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In search of new opportunities to develop Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) inhibitors that have selectivity over the off-target human PDE4 (hPDE4), different stages of a fragment-growing campaign were studied using a variety of biochemical, structural, thermodynamic, and kinetic binding assays. Remarkable differences in binding kinetics were identified and this kinetic selectivity was explored with computational methods, including molecular dynamics and interaction fingerprint analyses. These studies indicate that a key hydrogen bond between GlnQ.50 and the inhibitors is exposed to a water channel in TbrPDEB1, leading to fast unbinding. This water channel is not present in hPDE4, leading to inhibitors with a longer residence time. The computer-aided drug design protocols were applied to a recently disclosed TbrPDEB1 inhibitor with a different scaffold and our results confirm that shielding this key hydrogen bond through disruption of the water channel represents a viable design strategy to develop more selective inhibitors of TbrPDEB1. Our work shows how computational protocols can be used to understand the contribution of solvent dynamics to inhibitor binding, and our results can be applied in the design of selective inhibitors for homologous PDEs found in related parasites., (© 2024 Wiley‐VCH GmbH.)

Background: Early cardiopulmonary resuscitation and defibrillation is key to increasing survival following an out-of-hospital-cardiac-arrest (OHCA). However, automated external defibrillators (AEDs) are used in a very small percentage of cases. Despite large numbers of AEDs in the community, the absence of a unified system for registering their locations across the UK's ambulance services may have resulted in missed opportunities to save lives. Therefore, representatives from the resuscitation community worked alongside ambulance services to develop a single repository for data on the location of AEDs in the UK., Methods: A national defibrillator network, "The Circuit", was developed by the British Heart Foundation in collaboration with the Association of Ambulance Chief Executives, the UK ambulance services, the Resuscitation Council UK and St John Ambulance. The database allows individuals or organisations to record information about AED location, accessibility, and availability. The database synchronises with ambulance computer aided dispatch systems to provide UK ambulance services with real-time information on the nearest, available AED., Results: The Circuit was successfully rolled out to all 14 UK ambulance services. Since 2019, 82,108 AEDs have been registered. Of the AED data collected by The Circuit, 54% were not previously registered to any ambulance service, and are therefore new registrations., Conclusion: The Circuit provides ambulance services with a single point of access to AED locations in the UK. Since the launch of the system the number of defibrillators registered has doubled. Linking the Circuit data with patient outcome data will help understand whether improving the accessibility to AEDs is associated with increased survival., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Authors listed as affiliated to the BHF are employees of the BHF, a registered charity in England and Wales, Scotland and the Isle of Man. The BHF is the main funder of The Circuit and responsible for its administration. The author listed as affiliated to NHS England (NHSE) is a former employee of NHSE. NHSE is a co-funder of The Circuit. Authors listed as affiliated to the Resuscitation Council UK (RCUK) are employees of the Resuscitation Council UK a registered charity in England and Wales. The RCUK is a co-funder of The Circuit. Authors listed as affiliated to St John Ambulance (SJA) are employees of St John Ambulance a registered charity in England. SJA is a co-funder of The Circuit. Simon Dunn, Steve Irving, Sue Hampshire, Michael Bradfield, Charles Deakin, Simon Holmes, Stephanie Leckey, Nick Linker, Greg Lloyd, Julian Mark, Lisa McInnes, Simon Walsh, George Woods, Judy O’Sullivan and Gavin D Perkins are current or former members of The Circuit National Advisory Board. GDP holds research grants from the BHF, Resuscitation Council UK and the Laerdal Foundation, is a Trustee for the Resuscitation Council UK and Editor for Resuscitation and Resuscitation Plus journals.’., (© 2024 The Authors.)

Background: Youth (ages 12-24) rarely access services and supports to address substance use concerns. Peer support can facilitate service engagement and has been associated with positive substance use recovery outcomes in adults, yet few studies have examined this role among youth specifically. As such, this qualitative study explored the role of peer support in providing substance use services to youth in British Columbia and how best to support them in their role., Methods: Participatory action research methods were used by partnering with youth who had lived/living experience of substance use, including peer support workers, to co-design the research protocol and materials. An initial focus group and subsequent interviews were held with 18 peer support workers who provide services to youth (ages 12-24) based on their own lived experience with mental health and/or substance use. The discussions were audio-recorded, transcribed verbatim, and analysed thematically using an inductive approach., Results: Peer support workers' core experiences providing substance use services to youth centred around supporting youth throughout the whole process. This was accomplished by meeting youth where they are at, providing individualized care, and bridging the gap between other services and supports. However, participants experienced multiple organizational barriers hindering their ability to support youth and stressed the importance of having an employer who understands the work you are doing. This involved having someone advocating for the peer support role to promote collaboration, empowering peers to set boundaries and define their own role, and providing adequate training and mentorship. Finally, peer support workers described how their lived experience bridges connection and de-stigmatization at the individual, organizational, and community level, which was unique to their role., Conclusions: Peer support plays a unique role in youths' substance use journeys, given their own lived experience and flexibility within their role. However, their position is often misunderstood by employers and other service providers, leaving peers with inadequate support, training, and mentorship to do their job. The findings from this study call for improved integration of peer support into service environments, as well as standardized training that is in-depth and continuous., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: In the pathogenesis of inflammatory bowel disease (IBD), the advanced glycation end product receptor (RAGE) has been involved. IBD is classified into Chron's disease (CD) and ulcerative colitis (UC). The promoter gene of the RAGE gene was discovered to have had unique polymorphisms that increased its transcriptional activity. This study, therefore, used a systematic review and meta-analysis to examine the relationship between the RAGE gene polymorphism and the risk of IBD., Methods: Databases such as PubMed, Scopus, and Cochrane library were searched to identify the relationship between RAGE gene polymorphisms and IBD susceptibility. We identified three Single Nucleotide Polymorphism (SNPs) (RAGE-429T/C, 374T/A, and G82S). The data were analyzed by RevMan 5.4., Results: Four studies (932 cases/1366 controls) were included. The findings showed no relationship between RAGE -429T/C and -G82S polymorphisms and the risk of IBD in all genetic models significantly. TT genotype of RAGE -374T/A polymorphisms was related to increased CD risk (OR=1.37; 95%CI=1.04-1.81; P=0.02), while TA genotype was determined to be a protective factor (OR=0.75; 95%CI=0.57-0.99; P=0.04). In UC, A allele of RAGE -374T/A was related to increase risk (OR=1.26; 95%CI=1.04-1.53; P=0.02), while T allele was determined to decrease risk (OR=0.79; 95%CI= 0.65-0.96; P=0.02)., Conclusions: Our findings demonstrated that TT genotype and A allele of RAGE -374T/A polymorphisms were related to CD and UC risks, respectively, while the TA genotype and T allele possibly had a protective effect. RAGE -429T/C and RAGE -G82S polymorphisms were not related to increased IBD risk., Competing Interests: According to the authors, there is no conflict.

