coastal zone management.

1. Ecosystem Services and Global Trade of Natural Resources: An Introduction Thomas Koellner Part 1: Foundations for Understanding the Trade of Natural Resources and its Implication for Ecosystem Services 2. Global Human Dependence on Ecosystem Services Jordan Levine and Kai M.A. Chan 3. Economics of Global Trade and Ecosystem Services David Zilberman 4. International Trade Policies and Ecosystem Services David Blandford 5. The Need for Global Governance of Ecosystem Services: a Human-Environment Systems Perspective on Biofuel Production Roland W. Scholz Part 2: Ecosystem impacts of global flows of virtual land, water and sea in the physical economy 6. Ecosystem Impacts of Virtual Land Use Embodied in Traded Goods and Services Thomas Koellner and Manel van der Sleen 7. Ecosystem Impacts of Virtual Water Embodied in Global Trade of Agricultural Products Hong Yang, Jungo Liu, Alexander J.B. Zehnder, and Johan Rockstrom 8. Global Trade of Fisheries Products-implications for marine ecosystems and their services Lisa Deutsch, Max Troell, Karin Limburg and Miriam Huitric Part 3: Accounting Tools for Global Ecosystem Services 9. Life Cycle Assessment and Ecosystem Services Thomas Koellner, Stephan Pfister and Annette Koehler 10. Ecosystem Services in Green National Accounting Jean-Louis Weber Part 4: Instruments for Global Governance of Ecosystem Services 11. Fair Trade, Environmental Labels, Bans and Ecosystem Services Ulrike Grote and Pradyot R Jena 12. International Payments for Ecosystem Services: Principles and Practices Graciela Chichilnisky 13. International Biodiversity Offsets Annah L. Peterson, Chloe Hill, Louise A. Gallagher 14. Landscape Labeling: Combining Certification with Ecosystem Service Conservation at Landscape Scales Jaboury Ghazoul Conclusion 15. Governance of Ecosystem Services in a World of Global Trade Thomas Koellner et al.

In this chapter we take a complex systems approach to exploring the linkages among the phenomenon of urbanization, the changing value systems and world perspectives of urban dwellers, the sometimes distant connections to the food production systems that support cities, and the often invisible ecosystem services that support food production and in turn are affected by food production.

Item does not contain fulltext BACKGROUND: The aim of this study was to detect normal changes in fetal two-dimensional speckle-tracking echocardiography-derived values for global and regional longitudinal left and right ventricular strain, strain rate, and time to peak (T2P) global strain during pregnancy. METHODS: Forty-four healthy fetuses were examined prospectively during the second-trimester and third-trimester ultrasound examinations (20-24 and 30-34 weeks, respectively). Clips with high frame rates (mean, 120 frames/sec) of two-dimensional (B-mode) grayscale images of apical or basal four-chamber views of both ventricles were used for offline analyses of global and regional walls and segments (basal, mid, and apical) of myocardial strain and strain rate as well as T2P global strain in the longitudinal direction. RESULTS: There were statistically significant decreases in global and regional strain of the right ventricle between the second and third trimesters. No statistically significant changes were observed in global and regional strain of the left ventricle. Global and regional strain rates of both ventricles decreased in a similar way during pregnancy. The mean T2P longitudinal left ventricular global strain (adjusted for heart rate) increased mildly during fetal life. Whereas T2P longitudinal strain of the left ventricle at 20 to 24 weeks was statistically significantly shorter than that of the right ventricle, no difference in T2P longitudinal strain was found at 30 to 34 weeks of gestation between both ventricles. CONCLUSIONS: The establishment of these changes between the second-trimester and third-trimester two-dimensional speckle-tracking echocardiography-derived reference values is a mandatory prerequisite for its use in evaluating (pathologic) changes in both ventricular functions during pregnancy. 01 oktober 2013