Search

Abstract Introduction Sarcopenia is defined by low measures of muscle quantity, quality and reduced physical performance. It is associated with higher levels of frailty. Individuals with diabetes mellitus (DM) undergo sarcopenia at an accelerated rate resulting in structural changes potentially culminating in limb loss. Aims To review the evidence on methods of detecting and measuring sarcopenic changes on magnetic resonance imaging (MRI) in the foot in patients with diabetes. Methods A literature review was conducted in accordance with PRISMA guidelines. We searched Embase and Medline (via Ovid), CINAHL (via Ebsco Host), Web of Science and Scopus as well as the grey literature. The MeSH terms “sarcopenia” AND “diabetes mellitus” AND “magnetic resonance imaging” were employed in the primary search string. Results 874 studies were identified. 404 articles were excluded in the title and abstract screening. 33 studies were assessed for eligibility after abstract and title screening was completed by two reviewers. 7 studies evaluating sarcopenia in the foot were included in the final review. Conclusion Sarcopenic changes are evident on MRI of the foot in patients with diabetes and is profound in patients with diabetic neuropathy. The general extent and severity of sarcopenia seems to correlate with clinical scores to assess neuropathy and is implicated in the development of diabetic foot disease.

Abstract Background The incidence of Pulmonary Hypertension (PH) and Pulmonary Arterial Hypertension (PAH) is believed to be on the rise and is associated with poor outcomes. Methods We extracted age-standardized mortality rates (ASMRs) for decedents ≥ 18 years of age from the World Health Organization Mortality Database, using International Classification of Diseases 10th edition codes for PH and PAH, covering the period from 2001 to 2019. The UK and European Union countries with at least 1,000,000 inhabitants and at least 75% of available data points over the study period were included. Results Between 2001 and 2019, in countries with available data, the median ASMR for PH increased by + 1.19 per 1,000,000 (+ 22.51%) in females and + 0.36 per 1,000,000 (+ 6.06%) in males. Out of 19 countries, 13 demonstrate an increase in female PH ASMR, and 12 reported an increase in male PH ASMR. In contrast, median PAH ASMR decreased by -0.29 per 1,000,000 (-28.74%) in females and remained relatively unchanged in males, with a minor increase of + 0.01 per 1,000,000 (+ 1.07%). Notably, there was significant inter-country heterogeneity, with countries such as Hungary, Romania, and Poland displaying results incongruous with the rest of Europe. Conclusions While publicly available mortality statistics for PH may be unreliable, these data suggest an overall increase in mortality across Europe from 2001 to 2019. However, mortality from PAH has shown a decrease in females and a modest increase in males. This underscores the urgent need for robust and high-quality mortality reporting, including international registries, for both PH and PAH.

Abstract The preclinical study of atherosclerosis has traditionally centred around the use of small animal models, translating to large animal models, prior to first-in-man studies. We propose to disrupt this paradigm by designing an ex vivo pump perfused human limb model. The novel model consists of taking a freshly amputated limb and incorporating it into an ex situ pump-perfused bypass system (akin to extracorporeal membrane oxygenation), circulating warmed, oxygenated blood. The circuit incorporates an introducer sheath and guiding catheter for intravascular imaging and X-ray angiography. Regular monitoring is performed using blood gas analysis, aiming for physiological parameters. The model maintains oxygen saturations > 99% for the length of perfusion (up to 6-h). Clinical grade X-ray angiography, intravascular ultrasound and optical coherence tomography have been successfully performed. Indocyanine green, a near-infrared fluorescent dye that localises to atherosclerotic plaque, has been injected into the system and left to circulate for 90-min. Fluorescence reflectance imaging of the dissected arterial bed confirmed uptake in areas of calcific atherosclerotic plaque on intravascular imaging. This is the first demonstration of an ex vivo pump-perfused “living” limb experimental model of atherosclerosis, which shows promise for future studies in translational interventional imaging and molecular targeting.

Abstract The global incidence of gout has increased rapidly, likely secondary to the increase in the prevalence of conditions that predispose to gout, such as obesity. Depending on the population studied, the prevalence of gout ranges from less than 1 to 6.8%. Thus, gout can be a significant burden on healthcare systems. The objective of this study is to observe the trends in the incidence, prevalence, and disability-adjusted life years (DALYs) of gout between 1990 and 2019 globally and in the European Union (EU) 15+ nations. We extracted data from the Global Burden of Disease Study database based on the International Classification of Diseases (ICD) versions 10 and 9. Incidence, prevalence, and disability-adjusted life years (DALYs) were extracted for individual EU15+ countries and globally in males and females between 1990 and 2019. Joinpoint regression analysis was used to describe trends. Between 1990 and 2019, gout prevalence, incidence, and DALYs increased in both males (+ 21.42%, + 16.87%, + 21.49%, respectively) and females (+ 21.06%, + 18.75%, + 20.66%, respectively) globally. The United States of America had the highest increase in prevalence (males: + 90.6%; females + 47.1%), incidence (males: + 63.73%; females: + 39.11%) and DALYs (males: + 90.43%; females: + 42.75%). Incidence, prevalence, and DALYs from gout are increasing worldwide and in most of the EU15+ countries for males and females. Studies have reported the association of gout with comorbidities such as metabolic syndrome, diabetes mellitus, and cardiovascular disease. Health policies and resource allocation are required to increase awareness and modify risk factors globally.

