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Abstract Background Spinal cord stimulation (SCS) has demonstrated multiple benefits in treating chronic pain and other clinical disorders related to sensorimotor dysfunctions. However, the underlying mechanisms are still not fully understood, including how electrode placement in relation to the spinal cord neuroanatomy influences epidural spinal recordings (ESRs). To characterize this relationship, this study utilized stimulation applied at various anatomical sections of the spinal column, including at levels of the intervertebral disc and regions correlating to the dorsal root entry zone. Method Two electrode arrays were surgically implanted into the dorsal epidural space of the swine. The stimulation leads were positioned such that the caudal-most electrode contact was at the level of a thoracic intervertebral segment. Intraoperative cone beam computed tomography (CBCT) images were utilized to precisely determine the location of the epidural leads relative to the spinal column. High-resolution microCT imaging and 3D-model reconstructions of the explanted spinal cord illustrated precise positioning and dimensions of the epidural leads in relation to the surrounding neuroanatomy, including the spinal rootlets of the dorsal and ventral columns of the spinal cord. In a separate swine cohort, implanted epidural leads were used for SCS and recording evoked ESRs. Results Reconstructed 3D-models of the swine spinal cord with epidural lead implants demonstrated considerable distinctions in the dimensions of a single electrode contact on a standard industry epidural stimulation lead compared to dorsal rootlets at the dorsal root entry zone (DREZ). At the intervertebral segment, it was observed that a single electrode contact may cover 20-25% of the DREZ if positioned laterally. Electrode contacts were estimated to be ~0.75 mm from the margins of the DREZ when placed at the midline. Furthermore, ventral rootlets were observed to travel in proximity and parallel to dorsal rootlets at this level prior to separation into their respective sides of the spinal cord. Cathodic stimulation at the level of the intervertebral disc, compared to an ‘off-disc’ stimulation (7 mm rostral), demonstrated considerable variations in the features of recorded ESRs, such as amplitude and shape, and evoked unintended motor activation at lower stimulation thresholds. This substantial change may be due to the influence of nearby ventral roots. To further illustrate the influence of rootlet activation vs. dorsal column activation, the stimulation lead was displaced laterally at ~2.88 mm from the midline, resulting in variances in both evoked compound action potential (ECAP) components and electromyography (EMG) components in ESRs at lower stimulation thresholds. Conclusion The results of this study suggest that the ECAP and EMG components of recorded ESRs can vary depending on small differences in the location of the stimulating electrodes within the spinal anatomy, such as at the level of the intervertebral segment. Furthermore, the effects of sub-centimeter lateral displacement of the stimulation lead from the midline, leading to significant changes in electrophysiological metrics. The results of this pilot study reveal the importance of the small displacement of the electrodes that can cause significant changes to evoked responses SCS. These results may provide further valuable insights into the underlying mechanisms and assist in optimizing future SCS-related applications.

IntroductionThe present study investigated the role of training intensity in the dose–response relationship between endurance training and cardiorespiratory fitness (CRF). The hypothesis was that beginners would benefit from an increase in training intensity after an initial training phase, even if the energy expenditure was not altered. For this purpose, 26 weeks of continuous moderate training (control group, CON) was compared to training with gradually increasing intensity (intervention group, INC) but constant energy expenditure.MethodsThirty-one healthy, untrained subjects (13 men, 18 women; 46 ± 8 years; body mass index 25.4 ± 3.3 kg m−2; maximum oxygen uptake, VO2max 34 ± 4 ml min−1 kg−1) trained for 10 weeks with moderate intensity [3 days/week for 50 min/session at 55% heart rate reserve (HRreserve)] before allocation to one of two groups. A minimization technique was used to ensure homogeneous groups. While group CON continued with moderate intensity for 16 weeks, the INC group trained at 70% HRreserve for 8 weeks and thereafter participated in a 4 × 4 training program (high-intensity interval training, HIIT) for 8 weeks. Constant energy expenditure was ensured by indirect calorimetry and corresponding adjustment of the training volume. Treadmill tests were performed at baseline and after 10, 18, and 26 weeks.ResultsThe INC group showed improved VO2max (3.4 ± 2.7 ml kg−1 min−1) to a significantly greater degree than the CON group (0.4 ± 2.9 ml kg−1 min−1) (P = 0.020). In addition, the INC group exhibited improved Vmax (1.7 ± 0.7 km h−1) to a significantly greater degree than the CON group (1.0 ± 0.5 km h−1) (P = 0.001). The reduction of resting HR was significantly larger in the INC group (7 ± 4 bpm) than in the CON group (2 ± 6 bpm) (P = 0.001). The mean heart rate in the submaximal exercise test was reduced significantly in the CON group (5 ± 6 bpm; P = 0.007) and in the INC group (8 ± 7 bpm; P = 0.001), without a significant interaction between group and time point.ConclusionIncreasing intensity leads to greater adaptations in CRF than continuing with moderate intensity, even without increased energy expenditure. After 26 weeks of training in the moderate- and higher-intensity domain, energy-matched HIIT elicited further adaptations in cardiorespiratory fitness. Thus, training intensity plays a crucial role in the dose–response relationship between endurance training and fitness in untrained but healthy individuals. Clinical Trial Registrationhttps://www.drks.de/DRKS00031445, identifier DRKS00031445.

