Beta Burst-Driven Adaptive Deep Brain Stimulation Improves Gait Impairment and Freezing of Gait in Parkinson's Disease.

Background: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) that is often refractory to medication. Pathological prolonged beta bursts within the subthalamic nucleus (STN) are associated with both worse impairment and freezing behavior in PD, which are improved with deep brain stimulation (DBS). The goal of the current study was to investigate the feasibility, safety, and tolerability of beta burst-driven adaptive DBS (aDBS) for FOG in PD. Methods: Seven individuals with PD were implanted with the investigational Summit™ RC+S DBS system (Medtronic, PLC) with leads placed bilaterally in the STN. A PC-in-the-loop architecture was used to adjust stimulation amplitude in real-time based on the observed beta burst durations in the STN. Participants performed either a harnessed stepping-in-place task or a free walking turning and barrier course, as well as clinical motor assessments and instrumented measures of bradykinesia, OFF stimulation, on aDBS, continuous DBS (cDBS), or random intermittent DBS (iDBS). Results: Beta burst driven aDBS was successfully implemented and deemed safe and tolerable in all seven participants. Gait metrics such as overall percent time freezing and mean peak shank angular velocity improved from OFF to aDBS and showed similar efficacy as cDBS. Similar improvements were also seen for overall clinical motor impairment, including tremor, as well as quantitative metrics of bradykinesia. Conclusion: Beta burst driven adaptive DBS was feasible, safe, and tolerable in individuals with PD with gait impairment and FOG.

Data processing techniques impact quantification of cortico-cortical evoked potentials.

BACKGROUND: Cortico-cortical evoked potentials (CCEPs) are a common tool for probing effective connectivity in intracranial human electrophysiology. As with all human electrophysiology data, CCEP data are highly susceptible to noise. To address noise, filters and re-referencing are often applied to CCEP data, but different processing strategies are used from study to study. NEW METHOD: We systematically compare how common average re-referencing and filtering CCEP data impacts quantification. RESULTS: We show that common average re-referencing and filters, particularly filters that cut out more frequencies, can significantly impact the quantification of CCEP magnitude and morphology. We identify that high cutoff high pass filters (> 0.5 Hz), low cutoff low pass filters (< 200 Hz), and common average re-referencing impact quantification across subjects. However, we also demonstrate that the presence of noise may impact CCEP quantification, and preprocessing is necessary to mitigate this. We show that filtering is more effective than re-referencing or averaging across trials for reducing most common types of noise. COMPARISON WITH EXISTING METHODS: These results suggest that existing CCEP processing methods must be applied with care to maximize noise reduction and minimize changes to the data. We do not test every available processing strategy; rather we demonstrate that processing can influence the results of CCEP studies. We emphasize the importance of reporting all processing methods, particularly re-referencing methods. CONCLUSIONS: We propose a general framework for choosing an appropriate processing pipeline for CCEP data, taking into consideration the noise levels of a specific dataset. We suggest that minimal gentle filtering is preferable.

Evaluating enteric methane emissions within a herd of genetically divergent grazing dairy cows.

Enteric methane (CH4) emissions of 3 genetic groups (GG) of dairy cows were recorded across the grazing season (early March to late October). The 3 GG were (1) high economic breeding index (EBI) Holstein-Friesian (HF) representative of the top 1% of dairy cows in Ireland at the time of the study (elite), (2) national average (NA) EBI, which were representative of the average HF dairy cow in Ireland, and (3) purebred Jersey (JE) cows. Enteric CH4 was recorded using GreenFeed technology. Seasonal variation in CH4 was observed, with the lowest daily CH4 emissions and CH4 expressed per unit of dry matter intake occurring in spring (253 g/d and 15.56 g/kg, respectively), intermediate in summer (303 g/d and 18.26 g/kg, respectively), and greatest in autumn (324 g/d and 19.80 g/kg, respectively). Seasonal variation was also observed in the proportion of gross energy intake converted to CH4 (Ym); in the spring the Ym was lowest at 0.046, increasing to 0.053 and 0.058 in the summer and autumn, respectively. There was no difference in daily CH4 between the elite and NA, whereas JE had lower CH4 emissions compared with the elite. When expressed per unit of milk solids (fat + protein yield; MS), the elite and JE produced 6.8% and 9.7% less CH4 per kilogram of MS, respectively, compared with NA. There was no difference between the GG for CH4 per unit of DMI or the Ym. This research emphasizes the variation in CH4 emissions across the grazing season and among cows of differing genetic merit for CH4 emission intensities but not for CH4 per unit of DMI or the Ym.

