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Vint proteins have been identified in unicellular metazoans as a novel hedgehog-related gene family, merging the von Willebrand factor type A domain and the Hedgehog/INTein (HINT) domains. We present the first three-dimensional structure of the Vint domain from Tetrahymena thermophila corresponding to the auto-processing domain of hedgehog proteins, shedding light on the unique features, including an adduct recognition region (ARR). Our results suggest a potential binding between the ARR and sulfated glycosaminoglycans like heparin sulfate. Moreover, we uncover a possible regulatory role of the ARR in the auto-processing by Vint domains, expanding our understanding of the HINT domain evolution and their use in biotechnological applications. Vint domains might have played a crucial role in the transition from unicellular to multicellular organisms.
In order to assess the impact of a music therapy workshop on the self-esteem of residents in residential care facilities for dependent elderly people, we developed eight music therapy sessions based on their musical sensibilities and tastes. Ten participants were assessed before and after the intervention in terms of self-esteem, anxiety, depression, quality of life, and problematic behaviors. Only self-esteem improved, highlighting the value of such care.
According to the above-mentioned, the study aiming at description of clinico-diasgnostical peculiarities of withdrawal states caused by consumption of Ephedra plant home-made drug - "Vint" has been conducted. 50 patients 20-65 of age, hospitalized with ephedrone withdrawal effect (withdrawal effect caused by consumption of the drug prepared from Ephedra plant or classic "Vint"), were involved in the study conducted at Narcological Clinic "Neogeni". The patients were divided into two main groups: in the first group were united the patients with the withdrawal effect caused by consumption of the drug prepared from Ephedra plant and in the second group -"classical pharmaceutical "Vint" consumers. Patients were selected and diagnosed according to the ICD-10 criteria. The study was conducted on the basis of informed consent, keeping with the bioethical principles. The withdrawal state, particularly expression of its individual symptoms has been evaluated in patients of both groups. Intensity of withdrawal state was assessed before treatment and after 2 weeks of stationary/inpatient treatment according to Amphetamine Withdrawal Assessment Scale (Amphetamine Withdrawal Assessment Scale, Drug & Alcohol Services Council, SA, 2002). The affective anxieties in patients of the study group were assessed on the base of Beck Anxiety Inventory scale/scoring and Spielberger State-Trait Anxiety Inventory (STAI). The craving intensity was measured according to the Brief Substance Craving Scale. As a result of the study, it was concluded that after termination consuming the Ephedra plant-produced preparation "Vint" the patients had developed: more severe withdrawal state and relatively less - moderate and mild withdrawal states. The rate of craving for drug, depression, personal and situational anxiety were high as well. The Patients of the first group developed a relatively severe withdrawal state, the rates of depression and craving were high as well; as for the indicators of individual and situational anxiety no substantial changes were revealed. 2-week complex treatment resulted in expressed positive dynamics in regards to the above-mentioned disorders. It is noteworthy to mention that after treatment no suicidal ideation or psychotic disorders were observed in any patient. The severity of withdrawal state, as well as the indicators of depression and anxiety were significantly decreased.
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), can lead to significant morbidity and mortality in adults with type 2 diabetes (T2D) and obesity. This study evaluated whether participation in an individualized, nutrition-focused telemedicine care model emphasizing carbohydrate reduction (Virta Individualized Nutrition Therapy, VINT) was associated with reduced onset of MASLD, MASH, and advanced liver disease. Adults with T2D, prediabetes, overweight,or obesity who enrolled in VINT (2015-2024) were identified in the Komodo Healthcare Map and matched 1:1 to usual care (UC) controls (n=5031 per group). Using 3 complementary analytic approaches, incidence and time-to-event analyses were performed for new-onset liver disease. Across all strategies, VINT participants consistently showed a lower incidence of any liver-related diagnosis (27.3 vs. 42.8 per 1000 person-years; HR=0.61, p <0.001), MASH-and-beyond (4.2 vs. 10.7; HR=0.38, p <0.001), advanced liver disease (2.8 vs. 8.7; HR=0.33, p <0.001), and any liver complications (2.0 vs. 7.7; HR=0.25, p <0.001). VINT participants who lost ≥15% body weight were at lower risk of new-onset liver disease (21.2 vs. 31.8 per 1000 person-years; HR=0.66, p =0.02) compared with VINT participants who lost less weight. Participation in individualized nutrition-focused telemedicine care was associated with significantly lower incidence and risk of new-onset MASLD, MASH, and advanced liver disease. These findings support lifestyle-first interventions that are potentially scalable to reduce liver disease burden in adults with T2D and obesity.
