Quasi-2D Fermi surface in the anomalous superconductor UTe2.

The heavy fermion paramagnet UTe2 exhibits numerous characteristics of spin-triplet superconductivity. Efforts to understand the microscopic details of this exotic superconductivity have been impeded by uncertainty regarding the underlying electronic structure. Here we directly probe the Fermi surface of UTe2 by measuring magnetic quantum oscillations in pristine quality crystals. We find an angular profile of quantum oscillatory frequency and amplitude that is characteristic of a quasi-2D Fermi surface, which we find is well described by two cylindrical Fermi sheets of electron- and hole-type respectively. Additionally, we find that both cylindrical Fermi sheets possess considerable undulation but negligible small-scale corrugation, which may allow for their near-nesting and therefore promote magnetic fluctuations that enhance the triplet pairing mechanism. Importantly, we find no evidence for the presence of any 3D Fermi surface sections. Our results place strong constraints on the possible symmetry of the superconducting order parameter in UTe2.

Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

Fluorescent Tracers for In Vivo Imaging of Lymphatic Targets.

The lymphatic system continues to gain importance in a range of conditions, and therefore, imaging of lymphatic vessels is becoming more widespread for research, diagnosis, and treatment. Fluorescent lymphatic imaging offers advantages over other methods in that it is affordable, has higher resolution, and does not require radiation exposure. However, because the lymphatic system is a one-way drainage system, the successful delivery of fluorescent tracers to lymphatic vessels represents a unique challenge. Each fluorescent tracer used for lymphatic imaging has distinct characteristics, including size, shape, charge, weight, conjugates, excitation/emission wavelength, stability, and quantum yield. These characteristics in combination with the properties of the target tissue affect the uptake of the dye into lymphatic vessels and the fluorescence quality. Here, we review the characteristics of visible wavelength and near-infrared fluorescent tracers used for in vivo lymphatic imaging and describe the various techniques used to specifically target them to lymphatic vessels for high-quality lymphatic imaging in both clinical and pre-clinical applications. We also discuss potential areas of future research to improve the lymphatic fluorescent tracer design.

MitoQ supplementation augments acute exercise-induced increases in muscle PGC1α mRNA and improves training-induced increases in peak power independent of mitochondrial content and function in untrained middle-aged men.

The role of mitochondrial ROS in signalling muscle adaptations to exercise training has not been explored in detail. We investigated the effect of supplementation with the mitochondria-targeted antioxidant MitoQ on a) the skeletal muscle mitochondrial and antioxidant gene transcriptional response to acute high-intensity exercise and b) skeletal muscle mitochondrial content and function following exercise training. In a randomised, double-blind, placebo-controlled, parallel design study, 23 untrained men (age: 44 ± 7 years, VO2peak: 39.6 ± 7.9 ml/kg/min) were randomised to receive either MitoQ (20 mg/d) or a placebo for 10 days before completing a bout of high-intensity interval exercise (cycle ergometer, 10 × 60 s at VO2peak workload with 75 s rest). Blood samples and vastus lateralis muscle biopsies were collected before exercise and immediately and 3 h after exercise. Participants then completed high-intensity interval training (HIIT; 3 sessions per week for 3 weeks) and another blood sample and muscle biopsy were collected. There was no effect of acute exercise or MitoQ on systemic (plasma protein carbonyls and reduced glutathione) or skeletal muscle (mtDNA damage and 4-HNE) oxidative stress biomarkers. Acute exercise-induced increases in skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) mRNA expression were augmented in the MitoQ group. Despite this, training-induced increases in skeletal muscle mitochondrial content were similar between groups. HIIT-induced increases in VO2peak and 20 km time trial performance were also similar between groups while training-induced increases in peak power achieved during the VO2peak test were augmented in the MitoQ group. These data suggest that training-induced increases in peak power are enhanced following MitoQ supplementation, which may be related to the augmentation of skeletal muscle PGC1α expression following acute exercise. However, these effects do not appear to be related to an effect of MitoQ supplementation on exercise-induced oxidative stress or training-induced mitochondrial biogenesis in skeletal muscle.

