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Mpox is a zoonotic disease caused by the Monkeypox virus (MPXV), and since May 2022, tens of thousands of cases have been reported in non‐endemic countries. We aimed to evaluate the suitability of different sample types for mpox diagnostic and assess the temporal dynamics of viral load. We evaluated 1914 samples from 953 laboratory‐confirmed cases. The positivity rate was higher for lesion (91.3%) and rectal swabs (86.1%) when compared with oropharyngeal swabs (69.5%) and urines (41.2%), indicating higher viral loads for the former. Supporting this, lesion and rectal swabs showed lower median PCR Ct values (Ct = 23 and Ct = 24), compared to oropharyngeal swabs and urines (Ct = 31). Stable MPXV loads were observed in swabs from lesions up to 30 days after symptoms onset, contrasting with a considerable decrease in viral load in rectal and oropharyngeal swabs. Overall, these results point to lesion swabs as the most suitable samples for detecting MPXV in the 2022–2023 multicountry outbreak and show comparable accuracy to rectal swabs up to 8 days after symptoms onset. These findings, together with the observation that about 5% of patients were diagnosed through oropharyngeal swabs while having negative lesions, suggest that multisite testing should be performed to increase diagnostic sensitivity. [ABSTRACT FROM AUTHOR]

AdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with potential antifibrotic effects. Whether AdipoRon can mitigate joint stiffness in a rabbit model of arthrofibrosis is unknown. We examined the efficacy of intravenous (IV) AdipoRon at mitigating contracture in a rabbit model of knee arthrofibrosis. Fifty‐six female New Zealand White rabbits were divided into three dosing groups: vehicle (dimethyl sulfoxide, DMSO), 2.5 mg/kg AdipoRon, and 5 mg/kg AdipoRon. AdipoRon, in DMSO, was administered IV preoperatively and for 5 days postoperatively (30 rabbits, Aim 1). AdipoRon was again dosed similarly after Kirschner wire (K‐wire) removal at 8 weeks (26 rabbits; Aim 2). The primary outcome of joint passive extension angle (PEA,°) was measured at 8, 10, 12, 16, and 24 weeks following index surgery. At 24 weeks, rabbits were euthanized and limbs were harvested to measure posterior capsular stiffness (N cm/°). In Aim 1, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 16‐week (p < 0.05). In Aim 2, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 10‐week (p < 0.05). In both aims, no significant differences were observed at later time points. Capsular stiffness was no different in any group. We are the first to report the efficacy of IV AdipoRon in a rabbit model of arthrofibrosis. We identified a significant dose‐dependent decrease in joint PEA at early time points; however, no differences were observed between groups at later time points. Clinical Significance: The present investigation provided the first assessment of AdipoRon's efficacy in mitigating knee stiffness in the current gold standard rabbit model of arthrofibrosis. Results of this investigation provided further evidence as to the potential role of AdipoRon as a preventative for arthrofibrosis in large mammals. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Magnetic resonance elastography (MRE) and vibration‐controlled transient elastography (VCTE) have the potential to assess disease progression; however, repeatability data in people with cirrhosis are lacking. We aimed to assess the effect of disease severity on measurement variability and contribute to the evidentiary basis for the qualification of repeating liver stiffness measurements (LSM) in practice and research. Methods: This prospective study included 49 adult participants (58.3% female) with cirrhosis who underwent same‐day repeat LSM examinations. The primary outcome was the same‐day, same‐operator repeatability coefficient% (RC%) and the within‐case coefficient of variation (wCV) for each modality. Secondary outcomes include the intra‐class correlation coefficient (ICC). The relationship between measurement variability (interquartile for VCTE, standard deviation for MRE) and disease severity (mean liver stiffness) was evaluated by linear regression with the coefficient of determination R2 reported. Results: Same‐day repeat MRE and VCTE exams were prospectively conducted in 33 and 45 participants, respectively. The RC% appeared 82% higher for VCTE versus MRE (38% vs. 21%), with consistent findings in head‐to‐head analyses. The wCV for VCTE and MRE was 14% and 8% respectively, indicating VCTE has 75% higher within‐subject measurement variation than MRE. ICC was excellent for LSM by VCTE (0.92) and MRE (0.96). Measurement variability increased with mean liver stiffness for VCTE (R2 = 0.78) and MRE (R2 = 0.93). Conclusion: Both VCTE and MRE demonstrated increased measurement variability with disease severity. However, MRE outperformed VCTE in terms of technical repeatability in patients with cirrhosis. These repeatability estimates may improve the qualification of NITs in practice. [ABSTRACT FROM AUTHOR]