The experience of pain has been dissociated into two interwoven aspects: a sensory-discriminative aspect and an affective-motivational aspect. We aimed to explore which of the pain descriptors is more deeply rooted in the human brain. Participants were asked to evaluate applied cold pain. The majority of the trials showed distinct ratings: some were rated higher for unpleasantness and others for intensity. We compared the relationship between functional data recorded from 7 T MRI with unpleasantness and intensity ratings and revealed a stronger relationship between cortical data and unpleasantness ratings. The present study underlines the importance of the emotional-affective aspects of pain-related cortical processes in the brain. The findings corroborate previous studies showing a higher sensitivity to pain unpleasantness compared to ratings of pain intensity. For the processing of pain in healthy subjects, this effect may reflect the more direct and intuitive evaluation of emotional aspects of the pain system, which is to prevent harm and to preserve the physical integrity of the body., (© 2023. The Author(s).)

Wetted-foam layers are of significant interest for inertial-confinement-fusion capsules, due to the control they provide over the convergence ratio of the implosion and the opportunity this affords to minimize hydrodynamic instability growth. However, the equation of state for fusion-relevant foams are not well characterized, and many simulations rely on modeling such foams as a homogeneous medium with the foam average density. To address this issue, an experiment was performed using the VULCAN Nd:glass laser at the Central Laser Facility. The aim was to measure the principal Hugoniot of TMPTA plastic foams at 260mg/cm^{3}, corresponding to the density of liquid DT-wetted-foam layers, and their "hydrodynamic equivalent" capsules. A VISAR was used to obtain the shock velocity of both the foam and an α-quartz reference layer, while streaked optical pyrometry provided the temperature of the shocked material. The measurements confirm that, for the 20-120 GPa pressure range accessed, this material can indeed be well described using the equation of state of the homogeneous medium at the foam density.

The suprachiasmatic nucleus (SCN) is the most important circadian clock in mammals. The SCN synchronizes to environmental light via the retinohypothalamic tract (RHT), which is an axon cluster derived from melanopsin-expressing intrinsic photosensitive retinal ganglion cells. Investigations on the development of the nonimage-forming pathway and the RHT are scarce. Previous studies imply that light stimulation during postnatal development is not needed to make the RHT functional at adult stages. Here, we examined the effects of light deprivation (i.e., constant darkness (DD) rearing) during postnatal development on the expression in the ventral SCN of two crucial proteins for the synchronization of circadian rhythms to light: the presynaptic vesicular glutamate transporter type 2 (vGluT2) and the GluN2B subunit of the postsynaptic NMDA receptor. We found that animals submitted to DD conditions exhibited a transitory reduction in the expression of vGluT2 (at P12-19) and of GluN2B (at P7-9) that was compensated at older stages. These findings support the hypothesis that visual stimulation during early ages is not decisive for normal development of the RHT-SCN pathway., (© 2022 Wiley Periodicals LLC.)

The COVID-19 pandemic has led to a rapid escalation in use of home monitoring and video consultations in children with a variety of chronic respiratory conditions. Our department set up a home spirometry service from scratch once it became evident that we needed to keep patients away from hospital clinics whenever possible. We faced a number of challenges but now have around 400 children using home spirometers. There are a number of portable spirometers available, some with online platforms. The technology, particularly the software/apps interface, has been improved by the companies in response to issues that have arisen. We believe the use of home monitoring is here to stay., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Substance use among youth (ages 12-24) is troublesome given the increasing risk of harms associated. Even more so, substance use services are largely underutilized among youth, most only accessing support when in crisis. Few studies have explored young people's help-seeking behaviours to address substance use concerns. To address this gap, this study explored how youth perceive and experience substance use services in British Columbia (BC), Canada., Methods: Participatory action research methods were used by partnering with BC youth (under the age of 30) from across the province who have lived and/or living experience of substance use to co-design the research protocol and materials. An initial focus group and interviews were held with 30 youth (ages 12-24) with lived and/or living experience of substance use, including alcohol, cannabis, and illicit substances. The discussions were audio-recorded, transcribed verbatim, and analyzed thematically using a data-driven approach., Results: Three main themes were identified and separated by phase of service interaction, starting with: Prevention/Early intervention, where youth described feeling unworthy of support; Service accessibility, where youth encountered many barriers finding relevant substance use services and information; and Service delivery, where youth highlighted the importance of meeting them where they are at, including supporting those who have milder treatment needs and/or do not meet the diagnosis criteria of a substance use disorder., Conclusions: Our results suggest a clear need to prioritize substance use prevention and early interventions specifically targeting youth and young adults. Youth and peers with lived and/or living experience should be involved in co-designing and co-delivering such programs to ensure their relevance and credibility among youth. The current disease model of care leaves many of the needs of this population unmet, calling for a more integrated youth-centred approach to address the multifarious concerns linked to young people's substance use and service outcomes and experiences., (© 2022. The Author(s).)

Curvilinearity, as calculated from multiple-breath washout, is abnormal in a small number of children with cystic fibrosis when other tests are still normal https://bit.ly/3p9QAV4., Competing Interests: Conflict of interest: S. Irving has nothing to disclose. Conflict of interest: K. Bayfield has nothing to disclose. Conflict of interest: J.C. Davies has nothing to disclose. Conflict of interest: A. Bush has nothing to disclose., (Copyright ©The authors 2022.)

Shalon Irving's 2017 death brought national attention to maternal mortality among Black women in the US. This essay remembers her life and legacy.

Background: Adding a slow vital capacity (SVC) to multiple breath washout (MBW) allows quantification of otherwise overlooked signal from under/un-ventilated lung units (UVLU) and may provide a more comprehensive assessment of airway disease than conventional lung clearance index (LCI 2.5 )., Methods: We conducted a pilot study on people undergoing MBW tests: 10 healthy controls (HC) and 43 cystic fibrosis (CF) subjects performed an SVC after the standard end of test. We term the new outcome LCI with Short extension (LCI ShX ). We assessed (i) CF/ HC differences, (ii) variability (iii) effect of pulmonary exacerbation (PEx)/treatment and (iv) relationship with CF computed tomography (CFCT) scores., Results: HC/ CF group differences were larger with LCI ShX than LCI 2.5 (P<0.001). Within the CF group UVLU was highly variable and when abnormal it did not correlate with corresponding LCI 2.5 . Signal showed little variability during clinical stability (n = 11 CF; 2 visits; median inter-test variability 2.6% LCI ShX, 2.5% LCI 2.5 ). PEx signal was significantly greater for LCI ShX both for onset and resolution. Both MBW parameters correlated significantly with total lung CT scores and hyperinflation but only LCI ShX correlated with mucus plugging., Conclusions: UVLU captured within the LCI ShX varies between individuals; the lack of relationship with LCI 2.5 demonstrates that new, additional information is being captured. LCI ShX repeatability during clinical stability combined with its larger signal around episodes of PEx may lend it superior sensitivity as an outcome measure. Further studies will build on this pilot data to fully establish its utility in monitoring disease status., Competing Interests: Declaration of Competing Interest Christopher Short, Clare Saunders, Dominic Hughes, Samantha Irving, Laura Gardener, Mark Rosenthal and Paul Robinson report no conflicts of interest. Thomas Semple reports speakers fees - Vertex Pharmaceuticals. Research grants – Chiesi Pharmaceuticals. Consultancy fees - Boehringer-Ingelheim and Calyx. Prof. Jane Davies has performed clinical trial leadership roles, educational and/ or advisory activities for the following: Abbvie, Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Eloxx, Enterprise, Galapagos NV, ImevaX GmbH, Ionis, Nivalis Therapeutics, Inc., Novartis, ProQR Therapeutics III B.V., Proteostasis Therapeutics, INC., Pulmocide Raptor Pharmaceuticals, Inc, Vertex Pharmaceuticals., (Copyright © 2021. Published by Elsevier B.V.)