Temporal profiles describing markers of inflammation and metabolism during the transition period of pasture-based, seasonal-calving dairy cows.

The physiology of the dairy cow while transitioning from pregnancy to lactation is complex, with multifactorial processes studied extensively for the role they play in manifestation of disease along with associated economic losses and compromised animal welfare. Manuscripts outlining associations among nutrition, production, physiology, and genetics variables and transition cow disorders are common in literature, with blood analytes that are central to energy metabolism (e.g., nonesterified fatty acids; NEFA, ß-hydroxybutyrate; BHB) often reported. Immunity and inflammation have increasingly been explored in the pathogenesis and persistence of disorders, with cytokines and acute phase proteins well documented. However, most of these studies have involved cows fed total mixed rations, which may not always reflect profiles of blood analytes and other physiological indicators of transition cow health in grazing cows consuming fresh pasture. Considering the comparatively lesser characterization of these analytes and markers in pasture-based, seasonal-calving dairy cows, we compiled a database consisting of 2,610 cow lactations that span 20 yr of transition cow research in New Zealand. Using this database, analyte profiles from approximately 28 d precalving to 35 d postcalving were identified in dairy cows with a range of genetics, milk production potentials, and pasture-based farm management systems. These profiles characterize changes in energy reserves and metabolism (NEFA, BHB, glucose, insulin, growth hormone, insulin-like growth factor-1, leptin, body condition score, body weight), liver function (globulin, aspartate aminotransferase, glutamate dehydrogenase, gamma-glutamyl transpeptidase, bilirubin, cholesterol, liver triacylglycerides), protein metabolism (albumin, total protein, albumin:globulin ratio, creatinine, urea, creatine kinase), mineral balance (calcium, magnesium, phosphate, potassium, sodium, chloride, bicarbonate), inflammation (IL-1ß, IL-6, haptoglobin, reactive oxygen species, total antioxidant capacity), and uterine health (polymorphonuclear cells, macrophage cells, vaginal discharge score). Temporal changes are generally consistent with previously characterized homeorhetic changes experienced by the dairy cow during the transition from pregnancy to lactation in both pastoral and housed systems. Some of the profiles had not previously been presented for pastoral systems, or in some cases, presented for either system. Our results indicate that moderate-yielding dairy cows undergo similar homeorhetic changes to high-yielding housed cows; however, differences in diet composition result in greater BHB concentrations than expected, based on their milk production and NEFA concentrations. In addition, most cows were able to transition to a state of higher energy requirement following calving, albeit with an increased metabolic challenge in the liver, and only a small percentage of cows were classified with severe hepatic lipidosis or severe hyperketonemia. Increases in metabolic function of the liver were accompanied by changes in indicators of the immune system and changes in mineral balance that, combined, probably reflect the innate response to the transition from gestation to lactation.

Peri-operative management of percutaneous fetoscopic spina-bifida repair: a descriptive review of five cases from the United Kingdom, with focus on anaesthetic implications.

We present a case-based review of the first five percutaneous fetoscopic in-utero spina bifida repair procedures undertaken in the UK. Our focus is on implications of anaesthesia and analgesia for the mother and fetus, provision of uterine relaxation and fetal immobilisation while providing conditions conducive to surgical access. Minimising risks for fetal acidosis, placental and fetal hypoperfusion, maternal and fetal sepsis and maternal fluid overload were the foremost priorities. We discuss optimisation strategies undertaken to ensure fetal and maternal well-being under anaesthesia, shortcomings in the current approach, and possible directions for improvement.

Identifying hospital-acquired infections using retrospective record review from the Irish National Adverse Events Study (INAES) and European point prevalence survey case definitions.

