Bifidobacterium longum 1714 improves sleep quality and aspects of well-being in healthy adults: a randomized, double-blind, placebo-controlled clinical trial.

Stress and sleep are linked with overall well-being. Bifidobacterium longum 1714 has been shown to influence stress responses and modulate neural responses during social stress, and influence sleep quality during examination stress in healthy adults. Here, we explored the ability of this strain to alter sleep quality in adults using subjective and objective measures. Eighty-nine adults (18-45y) with impaired sleep quality assessed with the Pittsburgh Sleep Quality Index (PSQI) and with a global score ≥ 5 were randomized to receive B. longum 1714 or placebo daily for eight weeks. Assessing the effect of the strain on PSQI global score was the primary objective. Secondary objectives assessed sleep quality and well-being subjectively and sleep parameters using actigraphy objectively. While PSQI global score improved in both groups, B. longum 1714 significantly improved the PSQI component of sleep quality (p < 0.05) and daytime dysfunction due to sleepiness (p < 0.05) after 4 weeks and social functioning (p < 0.05) and energy/vitality (p < 0.05) after 8 weeks, compared to placebo. No significant effect on actigraphy measures were observed. The 1714 strain had a mild effect on sleep, demonstrated by a faster improvement in sleep quality at week 4 compared to placebo, although overall improvements after 8 weeks were similar in both groups. B. longum 1714 improved social functioning and increased energy/vitality in line with previous work that showed the strain modulated neural activity which correlated with enhanced vitality/reduced mental fatigue (ClinicalTrials.gov: NCT04167475).

Genomic attributes of airway commensal bacteria and mucosa.

Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance.

Costs of Digital Adherence Technologies for Tuberculosis Treatment Support, 2018-2021.

Digital adherence technologies are increasingly used to support tuberculosis (TB) treatment adherence. Using microcosting, we estimated healthcare system costs (in 2022 US dollars) of 2 digital adherence technologies, 99DOTS medication sleeves and video-observed therapy (VOT), implemented in demonstration projects during 2018-2021. We also obtained cost estimates for standard directly observed therapy (DOT). Estimated per-person costs of 99DOTS for drug-sensitive TB were $98 in Bangladesh (n = 719), $119 in the Philippines (n = 396), and $174 in Tanzania (n = 976). Estimated per-person costs of VOT were $1,154 in Haiti (87 drug-sensitive), $304 in Moldova (173 drug-sensitive), $452 in Moldova (135 drug-resistant), and $661 in the Philippines (110 drug-resistant). 99DOTS costs may be similar to or less expensive than standard DOT. VOT is more expensive, although in some settings, labor cost offsets or economies of scale may yield savings. 99DOTS and VOT may yield savings to local programs if donors cover infrastructure costs.

Insights into Permanent Encodings of Macroscopic Spike Patterns by Magnetic-Field-Directed Evaporative Self-Assembly from Ferrofluids.

Field-directed assembly has the potential to make large hierarchically ordered structures from nanoscale objects. Shear forces and optical, electric, and magnetic fields have been used for this purpose. Ferrofluids consist of magnetic nanoparticles hosted in mobile liquids. Though they exhibit rich structures and lattice patterns in response to an applied magnetic field, the patterns collapse when the field is removed. Recently, we adapted evaporation-induced self-assembly to obtain permanent encodings of the complex field response of magnetite nanoparticles in alkane media. The encodings are characterized by order that culminates in macrostructures comprising kinetically trapped spike patterns. The present work examines a number of variables that control pattern formation associated with this encoding. Control variables include applied magnetic field strength, magnetic field gradient, nanoparticle concentration, solvent evaporation conditions, and alkane solvent chain length. The pattern formation process is captured in six stages of evolution until the solvent host has evaporated and the pattern is permanently fixed. The macropatterns consist of hexagonal arrays that coexist with different pentagonal and heptagonal defects. The Voronoi entropy is calculated for different patterns that arise due to changes in the control parameters. Insight into order in the lattice patterns is achieved by extracting measurables like peak-to-peak spike wavelength, spike population, spike height, and base diameter from the patterns. The pattern measurables depend nonlinearly on the magnetic field gradient, solvent evaporation rate, and solvent chain length. Nanoparticle concentration does not impact the measurables significantly. Nonetheless, the results agree qualitatively with a linear expression for the critical magnetization and wavelength that explicitly contains the field gradient and surface tension.