Abstract Background Standardized training prescriptions often result in large variation in training response with a substantial number of individuals that show little or no response at all. The present study examined whether the response in markers of cardiorespiratory fitness (CRF) to moderate intensity endurance training can be elevated by an increase in training intensity. Methods Thirty-one healthy, untrained participants (46 ± 8 years, BMI 25.4 ± 3.3 kg m−2 and $${\dot{\text{V}}}$$ V ˙ O2max 34 ± 4 mL min−1 kg−1) trained for 10 weeks with moderate intensity (3 day week−1 for 50 min per session at 55% HRreserve). Hereafter, the allocation into two groups was performed by stratified randomization for age, gender and VO2max response. CON (continuous moderate intensity) trained for another 16 weeks at moderate intensity, INC (increased intensity) trained energy-equivalent for 8 weeks at 70% HRreserve and then performed high-intensity interval training (4 × 4) for another 8 weeks. Responders were identified as participants with VO2max increase above the technical measurement error. Results There was a significant difference in $${\dot{\text{V}}}$$ V ˙ O2max response between INC (3.4 ± 2.7 mL kg−1 min−1) and CON (0.4 ± 2.9 mL kg−1 min−1) after 26 weeks of training (P = 0.020). After 10 weeks of moderate training, in total 16 of 31 participants were classified as VO2max responders (52%). After another 16 weeks continuous moderate intensity training, no further increase of responders was observed in CON. In contrast, the energy equivalent training with increasing training intensity in INC significantly (P = 0.031) increased the number of responders to 13 of 15 (87%). The energy equivalent higher training intensities increased the rate of responders more effectively than continued moderate training intensities (P = 0.012). Conclusion High-intensity interval training increases the rate of response in VO2max to endurance training even when the total energy expenditure is held constant. Maintaining moderate endurance training intensities might not be the best choice to optimize training gains. Trial Registration German Clinical Trials Register, DRKS00031445, Registered 08 March 2023—Retrospectively registered, https://www.drks.de/DRKS00031445

Abstract Background Epidural electrical stimulation (EES) of the spinal cord has been FDA approved and used therapeutically for decades. However, there is still not a clear understanding of the local neural substrates and consequently the mechanism of action responsible for the therapeutic effects. Method Epidural spinal recordings (ESR) are collected from the electrodes placed in the epidural space. ESR contains multi-modality signal components such as the evoked neural response (due to tonic or BurstDR™ waveforms), evoked muscle response, stimulation artifact, and cardiac response. The tonic stimulation evoked compound action potential (ECAP) is one of the components in ESR and has been proposed recently to measure the accumulative local potentials from large populations of neuronal fibers during EES. Result Here, we first review and investigate the referencing strategies, as they apply to ECAP component in ESR in the domestic swine animal model. We then examine how ECAP component can be used to sense lead migration, an adverse outcome following lead placement that can reduce therapeutic efficacy. Lastly, we show and isolate concurrent activation of local back and leg muscles during EES, demonstrating that the ESR obtained from the recording contacts contain both ECAP and EMG components. Conclusion These findings may further guide the implementation of recording and reference contacts in an implantable EES system and provide preliminary evidence for the utility of ECAP component in ESR to detect lead migration. We expect these results to facilitate future development of EES methodology and implementation of use of different components in ESR to improve EES therapy.