Analyses of intrinsic network activity have been instrumental in revealing cortical processes that are altered in chronic pain patients. In a novel approach, we aimed to elucidate how intrinsic functional networks evolve in regard to the fluctuating intensity of the experience of chronic pain. In a longitudinal study with 156 fMRI sessions, 20 chronic back pain patients and 20 chronic migraine patients were asked to continuously rate the intensity of their endogenous pain. We investigated the relationship between the fluctuation of intrinsic network activity with the time course of subjective pain ratings. For chronic back pain, we found increased cortical network activity for the salience network and a local pontine network, as well as decreased network activity in the anterior and posterior default mode network for higher pain intensities. Higher pain intensities in chronic migraine were accompanied with lower activity in a prefrontal cortical network. By taking the perspective of the individual, we focused on the variability of the subjective perception of pain, which include phases of relatively low pain and phases of relatively high pain. The present design of the assessment of ongoing endogenous pain can be a powerful and promising tool to assess the signature of a patient's endogenous pain encoding., (© 2021. The Author(s).)

Purpose: PCNL requires a lithotrite to efficiently break stones, and some devices include active suction to remove the fragments. We set out to determine the efficacy and safety of the Swiss LithoClast® Trilogy, in a prospective European multicentre evaluation and compared it to published stone clearance rates for Trilogy based on surface area (68.9 mm 2 /min) and using the 3D calculated stone volume (526.7 mm 3 /min)., Methods: Ten European centres participated in this prospective non-randomized study of Trilogy for PCNL. Objective measures of stone clearance rate, device malfunction, complications and stone-free rates were assessed. Each surgeon subjectively evaluated ergonomic and device effectiveness, on a 1-10 scale (10 = extremely ergonomic/effective) and compared to their usual lithotrite on a 1-10 scale (10 = extremely effective)., Results: One hundred and fifty seven PCNLs using Trilogy were included (53% male, 47% female; mean age 55 years, range 13-84 years). Mean stone clearance rate was 65.55 mm 2 /min or 945 mm 3 /min based on calculated 3D volume. Stone-free rate on fluoroscopy screening at the end of the procedure was 83%. Feedback for suction effectiveness was 9.0 with 9.1 for combination and 9.0 for overall effectiveness compared to lithotrite used previously. Ergonomic score was 8.1, the least satisfactory element. Complications included 13 (8.2%) Clavien-Dindo Grade II and 2 (1.3%) Grade III. Probe breakage was seen in 9 (5.7%), none required using a different lithotrite., Conclusions: We have demonstrated that Trilogy is highly effective at stone removal. From a user perspective, the device was perceived by surgeons to be highly effective overall and compared to the most commonly used previous lithotrite, with an excellent safety profile., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To examine the efficacy of "slow" signs and patroller presence at "slow" signs to reduce speeds of snowsports participants, compared to a condition where no sign or patroller are present, independent of other factors that may contribute to skier slowing (such as prior knowledge, trail convergence, etc.)., Design and Methods: Snowsports participant speeds were measured on "more difficult" trails using a radar gun at two ski areas with: (1) no-sign - the usual condition for the trail, and (2) slow-sign - a large "slow" sign was posted in the middle of the trail. At one ski area, a third condition was also tested: (3) slow+patroller - a ski patroller stood at the slow sign. Participant equipment type and estimated ability were also recorded., Results: At one ski area, there was no significant difference in speed between conditions. At the second ski area, the differences in mean (SD) speeds were small but significant for the no-sign, slow-sign, and slow+patroller conditions: 10.9 (3.0), 10.3 (2.9), and 9.8 (2.6)m/s. Effects were driven by non-beginner skiers; on average, beginner skiers and all snowboarders were slower than non-beginner skiers and did not adjust their speed in response to the signage conditions., Conclusions: Reductions in speed for the slow-sign and slow+patroller conditions compared to the no-sign condition were small (0.5 and 1.1m/s) compared to the variation in chosen skier speed reported in other studies. The small differences in chosen speeds make it unlikely that slow sign and patroller presence alone would produce meaningful reductions in collision likelihood or severity of impacts., (Copyright © 2020. Published by Elsevier Ltd.)