UA-2012 (and related non-myristoylated analog UA-1907) is a lead alpha-helical cyclic peptide which inhibits the focal adhesion kinase (FAK)-paxillin protein-protein interaction (PPI) and is being evaluated for the treatment of cutaneous melanoma. However, the development of an empirical approach to measure PPI inhibitor selectivity remains an important need. We report the development of a pulldown-MS proteomic approach, including a custom synthesized non-myristoylated UA-1907-agarose probe, to evaluate the binding selectivity of candidate FAK PPI inhibitors. Melanoma lysates were probed with UA-1907-conjugated agarose beads and eluted associated proteins were analyzed through untagged mass-spectroscopy proteomics. The identified proteins led to the development of a custom focal adhesion (FA) selectivity panel comprised of recombinant VinT, VinH, PARVA, PARVB, Talin-1 Rod 8, and the FAK FAT domain. Surface plasmon resonance (SPR) screening of these FA proteins against UA-1907 determined that only the FAK-FAT domain has a nanomolar binding affinity (KD) for UA-1907, whereas other FA proteins have no binding. Overall, we report the development of a customized pulldown-MS approach to characterize PPI drug selectivity that has utility in the FAK drug discovery field.
Hypertension is the most prevalent RF for cerebrovascular disease (CVD). Although previous studies have employed ultrasonography and phase-contrast magnetic resonance image (MRI) to assess cerebral hemodynamics, the quantitative impact of hypertension on cerebral arterial flow characteristics remains incompletely understood. This study focused on the relationship between hypertension, other risk factors (RF), and arterial velocity gradient using the signal intensity gradient (SIG) from time-of-flight magnetic resonance angiography (TOF-MRA). This cross-sectional study included individuals who underwent health screening at our institution between January 2015 and June 2021. Participants with no history of CVD who underwent intracranial TOF-MRA were included. Arterial wall SIGs was measured in the cerebral arteries. Participants were categorized into four groups according to vascular RFs: none (no RF), other RFs (RFs except hypertension), hypertension-only, and hypertension-plus (hypertension with other RFs). A total of 1154 healthy subjects (mean age 63.2 ± 9.5 years, 43.2% women) were enrolled. The hypertension-plus group had the highest systolic (125.3 ± 19.1 mm Hg) and diastolic (74.7 ± 10.5 mm Hg) blood pressures, HbA1c (6.1 ± 0.7%), intima-media thickness (0.86 ± 0.24 mm), and the highest rates of intracranial artery stenosis (14.4%) and chronic kidney disease (6.1%). The hypertension-plus group showed the lowest SIG values among all cerebral arteries. After adjusting for confounding factors, the hypertension-plus group showed significantly lower SIG values in the intracranial arteries but not in the extracranial arteries. The arterial wall SIG was significantly associated with hypertension and other vascular RFs. SIG may offer quantitative information on the arteriopathic effects of hypertension, especially intracranial cerebral arteries.
Robust autonomous navigation in complex, dynamic indoor environments remains a central challenge in robotics, requiring agents to make adaptive decisions in real time under partial observability and uncertain obstacle motion. This paper presents DreamerNav, a robot-agnostic navigation framework that extends DreamerV3, a state-of-the-art world model-based reinforcement learning algorithm, with multimodal spatial perception, hybrid global-local planning, and curriculum-based training. By formulating navigation as a Partially Observable Markov Decision Process (POMDP), the system enables agents to integrate egocentric depth images with a structured local occupancy map encoding dynamic obstacle positions, historical trajectories, points of interest, and a global A* path. A Recurrent State-Space Model (RSSM) learns stochastic and deterministic latent dynamics, supporting long-horizon prediction and collision-free path planning in cluttered, dynamic scenes. Training is carried out in high-fidelity, photorealistic simulation using NVIDIA Isaac Sim, gradually increasing task complexity to improve learning stability, sample efficiency, and generalization. We benchmark against NoMaD, ViNT, and A*, showing superior success rates and adaptability in dynamic environments. Real-world proof-of-concept trials on two quadrupedal robots without retraining further validate the framework's robustness and quadruped robot platform independence.