Reliable reconstruction of past sea surface temperature (SST) is of prime importance for understanding the Earth’s sensitivity to external forcing. Yet, it remains a major challenge in paleoceanography because comparison between SST estimates from different proxies reveals mismatches and raise the question as to what the contrasting proxies actually record. A better understanding of these mismatches in the light of seasonal occurrence of the proxy bearing organisms (archives) and water mass changes help to assess climate models. Here, we analyze data from the last deglaciation using a sediment core site situated at the northern boundary of the North Atlantic subtropical gyre influenced by fast latitudinal migrations of the subtropical Azores Front (AF) and resulting changes in water masses that may affect the SST records. Differences between the SST estimates from different deglacial SST reconstructions obtained from (1) Mg/Ca in planktic foraminifer tests, (2) alkenone UK′37, and (3) planktic foraminifer assemblages (SIMMAX), are assumed to result from the ecology of the proxy bearing organisms, and are assessed for the impact on different SST reconstructions from local seawater δ18O (δ18Ow) reconstructions. The general trends of SSTs from all four proxies confirm the well-known deglacial succession of warm and cold events. Mismatches between amplitudes of temperature changes are explained by differences in the phenology of the proxy-bearing organisms and local changes in hydrography. The combination of δ18O SST from the three different archives of δ18Ow reconstructions may cause offsets that exceed the climate driven signals.

The faunal remains from the late Neolithic site of Ness of Brodgar on the Orkney Islands (UK) provide a unique opportunity to investigate past adaptations of animal husbandry strategies to the Northern island environment, as well as the potential management of red deer. In this study, sheep and red deer mandibles and loose teeth (dP4 & M3) from the Ness of Brodgar were studied to construct age-at-death profiles, and analysed for δ13C, δ15N and δ18O. The mortality profile showed that around half of the analysed sheep were slaughtered when they reached maturity (i.e. after 2–4 years of life), consistent with a husbandry regime targeted at meat production. The stable isotope evidence indicates seaweed consumption in winter by several sheep (domesticates), but not by red deer (wild, possibly managed fauna). This dietary difference may have resulted from anthropogenically mediated influences, e.g. restriction of red deer habitats to upland areas. The varying extent of seaweed consumption between individual sheep and between Neolithic Orkney sites suggests differences in sheep husbandry practices across Orkney, indicating that the adaptation to consume seaweed was not ubiquitous on Orkney in the Neolithic, and did not follow a linear development. [ABSTRACT FROM AUTHOR]

Human impacts can induce ecosystems to cross tipping points and hence unexpected and sudden changes in ecosystem services that are difficult or impossible to reverse. The world´s oceans suffer from cumulative anthropogenic pressures like overexploitation and climate change and are especially vulnerable to such regime shifts. Yet an outstanding question is whether regime changes in marine ecosystems are irreversible. Here we first review the evidence for regime shifts in the North Sea ecosystem, one of the heaviest impacted and best studied marine ecosystems in the world. We then used catastrophe theory to show that fishing and warming have caused a previously undetected and potentially irreversible regime shift. Our study emphasizes the combined effects of local and global human impacts in driving significant ecosystem shifts and suggests that adaptation is likely the central avenue forward for maintaining services in the face of global climate change.

Introduction: Vagus nerve stimulation (VNS) is an FDA-approved neuromodulatory treatment used in the clinic today for epilepsy, depression, and cluster headaches. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood. In parallel, the glymphatic and meningeal lymphatic systems have recently been described as methods by which the brain maintains a healthy homeostasis and removes waste without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins. Objective/Hypothesis: As VNS has well-documented effects on many of the pathways recently linked to the clearance systems of the brain, we hypothesized that VNS could increase CSF penetrance in the brain. Methods: We injected a low molecular weight lysine-fixable fluorescent tracer (TxRed-3kD) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following an application of a clinically-derived VNS paradigm (30 Hz, 10% duty cycle). Results: We found that the clinical VNS group showed a significant increase in CSF tracer penetrance as compared to the naïve control and sham groups. Conclusion: (s): This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies.