Best Current Practice and Research Priorities in Active Surveillance for Prostate Cancer-A Report of a Movember International Consensus Meeting.

BACKGROUND: Active surveillance (AS) is recommended for low-risk and some intermediate-risk prostate cancer. Uptake and practice of AS vary significantly across different settings, as does the experience of surveillance-from which tests are offered, and to the levels of psychological support. OBJECTIVE: To explore the current best practice and determine the most important research priorities in AS for prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A formal consensus process was followed, with an international expert panel of purposively sampled participants across a range of health care professionals and researchers, and those with lived experience of prostate cancer. Statements regarding the practice of AS and potential research priorities spanning the patient journey from surveillance to initiating treatment were developed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Panel members scored each statement on a Likert scale. The group median score and measure of consensus were presented to participants prior to discussion and rescoring at panel meetings. Current best practice and future research priorities were identified, agreed upon, and finally ranked by panel members. RESULTS AND LIMITATIONS: There was consensus agreement that best practice includes the use of high-quality magnetic resonance imaging (MRI), which allows digital rectal examination (DRE) to be omitted, that repeat standard biopsy can be omitted when MRI and prostate-specific antigen (PSA) kinetics are stable, and that changes in PSA or DRE should prompt MRI ± biopsy rather than immediate active treatment. The highest ranked research priority was a dynamic, risk-adjusted AS approach, reducing testing for those at the least risk of progression. Improving the tests used in surveillance, ensuring equity of access and experience across different patients and settings, and improving information and communication between and within clinicians and patients were also high priorities. Limitations include the use of a limited number of panel members for practical reasons. CONCLUSIONS: The current best practice in AS includes the use of high-quality MRI to avoid DRE and as the first assessment for changes in PSA, with omission of repeat standard biopsy when PSA and MRI are stable. Development of a robust, dynamic, risk-adapted approach to surveillance is the highest research priority in AS for prostate cancer. PATIENT SUMMARY: A diverse group of experts in active surveillance, including a broad range of health care professionals and researchers and those with lived experience of prostate cancer, agreed that best practice includes the use of high-quality magnetic resonance imaging, which can allow digital rectal examination and some biopsies to be omitted. The highest research priority in active surveillance research was identified as the development of a dynamic, risk-adjusted approach.

A model for calculating the mechanical demands of overground running.

An energy-based approach to quantifying the mechanical demands of overground, constant velocity and/or intermittent running patterns is presented. Total mechanical work done (Wtotal) is determined from the sum of the four sub components: work done to accelerate the centre of mass horizontally (Whor), vertically (Wvert), to overcome air resistance (Wair) and to swing the limbs (Wlimbs). These components are determined from established relationships between running velocity and running kinematics; and the application of work-energy theorem. The model was applied to constant velocity running (2-9 m/s), a hard acceleration event and a hard deceleration event. The estimated Wtotal and each sub component were presented as mechanical demand (work per unit distance) and power (work per unit time), for each running pattern. The analyses demonstrate the model is able to produce estimates that: 1) are principally determined by the absolute running velocity and/or acceleration; and 2) can be attributed to different mechanical demands given the nature of the running bout. Notably, the proposed model is responsive to varied running patterns, producing data that are consistent with established human locomotion theory; demonstrating sound construct validity. Notwithstanding several assumptions, the model may be applied to quantify overground running demands on flat surfaces.

Age-related asymmetry in anticipatory postural movements during unilateral arm movement and imagery.