The environment of an organism exerts selective pressures that affect mobility, feeding, reproduction as well as predator–prey and conspecific interactions. Land use changes induced by human activities modify these selective pressures and may result in the adaptation of organisms. Amphibians are ectotherms that typically show a biphasic life cycle with an aquatic and terrestrial phase, which makes them particularly sensitive to environmental change. We studied the impact of habitat modifications on palmate newt populations in the Ile de France region across four types of habitats: urban, mixed, agricultural, and natural with at least two replicates for each habitat type. We measured the morphology of newts using callipers, quantified maximal running and swimming speed and acceleration using high‐speed video recordings, and quantified the swelling of the hind limb linked to an inflammatory reaction. Our results show that in urban habitats, newts are larger and heavier and have a better body condition. Females, moreover, have a larger head in natural habitats, possibly due to diet specialisation of females during the breeding season. In mixed and agricultural habitats, newts have longer limbs and show a tendency to run faster, possibly associated with the selective pressures on movement in mixed habitats. Differences in inflammatory responses were observed between sexes but not habitat types. Overall, our results show differences in morphology and trends for differences in performance in newts living in different habitats suggesting that animals are adapting to human‐induced changes in their environment. [ABSTRACT FROM AUTHOR]

Summary: Background: Genetic factors contribute to the risk and severity of metabolic dysfunction‐associated steatotic liver disease (MASLD). However, the utility of genetic testing in risk stratification remains poorly characterised. Aims: To examine the influence of genetic risk on advanced fibrosis and cirrhosis in patients with type 2 diabetes mellitus (T2DM) and the utility of a polygenic risk score (PRS) in screening guidelines. Methods: We prospectively enrolled adults aged ≥50 years with T2DM recruited from clinics. PRS was the sum of risk alleles in PNPLA3, TM6SF2 and SERPINA1 minus the protective variant in HSD17B13. We performed magnetic resonance elastography and vibration‐controlled transient elastography to assess for advanced fibrosis and cirrhosis. Results: Of 382 included patients, the mean age and BMI were 64.8 (±8.4) years and 31.7 (±6.2) kg/m2 respectively. The prevalence of advanced fibrosis and cirrhosis were 12.3% and 5.2% respectively; higher PRS was associated with increased risk of cirrhosis (2.7% vs. 7.5%, p = 0.037). High PRS was associated with increased risk of advanced fibrosis among those with fibrosis‐4 index (FIB‐4) index <1.3 (9.6% vs. 2.3%, p = 0.036) but was not significantly different in other FIB‐4 categories. Incorporating PRS determination into the American Gastroenterological Association and American Association for the Study of Liver Diseases screening guidelines prevented approximately 20% of all participants with advanced fibrosis from being inappropriately classified as low risk. Conclusions: Utilising a well‐phenotyped, prospective cohort of adults with T2DM, we found that adding an assessment of genetic risk to recommendations to screen at‐risk populations may improve risk prediction. [ABSTRACT FROM AUTHOR]

Summary: Background: There are limited data on the prevalence and treatment of at‐risk metabolic dysfunction‐associated steatohepatitis (MASH) among patients with type 2 diabetes (T2DM) in the United States. Aim: To estimate the prevalence of at‐risk MASH in a prospectively recruited cohort of adults with T2DM using new nomenclature endorsed by multiple societies. Methods: This prospective study enrolled adults aged ≥50 with T2DM from primary care and endocrinology clinics in southern California from 2016 to 2023. Metabolic dysfunction‐associated steatotic liver disease (MASLD) was defined by an magnetic resonance imaging proton density fat fraction ≥5% and at least one metabolic risk factor without any other chronic liver disease or secondary cause for hepatic steatosis. Results: We included 530 adult patients with T2DM. The mean (±SD) age and body mass index (BMI) were 64.4 (±8.1) years and 31.5 (±6.1) kg/m2, respectively. Among patients with T2DM, the prevalence of MASLD, at‐risk MASH and cirrhosis was 69.6%, 13.6% and 6.8%, respectively. Among patients with co‐existing T2DM and obesity, the prevalence of MASLD, at‐risk MASH and cirrhosis was 77.8%, 15.9% and 9.0%, respectively, and was higher than in participants without obesity (p < 0.0001, 0.0543 and 0.0128, respectively). Conclusion: Among adults aged ≥50 years with T2DM, the prevalence of MASLD, at‐risk MASH and cirrhosis is high, posing a significant risk for liver‐related morbidity and mortality. Approximately 14% of patients with T2DM may be candidates for pharmacologic therapies specific to MASH‐related fibrosis. [ABSTRACT FROM AUTHOR]

Summary: Background & Aims: The natural progression of hepatic decompensation in metabolic dysfunction‐associated steatotic liver disease (MASLD) is not well‐characterised. We aimed to describe it by conducting a retrospective analysis. Methods: This longitudinal, retrospective analysis of well‐characterised MASLD cohorts followed for hepatic decompensation and death. The sequence of liver‐related events was evaluated, and the median time between hepatic decompensation episodes and death versus. transplantation was measured. Results: Of the 2016 patients identified, 220 (11%) developed at least one episode of hepatic decompensation during a median follow‐up of 3.2 years. Ascites was the most common first liver‐related event [153 (69.5%)], followed by hepatic encephalopathy (HE) [55 (25%)] and variceal haemorrhage (VH) [30 (13.6%)]. Eighteen out of the 220 (8.1%) patients had more than one liver‐related event as their first hepatic decompensation. Among the patients who had the first episode, 87 (39.5%) had a second episode [44 (50.5%) HE, 31 (35.6%) ascites, and 12 (13.7%) VH]. Eighteen out of 220 (8.1%) had a third episode [10 (55.5%) HE, 6 (33.3%) VH, and 2 (11.1%) ascites]. Seventy‐three out of 220 (33.1%) died, and 31 (14%) received liver transplantation. The median time from the first episode to the second was 0.7 years and 1.3 years from the second episode to the third. The median survival time from the first episode to death or transplantation was 2.0 years. Conclusion: The most common first liver‐related event in MASLD patients is ascites. The median survival from the first hepatic decompensation to either death or transplantation is 2 years. [ABSTRACT FROM AUTHOR]