The Labrador Sea is important for the modern global thermohaline circulation system through the formation of intermediate Labrador Sea Water (LSW) that has been hypothesized to stabilize the modern mode of North Atlantic deep-water circulation. The rate of LSW formation is controlled by the amount of winter heat loss to the atmosphere, the expanse of freshwater in the convection region and the inflow of saline waters from the Atlantic. The Labrador Sea, today, receives freshwater through the East and West Greenland currents (EGC, WGC) and the Labrador Current (LC). Several studies have suggested the WGC to be the main supplier of freshwater to the Labrador Sea, but the role of the southward flowing LC in Labrador Sea convection is still debated. At the same time, many paleoceanographic reconstructions from the Labrador Shelf focussed on late deglacial to early Holocene meltwater run-off from the Laurentide Ice Sheet (LIS), whereas little information exists about LC variability since the final melting of the LIS about 7000 years ago. In order to enable better assessment of the role of the LC in deep-water formation and its importance for Holocene climate variability in Atlantic Canada, this study presents high-resolution middle to late Holocene records of sea surface and bottom water temperatures, freshening, and sea ice cover on the Labrador Shelf during the last 6000 years. Our records reveal that the LC underwent three major oceanographic phases from the mid- to late Holocene. From 6.2 to 5.6 ka, the LC experienced a cold episode that was followed by warmer conditions between 5.6 and 2.1 ka, possibly associated with the late Holocene thermal maximum. While surface waters on the Labrador Shelf cooled gradually after 3 ka in response to the neoglaciation, Labrador Shelf subsurface or bottom waters show a shift to warmer temperatures after 2.1 ka. Although such an inverse stratification by cooling of surface and warming of subsurface waters on the Labrador Shelf would suggest a diminished convection during the last 2 millennia compared to the mid-Holocene, it remains difficult to assess whether hydrographic conditions in the LC have had a significant impact on Labrador Sea deep-water formation.

Background & aimsThe pathogenic mechanism of pancreatitis is poorly understood. Recent evidence implicates defective autophagy in pancreatitis responses; however, the pathways mediating impaired autophagy in pancreas remain largely unknown. Here, we investigate the role of lysosome associated membrane proteins (LAMPs) in pancreatitis.MethodsWe analyzed changes in LAMPs in experimental models and human pancreatitis, and the underlying mechanisms: LAMP de-glycosylation and degradation. LAMP cleavage by cathepsin B (CatB) was analyzed by mass spectrometry. We used mice deficient in LAMP-2 to assess its role in pancreatitis.ResultsPancreatic levels of LAMP-1 and LAMP-2 greatly decrease across various pancreatitis models and in human disease. Pancreatitis does not trigger LAMPs' bulk de-glycosylation, but induces their degradation via CatB-mediated cleavage of LAMP molecule close to the boundary between luminal and transmembrane domains. LAMP-2 null mice spontaneously develop pancreatitis that begins with acinar cell vacuolization due to impaired autophagic flux, and progresses to severe pancreas damage characterized by trypsinogen activation, macrophage-driven inflammation, and acinar cell death. LAMP-2 deficiency causes a decrease in pancreatic digestive enzymes content, stimulates the basal and inhibits CCK-induced amylase secretion by acinar cells. The effects of LAMP-2 knockout and acute cerulein pancreatitis overlap, which corroborates the pathogenic role of LAMP decrease in experimental pancreatitis models.ConclusionsThe results indicate a critical role for LAMPs, particularly LAMP-2, in maintaining pancreatic acinar cell homeostasis, and provide evidence that defective lysosomal function, resulting in impaired autophagy, leads to pancreatitis. Mice with LAMP-2 deficiency present a novel genetic model of human pancreatitis caused by lysosomal/autophagic dysfunction.

Background & aimsThe pathogenic mechanism of pancreatitis is poorly understood. Recent evidence implicates defective autophagy in pancreatitis responses; however, the pathways mediating impaired autophagy in pancreas remain largely unknown. Here, we investigate the role of lysosome associated membrane proteins (LAMPs) in pancreatitis.MethodsWe analyzed changes in LAMPs in experimental models and human pancreatitis, and the underlying mechanisms: LAMP de-glycosylation and degradation. LAMP cleavage by cathepsin B (CatB) was analyzed by mass spectrometry. We used mice deficient in LAMP-2 to assess its role in pancreatitis.ResultsPancreatic levels of LAMP-1 and LAMP-2 greatly decrease across various pancreatitis models and in human disease. Pancreatitis does not trigger LAMPs' bulk de-glycosylation, but induces their degradation via CatB-mediated cleavage of LAMP molecule close to the boundary between luminal and transmembrane domains. LAMP-2 null mice spontaneously develop pancreatitis that begins with acinar cell vacuolization due to impaired autophagic flux, and progresses to severe pancreas damage characterized by trypsinogen activation, macrophage-driven inflammation, and acinar cell death. LAMP-2 deficiency causes a decrease in pancreatic digestive enzymes content, stimulates the basal and inhibits CCK-induced amylase secretion by acinar cells. The effects of LAMP-2 knockout and acute cerulein pancreatitis overlap, which corroborates the pathogenic role of LAMP decrease in experimental pancreatitis models.ConclusionsThe results indicate a critical role for LAMPs, particularly LAMP-2, in maintaining pancreatic acinar cell homeostasis, and provide evidence that defective lysosomal function, resulting in impaired autophagy, leads to pancreatitis. Mice with LAMP-2 deficiency present a novel genetic model of human pancreatitis caused by lysosomal/autophagic dysfunction.