Characterising sustainability certification standards in dairy production.

Despite the increasing use of private certification standards to meet the demand for sustainable dairy production, research into these standards is lacking. In this paper, we characterised sustainability certification standards currently used in dairy production. A literature search for dairy sustainability initiatives revealed one hundred-and-sixteen possible standards. In total, 19 of these were determined to qualify as 'sustainability certification standards' based on our selection criteria and were available in English or Dutch language. The standards were analysed using publicly available documents of the most recent version. The analysis included three key components: (i) general characteristics of the standard (such as the geographic origin, year founded, most recent updates), (ii) a thematic coverage analysis of the sustainability themes covered in each standard and (iii) evaluation of the inherent trade-offs within each standard utilising the opposing aspects of credibility, accessibility, and continuous improvement (the 'devil's triangle'). The comparison of general characteristics of the 19 standards revealed a wide variation in the characteristics of standards such as organisation type (i.e. nongovernmental organisations, individual dairy processor or other dairy sector actors), the number of indicators included, but also in the sustainability themes they cover, and how they balance the credibility, accessibility, and continuous improvement. The environmental pillar is most frequently and comprehensively addressed, whereas the economic pillar is least frequently and least comprehensively addressed. The 'devil's triangle' trade-off analysis revealed that credibility and accessibility, from the standard's perspective, are often transparently described and assured within the documents of standards. In contrast, continuous improvement is infrequently focused upon by standards. Overall, the variability in standards may allow farmers to choose a standard that aligns with his/her conviction or stage of development but might also create consumer or farmer mistrust in standards.

Actin nano-architecture of phagocytic podosomes.

Podosomes are actin-enriched adhesion structures important for multiple cellular processes, including migration, bone remodeling, and phagocytosis. Here, we characterize the structure and organization of phagocytic podosomes using interferometric photoactivated localization microscopy, a super-resolution microscopy technique capable of 15-20 nm resolution, together with structured illumination microscopy and localization-based super-resolution microscopy. Phagocytic podosomes are observed during frustrated phagocytosis, a model in which cells attempt to engulf micropatterned IgG antibodies. For circular patterns, this results in regular arrays of podosomes with well-defined geometry. Using persistent homology, we develop a pipeline for semi-automatic identification and measurement of podosome features. These studies reveal an hourglass shape of the podosome actin core, a protruding knob at the bottom of the core, and two actin networks extending from the core. Additionally, the distributions of paxillin, talin, myosin II, α-actinin, cortactin, and microtubules relative to actin are characterized.

Burns management in the military and humanitarian setting.

Burns are an unpredictable element of the modern battlespace and humanitarian operations. Most military burns are small and may not be a significant challenge for deployed healthcare assets but usually render the individual combat ineffective until healed. However, larger burns represent a more significant challenge because of the demand for fluid resuscitation therapy, early surgical intervention and regular wound management that can rapidly deplete surgical capabilities. Beyond the initial injury, longer-term consequences, such as psychological morbidity and loss of functional independence, are rarely considered as part of an ongoing care plan. Globally, most of the morbidity and mortality associated with burns are seen in less economically developed countries and are frequently associated with conflicts and natural disasters, but with simple interventions and resources, outcomes in these environments can be markedly improved. Prehospital providers should be confident to manage the initial assessment of a burn, including triaging for evacuation and packaging for safe transfer. This article provides an overview for prehospital providers on the management of thermal burns in military and humanitarian settings, with additional considerations for the management of chemical and electrical injuries.

Biosensors based on peptide exposure show single molecule conformations in live cells.