The 'virtual school' is an approach to supporting care‐experienced children and young people in education. The Virtual School Head (VSH) has been a statutory role within the education landscape in England since 2014. In Scotland, where the education, social care and legal systems are distinct from those in England, there has been a recent increase in the number of local authorities utilising this concept. This research aimed to explore the role and remit of Virtual School Head Teachers (VSHTs) in Scotland, and to identify similarities and differences with those of VSHs in England, to uncover learning about the emergence of this concept and role in a new context. We conducted semi‐structured interviews with relevant post‐holders in Scotland, using key concepts from the published literature on virtual schools in England, and analysed these qualitatively to identify themes. We discuss some of the similarities and differences we identified, noting that while the purpose of the role, and the means by which it functions, were largely common to both countries, there were also nuanced differences. Key similarities included the importance of positioning within the local authority, and the development of relationships with social work. Differences were largely underpinned by the educational and legal contexts in which the post‐holders operated, and included control of budgets and specificity of remit. This research contributes to our understanding of the role of the VSHT in Scotland, and identifies some emerging features as the virtual school concept is translated to a new context. [ABSTRACT FROM AUTHOR]

Ethylenediaminetetraacetic acid (EDTA), which has two amine and four carboxylate protonation sites, forms stable complexes with lanthanide ions. This work analyzes the coordination structure, in atomic resolution, of the Eu3+ ion complexed with EDTA in all its protonation states in aqueous solution. Eu‐EDTA complexes were modeled using classical molecular dynamics (MD) simulations using force field parameters optimized with ab initio molecular dynamics (AIMD) simulations. Structures from the MD simulations were used to predict extended X‐ray absorption fine structure (EXAFS) spectra and compared with EXAFS measurements of the Eu3+ aqua ion and Eu‐EDTA complexes at pH 3 and 11. This work details how Eu‐EDTA complex coordination structures change with increasing protonation of the EDTA ligand in the complex, from the tightly bound unprotonated complex to the unbinding of the fully protonated EDTA ligand from the Eu3+ ion as both become solvated by water. Agreement between predicted and measured EXAFS spectra supports the findings from simulation. [ABSTRACT FROM AUTHOR]

Diethylenetriaminepentaacetic acid (DTPA) is a chelating agent whose complex with the Gd3+ ion is used in medical imaging. DTPA is also used in lanthanide‐actinide separation processes. As protonation of the DTPA ligand can facilitate dissociation of the Gd3+ ion from the Gd‐DTPA complex, this work investigates the coordination structures of the aqueous Gd3+ ion and its environment when chelated by DTPA in eight different DTPA protonation states. Both classical and ab initio molecular dynamics (MD) simulations are conducted to model the solvated complexes. Extended X‐ray absorption fine structure (EXAFS) measurements of the Gd3+aqua ion, and the Gd‐DTPA complex at pH 1 and 11, are compared to EXAFS spectra predicted from the MD simulations to verify the accuracy of the MD structures. The findings of this work provide atomic‐level details into the fluctuating Gd‐DTPA complex environment as the DTPA ligand gradually detaches from the Gd3+ ion with increased protonation. [ABSTRACT FROM AUTHOR]

Arthrofibrosis, which causes joint motion restrictions, is a common complication following total knee arthroplasty (TKA). Key features associated with arthrofibrosis include myofibroblast activation, knee stiffness, and excessive scar tissue formation. We previously demonstrated that adiponectin levels are suppressed within the knee tissues of patients affected by arthrofibrosis and showed that AdipoRon, an adiponectin receptor agonist, exhibited anti‐fibrotic properties in human mesenchymal stem cells. In this study, the therapeutic potential of AdipoRon was evaluated on TGFβ1‐mediated myofibroblast differentiation of primary human knee fibroblasts and in a mouse model of knee stiffness. Picrosirius red staining revealed that AdipoRon reduced TGFβ1‐induced collagen deposition in primary knee fibroblasts derived from patients undergoing primary TKA and revision TKA for arthrofibrosis. AdipoRon also reduced mRNA and protein levels of ACTA2, a key myofibroblast marker. RNA‐seq analysis corroborated the anti‐myofibrogenic effects of AdipoRon. In our knee stiffness mouse model, 6 weeks of knee immobilization, to induce a knee contracture, in conjunction with daily vehicle (DMSO) or AdipoRon (1, 5, and 25 mg/kg) via intraperitoneal injections were well tolerated based on animal behavior and weight measurements. Biomechanical testing demonstrated that passive extension angles (PEAs) of experimental knees were similar between vehicle and AdipoRon treatment groups in mice evaluated immediately following immobilization. Interestingly, relative to vehicle‐treated mice, 5 mg/kg AdipoRon therapy improved the PEA of the experimental knees in mice that underwent 4 weeks of knee remobilization following the immobilization and therapy. Together, these studies revealed that AdipoRon may be an effective therapeutic modality for arthrofibrosis. [ABSTRACT FROM AUTHOR]