Abstract Antiplatelet therapy through inhibition of the adenosine diphosphate (ADP)/P2Y12 pathway is commonly used in the treatment of acute coronary syndrome (ACS). Although efficient in preventing platelet activation and thrombus formation, it increases the risk of bleeding complications. In patients with ACS receiving platelet aggregation inhibitors, that is, P2Y12 blockers (n = 923), we investigated the relationship between plasma and platelet‐associated CD40L levels and bleeding events (n = 71). Treatment with P2Y12 inhibitors in patients with ACS did not affect plasma‐soluble CD40L levels, but decreased platelet CD40L surface expression (pCD40L) and platelet‐released CD40L (rCD40L) levels in response to stimulation as compared to healthy controls. In vitro inhibition of the ADP pathway in healthy control platelets reduced both pCD40L and rCD40L levels. In a multivariable analysis, the reduced pCD40L level observed in ACS patients was significantly associated with the risk of bleeding occurrence (adjusted odds ratio = 0.15; 95% confidence interval = 0.034‐0.67). P2Y12 inhibitor‐treated (ticagrelor) mice exhibited a 2.5‐fold increase in tail bleeding duration compared with controls. A significant reduction in bleeding duration was observed on CD40L+/+ but not CD40L−/− platelet infusion. In addition, CD40L blockade in P2Y12 inhibitor–treated blood samples from a healthy human reduced thrombus growth over immobilized collagen under arterial flow. In conclusion, measurement of pCD40L may offer a novel approach to assessing bleeding risk in patients with ACS who are being treated with P2Y12 inhibitors.

To assess the regional multi-decadal to multi-centennial climate variability along the southern Iberian Peninsula during the mid- to late-Holocene record of paleo-environmental indicators from marine sediments were established for two sites in the Alboran Sea (ODP-161-976A) and the Gulf of Cádiz (GeoB5901-2). High-resolution records of organic geochemical properties and planktic foraminiferal assemblages are used to decipher precipitation and vegetation changes as well as hydrological conditions with respect to sea surface temperature (SST) and marine primary productivity (MPP). As a proxy for precipitation change, records of plant-derived n-alkane composition suggest a series of five distinct dry episodes in southern Iberia at 5.4±0.3 ka cal BP, from 5.1 to 4.9±0.1 ka cal BP, from 4.8 to 4.7±0.1 ka cal BP, from 4.4 to 4.3±0.1 ka cal BP, and at 3.7±0.1 ka cal BP. During each dry episode the vegetation suffered from reduced water availability. Interestingly, the dry phase from 4.4 to 4.3±0.1 ka cal BP is followed by a rapid shift towards wetter conditions revealing a more complex pattern in terms of its timing and duration than was described for the 4.2 ka event in other regions. The series of dry episodes as well as closely connected hydrological variability in the Alboran Sea were probably driven by NAO-like (North Atlantic Oscillation) variability. In contrast, surface waters in the Gulf of Cádiz appear to have responded more directly to North Atlantic cooling associated with Bond events. In particular, during Bond events 3 and 4, a pronounced increase in seasonality with summer warming and winter cooling is found.

Background: The auricular branch of the vagus nerve runs superficially, which makes it a favorable target for non-invasive stimulation techniques to modulate vagal activity. For this reason, there have been many early-stage clinical trials on a diverse range of conditions. These trials often report conflicting results for the same indication.Methods: Using the Cochrane Risk of Bias tool we conducted a systematic review of auricular vagus nerve stimulation (aVNS) randomized controlled trials (RCTs) to identify the factors that led to these conflicting results. The majority of aVNS studies were assessed as having “some” or “high” risk of bias, which makes it difficult to interpret their results in a broader context.Results: There is evidence of a modest decrease in heart rate during higher stimulation dosages, sometimes at above the level of sensory discomfort. Findings on heart rate variability conflict between studies and are hindered by trial design, including inappropriate washout periods, and multiple methods used to quantify heart rate variability. There is early-stage evidence to suggest aVNS may reduce circulating levels and endotoxin-induced levels of inflammatory markers. Studies on epilepsy reached primary endpoints similar to previous RCTs testing implantable vagus nerve stimulation therapy. Preliminary evidence shows that aVNS ameliorated pathological pain but not evoked pain.Discussion: Based on results of the Cochrane analysis we list common improvements for the reporting of results, which can be implemented immediately to improve the quality of evidence. In the long term, existing data from aVNS studies and salient lessons from drug development highlight the need for direct measures of local neural target engagement. Direct measures of neural activity around the electrode will provide data for the optimization of electrode design, placement, and stimulation waveform parameters to improve on-target engagement and minimize off-target activation. Furthermore, direct measures of target engagement, along with consistent evaluation of blinding success, must be used to improve the design of controls—a major source of concern identified in the Cochrane analysis. The need for direct measures of neural target engagement and consistent evaluation of blinding success is applicable to the development of other paresthesia-inducing neuromodulation therapies and their control designs.