Reaching movements of the arms are accompanied by anticipatory (APM) and compensatory postural motion (CPM) that counteract the resulting perturbations to body stability. Recent research has shown that these postural actions are also observable in the context of imagined arm movements. As motor imagery (MI) shares many neurophysiological and behavioral characteristics with physical movements, and MI training can affect subsequent performance, MI tasks provide a good setting for studying the anticipatory aspects of postural control. This study investigated APMs and CPMs of the head and hip of healthy young and older adults in the temporal vicinity of physical and imagined forward raises of the dominant and non-dominant arm. When MI of the dominant arm was self-initiated, both age groups showed APM in the anteroposterior plane. When the self-initiated MI was of the non-dominant arm, only the older group showed anteroposterior APM. The older group did not show APM when an expected arm movement (or MI) was made to an external signal. This suggests an age-related deficit in coordinating postural preparation with external events. Only the older group showed mediolateral APM, and only for dominant arm MI, indicating sensitivity to potential perturbation to the weaker, non-dominant side of the body. Overall, the older group showed more anticipatory postural motion at the head. Systematic APM for manual MI suggests that MI training may be an effective intervention for anticipatory postural control. An integrated model of postural support for executed and imagined limb movements is suggested.

Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein-Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases.

Interleukin 17A (IL-17A) is an interleukin cytokine whose dysregulation is implicated in autoimmune disorders such as psoriasis, and monoclonal antibodies against the IL-17A pathway are now well-established and very effective treatments. This article outlines the work that led to the identification of 23 as an oral, small-molecule protein-protein interaction modulator (PPIm) clinical development candidate. Protein crystallography provided knowledge of the key binding interactions between small-molecule ligands and the IL-17A dimer, and this helped in the multiparameter optimization toward identifying an orally bioavailable, Rule of 5 compliant PPIm of IL-17A. Overlap of early ligands led to a series of benzhydrylglycine-containing compounds that allowed the identification of dimethylpyrazole as a key substituent that gave PPIm with oral bioavailability. Exploration of the amino acid portion of the structure then led to dicyclopropylalanine as a group that gave potent and metabolically stable compounds, including the development candidate 23.

Shorter constant work rate cycling tests as proxies for longer tests in highly trained cyclists.

Severe-intensity constant work rate (CWR) cycling tests simulate the high-intensity competition environment and are useful for monitoring training progression and adaptation, yet impose significant physiological and psychological strain, require substantial recovery, and may disrupt athlete training or competition preparation. A brief, minimally fatiguing test providing comparable information is desirable. Purpose To determine whether physiological variables measured during, and functional decline in maximal power output immediately after, a 2-min CWR test can act as a proxy for 4-min test outcomes. Methods Physiological stress ([Formula: see text] kinetics, heart rate, blood lactate concentrations ([La-]b)) was monitored and performance fatigability was estimated (as pre-to-post-CWR changes in 10-s sprint power) during 2- and 4-min CWR tests in 16 high-level cyclists ([Formula: see text] ml∙kg-1∙min-1). The relationship between the 2- and 4-min CWR tests and the physiological variables that best relate to the performance fatigability were investigated. Results The 2-min CWR test evoked a smaller decline in sprint mechanical power (32% vs. 47%, p<0.001). Both the physiological variables (r = 0.66-0.96) and sprint mechanical power (r = 0.67-0.92) were independently and strongly correlated between 2- and 4-min tests. Differences in [Formula: see text] and [La-]b in both CWR tests were strongly associated with the decline in sprint mechanical power. Conclusion Strong correlations between 2- and 4-min severe-intensity CWR test outcomes indicated that the shorter test can be used as a proxy for the longer test. A shorter test may be more practical within the elite performance environment due to lower physiological stress and performance fatigability and should have less impact on subsequent training and competition preparation.

Resonance Raman Vibrational Mode Enhancement of Adsorbed Benzenethiols on CdSe Is Predominantly Franck-Condon in Nature and Governed by Symmetry.