Summary: Background: Progression to cirrhosis in non‐alcoholic steatohepatitis (NASH) is associated with a decrease in liver fat. However, the prognostic significance of liver fat content in NASH‐related significant fibrosis and cirrhosis is unclear. Aim: To investigate the risk of decompensation, hepatocellular carcinoma (HCC) and mortality stratified by liver fat content in NASH‐related significant fibrosis and cirrhosis. Methods: In this meta‐analysis of individual participant data, 456 patients with both magnetic resonance elastography (MRE) and MRI‐derived protein density fat fraction (MRI‐PDFF) were enrolled, and 296 patients with longitudinal follow‐up were analysed. MRE combined with fibrosis‐4 (MEFIB‐index), and MRI‐PDFF were used to measure liver fibrosis and fat, respectively. MEFIB‐negative, MEFIB‐positive+ MRI‐PDFF ≥5% and MEFIB‐positive+ MRI‐PDFF <5% were defined as no significant liver fibrosis, NASH with significant fibrosis and higher liver fat content, and NASH with significant fibrosis and low liver fat content groups, respectively. The primary outcome was hepatic decompensation, HCC and death. Results: The rates of decompensation, HCC and mortality were highest in the NASH with significant fibrosis and low liver fat group (33%, 17% and 17%, respectively), followed by the NASH with significant fibrosis and higher liver fat group (18%, 13% and 13% respectively), and lowest in the no significant fibrosis (MEFIB‐negative) group (0%, 1% and 2% respectively). In multivariable‐adjusted analysis, low liver fat content was strongly associated (HR = 42.2 [95% CI: 7.5–235.5, p < 0.0001]) with HCC, decompensation and death. Sensitivity analyses for patients with cirrhosis (MRE ≥5 kPa) determined consistent findings. Conclusions: Low liver fat content in patients with burnt‐out NASH‐related significant fibrosis and cirrhosis is associated with an increase in hepatic decompensation, HCC and mortality. [ABSTRACT FROM AUTHOR]

Genetics and omics studies of Alzheimer's disease and other dementia subtypes enhance our understanding of underlying mechanisms and pathways that can be targeted. We identified key remaining challenges: First, can we enhance genetic studies to address missing heritability? Can we identify reproducible omics signatures that differentiate between dementia subtypes? Can high‐dimensional omics data identify improved biomarkers? How can genetics inform our understanding of causal status of dementia risk factors? And which biological processes are altered by dementia‐related genetic variation? Artificial intelligence (AI) and machine learning approaches give us powerful new tools in helping us to tackle these challenges, and we review possible solutions and examples of best practice. However, their limitations also need to be considered, as well as the need for coordinated multidisciplinary research and diverse deeply phenotyped cohorts. Ultimately AI approaches improve our ability to interrogate genetics and omics data for precision dementia medicine. Highlights: We have identified five key challenges in dementia genetics and omics studies.AI can enable detection of undiscovered patterns in dementia genetics and omics data.Enhanced and more diverse genetics and omics datasets are still needed.Multidisciplinary collaborative efforts using AI can boost dementia research. [ABSTRACT FROM AUTHOR]

Summary: Background: There are limited data regarding the longitudinal association between MEFIB‐Index (MRE combined with FIB‐4) versus MAST‐Score (MRI‐aspartate aminotransferase) and hepatic decompensation. Aim: To examine the longitudinal association between MEFIB‐Index versus MAST‐Score in predicting hepatic decompensation in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). Methods: This was a longitudinal, retrospective analysis of subjects from United States, Japan, and Turkey who underwent a baseline MRE and MRI‐PDFF and were followed for hepatic decompensation. Cox‐proportional hazard analyses were used to assess the association between MEFIB‐Index versus MAST‐Score with a composite primary outcome (hepatic decompensation) defined as ascites, hepatic encephalopathy, and varices needing treatment. Results: This meta‐analysis of individual participants (IPDMA) included 454 patients (58% women) with a mean (±SD) age of 56.0 (±13.5) years. The MEFIB‐Index (MRE ≥3.3 kPa + FIB 4 ≥1.6) and MAST‐Score (>0.242) were positive for 34% and 9% of the sample, respectively. At baseline, 23 patients met criteria for hepatic decompensation. Among 297 patients with available longitudinal data with a median (IQR) of 4.2 (5.0) years of follow‐up, 25 incident cases met criteria for hepatic decompensation. A positive MEFIB‐Index [HR = 49.22 (95% CI: 6.23–388.64, p < 0.001)] and a positive MAST‐Score [HR = 3.86 (95% CI: 1.46–10.17, p < 0.001)] were statistically significant predictors of the incident hepatic decompensation. MEFIB‐Index (c‐statistic: 0.89, standard error (SE) = 0.02) was statistically superior to the MAST‐Score (c‐statistic: 0.81, SE = 0.03) (p < 0.0001) in predicting hepatic decompensation. Conclusion: A combination of MRI‐based biomarker and blood tests, MEFIB‐Index and MAST‐Score can predict the risk of hepatic decompensation in patients with MASLD. [ABSTRACT FROM AUTHOR]