The respiratory prescribing strategy previously published by the Scottish Government did not include any environmental sustainability information and required updating to incorporate this. It was recognized that ~3% of the carbon footprint of NHS Scotland results from the use of pressurized metered dose inhalers due to the high global warming potential of inhaler propellants. The aims of the guide were to support clinicians and people with respiratory illness in the appropriate use of medicines, while applying the principles of value-based health care and realistic medicine, including environmental sustainability. Person-centred medication review, including optimising appropriate inhaler use, is promoted using the 7-step methodology described in the Scottish polypharmacy guidance. Stakeholders, including people with lived experience, third sector patient organizations and multidisciplinary team representatives from across primary and secondary care were invited to update the respiratory guide. Open consultation was undertaken before publication. Tools and resources to assist in implementation of the recommendations were developed, including data and patient facing resources. The 'Quality Prescribing Strategy for Respiratory Conditions: a guide for improvement (2024-2027)' was published by the Scottish Government in April 2024. It highlights key recommendations for respiratory prescribing, to improve care of people living with respiratory conditions and to reduce environmental impact of respiratory care. The guide supports the implementation of national UK-based guidance, including the Scottish Intercollegiate Guidelines Network and National Institute for Health and Care Excellence guidance, together with the indicators and tools to drive improvement in prescribing and patient care by assisting clinicians with practical guidance and prescribing resources. It also supports healthcare organizations and sustainability committees to prioritize actions.
This guideline will provide up-to-date and evidence-based recommendations for the safe use of biologic and targeted synthetic DMARDs in individuals with inflammatory arthritis (IA) across the life course. Important updates from the 2019 iteration of this guideline will include the incorporation of newer pharmacotherapies (such as Janus kinase inhibitors) and an extension of the target clinical population to cover children and young people with IA. The guideline will be updated and produced in accordance with the British Society for Rheumatology protocol for developing clinical guidelines, updated 2023.
This study aims to investigate how A1 segment asymmetry-also known as A1 dominancy-influences the development of the anterior communicating artery aneurysm (AcomA) as it affects hemodynamic conditions within the circle of Willis (COW). Using time-of-flight magnetic resonance angiography (TOF-MRA), the research introduces a novel approach to assessing shear stress in A1 segments to uncover the hemodynamic factors contributing to AcomA formation. An observational study was conducted over 6 years at a tertiary university hospital's outpatient clinic. Recruited patients who underwent TOF-MRA imaging were divided into AcomA and non-AcomA groups. MRA images were analyzed using semi-automatic software (VINT, Mediimg, Inc.) to calculate the signal intensity gradient (SIG), which reflects wall shear stress. The comparison metrics included general demographics, anatomical characteristics, and hemodynamic attributes of the COW, mainly focusing on A1 segment asymmetry. Among the 700 subjects, 106 were categorized into the AcomA group, while 594 were placed in the non-AcomA group. The AcomA group showed a more significant difference in the bilateral A1 diameter (49.0% vs. 20.8%, p < 0.001) and a greater prevalence of unilateral A1 aplasia (32.1% vs. 6.7%, p < 0.001) compared to the non-AcomA group. Increased bilateral A1 asymmetry in the AcomA group corresponded with notable variations in A1 SIG, indicating increased wall shear stress. The occurrence of AcomA is associated with both anatomical factors of the circle of Willis, represented by the bilateral A1 diameter ratio, and hemodynamic factors, represented by the bilateral A1 SIG ratio, suggesting that both factors are almost equally significant. Our findings suggest that A1 segment asymmetry influences hemodynamic changes within the COW, contributing to AcomA formation. Hemodynamic factors provide an intuitive understanding of how anatomical characteristics within the COW can lead to aneurysm development.
Extreme storms can trigger abrupt and often lasting changes in ecosystems by affecting foundational (habitat-forming) species. While the frequency and intensity of extreme events are projected to increase under climate change, its impacts on seagrass ecosystems remain poorly documented. In January 2020, the Spanish Mediterranean coast was hit by Storm Gloria, one of the most devastating recent climate events in terms of intensity and duration. We conducted rapid surveys of 42 Posidonia oceanica meadows across the region to evaluate the extent and type of impact (burial, unburial and uprooting). We investigated the significance of oceanographic (wave impact model), geomorphological (latitude, depth, exposure), and structural (patchiness) factors in predicting impact extent and intensity. The predominant impact of Storm Gloria was shoot unburial. More than half of the surveyed sites revealed recent unburial, with up to 40 cm of sediment removed, affecting over 50 % of the meadow. Burial, although less extensive, was still significant, with 10-80 % of meadow cover being buried under 7 cm of sediment, which is considered a survival threshold for P. oceanica. In addition, we observed evident signs of recently dead matte in some meadows and large amounts of detached drifting shoots on the sea bottom or accumulated as debris on the beaches. Crucially, exposed and patchy meadows were much more vulnerable to the overall impact than sheltered or continuous meadows. Given how slow P. oceanica is able to recover after disturbances, we state that it could take from decades to centuries for it to recoup its losses. Seagrass ecosystems play a vital role as coastal ecological infrastructure. Protecting vulnerable meadows from anthropogenic fragmentation is crucial for ensuring the resilience of these ecosystems in the face of the climate crisis.