Here, we report mode-specific resonance Raman enhancements of ligands covalently bound to the surface of colloidal CdSe nanocrystals (NCs). By the systematic comparison of a set of structural derivatives, the extent of resonance Raman enhancement is shown to be directly related to the molecular symmetry of the bound ligands. The enhancement dependence on molecular symmetry is further discussed in terms of Franck-Condon and Herzberg-Teller contributions and their associated selection rules. We further show that resonance Raman may be used to distinguish between possible surface binding motifs of bidentate ligands under continuous wave excitation. More generally, this work demonstrates the usefulness of resonance Raman as a characterization tool when characterizing adsorbed molecular species on semiconductor NC surfaces.

Microwave Radiometry at Frequencies From 500 to 1400 MHz: An Emerging Technology for Earth Observations.

Microwave radiometry has provided valuable spaceborne observations of Earth's geophysical properties for decades. The recent SMOS, Aquarius, and SMAP satellites have demonstrated the value of measurements at 1400 MHz for observing surface soil moisture, sea surface salinity, sea ice thickness, soil freeze/thaw state, and other geophysical variables. However, the information obtained is limited by penetration through the subsurface at 1400 MHz and by a reduced sensitivity to surface salinity in cold or wind-roughened waters. Recent airborne experiments have shown the potential of brightness temperature measurements from 500-1400 MHz to address these limitations by enabling sensing of soil moisture and sea ice thickness to greater depths, sensing of temperature deep within ice sheets, improved sensing of sea salinity in cold waters, and enhanced sensitivity to soil moisture under vegetation canopies. However, the absence of significant spectrum reserved for passive microwave measurements in the 500-1400 MHz band requires both an opportunistic sensing strategy and systems for reducing the impact of radio-frequency interference. Here, we summarize the potential advantages and applications of 500-1400 MHz microwave radiometry for Earth observation and review recent experiments and demonstrations of these concepts. We also describe the remaining questions and challenges to be addressed in advancing to future spaceborne operation of this technology along with recommendations for future research activities.

Inter and intra-observer errors for postoperative total hip radiographic assessment using computer aided design.

Plain radiographic assessment of primary total hip arthroplasty following surgery remains to be the commonest radiological assessment. The current paper, studies the accuracy and concordance between observers reviewing these radiographs. A prospective radiographic and medical note review of ten patients who underwent total hip replacement for primary osteoarthritis, with a mean age of 69 years. Early and 6 weeks postoperative x-rays were assessed for hip profile and version profile using computer aided design (CAD) by two observers on two different occasions. The observers were Orthopaedic surgeons who perform arthroplasty of the hip. The results were analyzed statistically. Dimensions, including Femoral offset, medial offset and ilioischial offset showed a high degree of inter- film and intra-film correlation, with inter-class cor- relation (ICC) over 0.8. Except of the intra-film correlation of ilioischial offset measured on the post- operative films (p=0.067) by the first rater, all the intra and inter film correlation were significantly over the benchmark of 0.6. In terms of stem alignment, cup inclination and cup version, the intra-film correlation by rater n°2 ranges from 0.574 to 0.975 and were significantly over the benchmark of 0.6, except in the case of cup inclination measured on the 6 th​ week follow-up ; meanwhile the intra-film correlation by rater n°1 ranges from 0.581 to 0.819 and none were significantly over the benchmark of 0.6. The inter-rater reliability and inter-film correlation showed a dichotomy of results among different dimensions of the measurement. Dimensions of femoral offset, medial offset and ilioischial offset showed a substantial degree of reliability in terms of inter-rater reliability, inter-film correlation, and intra-rater/film reliability.

Quantification of maximal power output in well-trained cyclists.

This study aimed to compare mechanical variables derived from torque-cadence and power-cadence profiles established from different cycle ergometer modes (isoinertial and isokinetic) and modelling procedures (second- and third-order polynomials), whilst employing a novel method to validate the theoretical maximal power output (Pmax). Nineteen well-trained cyclists (n = 12 males) completed two experimental sessions comprising six, 6-s maximal isoinertial or isokinetic cycling sprints. Maximal pedal strokes were extracted to construct power-cadence relationships using second- and third-order polynomials. A 6-s sprint at the optimal cadence (Fopt) or optimal resistance (Topt) was performed to assess construct validity of Pmax. No differences were found in the mechanical parameters when derived from isokinetic (Pmax = 1311 ± 415, Fopt = 118 ± 12) or isoinertial modes (Pmax = 1320 ± 421, Fopt = 116 ± 19). However, R2 improved (P < 0.02) when derived from isoinertial sprints. Third-order polynomial modelling improved goodness of fit values (Standard Error, adjusted R2), but derived similar mechanical parameters. Finally, peak power output during the optimised sprint did not significantly differ from the theoretical Pmax in both cycling modes, thus providing construct validity. The most accurate P-C profile can be derived from isoinertial cycling sprints, modelled using third-order polynomial equations.