We describe an approach to study the conformation of individual proteins during single particle tracking (SPT) in living cells. "Binder/tag" is based on incorporation of a 7-mer peptide (the tag) into a protein where its solvent exposure is controlled by protein conformation. Only upon exposure can the peptide specifically interact with a reporter protein (the binder). Thus, simple fluorescence localization reflects protein conformation. Through direct excitation of bright dyes, the trajectory and conformation of individual proteins can be followed. Simple protein engineering provides highly specific biosensors suitable for SPT and FRET. We describe tagSrc, tagFyn, tagSyk, tagFAK, and an orthogonal binder/tag pair. SPT showed slowly diffusing islands of activated Src within Src clusters and dynamics of activation in adhesions. Quantitative analysis and stochastic modeling revealed in vivo Src kinetics. The simplicity of binder/tag can provide access to diverse proteins.

Life cycle assessment of pasture-based suckler steer weanling-to-beef production systems: Effect of breed and slaughter age.

Demand for beef produced from pasture-based diets is rising as it is perceived to be healthier, animal friendly and good for the environment. Animals reared on a solely grass forage diet, however, have a lower growth rate than cereal-fed animals and consequently are slaughtered at an older age. This study focused on the former by conducting life cycle assessments of beef production systems offering only fresh or conserved grass, and comparing them to a conventional pasture-based beef production system offering concentrate feeding during housing. The four suckler weanling-to-beef production systems simulated were: (i) Steers produced to slaughter entirely on a grass forage diet at 20 months (GO-20); (ii) Steers produced to slaughter entirely on a grass forage diet at 24 months (GO-24); (iii) Steers produced to slaughter on a grass forage diet with concentrate supplementation during housing (GC-24), and (iv) Steers produced to slaughter entirely on a grass forage diet at 28 months (GO-28). Two breed types were evaluated: early-maturing and late-maturing (LM). The environmental impacts assessed were global warming potential (GWP), non-renewable energy (NRE), acidification potential (AP), eutrophication potential (marine (MEP) and freshwater) were expressed per animal, per kg live weight gain (LWG), kg carcass weight gain, and kg meat weight gain (MWG). The GO-20 production system had the lowest environmental impact across all categories and functional units for both breeds. Extending age at slaughter increased environmental impact across all categories per animal. The LWG response of EM steers to concentrate feed supplementation in GC-24 was greater than the increase in total environmental impact resulting in GC-24 having a lower environmental impact across categories per kg product than GO-24. Concentrate feed supplementation had a similar effect on LM steers with the exception of NRE and AP. The increase in daily LWG in the third grazing season in comparison to the second grazing and housing resulted in GO-28 having lower GWP, NRE, AP, and MEP per kg product than GO-24. Early-maturing steers had lower environmental impact than LM when expressed per kg LWG. However the opposite occurred when impacts were expressed per kg MWG, despite LM steers producing the least LWG. The LM steers compensated for poor LWG performance by having superior carcass traits, which caused the breed to have the lowest environmental impact per kg MWG. The results reaffirms the importance of functional unit and suggests reducing the environmental impact of LWG does not always translate into improvements in the environmental performance of meat.

Greenhouse gas emissions and nitrogen efficiency of dairy cows of divergent economic breeding index under seasonal pasture-based management.

Greenhouse gas (GHG) emissions and nitrogen (N) efficiencies were modeled for 2 genetic groups (GG) of Holstein-Friesian cows across 3 contrasting feeding treatments (FT). The 2 GG were (1) high economic breeding index (EBI) animals representative of the top 5% of cows nationally (elite) and (2) EBI representative of the national average (NA). The FT represented (1) generous feeding of pasture, (2) a slight restriction in pasture allowance, and (3) a high-concentrate feeding system with adequate pasture allowance. Greenhouse gas and N balance models were parameterized using outputs generated from the Moorepark Dairy Systems model, a stochastic budgetary simulation model, having integrated biological data pertaining to the 6 scenarios (2 GG × 3 FT) obtained from a 4-yr experiment conducted between 2013 and 2016. On a per hectare basis, total system GHG emissions were similar for both elite and NA across the 3 FT. Per unit of product, however, the elite group had 10% and 11% lower GHG emissions per kilogram of fat- and protein-corrected milk and per kilogram of milk solids (MSO; fat + protein kg), respectively, compared with the NA across the 3 FT. The FT incorporating high concentrate supplementation had greater absolute GHG emissions per hectare as well as GHG per kilogram of fat- and protein-corrected milk and MSO. The elite group had a slightly superior N use efficiency (N output/N input) and lower N surplus (N input - N output) compared with the NA group. The high concentrate FT had an inferior N use efficiency and a higher N surplus. The results of the current study demonstrate that breeding for increased EBI will lead to a general improvement in GHG emissions per unit of product as well as improved N efficiency. The results also illustrate that reducing concentrate supplementation will reduce GHG emissions, GHG emissions intensity, while improving N efficiency in the context of pasture-based dairy production.