BACKGROUND: Point prevalence surveys (PPSs) collect data on hospital-acquired infections (HAIs) at one point in time but do not provide information on incidence over the entire admission or impact on patients or healthcare resources. Retrospective record review examines the entire admission to determine adverse event prevalence, incidence, preventability, physical impairment and additional length of stay. AIM: To establish whether European HAI surveillance definitions can be applied to the Irish National Adverse Events Study (INAES) retrospective record review data to determine HAI burden. METHODS: In the INAES, 1574 admissions were reviewed using a two-stage methodology and 247 adverse events were found. These were examined against European HAI case definitions to determine whether the event was an HAI. Results were compared with the 2011/12 European PPS data for Ireland. FINDINGS: The prevalence of HAI adverse events in INAES was 4.4% (95% confidence interval (CI) 3.1-6.1%) with an incidence of 3.8 (95% CI 2.5-5.2) HAI adverse events per 100 admissions. The PPS HAI prevalence for Ireland was 5.2%. HAI types and micro-organisms were similar in INAES and the PPS. Approximately three-quarters of INAES HAI adverse events were preventable, 7% caused permanent impairment and 7% contributed to death. A mean of 10 additional bed days were attributed to HAI adverse events, equivalent to €9400 per event. CONCLUSION: Retrospective record review is an accurate source of information on HAI incidence, preventability and impact that complements PPS prevalence rates. HAI adverse events result in higher costs to the healthcare system than other adverse events.

Peripheral blood mononuclear cells do not reflect skeletal muscle mitochondrial function or adaptation to high-intensity interval training in healthy young men.

Measurement of skeletal muscle mitochondrial respiration requires invasive biopsy to obtain a muscle sample. Peripheral blood mononuclear cell (PBMC) mitochondrial protein content appears to reflect training status in young men; however, no studies have investigated whether there are training-induced changes in PBMC mitochondrial respiration. Therefore, we determined whether PBMC mitochondrial respiration could be used as a marker of skeletal muscle mitochondrial respiration in young healthy men and whether PBMC mitochondrial respiration responds to short-term training. Skeletal muscle and PBMC samples from 10 healthy young (18-35 yr) male participants were taken before and after a 2-wk high-intensity interval training protocol. High-resolution respirometry was used to determine mitochondrial respiration from muscle and PBMCs, and Western blotting and quantitative PCR were used to assess mitochondrial biogenesis in PBMCs. PBMC mitochondrial respiration was not correlated with muscle mitochondrial respiration at baseline ( R2 = 0.012-0.364, P > 0.05). While muscle mitochondrial respiration increased in response to training (32.1-61.5%, P < 0.05), PBMC respiration was not affected by training. Consequently, PBMCs did not predict training effect on muscle mitochondrial respiration ( R2 = 0.024-0.283, P > 0.05). Similarly, gene and protein markers of mitochondrial biogenesis did not increase in PBMCs following training. This suggests PBMC mitochondrial function does not reflect that of skeletal muscle and does not increase following short-term high-intensity training. PBMCs are therefore not a suitable biomarker for muscle mitochondrial function in young healthy men. It may be useful to study PBMC mitochondrial function as a biomarker of muscle mitochondrial function in pathological populations with different respiration capacities. NEW & NOTEWORTHY Research in primates has suggested that peripheral blood mononuclear cells (PBMCs) may provide a less-invasive alternative to a muscle biopsy for measuring muscle mitochondrial function. Furthermore, trained individuals appear to have greater mitochondrial content in PBMCs. Here we show that in healthy young men, PBMCs do not reflect skeletal muscle mitochondrial function and do not adapt in response to a training intervention that increases muscle mitochondrial function, suggesting PBMCs are a poor marker of muscle mitochondrial function in humans.

Thrombolysis for stroke in Ireland: increasing access and maintaining safety in a challenging environment.