Alpha-mannosidosis is a glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (LAMAN), which markedly affects neurons of the central nervous system (CNS), and causes pathognomonic intellectual dysfunction in the clinical condition. Cognitive improvement consequently remains a major therapeutic objective in research on this devastating genetic error. Immune-tolerant LAMAN knockout mice were developed to evaluate the effects of enzyme replacement therapy (ERT) by prolonged administration of recombinant human enzyme. Biochemical evidence suggested that hippocampus may be one of the brain structures that benefits most from long-term ERT. In the present functional study, ERT was initiated in 2-month-old immune-tolerant alpha-mannosidosis mice and continued for 9 months. During the course of treatment, mice were trained in the Morris water maze task to assess spatial-cognitive performance, which was related to synaptic plasticity recordings and hippocampal histopathology. Long-term ERT reduced primary substrate storage and neuroinflammation in hippocampus, and improved spatial learning after mid-term (10 weeks+) and long-term (30 weeks+) treatment. Long-term treatment substantially improved the spatial-cognitive abilities of alpha-mannosidosis mice, whereas the effects of mid-term treatment were more modest. Detailed analyses of spatial memory and spatial-cognitive performance indicated that even prolonged ERT did not restore higher cognitive abilities to the level of healthy mice. However, it did demonstrate marked therapeutic effects that coincided with increased synaptic connectivity, reflected by improvements in hippocampal CA3-CA1 long-term potentiation (LTP), expression of postsynaptic marker PSD-95 as well as postsynaptic density morphology. These experiments indicate that long-term ERT may hold promise, not only for the somatic defects of alpha-mannosidosis, but also to alleviate cognitive impairments of the disorder.

Abstract Background The present study evaluates whether the quality of advanced cardiac life support (ALS) is improved with an interactive prototype assist device. This device consists of an automated external defibrillator linked to a ventilator and provides synchronised visual and acoustic instructions for guidance through the ALS algorithm and assistance for face-mask ventilations. Methods We compared the cardiopulmonary resuscitation (CPR) quality of emergency medical system (EMS) staff members using the study device or standard equipment in a mannequin simulation study with a prospective, controlled, randomised cross-over study design. Main outcome was the effect of the study device compared to the standard equipment and the effect of the number of prior ALS trainings of the EMS staff on the CPR quality. Data were analysed using analyses of covariance (ANCOVA) and binary logistic regression, accounting for the study design. Results In 106 simulations of 56 two-person rescuer teams, the mean hands-off time was 24.5% with study equipment and 23.5% with standard equipment (Difference 1.0% (95% CI: −0.4 to 2.5%); p = 0.156). With both types of equipment, the hands-off time decreased with an increasing cumulative number of previous CPR trainings (p = 0.042). The study equipment reduced the mean time until administration of adrenaline (epinephrine) by 23 s (p = 0.003) and that of amiodarone by 17 s (p = 0.016). It also increased the mean number of changes in the person doing chest compressions (0.6 per simulation; p

Climate mitigation targets must involve the agricultural sector, which contributes 10%–14% of global anthropogenic greenhouse gas (GHG) emissions. To evaluate options for implementing mitigation measures in the agricultural sector, farmers’ knowledge, positions, and attitudes towards agricultural GHG emissions, their accounting, and reduction need to be understood. Using an online survey, we asked 254 German farmers about their motivation to reduce GHG emissions and their acceptance of possible regulation schemes. We examined differences between relevant farming sectors, i.e., conventional versus organic and livestock keeping versus crop-cultivating farms. Results show that German farmers are aware of climatic changes and feel a general commitment to reducing GHG emissions but lack sufficient information. We identified agricultural magazines as the most effective tool for disseminating relevant knowledge. German farmers would feel motivated to adopt climate-friendly farming styles if products were labeled accordingly and if they received subsidies and public acknowledgment for their effort. As long as there is no regulation of agricultural GHGs through taxes or subsidies, personal motivation is yet the strongest motivation for voluntary emission reduction. Our findings are timely for the further development of strategies and instruments that reduce agricultural GHG emission and account for the farmers’ views. The dataset is available for further investigations.