Objectives: The injury mitigation capabilities of foam, ski-area padding was examined for headfirst impacts., Design and Methods: A custom-made pendulum impactor system was constructed using an instrumented, partial 50th-percentile-male Hybrid-III anthropomorphic testing device (ATD). For each test, the ATD was raised 1.0m, released, and swung into a 20-cm diameter wooden pole. Test trials were conducted with the wooden pole covered by ski area padding (five conditions of various foam types and thicknesses) or unpadded. Linear (linear acceleration and HIC 15 ) and angular (angular velocity, angular acceleration, and BrIC) kinematics were examined and used to estimate the likelihood of severe brain injury. Cervical spine loads were compared to the injury assessment reference values for serious injury. Further tests were conducted to examine the changes produced by the addition of a snowsport helmet., Results: 38 test trials were recorded with a mean (±sd) impact speed of 4.2 (±0.03) m/s. Head, resultant linear acceleration, HIC 15 , and associated injury likelihoods were tempered by ski area padding at the impact speed tested. Ski area padding did not reduce brain injury likelihood from rotational kinematics (p>0.05 for all comparisons) or reduce the cervical spine compression below injury assessment reference values. The addition of a helmet did not reduce significantly the likelihoods of brain or cervical spine injury., Conclusions: At the impact speed tested, ski area padding provided limited impact protection for the head (for linear kinematics) but did not protect against severe brain injuries due to rotational kinematics or serious cervical spine injuries., (Copyright © 2020 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Objectives: Develop a method to examine the effects of component geometry and force-deflection on the release process of Tech/Pin alpine touring (AT) ski boots and bindings., Design and Methods: For seven AT boots, we measured the critical geometric dimensions of the metal inserts at the toe region of the boots. Binding geometry (including the pins and rocker arms) and the force-angular deflection curves of typical AT bindings were measured. A kinematic model was derived to predict the contact force between the metal inserts of the AT boots and the pins of the AT bindings, dependent on angular displacement of the binding rocker arms. By combining the kinematic model, the force-angular deflection curves, and moment equilibrium, we determined the force and binding rotation angle needed to release the AT boot in a direction normal to the ski., Results: The metal AT boot insert geometry and AT binding pin geometry and dimensions can affect significantly the contact states and kinematics of release. Two load-deflection curves of similar peak loads can result in significantly different maximal forces and angles to release the binding, even when the geometry and dimensions of the binding pins and boot inserts remain unchanged., Conclusions: The geometry and dimensions of the binding (pins and rocker arm) and the boot inserts define the kinematics of the binding release. The model can be used to test the effects of varying parameters on the release and retention characteristics of Tech/Pin boot-binding systems to optimize the release and retention characteristics., (Copyright © 2020 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Children with severe asthma may be treated with biologic agents normally requiring 2-4 weekly injections in hospital. In March 2020, due to COVID-19, we needed to minimise hospital visits. We assessed whether biologics could be given safely at home. The multidisciplinary team identified children to be considered for home administration. This was virtually observed using a video link, and home spirometry was also performed. Feedback was obtained from carers and young people. Of 23 patients receiving biologics, 16 (70%) families agreed to homecare administration, 14 administered by parents/patients and 2 by a local nursing team. Video calls for omalizumab were observed on 56 occasions, mepolizumab on 19 occasions over 4 months (April-July). Medication was administered inaccurately on 2/75 occasions without any adverse events. Virtually observed home biologic administration in severe asthmatic children, supported by video calls and home spirometry, is feasible, safe and is positively perceived by children and their families., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The past two decades have seen a particular focus towards high-frequency neural activity in the gamma band (>30 Hz). However, gamma band activity shares frequency range with unwanted artefacts from muscular activity., New Method: We developed a novel approach to remove muscle artefacts from neurophysiological data. We re-analysed existing EEG data that were decomposed by a blind source separation method (independent component analysis, ICA), which helped to better spatially and temporally separate single muscle spikes. We then applied an adapting algorithm that detects these singled-out muscle spikes., Results: We obtained data almost free from muscle artefacts; we needed to remove significantly fewer artefact components from the ICA and we included more trials for the statistical analysis compared to standard ICA artefact removal. All pain-related cortical effects in the gamma band have been preserved, which underlines the high efficacy and precision of this algorithm., Conclusions: Our results show a significant improvement of data quality by preserving task-relevant gamma oscillations of presumed cortical origin. We were able to precisely detect, gauge, and carve out single muscle spikes from the time course of neurophysiological measures without perturbing cortical gamma. We advocate the application of the tool for studies investigating gamma activity that contain a rather low number of trials, as well as for data that are highly contaminated with muscle artefacts. This validation of our tool allows for the application on event-free continuous EEG, for which the artefact removal is more challenging., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Point-of-care ultrasound is becoming a ubiquitous diagnostic tool, and there has been increasing interest to teach novice practitioners. One of the challenges is the scarcity of qualified instructors, and with COVID-19, another challenge is the difficulty with social distancing between learners and educators. The purpose of our study was to determine if ultrasound-naïve operators can learn ultrasound techniques and develop the psychomotor skills to acquire ultrasound images after reviewing SonoSim® online modules., Methods: This was a prospective study evaluating first-year medical students. Medical students were asked to complete four SonoSim® online modules (aorta/IVC, cardiac, renal, and superficial). They were subsequently asked to perform ultrasound examinations on standardized patients utilizing the learned techniques/skills in the online modules. Emergency Ultrasound-trained physicians evaluated medical students' sonographic skills in image acquisition quality, image acquisition difficulty, and overall performance. Data are presented as means and percentages with standard deviation. All P values are based on 2-tailed tests of significance., Results: Total of 44 medical students participated in the study. All (100%) students completed the hands-on skills evaluation with a median score of 83.7% (IQR 76.7-88.4%). Thirty-three medical students completed all the online modules and quizzes with median score of 87.5% (IQR 83.8-91.3%). There was a positive association between module quiz performance and the hands-on skills performance (R-squared = 0.45; p < 0.001). There was no statistically significant association between module performance and hands-on performance for any of the four categories individually. In all four categories, the evaluators' observation of the medical students' difficulty obtaining views correlated with hands-on performance scores., Conclusions: Our study findings suggest that ultrasound-naïve medical students can develop basic hands-on skills in image acquisition after reviewing online modules.

Migraine is a complex neurological disorder affecting approximately 12% of the population. The pathophysiology is not yet fully understood, however the clinical features of the disease, such as the cyclic behaviour of attacks and vegetative symptoms, suggest a prominent role of the hypothalamus. Previous research has observed neuronal alterations at different time points during the migraine interval, specifically just before the headache is initiated. We therefore aimed to assess the trajectory of migraineurs' brain activity over an entire migraine cycle. Using functional magnetic resonance imaging (fMRI) with pseudo-continuous arterial spin labelling (ASL), we designed a longitudinal intra-individual study to detect the rhythmicity of (1) the cerebral perfusion and (2) the hypothalamic connectivity over an entire migraine cycle. Twelve episodic migraine patients were examined in 82 sessions during spontaneous headache attacks with follow-up recordings towards the next attack. We detected cyclic changes of brain perfusion in the limbic circuit (insula and nucleus accumbens), with the highest perfusion during the headache attack. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval towards the attack, then collapsing during the headache phase. The present data provide strong evidence for the predominant role of the hypothalamus in generating migraine attacks. Due to a genetically-determined cortical hyperexcitability, migraineurs are most likely characterised by an increased susceptibility of limbic neurons to the known migraine trigger. The hypothalamus as a metronome of internal processes is suggested to control these limbic circuits: migraine attacks may occur as a result of the hypothalamus losing control over the limbic system. Repetitive psychosocial stress, one of the leading trigger factors reported by patients, might make the limbic system even more vulnerable and lead to a premature triggering of a migraine attack. Potential therapeutic interventions are therefore suggested to strengthen limbic circuits with dedicated medication or psychological approaches., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Specialist tactical response police are required to frequently perform physically demanding tasks at high-risk capability levels, emphasizing the need for optimal physical fitness in this population. The aim of this study was to investigate the relationships between select measures of physical fitness and performance on an occupational-specific physical assessment (OSPA). A retrospective analysis on 18 male specialist police candidates (age = 32.1 ± 5.04 yrs; height = 183.72 ± 5.79 cm; body mass = 89.44 ± 8.56 kg; body mass index (BMI) = 26.45 ± 1.58 kg/m 2 ) was conducted. Data were comprised of anthropometric measures, assorted fitness measures and OSPA performance scores. A stepwise linear regression determined the influence of measured fitness parameters on OSPA performance. A regression featuring both the 1 RM military shoulder press and grip strength of the non-dominant hand was the most significant predictor of performance (adjusted r 2 = 0.565, p = 0.001). A separate model, exclusively using the 1 RM military shoulder press additionally predicted OSPA performance (adjusted r 2 = 0.240, p = 0.023). These results emphasize the importance of optimal upper-limb muscular strength and its impact on key occupational tasks in specialist police candidates.