Project Gatekeeper: An Entrance Control System Embedded Radiation Detection Capability for Security Applications.

Threat assessments continue to conclude that terrorist groups and individuals as well as those wanting to cause harm to society have the ambition and increasing means to acquire unconventional weapons such as improvised nuclear explosive devices and radiological disposal devices. Such assessments are given credence by public statements of intent by such groups/persons, by reports of attempts to acquire radioactive material and by law enforcement actions which have interdicted, apprehended or prevented attempts to acquire such material. As a mechanism through which to identify radioactive materials being transported on an individual's person, this work sought to develop a detection system that is of lower-cost, reduced form-factor and more covert than existing infrastructure, while maintaining adequate sensitivity and being retrofittable into an industry standard and widely utilised Gunnebo Speed Gate system. The system developed comprised an array of six off-set Geiger-Muller detectors positioned around the gate, alongside a single scintillator detector for spectroscopy, triggered by the systems inbuilt existing IR proximity sensor. This configuration served to not only reduce the cost for such a system but also allowed for source localisation and identification to be performed. Utilising the current setup, it was possible to detect a 1 µSv/h source carried into the Speed Gate in all test scenarios, alongside locating and spectrally analysing the material in a significant number.

Age-related differences in postural adjustments during limb movement and motor imagery in young and older adults.

Recent research has shown that systematic postural adjustments occur during periods of manual motor imagery (MI), but the timing (anticipatory or reactive) and directionality (against or in the direction of arm extension) of these postural motions relative to individual manual actions or imagery are not well understood. This study analyzed the anteroposterior hip and head motion of healthy young and older participants, while they imagined bilateral arm raises under self-initiated or environmentally triggered performance conditions. When MI was self-initiated, both age groups showed significant forward postural motion during the second prior to MI initiation. When MI (or physical arm movement) was environmentally triggered, however, older people did not show anticipatory forward postural motion, but did show compensatory backward head motion. These results suggest that manual MI is indeed accompanied by anticipatory postural motion, but this anticipation is attenuated in older people when they do not have control over the timing of manual movement onset.

Extension of the Notch intracellular domain ankyrin repeat stack by NRARP promotes feedback inhibition of Notch signaling.

Canonical Notch signaling relies on regulated proteolysis of the receptor Notch to generate a nuclear effector that induces the transcription of Notch-responsive genes. In higher organisms, one Notch-responsive gene that is activated in many different cell types encodes the Notch-regulated ankyrin repeat protein (NRARP), which acts as a negative feedback regulator of Notch responses. Here, we showed that NRARP inhibited the growth of Notch-dependent T cell acute lymphoblastic leukemia (T-ALL) cell lines and bound directly to the core Notch transcriptional activation complex (NTC), requiring both the transcription factor RBPJ and the Notch intracellular domain (NICD), but not Mastermind-like proteins or DNA. The crystal structure of an NRARP-NICD1-RBPJ-DNA complex, determined to 3.75 Å resolution, revealed that the assembly of NRARP-NICD1-RBPJ complexes relied on simultaneous engagement of RBPJ and NICD1, with the three ankyrin repeats of NRARP extending the Notch1 ankyrin repeat stack. Mutations at the NRARP-NICD1 interface disrupted entry of the proteins into NTCs and abrogated feedback inhibition in Notch signaling assays in cultured cells. Forced expression of NRARP reduced the abundance of NICD in cells, suggesting that NRARP may promote the degradation of NICD. These studies establish the structural basis for NTC engagement by NRARP and provide insights into a critical negative feedback mechanism that regulates Notch signaling.