Autophagy is considered a target for cancer treatment, although few compounds manipulating this process have been added to the anticancer arsenal in humans. Pharmacological manipulation of autophagy has therefore been considered in the treatment and chemosensitization of hepatocellular carcinoma (HCC), a heterogeneous malignancy that remains difficult to treat (limited impact of genomic discoveries for the implementation of personalized precision medicine). We analyzed the autophagy marker proteins p62 and LC3 in paired tumor and adjacent cirrhotic non-tumor tissues of human HCC. We show strong variability in p62 and LC3-II levels between tumor parts of different HCC patients and between tumor and non-tumor HCC in the same patient, suggesting heterogeneity in autophagy flux. This diversity in flux led us to consider a non-personalized method of autophagy targeting, combining simultaneous activation and blockade of autophagy, which could, in theory, benefit a substantial number of HCC patients, irrespective of tumor autophagic flux. We show that the combination of sodium butyrate (NaB, autophagy inducer) and chloroquine (CQ, autophagy blocker) has a marked and synergistic cytotoxic effect in vitro on all human liver cancer cell lines studied, compared with the cellular effect of each product separately, and with no deleterious effect on normal hepatocytes in culture. Cancer cell death was associated with accumulation of autophagosomes, induction of lysosome membrane permeabilization and increased oxidative stress. Our results suggest that simultaneous activation and blockade of autophagy may be a valuable approach against HCC, and that microbiota-derived products improve the sensitivity of HCC cells to antitumor agents.Abbreviations AV: annexin V; CI: combination index; CTSB: Cathepsin B; CTSD: Cathepsin D; CTSF: Cathepsin F; CQ: chloroquine; DEN: N-diethylnitrosamine; DMEM: Dulbecco’s modified eagle medium; FBS: fetal bovine serum; FSC: forward scatter; GNS: N-acetylglucosamine-6-sulfatase; HCC: hepatocellular carcinoma; HDACi: histone deacetylase inhibitor; HCQ: hydroxychloroquine; LMP: lysosomal membrane permeabilization; LAMP1: lysosome-associated membrane protein; LIPA: Lysosomal acid lipase; LSR: Lysosomal staining cells; MAP1LC3A: microtubule associated protein 1 light chain 3 alpha; NaB: sodium butyrate; NASH: non-alcoholic steatohepatitis; NRF2: nuclear factor erythroid 2–related factor 2; PI: propidium iodide; PMSF: phenylmethanesulfonyl fluoride; ROS: reactive oxygen species; SCARB2: Scavenger receptor class B member 2; SQSTM1/p62: sequestosome 1; SMPD1: Sphingomyelin phosphodiesterase 1; SSC: side scatter; TFEB: transcription factor EB.

High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) improved 5-year overall survival rates in relapsed/refractory germ cell tumors (GCTs) from 10% to 52%. Nearly 30% of GCT patients are deemed poor mobilizers after receiving several lines of prior therapy. There is limited data available regarding upfront plerixafor use in GCT patients. We predicted upfront plerixafor use would increase the amount of stem cells collected preventing subsequent mobilizations and improve time to curative therapy. A retrospective, single center, chart review of adult GCT patients who received plerixafor upfront for mobilization at a single center between January 1, 2013 and August 31, 2021 was performed.The primary objective was to evaluate the rate of successful peripheral blood CD34+ cell collections. Secondary objectives consisted of describing the impact of plerixafor use on mobilization and assessing auto-HSCT related outcomes. Sixteen patients received plerixafor upfront after an average of three prior lines of therapy (range: 2-5 lines). Successful collection (≥4 × 106 CD34+ cells/Kg collected within four days) was achieved in 15 (94%) patients in a median of one apheresis day (interquartile range: 1-2 days). All patients proceeded to an initial auto-HSCT and 12 patients (75%) completed both transplants as planned. Survival at 12 months was 50%.The significantly higher amount of CD34+ cells collected over less apheresis days demonstrated the clinical utility of upfront plerixafor and its potential to facilitate more efficient stem cell mobilization. There is a need for larger randomized studies with upfront plerixafor use in this unique patient population.