Protein arginine methyltransferase 5 (PRMT5) is an enzyme that can symmetrically dimethylate arginine residues in histones and nonhistone proteins by using S -adenosyl methionine (SAM) as the methyl donating cofactor. We have designed a library of SAM analogues and discovered potent, cell-active, and selective spiro diamines as inhibitors of the enzymatic function of PRMT5. Crystallographic studies confirmed a very interesting binding mode, involving protein flexibility, where both the cofactor pocket and part of substrate binding site are occupied by these inhibitors., Competing Interests: The authors declare no competing financial interest.

We investigated how the attenuation of pain with cognitive interventions affects brain connectivity using neuroimaging and a whole brain novel analysis approach. While receiving tonic cold pain, 20 healthy participants performed three different pain attenuation strategies during simultaneous collection of functional imaging data at seven tesla. Participants were asked to rate their pain after each trial. We related the trial-by-trial variability of the attenuation performance to the trial-by-trial functional connectivity strength change of brain data. Across all conditions, we found that a higher performance of pain attenuation was predominantly associated with higher functional connectivity. Of note, we observed an association between low pain and high connectivity for regions that belong to brain regions long associated with pain processing, the insular and cingulate cortices. For one of the cognitive strategies (safe place), the performance of pain attenuation was explained by diffusion tensor imaging metrics of increased white matter integrity., Competing Interests: ES, AS, AW, SI, VW, IT No competing interests declared

Rationale: We have previously shown that in rats, capsaicin (Cap) has antidepressant-like properties when assessed using the forced swimming test (FST) and that a sub-threshold dose of amitriptyline potentiates the effects of Cap. However, synergistic antidepressant-like effects of the joint administration of Cap and the selective serotonin reuptake inhibitor citalopram (Cit) have not been reported., Objectives: To assess whether combined administration of Cap and Cit has synergistic effects in the FST and to determine whether this combination prevents the side effects of Cit., Methods: Cap, Cit, and the co-administration of both substances were evaluated in a modified version of the FST (30-cm water depth) conducted in rats, as well as in the open field test (OFT), elevated plus maze (EPM), and Morris water maze (MWM)., Results: In line with previous studies, independent administration of Cap and Cit displayed antidepressant-like properties in the FST, while the combined injection had synergistic effects. In the OFT, neither treatment caused significant increments in locomotion. In the EPM, the time spent in the closed arms was lower in groups administered either only Cap or a combination of Cap and Cit than in groups treated with Cit alone. In the MWM, both Cap and the joint treatment (Cap and Cit) improved the working memory of rats in comparison with animals treated only with Cit., Conclusion: Combined administration of Cap and Cit produces a synergistic antidepressant-like effect in the FST and reduces the detrimental effects of Cit on anxiety and working memory.

Introduction: Lung clearance index (LCI) is a measure of airway disease that has been shown to be abnormal in asthma. We hypothesized that LCI would be higher (worse) in children with severe therapy-resistant asthma (STRA) compared with difficult asthma (DA) and healthy controls and that LCI would fall in response to parenteral steroids in STRA., Methods: Sixty-four children with asthma who were prescribed high-dose asthma therapy (GINA steps 4 or 5) performed LCI and spirometry. Forty-three had STRA and 21 DA. Thirty-nine of forty-three STRA patients attended for a clinically indicated bronchoscopy during which an intramuscular injection of triamcinolone was given. LCI, spirometry, and fractional exhaled nitric oxide (FeNO) were performed on the day of the bronchoscopy and repeated 4 weeks later., Results: LCI was more abnormal in STRA (median: 7.40, range: 5.58-12.34) than in DA (6.55, 5.77-7.75), P = .0006, and healthy controls (6.53, 5.57-7.35), P = .005. In contrast to the first second forced expired volume (FEV 1 ), LCI improved following systemic steroids; of 20 STRA patients with an abnormal LCI at baseline, 13 improved following triamcinolone. LCI and FeNO responses were concordant., Conclusions: There is a subgroup of children with STRA in whom LCI is elevated who improve following parenteral steroids. LCI may be a valuable additional domain in assessing steroid response in pediatric asthma., (© 2020 Wiley Periodicals, Inc.)

Addressing concerns with use of the Exhalyzer D multiple breath washout device http://bit.ly/2ug0fAi., Competing Interests: Conflict of interest: K.J. Bayfield has nothing to disclose. Conflict of interest: E. Alton has nothing to disclose. Conflict of interest: S. Irving has nothing to disclose. Conflict of interest: A. Bush has nothing to disclose. Conflict of interest: J.C. Davies reports grants from the European Cystic Fibrosis Clinical Trials Network and personal fees from pharmaceutical advisory boards during the conduct of the study., (Copyright ©ERS 2020.)

Objectives: To determine the feasibility of integrating pre-intubation ultrasound into airway course and assess emergency medicine (EM) residents' confidence and comfort level in using ultrasound for pre-intubation hemodynamic stabilization and identifying cricothyroid membrane after the training session., Materials and Methods: This is a retrospective study. Pre-intubation ultrasound training was delivered with the following ultrasound components (didactics and hands-on sessions using human models) to EM residents: (1) sonoanatomy and scanning technique to identify cricothyroid membrane and (2) pre-intubation echocardiography for recognition of acute right ventricular failure and pre-intubation hemodynamic stabilization., Results: A total of 56 EM residents participated in this study. Only 21% [95% confidence interval (CI), 10-31%] reported using ultrasound for pre-intubation hemodynamic stabilization. After the training session, 89% (95% CI, 81-97%) reported that ultrasound-based teaching increased their knowledge of pre-intubation hemodynamic stabilization compared with traditional teaching methods. On a scale of 1 (low) through 10 (high), the average comfort level for integrating ultrasound findings into medical decision making for pre-intubation hemodynamic stabilization was 6.8 (95% CI, 6.3-7.3). Seventy-nine percent (95% CI, 68-89%) reported that focused training in airway ultrasound is adequate to identify cricothyroid membrane. On a scale of 1 (low) through 10 (high), the average confidence level for identifying cricothyroid membrane using ultrasound was 6.6 (95% CI, 6.1-7.1)., Conclusion: At our institution, we successfully integrated pre-intubation ultrasound into an airway course. Emergency medicine residents had a moderate level of comfort and confidence level using ultrasound for pre-intubation hemodynamic stabilization and identifying cricothyroid membrane after the training session., How to Cite This Article: Adhikari S, Situ-LaCasse E, Acuña J, Irving S, Weaver C, Samsel K, et al. Integration of Pre-intubation Ultrasound into Airway Management Course: A Novel Training Program. Indian J Crit Care Med 2020;24(3):179-183., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2020; Jaypee Brothers Medical Publishers (P) Ltd.)