Stretch Receptor and Somatic Dysfunction: A Narrative Review.

From its founding by Andrew Taylor Still, MD, DO, through the work of many contributors, one of the cornerstones of osteopathic medicine has been its ability to aid health by promoting neuromuscular homeostasis. As part of the understanding of osteopathic medicine since the time of Still, the proper functioning of stretch receptor organs (SROs) of skeletal muscle have been recognized as having a central role in this homeostasis. In doing so, the complexities of these numerous and vital sensors are described, including recent findings regarding their structure, function, and the nature of their neural connections. In their homeostatic role, SROs conduct information centrally for integration in proprioceptive and autonomic reflexes. By virtue of their integral role in muscle reflexes, they are putatively involved in somatic dysfunction and segmental facilitation. In reviewing some well-established knowledge regarding the SRO and introducing more recent scientific findings, an attempt is made to offer insights on how this knowledge may be applied to better understand somatic dysfunction.

Routine monitoring for heparin-induced thrombocytopenia following lower limb arthroplasty: Is it necessary? A prospective study in a UK district general hospital.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening condition associated with heparin administration. Many orthopaedic units routinely prescribe low-molecular-weight heparins as thromboprophylaxis after hip and knee arthroplasty. HYPOTHESIS: We postulated that routine platelet monitoring following heparin administration is of no clinical benefit. We therefore asked: firstly, what was the rate of thrombocytopenia in a large population of patients undergoing lower limb arthroplasty? Secondly, did this rate justify routine platelet monitoring? MATERIALS AND METHODS: Unless contraindicated, all patients (n=1999, 53.05% female, mean age 69.23 years) at a UK district general hospital undergoing hip and knee arthroplasty were given daily prophylactic enoxaparin. Platelet counts were obtained between the 8th and 10th postoperative days and compared to preoperative baseline. A > 50% fall in platelet count was classified as "possible HIT". The minimal acceptable risk of thrombocytopenia was defined using The American College of Chest Physicians (ACCP) 2012 guidelines, which recommend monitoring platelet counts in patients receiving heparin where the expected risk of HIT is>1% and by descriptive cost-benefit analysis based on the cost of routine platelet monitoring in the clinical setting. RESULTS: Complete results were available for 1361 (68.1%) patients, comprising: 653 primary hips, 22 revision hips, 1 hip resurfacing, 665 primary knees, 19 revision knees and 1 unicompartmental knee replacement. Mean platelet level was 281.9×109/L preoperatively and 527.83×109/L postoperatively. Forty-four patients (3.2%) experienced a postoperative fall in platelet levels. However, no patient experienced a drop in platelets to less than 50% of the preoperative value. DISCUSSION: The incidence of HIT in the elective arthroplasty population is low. Therefore, routine postoperative monitoring of platelets is not necessary in this population of patients. LEVEL OF EVIDENCE: II, prospective study.

Perceptual Errors Support the Notion of Masking by Object Substitution.

Two experiments examined the effect of object substitution masking (OSM) on the perceptual errors in reporting the orientation of a target. In Experiment 1, a four-dot trailing mask was compared with a simultaneous-noise mask. In Experiment 2, the four-dot and noise masks were factorially varied. Responses were modelled using a mixture regression model and Bayesian inference to deduce whether the relative impacts of OSM on guessing and precision were the same as those of a noise mask, and thus whether the mechanism underpinning OSM is based on increasing noise rather than a substitution process. Across both experiments, OSM was associated with an increased guessing rate when the mask trailed target offset and a reduction in the precision of the target representation (although the latter was less reliable across the two experiments). Importantly, the noise mask also influenced both guessing and precision, but in a different manner, suggesting that OSM is not simply caused by increasing noise. In Experiment 2, the effects of OSM and simultaneous-noise interacted, suggesting the two manipulations involve common mechanisms. Overall results suggest that OSM is often a consequence of a substitution process, but there is evidence that the mask increases noise levels on trials where substitution does not occur.