The current study investigated the assessment of depression, anxiety, and stress during normal and COVID‐19 pandemic conditions. Generalisability theory (G‐theory) was applied to examine stable and dynamic aspects of psychological distress and the overall reliability of the Depression, Anxiety and Stress Scales (DASS‐21), using data from two independent samples collected on three occasions with 2‐ to 4‐week intervals. The US data (n = 115) was collected before the COVID‐19 pandemic, and the New Zealand (NZ) data (n = 114) was obtained during the pandemic. The total DASS‐21 demonstrated excellent reliability in measuring enduring symptoms of psychological distress (G =.94–.96) across both samples. While all DASS‐21 subscales demonstrated good reliability with the pre‐pandemic US sample, the subscales' reliability was below an acceptable level for the NZ sample. Findings from this study indicate that the overall psychological distress is enduring and can be reliably measured by the DASS‐21 across different conditions and populations, while shifts across depression, anxiety and stress levels are likely during emergency and uncertainty, as seen in the COVID‐19 pandemic. [ABSTRACT FROM AUTHOR]

Many patients with pulmonary arterial hypertension (PAH) experience substantial delays in diagnosis, which is associated with worse outcomes and higher costs. Tools for diagnosing PAH sooner may lead to earlier treatment, which may delay disease progression and adverse outcomes including hospitalization and death. We developed a machine‐learning (ML) algorithm to identify patients at risk for PAH earlier in their symptom journey and distinguish them from patients with similar early symptoms not at risk for developing PAH. Our supervised ML model analyzed retrospective, de‐identified data from the US‐based Optum® Clinformatics® Data Mart claims database (January 2015 to December 2019). Propensity score matched PAH and non‐PAH (control) cohorts were established based on observed differences. Random forest models were used to classify patients as PAH or non‐PAH at diagnosis and at 6 months prediagnosis. The PAH and non‐PAH cohorts included 1339 and 4222 patients, respectively. At 6 months prediagnosis, the model performed well in distinguishing PAH and non‐PAH patients, with area under the curve of the receiver operating characteristic of 0.84, recall (sensitivity) of 0.73, and precision of 0.50. Key features distinguishing PAH from non‐PAH cohorts were a longer time between first symptom and the prediagnosis model date (i.e., 6 months before diagnosis); more diagnostic and prescription claims, circulatory claims, and imaging procedures, leading to higher overall healthcare resource utilization; and more hospitalizations. Our model distinguishes between patients with and without PAH at 6 months before diagnosis and illustrates the feasibility of using routine claims data to identify patients at a population level who might benefit from PAH‐specific screening and/or earlier specialist referral. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Whether hepatocellular carcinoma (HCC) increases the familial risk for hepatic fibrosis has not been thoroughly explored, particularly in Mexican Americans who are disproportionately affected by obesity and metabolic syndrome. We evaluated the risk of significant hepatic fibrosis in first‐degree relatives of Mexican American adults with HCC. Methods: We performed a cross‐sectional analysis of a prospective cohort of Mexican American probands with HCC and first‐degree relatives enrolled in the Hispanic Liver Cancer Cohort study. We evaluated the prevalence of hepatic fibrosis in first‐degree relatives, defined by liver stiffness measurement (LSM) >= 7.0 kPa with transient elastography (TE). Secondary outcomes included the prevalence of definite hepatic steatosis, defined by controlled attenuation parameter >=288 dB/m. Results: We identified 70 probands diagnosed with HCC; 47% were female and the mean age was 62 years (±13 years). Among 112 first‐degree relatives with a mean age of 43 years (±14 years), 19 (17%) had significant fibrosis and 47 (42%) had definite hepatic steatosis, respectively. The prevalence of significant fibrosis was 20% in first‐degree relatives 40 years of age or older. Regression analysis revealed that diabetes (OR 3.2, 95% CI: 1.1–9.2, p = 0.03) and aspartate aminotransferase >=30 units/L (OR 4.0, 95% CI: 1.4–11.7, p = 0.01) were predictors of significant fibrosis in first‐degree relatives. Conclusions: Using a well‐phenotyped familial cohort, we found that the prevalence of significant fibrosis and definite hepatic steatosis are high in first‐degree relatives of Mexican Americans with HCC, particularly those with diabetes, suggesting that this population may benefit from screening for liver disease. [ABSTRACT FROM AUTHOR]