Evidence indicates the existence of an association between socioeconomic status (SES) and the prevalence of myopia in the adult population. In contrast, there are limited studies investigating this association in children. The purpose of this study was to investigate the association between the presence of myopia in 8-year-old children from southern Europe and SES defined as parental educational level and employment status. Participants aged 8 years old were recruited from 16 schools located in Terrassa, Spain (n = 813). Ten of these schools were classified as "high complexity" schools (low SES). Refractive error was assessed using non-cycloplegic retinoscopy. Parental questionnaires were used to gather socioeconomic information such as parental education level and employment status. Non-parametric Kruskal Wallis, Mann Whitney and Chi-square tests were used to evaluate the association between spherical equivalent (SE) and parental educational level and employment status as well as differences in the SE distribution between high-complexity and regular schools. Myopia was more prevalent than hyperopia in the population sample (11.1% vs 5.1 %). Chi-square tests revealed a significant association between attending "high-complexity" schools and the presence of myopia (p = 0.014). In contrast, no significant associations were found between SE and SES. A trend for higher prevalence of myopia in children whose mothers had low educational level and were unemployed was observed. While no significant associations are found between SE and parental education or employment status, myopia is more frequently found in schools with low SES ("high-complexity" schools), suggesting a potential link between SES and childhood myopia.
Global literature suggests that female surgical trainees have lower rates of independent operating (operative autonomy) than their male counterparts. The objective of this study was to identify any association between gender and lead/independent operating in speciality orthopaedic trainees within the UK national training programme. This was a retrospective case-control study using electronic surgical logbook data from 2009 to 2021 for 274 UK orthopaedic trainees. Total operative numbers and level of supervision were compared between male and female trainees, with correction for less than full-time training (LTFT), prior experience, and time out during training (OOP). The primary outcome was the percentage of cases undertaken as lead surgeon (supervised and unsupervised) by UK orthopaedic trainees by gender. All participants gave permission for their data to be used. In total, 274 UK orthopaedic trainees submitted data (65% men (n = 177) and 33% women (n = 91)), with a total of 285,915 surgical procedures logged over 1,364 trainee-years. Males were lead surgeon (under supervision) on 3% more cases than females (61% (115,948/189,378) to 58% (50,285/86,375), respectively; p < 0.001), and independent operator (unsupervised) on 1% more cases. A similar trend of higher operative numbers in male trainees was seen for senior (ST6 to 8) trainees (+5% and +1%; p < 0.001), those with no time OOP (+6% and +8%; p < 0.001), and those with orthopaedic experience prior to orthopaedic specialty training (+7% and +3% for lead surgeon and independent operator, respectively; p < 0.001). The gender difference was less marked for those on LTFT training, those who took time OOP, and those with no prior orthopaedic experience. This study showed that males perform 3% more cases as the lead surgeon than females during UK orthopaedic training (p < 0.001). This may be due to differences in how cases are recorded, but must engender further research to ensure that all surgeons are treated equitably during their training.
The aim of this study was to describe thigh muscle activation during cycling using intramuscular electromyographic recordings of eight thigh muscles, including the biceps femoris short head (BFS) and the vastus intermedius (Vint). Nine experienced cyclists performed an incremental test (start at 170 W and increased by 20 W every 2 min) on a bicycle ergometer either for a maximum of 20 min or to fatigue. Intramuscular electromyography (EMG) of eight muscles and kinematic data of the right lower limb were recorded during the last 20 s in the second workload (190 W). EMG data were normalized to the peak activity occurring during this workload. Statistical significance was assumed at p ≤ 0.05. The vastii showed a greater activation during the 1st quadrant compared to other quadrants. The rectus femoris (RF) showed a similar activation, but with two bursts in the 1st and 4th quadrants in three subjects. This behavior may be explained by the bi-articular function during the cycling movement. Both the BFS and Vint were activated longer than, but in synergy with their respective agonistic superficial muscles. Intramuscular EMG was used to verify muscle activation during cycling. The activation pattern of deep muscles (Vint and BFS) could, therefore, be described and compared to that of the more superficial muscles. The complex coordination of quadriceps and hamstring muscles during cycling was described in detail.