Objective: To distinguish between patients with amyloid-positive (A+) and -negative (A-) amnestic mild cognitive impairment (aMCI) by simultaneously investigating navigation performance, visual exploration behavior, and brain activations during a real-space navigation paradigm., Methods: Twenty-one patients with aMCI were grouped into A+ (n = 11) and A- cases by amyloid-PET imaging and amyloid CSF levels and compared to 15 healthy controls. Neuropsychological deficits were quantified by use of the Consortium to Establish a Registry for Alzheimer's Disease-plus cognitive battery. All participants performed a navigation task in which they had to find items in a realistic spatial environment and had to apply egocentric and allocentric route planning strategies. 18 F-fluorodeoxyglucose was injected at the start to detect navigation-induced brain activations. Subjects wore a gaze-controlled, head-fixed camera that recorded their visual exploration behavior., Results: A+ patients performed worse during egocentric and allocentric navigation compared to A- patients and controls ( p < 0.001). Both aMCI subgroups used fewer shortcuts, moved more slowly, and stayed longer at crossings. Word-list learning, figural learning, and Trail-Making tests did not differ in the A+ and A- subgroups. A+ patients showed a reduced activation of the right hippocampus, retrosplenial, and parietal cortex during navigation compared to A- patients ( p < 0.005)., Conclusions: A+ patients with aMCI perform worse than A- patients with aMCI in egocentric and allocentric route planning because of a more widespread impairment of their cerebral navigation network. Navigation testing in real space is a promising approach to identify patients with aMCI with underlying Alzheimer pathology., (© 2020 American Academy of Neurology.)

Multiple-breath washout (MBW) can be performed with different gases (sulfur hexafluoride (SF 6- ) and nitrogen (N 2 )) and different devices, all of which give discrepant results. This study aimed to confirm previously reported differences and explore factors influencing discrepant results; equipment factors or the physical properties of gases used., Methods: Healthy controls (HCs) and participants with cystic fibrosis (CF) completed MBW trials on two commercially available devices (Exhalyzer D (N 2 ) and Innocor (SF 6 )). Simultaneous washout of both gases at the same time on the commercial equipment and simultaneous washouts using a respiratory mass spectrometer (RMS) were completed in subsets. Primary outcomes were lung clearance index (LCI), breath number and time required to washout., Results: Breath number was higher with N 2 washout than SF 6 in both HCs and patients with CF, whether washouts were completed individually or simultaneously. The difference was greater in more advanced disease, largely caused by differences in the final part of the washout. Results from commercial devices were similar to those obtained with the RMS., Conclusions: N 2 MBW results were higher than SF 6 MBW, with some of the largest differences reported to date being observed. The biggest impact was at the end of the washout and this was even the case when gases were washed out simultaneously. N 2 and SF 6 MBW results are inherently different and should be considered as independent measurements., Competing Interests: Conflict of interest: K.J. Bayfield has nothing to disclose. Conflict of interest: A. Horsley reports personal fees from pharmaceutical advisory boards during the conduct of the study. Conflict of interest: E. Alton has nothing to disclose. Conflict of interest: S. Irving has nothing to disclose. Conflict of interest: A. Bush has nothing to disclose. Conflict of interest: J.C. Davies reports grants from the European Cystic Fibrosis Clinical Trials Network and personal fees from pharmaceutical advisory boards, during the conduct of the study., (Copyright ©ERS 2019.)

Officers serving in specialist tactical response police teams are highly trained personnel who are required to carry heavy loads and perform explosive tasks. The aim of this study was to determine whether performance on a loaded explosive occupational task (urban rush) or distance-based load carriage tasks (2.4 km or 10 km) were indicative of officer success on a specialist selection course (SSC). Eighteen male police officers (mean age = 32.11 ± 5.04 years) participated in the SSC over five consecutive days. Data were categorized into Group 1 (successful applicants, n = 11) and Group 2 (unsuccessful applicants, n = 7). Independent sample t -tests were performed to determine differences between groups, along with point-biserial correlations to investigate associations between anthropometric and event performance data and course completion success. Alpha levels were set at p = 0.05 a priori. Height ( p = 0.025), body weight ( p = 0.007), and 2.4 km loaded performance ( p = 0.013) were significantly different between groups, where being shorter (r pb (16) = -0.526, p < 0.05), lighter (r pb (16) = -0.615, p < 0.01), and faster (r pb (16) = -0.572, p < 0.05) were associated with course success. While a loaded 2.4 km event is associated with success, a ceiling effect for an explosive anaerobic task and a longer 10 km task may exist, whereby increases in performance are not associated with selection success.

One of the biggest challenges faced by healthcare providers is the treatment of chronic, non-healing wounds. This paper reports for the first time in the UK the results of five case studies in which a novel regenerating matrix-based therapy, CACIPLIQ20, was used. CACIPLIQ20 is a heparan sulphate mimetic designed to replace the destroyed heparan sulphate in the extracellular matrix of wound cells. All five patients in this case series had chronic, non-healing ulcers that had not improved with conventional care. Treatment included two applications of CACIPLIQ20 per week, for a maximum of 12 weeks. Three of the five wounds healed completely, and the remaining two showed significant improvements in size and quality. The treatment was well tolerated by the patients and also led to a significant reduction in pain. Moreover, CACIPLIQ20 treatment was found to be highly cost-effective when compared to conventional care, with the potential to save healthcare systems significant resources. Further studies are needed to build a strong evidence base on the use of this product, but these preliminary findings are certainly promising.