Aims: Epigenetic clocks are widely applied as surrogates for biological age in different tissues and/or diseases, including several neurodegenerative diseases. Despite white matter (WM) changes often being observed in neurodegenerative diseases, no study has investigated epigenetic ageing in white matter. Methods: We analysed the performances of two DNA methylation-based clocks, DNAmClockMulti and DNAmClockCortical, in post-mortem WM tissue from multiple subcortical regions and the cerebellum, and in oligodendrocyte-enriched nuclei. We also examined epigenetic ageing in control and multiple system atrophy (MSA) (WM and mixed WM and grey matter), as MSA is a neurodegenerative disease comprising pronounced WM changes and α-synuclein aggregates in oligodendrocytes. Results: Estimated DNA methylation (DNAm) ages showed strong correlations with chronological ages, even in WM (e.g., DNAmClockCortical, r = [0.80-0.97], p < 0.05). However, performances and DNAm age estimates differed between clocks and brain regions. DNAmClockMulti significantly underestimated ages in all cohorts except in the MSA prefrontal cortex mixed tissue, whereas DNAmClockCortical tended towards age overestimations. Pronounced age overestimations in the oligodendrocyte-enriched cohorts (e.g., oligodendrocyte-enriched nuclei, p = 6.1 x 10-5) suggested that this cell type ages faster. Indeed, significant positive correlations were observed between estimated oligodendrocyte proportions and DNAm age acceleration estimated by DNAmClockCortical (r > 0.31, p < 0.05), and similar trends were obtained with DNAmClockMulti. Although increased age acceleration was observed in MSA compared with controls, no significant differences were detected upon adjustment for possible confounders (e.g., cell-type proportions). Conclusions: Our findings show that oligodendrocyte proportions positively influence epigenetic age acceleration across brain regions and highlight the need to further investigate this in ageing and neurodegeneration. [ABSTRACT FROM AUTHOR]

Aims: Synaptic dysfunction in Parkinson's disease is caused by propagation of pathogenic α‐synuclein between neurons. Previously, in multiple system atrophy (MSA), pathologically characterised by ectopic deposition of abnormal α‐synuclein predominantly in oligodendrocytes, we demonstrated that the occurrence of memory impairment was associated with the number of α‐synuclein‐positive neuronal cytoplasmic inclusions (NCIs) in the hippocampus. In the present study, we aimed to investigate how abnormal α‐synuclein in the hippocampus can lead to memory impairment. Methods: We performed pathological and biochemical analyses using a mouse model of adult‐onset MSA and human cases (MSA, N = 25; Parkinson's disease, N = 3; Alzheimer's disease, N = 2; normal controls, N = 11). In addition, the MSA model mice were examined behaviourally and physiologically. Results: In the MSA model, inducible human α‐synuclein was first expressed in oligodendrocytes and subsequently accumulated in the cytoplasm of excitatory hippocampal neurons (NCI‐like structures) and their presynaptic nerve terminals with the development of memory impairment. α‐Synuclein oligomers increased simultaneously in the hippocampus of the MSA model. Hippocampal dendritic spines also decreased in number, followed by suppression of long‐term potentiation. Consistent with these findings obtained in the MSA model, post‐mortem analysis of human MSA brain tissues showed that cases of MSA with memory impairment developed more NCIs in excitatory hippocampal neurons along with α‐synuclein oligomers than those without. Conclusions: Our results provide new insights into the role of α‐synuclein oligomers as a possible pathological cause of memory impairment in MSA. [ABSTRACT FROM AUTHOR]

Amyloidosis is a systemic disease, characterized by deposition of amyloid fibrils in various organs, including the heart. For the diagnosis of cardiac amyloidosis (CA) it is required a high level of clinical suspicion and in the presence of clinical, laboratorial, and electrocardiographic red flags, a comprehensive multimodality imaging evaluation is warranted, including echocardiography, magnetic resonance, scintigraphy, and computed tomography, that will confirm diagnosis and define the CA subtype, which is of the utmost importance to plan a treatment strategy. We will review the use of multimodality imaging in the evaluation of CA, including the latest applications, and a practical flow-chart will sum-up this evidence. [ABSTRACT FROM AUTHOR]

Males evolved plastic strategies to respond to male–male competition and exhibit adaptive traits and behaviors maximizing their access to the females and limiting sperm competition. Mating behaviors allow males to express quick responses to current sexual audience, that is, the number of nearby conspecifics prone to mate. In contrast, physiological responses are frequently delayed because they are constrained by the time and resources having to be mobilized to produce and export sperm and associated products. This is especially critical in species for which males produce spermatophores. Here we investigated in what extend moth males (the tortricid moth Lobesia botrana) producing spermatophores exhibit plastic behavioral and physiological responses to different sexual audiences before and during mating and the consequences for their reproductive output. We found that males adjusted their mating behaviors and spermatophore size to a potentially elevated risk of sperm competition perceived before mating. In addition, males responded to the closed presence of females during mating by reducing their mating duration. Surprisingly, the various behavioral and physiological responses we highlighted here were not fully reflected in their reproductive performance as we did not reveal any effect on fecundity and fertility of their mate. The selective pressure exerted on males experiencing male–male competition could thus be sufficient to trigger adjustment in male mating behaviors but constrains physiological responses according to the perception of competition. [ABSTRACT FROM AUTHOR]