The viability of electroencephalogram (EEG) based vocal imagery (VIm) and vocal intention (VInt) Brain-Computer Interface (BCI) systems has been investigated in this study. Four different types of experimental tasks related to humming has been designed and exploited here. They are: (i) non-task specific (NTS), (ii) motor task (MT), (iii) VIm task, and (iv) VInt task. EEG signals from seventeen participants for each of these tasks were recorded from 16 electrode locations on the scalp and its features were extracted and analysed using common spatial pattern (CSP) filter. These features were subsequently fed into a support vector machine (SVM) classifier for classification. This analysis aimed to perform a binary classification, predicting whether the subject was performing one task or the other. Results from an extensive analysis showed a mean classification accuracy of 88.9% for VIm task and 91.1% for VInt task. This study clearly shows that VIm can be classified with ease and is a viable paradigm to integrate in BCIs. Such systems are not only useful for people with speech problems, but in general for people who use BCI systems to help them out in their everyday life, giving them another dimension of system control.
The purpose of this study was to investigate the hematological and inflammatory responses to 4 maximal high-intensity protocols, considering energy expenditure in each test. 9 healthy volunteers performed 4 high-intensity exercise tests of short [Wingate (WANT); Repeated-sprints (RSA)] and long durations [Continuous VO2 test (VCONT); intermittent VO2 test (VINT)] in a cycle-ergometer, until exhaustion. Hematological parameters and IL-6, IL-10 and creatine kinase (CK) levels were determined before (PRE), POST, 30 min, 1, 2, 12 and 24 h after the end of the protocols. Additionally, energy expenditure was determined. Leucocytes, erythrocytes and lymphocytes increased at POST and returned to PRE values at 30 min for all protocols. Lymphocytes had a second decreased at 2 h and granulocytes increased at 2 h when compared to PRE. Both variables returned to PRE values between 12-24 h into recovery. The magnitude of response for IL-6 was greater in VINT and for IL-10 in VCONT. There was no association of energy expenditure within each exercise protocol with the pattern of IL-6, IL-10 and CK responses to the exercise protocols. The present finding support that similar responses after continuous or intermittent acute protocols are observed when exercises are performed to volitional failure, regardless of the duration and mode of exercise.
Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score-4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5-13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. The UK National Institute for Health Research Health Technology Assessment Programme.
Since the end of 2015, reports by service providers have indicated a new trend in kitchen (homemade) production of an injection drug prepared from an ephedrine-containing conifer bush that is indigenous to the region. The aim of this report is to describe an emerging new homemade psychoactive drug synthesized from the ephedra plant, and the drug consumption methods associated with its' use in the Eurasia. Focus groups conducted with 16 people, self-identified as injection drug users (IDU's) who reported at least one incidence of ephedra preparation injection during the previous 30-days. Participants were male, mean age of 43 and mean length of drug use of 22.2 years. Participants identified "conifer vint" as the most frequently injected drug during the 30-day period preceding the focus group. The source plant of the drug identified, as "conifer vint" is plant-based ephedra extracted from a common conifer bush that grows wild and is pervasive in the region. The process of synthesis resembles the production of "vint" (conversion of ephedrine to methamphetamine by reduction) and involves several legal and widely available chemical precursors. The final product of the synthesis is a strong injectable CNS stimulant solution. Conclusions/Importance: The production and use of raw ephedra from a pervasive indigenous plant reflect a new trend in psychoactive drug preparation and use that warrants international attention and has global implications for emerging trends in drug use.
Poor sleep and chronic fatigue are common in people with chronic stroke (i.e. ≥ 6 months post-stroke). Exercise training is a viable, low-cost therapy for promoting sleep and reducing fatigue; however, the effects of exercise on sleep and fatigue in people with chronic stroke are unclear. Thus, we conducted a systematic review ascertaining the effects of exercise on sleep and fatigue in people with chronic stroke. We systematically searched EMBASE, MEDLINE, AgeLine, the Cochrane Database of Systematic Reviews, CINAHL, SPORTDiscus, SCOPUS, and reference lists of relevant reviews for articles that examined the effects of exercise on sleep or fatigue in chronic stroke. Search results were limited to adults ≥ 18 years, randomized controlled trials, non-randomized trials, and pre-post studies, which were published in English and examined the effects of exercise on sleep or fatigue in people with chronic stroke. We extracted study characteristics and information on the measurement of sleep and fatigue, and assessed study quality and risk of bias using the CONSORT criteria and Cochrane risk-of-bias tool, respectively. We found two studies that examined the effects of exercise on sleep, and two that examined the effects of exercise on fatigue. All studies reported positive effects of exercise training on sleep and fatigue; however, there were concerns of bias and study quality in all studies. There is preliminary evidence that exercise promotes sleep and reduces fatigue in people with chronic stroke; however, the extent to which exercise impacts these health parameters is unclear.