Objective: Pharmacokinetic and efficacy data from a phase 3 testosterone nasal gel (TNG) study were stratified by baseline endogenous testosterone level in patients with testosterone deficiency. Total testosterone (TT), LH, and FSH levels, as well as erectile function, mood, and lean body mass for each group were compared. In a subset of patients with very low baseline endogenous testosterone levels (<100 ng/dL), we investigated whether TNG is a suitable treatment option., Materials and Methods: Patients with testosterone deficiency (serum TT <300 ng/dL) were treated with TNG for 3 months, followed by safety extension periods of 90 and/or 180 days. Pharmacokinetic parameters were calculated from serum hormone levels on days 30 and 90, along with efficacy measurements, which were analyzed by comparison with baseline values. Baseline and/or predose TT values were used for patient stratification., Results: Prestudy and predose endogenous testosterone concentrations correlated. The maximal concentration of TT was nearly identical across all cohorts at days 30 and 90, whereas the average concentration over 24 hours had a slight positive dependence relative to predose levels. LH levels remained in the normal range but were decreased more in patients with higher starting baseline levels. These findings indicate that TNG works with an active hypothalamic-pituitary-gonadal axis that responds to each dose of TNG throughout the treatment period. Patients with the lowest endogenous testosterone levels received maximum exposure impact from each TNG dose. Patients with severe testosterone deficiency had similar efficacy improvements as the remainder of the study population., Conclusion: All testosterone-deficient cohorts were successfully treated with TNG.

Background: While considerable progress is being made to understand the health and self-management needs of youth with mental health disorders, little attention has focused on the mental health and recovery needs that the youth themselves identify-this despite a national priority to incorporate patient-oriented research into the development and assessment of mental health services. To address this gap, estimates of the extent to which existing patient-reported outcome measures (PROMs)-originally developed for use amongst adult populations-are clinically meaningful and psychometrically fit for use among youth are needed. In tandem, a recovery profile for youth can be constructed incorporating the youth perspective of the services provided within a community mental health setting., Methods/design: This study will utilize a mixed methods design incorporating qualitative focus group interviews and cross-sectional survey. Our process will begin with the hiring of a youth peer research partner who will provide lived experience expertise through all phases of the study. We will advertise, recruit, and conduct four focus groups with youth who receive services from the Foundry Vancouver Granville located in British Columbia, Canada. In the first two focus groups, we will recruit youth aged 15-18 years (n = 10). In the second two focus groups, we will recruit young adults aged 19-24 years (n = 10). In parallel, we will conduct a cross-sectional survey of the recovery and mental health needs of youth, informed by ten widely used and validated PROM. Thematic analysis techniques will guide the identification of predominant thematic trends in the qualitative focus group data. We will use Classical and Rasch measurement methods to test and analyze the reliability and validity of selected PROM measures for youth populations., Discussion: The proposed study has the potential to produce a preliminary conceptual and measurement model for understanding the mental health and recovery needs of youth with mental health disorders. This evidence will inform how youth mental health services can grow, support, and sustain the capacity for a collaborative, interdisciplinary and innovative patient-oriented research environment. Findings will also contribute much needed evidence to improve the standard of care for youth who experience mental health disorders in Canada and beyond.

Objective: To investigate long-term recovery of allocentric and egocentric spatial orientation as a sensitive marker for hippocampal and extrahippocampal network function in transient global amnesia (TGA)., Methods: A group of 18 patients with TGA performed an established real-space navigation paradigm, requiring allo- and egocentric spatial orientation abilities, 3 days (postacute stage) and 3 months (follow-up) after symptom onset. Visual exploration behavior and navigation strategy were documented by a gaze-controlled, head-fixed camera. Allo- and egocentric spatial orientation performance was compared to that of 12 age-matched healthy controls. Navigation-induced brain activations were measured using [ 18 F]-fluorodeoxyglucose-PET in a subgroup of 8 patients in the postacute stage and compared to those of the controls., Results: In the postacute stage, the patients navigated worse and had higher error rates than controls in allocentric ( p = 0.002), but not in egocentric, route planning ( p = 0.30), despite complete recovery of verbal ( p = 0.58) and figural memory ( p = 0.11). Until follow-up, allocentric navigation deficits improved, but higher error rates and reduced use of shortcuts persisted ( p < 0.0001). Patients still exhibited relatively more fixations of unique landmarks during follow-up ( p = 0.05). PET measurements during the postacute stage showed increased navigation-induced brain activations in the right hippocampus, bilateral retrosplenial, parietal, and mesiofrontal cortices, and cerebellar dentate nucleus in patients compared to controls ( p < 0.005)., Conclusions: Patients with TGA show selective and prolonged deficits of allocentric spatial orientation. Activations in right hippocampal and extrahippocampal hubs of the cerebral navigation network functionally substitute for the deficit in creating and updating the internal cognitive map in TGA., (© 2018 American Academy of Neurology.)

Specialist police are required to perform high risk and dangerous tasks that are physically demanding. The aims of this study were to establish the natures and contexts of tasks performed by specialist police officers and to explore the physical fitness regimes they undertake to maintain their operational fitness for these tasks. A survey approach was employed and members of operational units of the Australian and New Zealand Police Tactical Groups (PTG) participated in the survey. A total of nine (100%) PTG units cooperated, with 132 respondents (31% of the PTG operational members) from these units completing the online survey. The occupational task most commonly recently undertaken by PTG was a high-risk warrant execution (62% of respondents) followed by rural operations (11% of respondents). The nature and environment of operations varied, and external load was carried in all operational circumstances, with loads typically 21-25 kg. All officers undertook regular physical training, with 73% focusing the physical training on occupation-specific training. Whether the training was actually occupation-specific was difficult to determine, given the current lack of research identifying the physical fitness requirements of key occupational tasks undertaken by specialist police.

Objective: To establish a novel multimodal real-space navigation paradigm and define age- and gender-related normative values for navigation performance and visual exploration strategies in space., Methods: A group of 30 healthy subjects (mean age 45.9 ± 16.5 years, 16 men) performed a real-space navigation paradigm, requiring allo- and egocentric spatial orientation abilities. Visual exploration behaviour and navigation strategy were documented by a gaze-controlled, head-fixed camera. Allo- and egocentric spatial orientation performance were compared in younger and older subjects (age threshold 50 years) as well as men and women. Navigation-induced changes of regional cerebral glucose metabolism (rCGM) were measured by [ 18 F]-fluorodeoxyglucose-positron emission tomography in a subgroup of 15 subjects (8 men) and compared across age and gender., Results: The majority of healthy subjects (73.3%) completed the navigation task without errors. There was no gender difference in navigation performance. Normalized total error rates increased slightly, but significantly with age (r = 0.36, p = 0.05). Analysis of navigation path indicated a significantly reduced use of short cuts in older age (r = 0.44, p = 0.015). Visual exploration analysis revealed that older subjects made significantly more total saccades (r = 0.49, p = 0.006) and search saccades (r = 0.54, p = 0.002) during navigation. All visual exploration parameters were similar in men and women. Navigation-induced rCGM decreased with age in the hippocampus and precuneus and increased in the frontal cortex, basal ganglia and cerebellum. Women showed an increase of rCGM in the left hippocampus and right middle temporal gyrus, men in the superior vermis., Conclusion: Real-space navigation testing was a feasible and sensitive method to depict age-related changes in navigation performance and strategy. Normalized error rates, total mean durations per item and total number of saccades were the most sensitive and practical parameters to indicate deterioration of allocentric navigation strategies and right hippocampal function in age irrespective of gender.