BACKGROUND: In the setting of a national audit of acute stroke services, we examined the delivery of thrombolytic therapy for ischaemic stroke and whether current practice was achieving safe outcomes and consistent delivery for patients. METHOD: Data obtained from the recent national stroke audit was compared against previous Irish audit, the most recent SSNAP UK stroke audit and the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) study. RESULTS: Thrombolysis was provided in 27 acute hospitals throughout Ireland during the period assessed with 82% (22/27) providing 24/7 access, the remaining sites using redirect policies. Decision to thrombolyse was made by stroke trained consultants in 63% (17/27) of units, with general physicians and emergency medicine consultants covering the other units. Thrombolysis rate for non-haemorrhagic stroke was 11% (n = 80/742, CI 95% ±2.23) versus a 1% rate in the 2008 audit. Sites receiving patients through a redirect policy had the highest thrombolysis rate, an average of 24%. Nearly 30% of cases were thrombolysed on the weekend. Eighty-three percent of cases were managed in a stroke unit at some time during admission versus 54% of the national total cases. Thirty-seven percent of patients were ≥80 years old. The mortality rate was 11.3% versus the national mortality rate for non-thrombolysed ischaemic strokes of 10% (p > 0.5), and this is comparable to the SITS-MOST 2007 study 3-month mortality rate of 11.3% (p > 0.5). CONCLUSION: Stroke thrombolysis is being effectively and safely provided in acute stroke services in Ireland despite regular involvement of non-specialist staff. There is still potential to improve thrombolysis rate.

Beyond the front end: Investigating a thigh worn accelerometer device for step count and bout detection in Parkinson's disease.

Free-living ambulation with accelerometer-based devices is an attractive methodology to assess habitual behaviour within Parkinson's disease (PD). However, slowness of movement can contribute to difficulty in quantifying ambulatory/walking outcomes within this group by these devices. This study investigates the use of a commercial accelerometer device (activPAL™) in those with moderate PD to understand its proprietary software (inbuilt algorithm) limitations. The values provided by the proprietary software are evaluated in comparison to novel algorithms on the same raw data to examine limitations for use within this cohort. The bespoke algorithms help to alter sensitivity in outcomes stemming from the same accelerometer data while also highlighting how slight changes in algorithms can drastically inflate/deflate values. In general, results show that the proprietary software generally quantifies lower values of outcomes (step and bout count), which is similar to previous findings. Variations in algorithm functionality highlight large heterogeneity in bout and step counts resulting from a lack of how they are defined within the literature. The novel alternative ambulatory algorithms presented here should be considered for use on raw data from the activPAL™ in those with moderate/severe PD.

A dry powder combination of pyrazinoic acid and its n-propyl ester for aerosol administration to animals.

Combining the advantage of higher efficacy due to local pulmonary administration of pyrazinoic acid (POA) and potent effect of pyrazinoic acid ester (PAE) delivered as an aerosol would aid in tuberculosis therapy. A combination spray dried dry powder, composed of POA, PAE (n-propyl POA), maltodextrin and leucine, was prepared for aerosol delivery to animals. Solid-state characteristics of morphology (scanning electron microscopy) crystallinity (X-ray powder diffraction), thermal properties (thermogravimetric analysis and differential scanning calorimetry) and moisture content (Karl Fisher) were evaluated. Particle size distributions, by volume (laser diffraction) for the dispersed powder and by mass (inertial impaction) were determined. Efficient delivery of the powder to a nose only animal exposure chamber employed a novel rotating brush/micro-fan apparatus. Spherical, crystalline particles were prepared. The volume median diameter, ∼1.5µm, was smaller than the mass median aerodynamic diameter, ∼3.0µm, indicating modest aggregation. Drug content variations were observed across the particle size distribution and may be explained by PAE evaporative losses. Delivery to the nose-only exposure chamber indicated that boluses could be administered at approximately 3min intervals to avoid aerosol accumulation and effect uniform dose delivery with successive doses suitable for future pharmacokinetic and pharmacodynamic studies.

Patient behaviour at the time of stroke onset: a cross-sectional survey of patient response to stroke symptoms.