Online parenting programs are an effective way to teach behavioral management skills to parents in the absence of in‐person resources. This community‐engaged study aimed to examine strategies for disseminating online parenting resources in schools. Online resources were disseminated to parents in a Northern California school district. Dissemination strategies were informed by conversations with school principals, teachers, and parents and considered agent, message, and format. A total of 685 parents and teachers clicked on the online resources: 151 parents and 114 teachers attended synchronous classes. The use of dissemination strategies had a compounding influence on the number of synchronous class attendees and clicks. Emails sent by the school district yielded the greatest number of clicks, which was influenced by message content and format. A community–academic partnership (CAP) led to the dissemination of evidence‐based online parenting resources to a large population and led to lessons learned that could inform future research involving CAPs. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Patients with nonalcoholic fatty liver disease (NAFLD) cirrhosis benefit from referral to subspecialty care. While several clinical prediction rules exist to identify advanced fibrosis, the cutoff for excluding cirrhosis due to NAFLD is unclear. This analysis compared clinical prediction rules for excluding biopsy‐proven cirrhosis in NAFLD. Methods: Adult patients were enrolled in the NASH Clinical Research Network (US) and the Newcastle Cohort (UK). Clinical and laboratory data were collected at enrolment, and a liver biopsy was taken within 1 year of enrolment. Optimal cutoffs for each score (eg, FIB‐4) to exclude cirrhosis were derived from the US cohort, and sensitivity, specificity, positive predictive value, negative predictive value and AUROC were calculated. The cutoffs were evaluated in the UK cohort. Results: 147/1483 (10%) patients in the US cohort had cirrhosis. All prediction rules had similarly high NPV (0.95–0.97). FIB‐4 and NAFLD fibrosis scores were the most accurate in characterising patients as having cirrhosis (AUROC 0.84–0.86). 59/494 (12%) patients in the UK cohort had cirrhosis. Prediction rules had high NPV (0.92–0.96), and FIB‐4 and NAFLD fibrosis score the most accurate in the prediction of cirrhosis in the UK cohort (AUROC 0.87–0.89). Conclusions: This cross‐sectional analysis of large, multicentre international datasets shows that current clinical prediction rules perform well in excluding cirrhosis with appropriately chosen cutoffs. These clinical prediction rules can be used in primary care to identify patients, particularly those who are white, female, and <65, unlikely to have cirrhosis so higher‐risk patients maintain access to specialty care. [ABSTRACT FROM AUTHOR]

This study is among the first to investigate whether patterns of access to basic services could explain the disproportionately severe impact of COVID‐19 in slums. Using geolocated containment zones and COVID‐19 case data for Mumbai, India's most populous city, we find that cases and case fatality rates are higher in slums compared with formal residential buildings. Our results show that access to toilets for men is associated with lower COVID‐19 prevalence. However, the effect is opposite in the case of toilets for women. This could be because limited hours for safely using toilets and higher waiting times increase the risk of exposure, and women and children sharing toilet facilities results in crowding. Proximity to water pipelines has no effect on prevalence, likely because slumdwellers are disconnected from formal water supply networks. Indoor crowding does not seem to have an effect on case prevalence. Finally, while police capacity—measured by number of police station outposts—is associated with lower prevalence in nonslum areas, indicating effective enforcement of containment, this relationship does not hold in slums. The study highlights the urgency of finding viable solutions for slum improvement and upgrading to mitigate the effects of contagion for some of the most vulnerable populations. [ABSTRACT FROM AUTHOR]

Introduction. The anterior compartment of the arm consists of three muscles: the biceps brachii (BB), brachialis, and coracobrachialis muscle. The aim of the present study was to characterize possible variations in the supernumerary heads of the biceps brachii and use these to prepare an accurate classification of the area that could be used for planning surgical procedures in the region. Material and Methods. One hundred (51 left and 49 right, 52 females and 48 males) upper limbs fixed in 10% formalin solution were examined. Results. Four types of supernumerary BB heads were identified, with subtypes. Type I was the most common type, characterized by the two heads (64%); this was subdivided into Type IA, with a single muscle belly, and Type IB with two muscle bellies. The second most common type was Type II, which was characterized by the three BB heads (26%). This type was divided into four subtypes (A-D): Type IIa characterized by attachment to the middle part of the shaft of the humerus; Type IIb characterized by the origin to the coracoid process together with the short head of the BB; Type IIc characterized by origin to the tendon of the pectoralis major muscle; and Type IId characterized by the attachment to the capsule of the humeral joint. The third most common type was Type III, which was characterized by four heads (6%); this was divided into Type IIIa, where two heads originated from the humerus bone, and Type IIIb, where one head originated from the short heads and the second from the long head of the BB. The rarest type was Type IV (4%) which was characterized by five heads: the short head originated from the coracoid process and the long head originated from the supraglenoid tubercle, the third and fourth head originated from the shaft of the humerus, while the fifth head originated from the pectoralis major muscle. Conclusion. The biceps brachii is characterized by very high morphological variability. The new classification proposes four types of supernumerary head arrangement (I-IV), divided into subtypes. This classification has both clinical and anatomical significance. [ABSTRACT FROM AUTHOR]