BACKGROUND: RE-KINECT (NCT03062033), a real-world study of possible tardive dyskinesia (TD) in antipsychotic-treated patients, included a questionnaire to assess the effects of patients abnormal involuntary movements on caregivers. AIMS: To capture the experiences of caregivers who assisted individuals with abnormal involuntary movements that were confirmed by clinicians as being consistent with TD. METHODS: Qualified (nonpaid) caregivers were invited to complete a questionnaire that included the following: caregivers sociodemographic characteristics, their perceptions about the impact of abnormal involuntary movements on patients, and the impact of these movements on themselves (caregivers). RESULTS: Of the 41 participating caregivers, 25 (61.0%) were women, 20 (48.8%) were employed full time or part time, and 35 (85.4%) were family members or friends. Based on responses from caregivers who noticed patients abnormal involuntary movements and were caring for individuals who also noticed those movements, 48.0% of patients had a lot of severity in ≥1 body region and 76.0% had abnormal involuntary movements in ≥2 regions. Caregiver ratings were significantly correlated with patient ratings (but not with clinician ratings) for maximum severity of abnormal involuntary movements and the number of affected regions (both p

BackgroundTardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with antipsychotic use. Data from RE-KINECT, a real-world study of antipsychotic-treated outpatients, were analyzed to assess the effects of possible TD on patient health and social functioning.MethodsAnalyses were conducted in Cohort 1 (patients with no abnormal involuntary movements) and Cohort 2 (patients with possible TD per clinician judgment). Assessments included: EuroQoL's EQ-5D-5L utility (health); Sheehan Disability Scale (SDS) total score (social functioning); patient- and clinician-rated severity of possible TD ("none", "some", "a lot"); and patient-rated impact of possible TD ("none", "some", "a lot"). Regression models were used to analyze the following: associations between higher (worse) severity/impact scores and lower (worse) EQ-5D-5L utility (indicated by negative regression coefficients); and associations between higher (worse) severity/impact scores and higher (worse) SDS total score (indicated by positive regression coefficients).ResultsIn Cohort 2 patients who were aware of their abnormal movements, patient-rated TD impact was highly and significantly associated with EQ-5D-5L utility (regression coefficient: - 0.023, P

When the written language that children learn to read and write is distinct from the oral language they acquired as their mother tongue, they may encounter substantial challenges. The linguistic distance between two varieties of the same language could have an impact on the literacy acquisition journey. The present study focuses on Arabic, a prototypical case of diglossia, where the distance between the spoken and standard varieties has been intensively examined phonologically and lexically. However, a paucity of studies has addressed their morphological distance. This study takes one step in this direction by describing, analyzing, and quantifying the distance of morphemes in content words from spoken Palestinian dialect (SPD) to Modern Standard Arabic (MSA). It is the first to map this distance by form and function in the three predominant systems: derivation, inflection, and clitics in nouns and verbs. All morphemes were arranged on an axis targeting four main levels that varied in the extent of the morphological distance from SPD to MSA, beginning with 'identical' morphemes (same form, same function), followed by 'strongly overlapping' morphemes (morpho-phonological difference in form, same function), then 'partially overlapping' morphemes (different form, same function), and ending with 'unique' morphemes (unique form, same/different function). The mapping showed significant findings indicating that most morphemes are non-identical between SPD and MSA, comprising 81.4% of the total. Most of these non-identical morphemes (64.9%) were assembled to the 'partially overlapping' and 'unique' levels, appearing mainly in the verb inflection category. Implications for the possible impact of morphological distance on reading acquisition are discussed.

Objectives Understanding the burden of disease of sepsis is essential for monitoring the effectiveness of international strategies to improve sepsis care. Our objective was to describe the multinational trend of sepsis-related mortality for the period 1985–2019 from the WHO Mortality Database.Design Retrospective analysis of the WHO Mortality Database.Setting We included data from all countries defined by the WHO as having ‘high usability data’ and at least 10 years of total available data.Participants From the WHO list of 50 countries with high usability data, 14 (28%) were excluded due to excessive missingness. We included and analysed data separately for male and female.Primary and secondary outcome measures We analysed age-standardised mortality rates (ASMR) (weighted average of the age-specific mortality rates per 100 000 people, where the weights are the proportions of people in the corresponding age groups of the WHO standard population).Results We included 1104 country-years worth of data from 36 countries with high usability data, accounting for around 15% of the world’s population. The median ASMR for men decreased from 37.8 deaths/100 000 (IQR 28.4–46.7) in 1985–1987 to 25.8 deaths/100 000 (IQR 19.2–37) in 2017–2019, an approximately 12% absolute (31.8% relative) decrease. For women, the overall ASMR decreased from 22.9 deaths/100 000 (IQR 17.7–32.2) to 16.2 deaths/100 000 (IQR 12.6–21.6), an approximately 6.7% absolute decrease (29.3% relative decrease). The analysis of country-level data revealed wide variations in estimates and trends.Conclusions We observed a decrease in reported sepsis-related mortality across the majority of analysed nations between 1985 and 2019. However, significant variability remains between gender and health systems. System-level and population-level factors may contribute to these differences, and additional investigations are necessary to further explain these trends.