Fully implanted adaptive deep brain stimulation in freely moving essential tremor patients.

OBJECTIVE: Deep brain stimulation (DBS) is a safe and established treatment for essential tremor (ET) and several other movement disorders. One approach to improving DBS therapy is adaptive DBS (aDBS), in which stimulation parameters are modulated in real time based on biofeedback from either external or implanted sensors. Previously tested systems have fallen short of translational applicability due to the requirement for patients to continuously wear the necessary sensors or processing devices, as well as privacy and security concerns. APPROACH: We designed and implemented a translation-ready training data collection system for fully implanted aDBS. Two patients chronically implanted with electrocorticography strips over the hand portion of M1 and DBS probes in the ipsilateral ventral intermediate nucleus of the thalamus for treatment of ET were recruited for this study. Training was conducted using a translation-ready distributed training procedure, allowing a substantially higher degree of control over data collection than previous works. A linear classifier was trained using this system, biased towards activating stimulation in accordance with clinical considerations. MAIN RESULTS: The clinically relevant average false negative rate, defined as fraction of time during which stimulation dropped below [Formula: see text] clinical levels during movement epochs, was 0.036. Tremor suppression, calculated through analysis of gyroscope data, was 33.2% more effective on average with aDBS than with continuous DBS. During a period of free movement with aDBS, one patient reported a slight paresthesia; patients noticed no difference in treatment efficacy between systems. SIGNIFICANCE: Here is presented the first translation-ready training procedure for a fully embedded aDBS control system for MDs and one of the first examples of such a system in ET, adding to the consensus that fully implanted aDBS systems are sufficiently mature for broader deployment in treatment of movement disorders.

Coronavirus antibody positive tests and continued use of personal protective equipment throughout the pandemic.

The COVID-19 pandemic has thrust not only a novel virus onto the world, but new challenges resulting in novel approaches. Governments have reduced regulation in order to facilitate timely advances to combat the disease. Antibody testing has rapidly been deployed but it is creating challenges for staff and patients. Mask use has come to the forefront and human factor (HF) strategies must be examined to reduce risk associated with lack of engagement from both healthcare staff and patients. In this we explore these issues and suggest some solutions.

Reducing medical error during a pandemic.

On 30 January 2020, the WHO declared the coronavirus disease 2019 (COVID-19) a public health emergency of international concern. By 11 March 2020, it was designated a pandemic owing to its rapid worldwide spread. In this short article we provide some information that might be useful and help equip colleagues to reduce medical error during a pandemic. We advocate a systems-based approach, rather than an individual's sole responsibility, and, look at ways to provide safer healthcare.

LIFE BEEF CARBON: a common framework for quantifying grass and corn based beef farms' carbon footprints.