Objectives: Fitness is essential to specialist police forces, who have higher occupational demands than general police, and vital to performance and mission success. However, little research has been done profiling the metabolic fitness of these units and how they compare to other populations. The objective of this study was to profile the aerobic fitness of a specialist police unit., Methods: Body weight was measured to account for any impact on metabolic fitness, while VO2 max was estimated via number of shuttles completed on the 20 m Progressive Shuttle Run Test (PSRT) (n=47) on two dates one calendar year apart., Results: There were no significant (p=.116) differences (mean difference 0.40±1.70 kg) in body weight between the initial measures (mean=88.84±8.25 kg) and the final measure (mean=89.24±8.77 kg) 13 months later. PSRT results increased significantly (p<.005) between the initial (mean=72.62±11.76 shuttles) and final assessments (77.51±11.46 shuttles), with a mean increase of 4.89 (± 2.94) shuttles and a small effect size (d=0.42). The mean VO2 max of the specialist police unit was 51.06±3.61 ml/min/kg following the first assessment, and 52.56±3.46 ml/min/kg following the second assessment. This was a significant finding (p<.001), with a mean difference of 1.19±1.27 ml/min/kg and a small effect size (d=0.23)., Conclusions: Elite police forces have a higher metabolic fitness than the general population and general duties police officers. Having and maintaining this fitness level is imperative for their operational success and preventing injuries. This research suggests that despite the challenges posed by operational requirements, high fitness standards can not only be maintained, but also improved.

Despite the availability of long-term data demonstrating the benefits of timely and aggressive intensification of antihyperglycaemic regimens among individuals with type 2 diabetes, intensification beyond basal insulin continues to be suboptimal and a global challenge. This review summarizes the evidence surrounding the various options of advancing glucose-lowering management beyond basal insulin and provides a practical algorithm to assist in optimizing patient care and enhancing glycaemic target achievements., (© 2018 John Wiley & Sons Ltd.)

Introduction: Topographical disorientation is defined as the inability to recognize familiar or unfamiliar environments. While its slowly progressive development is a common feature of neurodegenerative processes like Alzheimer's dementia, acute presentations are less frequent and mostly caused by strategic lesions within the cerebral navigation network. Depending on the lesion site, topographical disorientation can originate from deficits in landmark recognition and utilization for route planning (egocentric navigation deficit), or disturbance of an overarching cognitive map of the spatial environment (allocentric navigation deficit). However, objective measurements of spatial navigation performance over time are largely missing in patients with topographical disorientation., Methods: We here report a 55-year-old patient with acute topographical disorientation as the single symptom of right-sided hippocampal hemorrhage and present quantitative gaze-monitoring head camera-based analyses of his path-finding strategy and visual exploration behavior in a real space navigation paradigm., Results: The patient exhibited severe allocentric and also egocentric navigation deficits during the acute phase, shown by higher error rates at finding target items. In addition, he showed a more extensive use of search saccades toward, and fixations on, landmarks that could potentially serve as spatial cues. These deficits had been completely compensated for after four months, when the patient performed unremarkably in the real space navigation task, and used even more strongly allocentric path optimization strategies than age-matched controls., Conclusions: This case report highlights the integral function and right-sided dominance of the hippocampal formation in the cerebral navigation network in humans. It shows that the cognitive map can be restored completely despite a residual hippocampal lesion, which illustrates the enormous plasticity of the cerebral navigation network in humans., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Police officers are required to carry external loads as part of their occupation. One means of preparing officers to carry loads is through physical conditioning. The aim of this study was to investigate whether strength, power or aerobic endurance had the greatest association with load carriage performance. Retrospective data from 42 male specialist tactical police officers (mean body weight = 88.8±8.25 kg) informed this study. Baseline data were provided for strength (1 Repetition Maximum [RM] bench press, deadlift, squat and pull-up), lower body power (vertical jump, 10m sprint) and aerobic ('beep' test) performance. In addition, officers completed three 5km load carriage trials (3 to 4 months apart) with 25 kg packs as fast as possible. Pearson's correlations were used to look for associations between measures with an analysis of variance used to detect changes in load carriage performance. Alpha levels were set a priori at 0.05. All variables of strength and power were significantly correlated with performance except for 1RM deadlift and the 10m sprint for the last two load carriage trails. Of all fitness measures, aerobic fitness was the most highly significant correlation with the load carriage trials (r=-0.712, -0.709 and -0.711 for trials respectively). Time to completion improved across the three load carriage trials (p<.001). These findings support the approach that optimal load carriage performance may be achieved by performing load carriage tasks in conjunction with aerobic fitness and full body strength/lower limb power training.

The rising cost of the opioid antagonist and overdose reversal agent naloxone is an urgent public health problem. The recent and dramatic price increase of Evzio, a naloxone auto-injector produced by Kaléo, shows how pharmaceutical manufacturers entering the naloxone marketplace rely on market exclusivity guaranteed by the patent system to charge prices at what the market can bear, which can restrict access to life-saving medication. We argue that 28 U.S.C. § 1498, a section of the federal code that allows the government to use patent-protected products for its own purposes in exchange for reasonable compensation, could be used to procure generic naloxone auto-injectors, or at least bring Kaléo to the negotiating table. Precedent exists for the use of § 1498 to procure pharmaceuticals, and it could give meaning to the federal government's recent declaration of a public health emergency around the opioid epidemic, discourage new market entrants from charging exorbitant prices, and yield important public health benefits.

Purpose: Primary ciliary dyskinesia (PCD) is characterised by repeated upper and lower respiratory tract infections, neutrophilic airway inflammation and obstructive airway disease. Different ultrastructural ciliary defects may affect lung function decline to different degrees. Lung clearance index (LCI) is a marker of ventilation inhomogeneity that is raised in some but not all patients with PCD. We hypothesised that PCD patients with microtubular defects would have worse (higher) LCI than other PCD patients., Methods: Spirometry and LCI were measured in 69 stable patients with PCD. Age at testing, age at diagnosis, ethnicity, ciliary ultrastructure, genetic screening result and any growth of Pseudomonas aeruginosa was recorded., Results: Lung clearance index was more abnormal in PCD patients with microtubular defects (median 10.24) than those with dynein arm defects (median 8.3, p = 0.004) or normal ultrastructure (median 7.63, p = 0.0004). Age is correlated with LCI, with older patients having worse LCI values (p = 0.03, r = 0.3)., Conclusion: This study shows that cilia microtubular defects are associated with worse LCI in PCD than dynein arm defects or normal ultrastructure. The patient's age at testing is also associated with a higher LCI. Patients at greater risk of obstructive lung disease should be considered for more aggressive management. Differences between patient groups may potentially open avenues for novel treatments.