IntroductionPrevious cross-sectional investigations by Shany and colleagues have provided evidence of double dissociation among dyslexics between word reading accuracy and (pure) word reading rate. A rate-disabled subtype (with intact reading accuracy) evinced deficits only in rapid naming (RAN); An accuracy-disabled subtype (with intact reading rate) showed deficits in phonological awareness (PA) and morphological awareness (MA) but not RAN.MethodThe present longitudinal study followed 639 Palestinian Arabic-speaking children from preschool to Grade 1 with the aim of determining (1) whether a dissociation between PA C MA and RAN is apparent among pre-literate preschoolers, (2) whether the PA C MA-disabled subgroup constitutes a mild form of Developmental Language Disorder (DLD), (3) whether our three disabled subgroups (PA C MA-only, RAN-only, and PA C MA-plus-RAN) can be differentiated on preschool early literacy measures and, (4) whether the three at-risk subgroups develop into selectively rate-disabled, accuracy-disabled, or doubly-disabled (accuracy C rate) readers in Grade 1?ResultsOur findings confirmed the existence of two distinct selectively disabled/at-risk subgroups in preschool: a RAN-only subgroup with intact PA and MA and a PA C MA subgroup with broad impairments across language measures but intact RAN. Grade 1 reading data also confirmed that the RAN-disabled subgroup became slow but accurate readers, whereas the PA C MA subgroup developed into inaccurate and slow readers.DiscussionOur study indicates partial dissociation between early dyslexia subtypes, each displaying distinct and non-overlapping cognitive-linguistic profiles in preschool. The study also revealed a strong association between reading accuracy and reading rate among beginning readers. This study emphasizes the importance of considering heterogeneity in reading outcomes as well as multiple oral language skills beyond the well-documented role of PA.

Abstract Background and Aims Traditional apprenticeship‐based surgical training presents with challenges, especially in acute scenarios. Simulation provides the current standard of facilitating surgical training in a low‐risk environment but is restricted by limited accessibility and high costs. Virtual reality (VR) offers immersive three‐dimensional computer‐generated training scenarios and can connect users from various locations. We aimed to compare the performance of junior doctors to manage an acute surgical scenario using VR and mannequin‐based simulation. We hypothesised that VR would be as effective as mannequin‐based simulation in performance outcomes. Methods This multicentre, randomised controlled pilot study was conducted with eighteen junior doctor volunteers (Foundation and Core Trainee Year 1). Ten were randomly allocated to VR and eight to mannequin‐based simulation. Participants completed questionnaires and a 15‐min pneumothorax scenario. Quantitative metrics included overall score, time‐to‐critical decisions, and academic buoyancy scores (ABS). Qualitative metrics included participants' likes and dislikes of their allocated simulation modality. Results VR participants scored significantly higher than mannequin‐based simulation participants in overall scores (74.30% (SD ± 5.08%) vs. 59.75% (SD ± 10.14) (p = 0.04)), and technical skills aspects (77.20% (SD ± 8.01%) vs. 65.00% (SD ± 8.21%) (p = 0.01)). Mannequin‐based simulation participants initiated critical decisions faster and demonstrated a trend towards a faster mean time‐to‐completion (p = 0.06). ABS scores increased for both study groups, though was only significant for VR participants (p ≤ 0.01). VR participants liked how VR fostered independent learning but disliked the formulaic content and impaired communication‐learning compared to mannequin‐based simulation. Conclusion Both VR and mannequin‐based simulation training are effective in training junior doctors in acute surgical scenarios but present different educational benefits. Future research should recruit a larger sample size for a full comparative randomised controlled trial.

This article will not look at the incarceration of Ahmad Manasra through the prism of state violence against him, but more specifically through his radical call for “life-making”—as an abolitionist liveability against state criminality. We join Ahmad in taking a critical stance towards the politics of life—and what Aysha Odeh and Robin Kelley refer to as “freedom dreams”—refuting the state’s carceral network and the acceptance of the settler colonial necropolitical structure. In doing so, the article conceptualizes Ahmad Manasra’s multiple modes of refusal as acts of defiance against the brutality of state “unchilding,” arguing that his unending search for freedom are radical abolitionist cries that cannot be overlooked.