BACKGROUND AND PURPOSE: Revascularisation treatment with thrombolysis must be initiated within 4.5 h following ischaemic stroke symptom onset. Despite its proven benefits, thrombolysis therapy is underused, with patient delay in presenting to hospital with symptoms identified as the leading barrier. This study aimed to examine help-seeking behaviour at stroke onset, in order to understand delays in accessing acute medical care for stroke symptoms. METHODS: 149 consecutive patients hospitalised with ischaemic stroke were interviewed at 72 h poststroke with the Stroke Awareness Questionnaire and the Response to Symptoms Questionnaire. RESULTS: Sixty per cent of stroke cases presented to the ED within 3.5 h of stroke onset. Knowledge of stroke symptoms and risk factors was poor, with 40% unable to correctly define a stroke. Bystander recognition of symptoms (p=0.03) and bystander initiation of Emergency Medical Services was associated with ED presentation within 3.5 h (p=0.03). CONCLUSIONS: This study provides insights into patient response when a stroke occurs, with the presence and action of others highlighted as critical in fast response to stroke symptoms. Knowledge of stroke warning signs and risk factors was low among stroke survivors. Findings highlight the complexity of changing help-seeking behaviour during stroke onset, and provide directions for public education efforts to reduce prehospital delay.

Estimating cut points: A simple method for new wearables.

UNLABELLED: Wearable technology is readily available for continuous assessment due to a growing number of commercial devices with increased data capture capabilities. However, many commercial devices fail to support suitable parameters (cut points) derived from the literature to help quantify physical activity (PA) due to differences in manufacturing. A simple metric to estimate cut points for new wearables is needed to aid data analysis. OBJECTIVE: The purpose of this pilot study was to investigate a simple methodology to determine cut points based on ratios between sedentary behaviour (SB) and PA intensities for a new wrist worn device (PRO-Diary™) by comparing its output to a validated and well characterised 'gold standard' (ActiGraph™). STUDY DESIGN: Twelve participants completed a semi-structured (four-phase) treadmill protocol encompassing SB and three PA intensity levels (light, moderate, vigorous). The outputs of the devices were compared accounting for relative intensity. RESULTS: Count ratios (6.31, 7.68, 4.63, 3.96) were calculated to successfully determine cut-points for the new wrist worn wearable technology during SB (0-426) as well as light (427-803), moderate (804-2085) and vigorous (≥ 2086) activities, respectively. CONCLUSION: Our findings should be utilised as a primary reference for investigations seeking to use new (wrist worn) wearable technology similar to that used here (i.e., PRO-Diary™) for the purposes of quantifying SB and PA intensities. The utility of count ratios may be useful in comparing devices or SB/PA values estimated across different studies. However, a more robust examination is required for different devices, attachment locations and on larger/diverse cohorts.

Inhaled drug treatment for tuberculosis: Past progress and future prospects.

Since the 1990s the rising incidence of multiple drug resistant TB, particularly in the context of human immunodeficiency virus co-infected patients, has threatened global TB control. At that time funding agencies began to support formal investigation of aerosol therapy which until then had been the subject of case reports of individual investigators. Over the last decade, proponents of aerosol therapy have increased in number within the TB research community as the incidence of multiple and extremely drug resistant TB has increased dramatically around the world. Aerosol therapy offers the potential to deliver drug at target concentrations directly into the lungs, use the alveolar-capillary interface to achieve systemic levels, while reducing the risk of systemic toxicity seen with parentally administered doses. In addition, there are insufficient new drugs in the pipeline to anticipate the appearance of a new regimen in time to assure future control of drug resistance. Consequently, alternative strategies are critical to achieving global TB control, and inhaled therapies should be considered as one such strategy.

Spray Dried Aerosol Particles of Pyrazinoic Acid Salts for Tuberculosis Therapy. [Corrected].