Europe's roadmap to a low-carbon economy aims to cut greenhouse gas (GHG) emissions 80% below 1990 levels by 2050. Beef production is an important source of GHG emissions and is expected to increase as the world population grows. LIFE BEEF CARBON is a voluntary European initiative that aims to reduce GHG emissions per unit of beef (carbon footprint) by 15% over a 10-year period on 2172 farms in four large beef-producing countries. Changes in farms beef carbon footprint are normally estimated via simulation modelling, but the methods current models apply differ. Thus, our initial goal was to develop a common modelling framework to estimate beef farms carbon footprint. The framework was developed for a diverse set of Western Europe farms located in Ireland, Spain, Italy and France. Whole farm and life cycle assessment (LCA) models were selected to quantify emissions for the different production contexts and harmonized. Carbon Audit was chosen for Ireland, Bovid-CO2 for Spain and CAP'2ER for France and Italy. All models were tested using 20 case study farms, that is, 5 per country and quantified GHG emissions associated with on-farm live weight gain. The comparison showed the ranking of beef systems gross carbon footprint was consistent across the three models. Suckler to weaning or store systems generally had the highest carbon footprint followed by suckler to beef systems and fattening beef systems. When applied to the same farm, Carbon Audit's footprint estimates were slightly lower than CAP'2ER, but marginally higher than Bovid-CO2. These differences occurred because the models were adapted to a specific region's production circumstances, which meant their emission factors for key sources; that is, methane from enteric fermentation and GHG emissions from concentrates were less accurate when used outside their target region. Thus, for the common modelling framework, region-specific LCA models were chosen to estimate beef carbon footprints instead of a single generic model. Additionally, the Carbon Audit and Bovid-CO2 models were updated to include carbon removal by soil and other environmental metrics included in CAP'2ER, for example, acidification. This allows all models to assess the effect carbon mitigation strategies have on other potential pollutants. Several options were identified to reduce beef farms carbon footprint, for example, improving genetic merit. These options were assessed for beef systems, and a mitigation plan was created by each nation. The cumulative mitigation effect of the LIFE BEEF CARBON plan was estimated to exceed the projects reduction target (-15%).

Attempted use of PACE for riboswitch discovery generates three new translational theophylline riboswitch side products.

OBJECTIVE: The purpose of this project was to use an in vivo method to discover riboswitches that are activated by new ligands. We employed phage-assisted continuous evolution (PACE) to evolve new riboswitches in vivo. We started with one translational riboswitch and one transcriptional riboswitch, both of which were activated by theophylline. We used xanthine as the new target ligand during positive selection followed by negative selection using theophylline. The goal was to generate very large M13 phage populations that contained unknown mutations, some of which would result in new aptamer specificity. We discovered side products of three new theophylline translational riboswitches with different levels of protein production. RESULTS: We used next generation sequencing to identify M13 phage that carried riboswitch mutations. We cloned and characterized the most abundant riboswitch mutants and discovered three variants that produce different levels of translational output while retaining their theophylline specificity. Although we were unable to demonstrate evolution of new riboswitch ligand specificity using PACE, we recommend careful design of recombinant M13 phage to avoid evolution of "cheaters" that short circuit the intended selection pressure.

Systematic review and meta-analysis: Efficacy of patented probiotic, VSL#3, in irritable bowel syndrome.

BACKGROUND: VSL#3 is a patented probiotic for which several clinical trials suggest benefits on motor function, bloating, and symptoms of irritable bowel syndrome (IBS). OBJECTIVES: To quantify effects of VSL#3 on abdominal pain, stool consistency, overall response, abdominal bloating, and quality of life (QOL) in IBS through meta-analysis. METHODS: MEDLINE (OvidSP and PubMed), EMBASE, Web of Science, and Scopus were searched up to May 2017. Using a fixed effects model, we pooled data from intention-to-treat analyses of randomized trials (RCTs) comparing VSL#3 to placebo in IBS. Data were reported as relative risk (RR), overall mean difference (MD), or standardized MD (SMD) with 95% confidence intervals (CI). Quality of evidence was rated using the GRADE approach. KEY RESULTS: Among 236 citations, 5 RCTs (243 patients) were included. No significant differences were observed for abdominal pain (SMD = -0.03; 95% CI -0.29 to 0.22), bloating (SMD = -0.15; 95% CI -0.40 to 0.11), proportion of bowel movements with normal consistency (overall MD = 0; 95% CI -0.09 to 0.08), or IBS-QOL (SMD = 0.08; 95% CI -0.22 to 0.39). VSL#3 was associated with a nearly statistically significant increase in overall response (RR = 1.39; 95% CI 0.99-1.98). CONCLUSIONS & INFERENCES: In this systematic review and meta-analysis, there was a trend toward improvement in overall response with VSL#3, but no clear evidence effectiveness for IBS. However, the number and sample sizes of the trials are small and the overall quality of evidence for 3 of the 5 outcomes was low. Larger trials evaluating validated endpoints in well-defined IBS patients are warranted.

The impact of age on major orthopaedic trauma: an analysis of the United Kingdom Trauma Audit Research Network database.