Background & Aims: The pathogenic mechanism of pancreatitis is poorly understood. Recent evidence implicates defective autophagy in pancreatitis responses; however, the pathways mediating impaired autophagy in pancreas remain largely unknown. Here, we investigate the role of lysosome associated membrane proteins (LAMPs) in pancreatitis. Methods: We analyzed changes in LAMPs in experimental models and human pancreatitis, and the underlying mechanisms: LAMP deglycosylation and degradation. LAMP cleavage by cathepsin B (CatB) was analyzed by mass spectrometry. We used mice deficient in LAMP-2 to assess its role in pancreatitis. Results: Pancreatic levels of LAMP-1 and LAMP-2 greatly decrease across various pancreatitis models and in human disease. Pancreatitis does not trigger the LAMPsâ bulk deglycosylation but induces their degradation via CatB-mediated cleavage of the LAMP molecule close to the boundary between luminal and transmembrane domains. LAMP-2 null mice spontaneously develop pancreatitis that begins with acinar cell vacuolization due to impaired autophagic flux, and progresses to severe pancreas damage characterized by trypsinogen activation, macrophage-driven inflammation, and acinar cell death. LAMP-2 deficiency causes a decrease in pancreatic digestive enzymes content, and stimulates the basal and inhibits cholecystokinin-induced amylase secretion by acinar cells. The effects of LAMP-2 knockout and acute cerulein pancreatitis overlap, which corroborates the pathogenic role of LAMP decrease in experimental pancreatitis models. Conclusions: The results indicate a critical role for LAMPs, particularly LAMP-2, in maintaining pancreatic acinar cell homeostasis and provide evidence that defective lysosomal function, resulting in impaired autophagy, leads to pancreatitis. Mice with LAMP-2 deficiency present a novel genetic model of human pancreatitis caused by lysosomal/autophagic dysfunction. Keywords: Amylase Secretion, Autophagy, Cathepsin B, Cerulein

Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal Kv1-channels.

Cardiomyopathies might lead to end-stage heart disease with the requirement of drastic treatments like bridging up to transplant or heart transplantation. A not precisely known proportion of these diseases are genetically determined. We genotyped 43 index-patients (30 DCM, 10 ARVC, 3 RCM) with advanced or end stage cardiomyopathy using a gene panel which covered 46 known cardiomyopathy disease genes. Fifty-three variants with possible impact on disease in 33 patients were identified. Of these 27 (51%) were classified as likely pathogenic or pathogenic in the MYH7, MYL2, MYL3, NEXN, TNNC1, TNNI3, DES, LMNA, PKP2, PLN, RBM20, TTN, and CRYAB genes. Fifty-six percent (n = 24) of index-patients carried a likely pathogenic or pathogenic mutation. Of these 75% (n = 18) were familial and 25% (n = 6) sporadic cases. However, severe cardiomyopathy seemed to be not characterized by a specific mutation profile. Remarkably, we identified a novel homozygous PKP2-missense variant in a large consanguineous family with sudden death in early childhood and several members with heart transplantation in adolescent age.

Global change challenges coupled natural-human systems such as fisheries social-ecological systems (SES) because they are confined by spatial and functional ecosystem boundaries. Understanding the capacity of an SES to adapt to changing environmental or socio-economic conditions is complex and entails an analysis of the system's properties such as resilience, resistance, vulnerability, and adaptive capacity. We used a modified Ostrom framework to structure our analyses and to define the SES components, attributes and indicators of the German mixed demersal fishery SES operating in the southern North Sea. Combining analyses of 20-year time series of environmental and socio-economic data with network analysis and semi-structured interviews allowed for a detailed description of past SES adaptations. Hence, our analysis revealed autonomous adaptations of the SES to environmental and socio-economic change, which entailed a shift in target species, fishing strategies as well as a distinct decrease in number of actors. We found that the adaptive capacity of the SES has declined over time, and that the SES is now on the brink of being unable to withstand future environmental and socio-economic change. It is therefore captured in an undesirable state, reflecting a social-ecological trap where social and environmental feedbacks negatively reinforce each other. The main barriers to the adaptive capacity of the SES are related to fishing cultures, economic structures, policy frameworks and increasing conflicts over the use of marine space. An in-depth understanding of the linkages between the identified key SES components and related indicators is a prerequisite for developing future management approaches to enhance the adaptive capacity of SES to global change. Our findings highlight the need for tailored and context-specific co-management approaches for all decision-making processes affecting SES. [Display omitted] • Global change trials the resistance and resilience of fisheries socio-ecological systems (SES). • We assessed adaptation strategies of a fisheries SES in the southern North Sea. • Autonomous adaptation strategies comprised changes of target species, fishing strategies, and number of actors. • Barriers to adaptation included prevailing fishing cultures, governance structures, and spatial use conflicts. • Understanding the dynamics of SES components enables tailored management approaches to increase adaptive capacity. [ABSTRACT FROM AUTHOR]