Tuberculosis is the most serious infectious disease caused by a single organism, Mycobacterium tuberculosis (Mtb). The standard of care is a protracted and complex drug treatment regimen made more complicated and of longer duration by the incidence of multiple and extensively drug resistant disease. Pulmonary delivery of aerosols as a supplement to the existing regimen offers the advantage of delivering high local drug doses to the initial site of infection and most prominent organ system involved in disease. Pyrazinamide is used in combination with other drugs to treat tuberculosis. It is postulated that the action of pyrazinoic acid (POA), the active moiety of pyrazinamide, may be enhanced by local pH adjustment, when presented as a salt form. POA was prepared as leucine (POA-leu) and ammonium salts (POA-NH4), spray dried, and characterized in terms of physicochemical properties (melting point, crystallinity, moisture content), aerodynamic performance (aerodynamic particle size distribution, emitted dose), and in vitro inhibitory effect on two mycobacteria (Mtb and Mycobacterium bovis). Particles were prepared in sizes suitable for inhalation (3.3 and 5.4 µm mass median aerodynamic diameter and 61 and 40% of the aerodynamic particle size distribution less than 4.46 µm, as measured by inertial impaction, for POA-leu and POA-NH4, respectively) and with properties (stoichiometric 1:1 ratio of salt to drug, melting points at ∼180 °C, with water content of <1%) that would support further development as an inhaled dosage form. In addition, POA salts demonstrated greater potency in inhibiting mycobacterial growth compared with POA alone, which is promising for therapy.

Instrumented assessment of test battery for physical capability using an accelerometer: a feasibility study.

Recent work has identified subdomains (tests) of physical capability that are recommended for assessment of the healthy ageing phenotype (HAP). These include: postural control, locomotion, endurance, repeated sit-to-stand-to-sit and TUG. Current assessment methods lack sensitivity and are error prone due to their lack of consistency and heterogeneity of reported outcomes; instrumentation with body worn monitors provides a method to address these potential weaknesses. This work proposes the use of a single tri-axial accelerometer-based device with appropriate algorithms (referred to here as a body worn monitor, BWM) for the purposes of instrumented testing during physicality capability assessment. In this pilot study we present 14 BWM-based outcomes across the subdomains which include magnitude, frequency and spatio-temporal characteristics. Where possible, we compared BWM outcomes with manually recorded values and found no significant differences between locomotion and TUG tasks (p ≥ 0.319). Significant differences were found for the total distance walked during endurance (p = 0.037) and times for repeated sit-to-stand-to-sit transitions (p < 0.000). We identified reasons for differences and make recommendations for future testing. We were also able to quantify additional characteristics of postural control and gait which could be sensitive outcomes for future HAP assessment. Our findings demonstrate the feasibility of this method to enhance measurement of physical capacity. The methodology can also be applied to a wide variety of accelerometer-based monitors and is applicable to a range of intervention-based studies or pathological assessment.

iCap: Instrumented assessment of physical capability.

OBJECTIVES: The aims of this study were to (i) investigate instrumented physical capability (iCap) as a valid method during a large study and (ii) determine whether iCap can provide important additional features of postural control and gait to categorise cohorts not previously possible with manual recordings. STUDY DESIGN: Cross-sectional analysis involving instrumented testing on 74 adults who were recruited as part of a pilot intervention study; LiveWell. Participants wore a single accelerometer-based monitor (lower back) during standardised physical capability tests so that outcomes could be compared directly with manual recordings (stopwatch and measurement tape) made concurrently. MAIN OUTCOME MEASURES: Time, distance, postural control and gait characteristics. RESULTS: Agreement between manual and iCap ranged from moderate to excellent (0.649-0.983) with mean differences between methods low and deemed acceptable. Additionally, iCap successfully quantified (i) postural control characteristics which showed sensitivity to distinguish between 5 variations of the standing balance test and (ii) 14 gait characteristics known to be sensitive to age/pathology. CONCLUSIONS: Our findings show that iCap can provide robust quantitative data about physical capability during standardised tests while also providing sensitive (age/pathology) postural control and gait characteristics not previously quantifiable with manual recordings. The methodology which we propose may have practical utility in a wide range of clinical and public health surveys and studies, including intervention studies, where assessment could be undertaken within diverse settings. This will need to be tested in further validation studies in a wider range of settings.