AIMS: To compare the early management and mortality of older patients sustaining major orthopaedic trauma with that of a younger population with similar injuries. PATIENTS AND METHODS: The Trauma Audit Research Network database was reviewed to identify eligible patients admitted between April 2012 and June 2015. Distribution and severity of injury, interventions, comorbidity, critical care episodes and mortality were recorded. The population was divided into young (64 years or younger) and older (65 years and older) patients. RESULTS: Of 142 765 adults sustaining major trauma, 72 942 (51.09 %) had long bone or pelvic fractures and 45.81% of these were > 65 years old. Road traffic collision was the most common mechanism in the young (40.4%) and, in older people, fall from standing height (80.4%) predominated. The 30 day mortality in older patients with fractures is greater (6.8% versus 2.5%), although critical care episodes are more common in the young (18.2% versus 9.7%). Older people are less likely to be admitted to critical care beds and are often managed in isolation by surgeons. Orthopaedic surgery is the most common admitting and operating specialty and, in older people, fracture surgery accounted for 82.1% of procedures. CONCLUSION: Orthopaedic trauma in older people is associated with mortality that is significantly greater than for similar fractures in the young. As with the hip fracture population, major trauma in the elderly is a growing concern which highlights the need for a review of admission pathways and shared orthogeriatric care models. Cite this article: Bone Joint J 2017;99-B:1677-80.

Electrophysiological insights into control over recollection.

Electrophysiological correlates of successful episodic retrieval were measured in an experiment where participants switched frequently between two different episodic retrieval conditions. They completed three trials of each condition before switching to the other condition. The key contrasts were between neural indices of successful retrieval that were separated according to the number of successive trials of the same condition that had been completed. An electrophysiological correlate of recollection--the left-parietal event-related potential (ERP) old/new effect--was smaller on the first and second trial than on the third successive trial that participants completed for each condition. This ERP old/new effect is assumed to index the extent to which recollection has occurred, and this outcome suggests that control over recovery of task-relevant episodic content is compromised when additional cognitive demands are imposed around the time of retrieval.

An electrophysiological study of boundary conditions for control of recollection in the exclusion task.

Event-related potentials (ERPs) were collected in a memory retrieval task that was designed to assess the resolution with which people exerted control over memory retrieval. Participants were first required to indicate whether the objects denoted by concrete nouns (i) had pleasant or unpleasant connotations, (ii) were typically smaller or larger than a shoebox, or (iii) were easy or difficult to draw. They then completed a retrieval task where old (studied) and new words were presented. Participants pressed one key for words encountered in the drawing task, and a second key for all other test words (new words as well as those encountered in the pleasantness and size judgment tasks). The left-parietal ERP old/new effect--an electrophysiological index of recollection--was reliable for words from the drawing task only. This finding is consistent with the view that participants were successful at prioritising recollection of some kinds of information over others. The data also provide an insight into the resolution with which this prioritisation can be implemented, because there was little evidence of a left-parietal ERP old/new effect for words to which a size judgment was made, despite the fact that visual imagery is likely to have been employed for drawing as well as for size judgments.

Detrimental effects of reloading recovery on force, shortening velocity, and power of soleus muscles from hindlimb-unloaded rats.

To better understand how atrophied muscles recover from prolonged nonweight-bearing, we studied soleus muscles (in vitro at optimal length) from female rats subjected to normal weight bearing (WB), 15 days of hindlimb unloading (HU), or 15 days HU followed by 9 days of weight bearing reloading (HU-R). HU reduced peak tetanic force (P(o)), increased maximal shortening velocity (V(max)), and lowered peak power/muscle volume. Nine days of reloading failed to improve P(o), while depressing V(max) and intrinsic power below WB levels. These functional changes appeared intracellular in origin as HU-induced reductions in soleus mass, fiber cross-sectional area, and physiological cross-sectional area were partially or completely restored by reloading. We calculated that HU-induced reductions in soleus fiber length were of sufficient magnitude to overextend sarcomeres onto the descending limb of their length-tension relationship upon the resumption of WB activity. In conclusion, the force, shortening velocity, and power deficits observed after 9 days of reloading are consistent with contraction-induced damage to the soleus. HU-induced reductions in fiber length indicate that sarcomere hyperextension upon the resumption of weight-bearing activity may be an important mechanism underlying this response.