Vagus nerve stimulation (VNS) is an FDA-approved neuromodulatory treatment used in the clinic today for epilepsy, depression, and cluster headaches. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood. In parallel, the glymphatic and meningeal lymphatic systems have recently been described as methods by which the brain maintains a healthy homeostasis and removes waste without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins. As VNS has well-documented effects on many of the pathways recently linked to the clearance systems of the brain, we hypothesized that VNS could increase CSF penetrance in the brain. We injected a low molecular weight lysine-fixable fluorescent tracer (TxRed-3kD) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following an application of a clinically-derived VNS paradigm (30 Hz, 10% duty cycle). We found that the clinical VNS group showed a significant increase in CSF tracer penetrance as compared to the naïve control and sham groups. (s) : This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies. • The waste clearance systems of the brain are important for healthy brain homeostasis. • Clinically patterned vagus nerve stimulation enhanced cerebrospinal fluid penetrance. • These findings represent a new potential therapeutic mechanism of vagus stimulation. [ABSTRACT FROM AUTHOR]

• In a non pre-selected cohort, percutanous pulmonary valve implantation (PPVI) could be performed in 80/382 patients (20.9%). • A large right ventricular outflow tract, small patient size, and coronary compression were the major obstacles. • Future device developments may expand the indication pool for PPVI. Percutaneous pulmonary valve implantation (PPVI) numbers are rising but are still minor compared to surgery due to several contraindications. We sought to analyze the impact of PPVI compared to standard surgery in an unselected cohort with dysfunctional right ventricular outflow tract (RVOT). Reasons for PPVI failure and possible contraindications were explored. Between 2010 and 2015 all consecutive patients who underwent surgery or intervention for a dysfunctional RVOT were investigated. A total of 382 cases was identified – 246 patients underwent successful valve insertion: 166 surgeries (166/246 = 67.4%) with 55/166 homografts (33.1%), 106 Contegra® grafts (63.8%), 5 Hancock valves (3.0%). Overall, 70/246 patients presented a priori with an enlarged RVOT > 28 mm (28.5%) not appropriate for PPVI and 14/246 (5.7%) had additional defects necessitating surgery. Some 31/246 patients had surgery for initial repair of congenital defects or were too small (<20 kg) for PPVI (12.6%). 80 underwent successful PPVI (32.5% of 246 valves implanted) [51 Edwards Sapien® valves (63.7%), 29 Melody valves (36.3%)]. The RVOT was too large for PPVI in 22/246 patients (8.9%). A total 20/246 patients (8.1%) showed coronary compression after balloon interrogation. In 4/246 patients PPVI was not possible due to technical issues (1.4%). PPVI could be performed successfully in 80/382 patients (20.9%). An enlarged RVOT, small patient size, and coronary compression were the major obstacles for interventional management. Future developments for larger RVOTs and smaller body weight may expand the indication for PPVI. [ABSTRACT FROM AUTHOR]

The expectations on protected areas to deliver not only biodiversity conservation but also to provide an array of different ecosystem services rise. Sequestration and storage of carbon are promising services that protected areas may provide. This study integrates spatially explicit data on terrestrial Natura 2000 sites, soil organic carbon, and agricultural land values to estimate the potential for climate-smart conservation planning in the European Union. The objectives of this study are to analyse spatial relations between protected areas soil carbon content, and land values on the European Union's land area as well as to locate and quantify the proportion of land with high carbon and low economic value within and outside protected areas. We apply a unique interdisciplinary framework with methods ranging from analyses based on geographical information systems, agricultural economics to statistics. Findings indicate that there is a significant overlap between Natura 2000 sites and regions with high carbon content across Europe. Statistical analyses show that carbon-rich regions have significantly lower land values than other areas. Our results suggest that biodiversity protection and mitigation of climate change through conservation of soil carbon could be simultaneously achieved in Europe's protected areas and beyond. We conclude that there is a notable potential for climate-smart conservation in Europe that needs further investigation. [ABSTRACT FROM AUTHOR]