Aims: A decrease in carbohydrate antigen 125 (CA‐125) predicts survival advantage in chronic heart failure (HF); the impact of its variation in acute HF is unknown. We studied the association of CA‐125 decrease with prognosis in acute HF. Methods and results: We studied acute hospitalized HF patients. Predictors of admission and discharge CA‐125 were determined by linear regression. Follow‐up was 1 year; endpoint was all‐cause death. The association of admission and discharge CA‐125 with mortality was assessed using a Cox‐regression analysis. A Cox‐regression analysis was also used to assess the prognostic impact of CA‐125 decrease during hospitalization. Analysis was stratified by length of hospital stay (LOS). We studied 363 patients, 51.5% male, mean age 75 ± 12 years, 51.5% ischaemic, 30.0% with preserved ejection fraction, and 57.3% with reduced ejection fraction; patients presented elevated comorbidity burden. Median LOS was 7 (5–11) days. In the subgroup of 262 patients with CA‐125 measured both at admission and at discharge, we reported a significant increase in its levels: 56.0 (26.0–160.7) U/mL to 74.0 (32.3–195.0) U/mL. Independent predictors of admission CA‐125 were higher BNP and lower creatinine. Predictors of discharge CA‐125 were higher discharge BNP, lower discharge albumin, and younger age. Both admission and discharge CA‐125 predicted mortality. During follow‐up, 75 (31.8%) patients died. A decrease in CA‐125 predicted a 68% reduction in the 1 year death risk only in patients with LOS > 10 days. Conclusions: Our results suggest that an early re‐evaluation (>10 days) with CA‐125 measurement after an acute HF hospitalization may be of interest in patient management. [ABSTRACT FROM AUTHOR]

Summary: Background: Retrospective studies report that visualisation of the liver may be severely limited using ultrasound (US), potentially contributing to diminished sensitivity for detection of hepatocellular carcinoma (HCC) among patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, but there are limited prospective data. Aims: To compare liver visualisation scores prospectively for US and abbreviated hepatobiliary phase (HBP) magnetic resonance imaging (AMRI) in a cohort of participants with NAFLD cirrhosis and a clinical indication for HCC surveillance. Methods: This prospective multicenter study included 54 consecutive participants (67% women) with NAFLD cirrhosis who underwent contemporaneous US as well as HBP‐AMRI with gadoxetic acid. Primary outcome was the proportion of imaging examinations with severe limitations in liver visualisation (visualisation score C) compared head‐to‐head between US and AMRI. Results: The mean (± standard deviation) age was 63.3 years (±8.4) and body mass index was 32.0 kg/m2 (±6.0). Nineteen participants (35%) had severe visualisation limitations on US, compared with 10 (19%) with AMRI, p < 0.0001. Nine (17%) participants had <90% of the liver visualised on US, compared with only 1 (2%) participant with AMRI, p < 0.0001. Obesity was a strong and independent predictor for severe visualisation limitation on US (OR 5.1, CI 1.1–23.1, p = 0.03), after adjustment for age, sex and ethnicity. Conclusion: More than one‐third of participants with NAFLD cirrhosis had severe visualisation limitations on US for HCC screening, compared with one‐sixth on AMRI. US adequacy should be reported in all clinical studies and when suboptimal then AMRI may be considered for HCC screening. [ABSTRACT FROM AUTHOR]

The actin motor protein myosin VI is a multivalent protein with diverse functions. Here, we identified and characterised a myosin VI ubiquitous interactor, the oral‐facial‐digital syndrome 1 (OFD1) protein, whose mutations cause malformations of the face, oral cavity, digits and polycystic kidney disease. We found that myosin VI regulates the localisation of OFD1 at the centrioles and, as a consequence, the recruitment of the distal appendage protein Cep164. Myosin VI depletion in non‐tumoural cell lines causes an aberrant localisation of OFD1 along the centriolar walls, which is due to a reduction in the OFD1 mobile fraction. Finally, loss of myosin VI triggers a severe defect in ciliogenesis that could be, at least partially, ascribed to an impairment in the autophagic removal of OFD1 from satellites. Altogether, our results highlight an unprecedent layer of regulation of OFD1 and a pivotal role of myosin VI in coordinating the formation of the distal appendages and primary cilium with important implications for the genetic disorders known as ciliopathies. Synopsis: The actin motor myosin VI is critical for the correct localization of the Oral‐facial‐digital syndrome 1 protein (OFD1) at the centrioles distal tip and for OFD1 removal from the centriolar satellites during primary ciliogenesis. Myosin VI localizes at centrioles and interacts with the centriolar protein OFD1.Loss of myosin VI causes cell cycle arrest in p53‐proficient cells.Myosin VI depletion induces an aberrant accumulation of OFD1 at centrioles caused by altered OFD1 turnover.The myosin VI‐OFD1 axis is essential for primary ciliogenesis. [ABSTRACT FROM AUTHOR]

Peer victimization is common and linked to maladjustment. Prior research has typically identified four peer victimization subgroups: aggressors, victims, aggressive‐victims, and uninvolved. However, findings related to sex and racial‐ethnic differences in subgroup membership have been mixed. Using data collected in September of 2002 and 2003, this study conducted confirmatory latent class analysis of a racially‐ethnically diverse sample of 5415 sixth graders (49% boys; 50.6% Black; 20.9% Hispanic) representing two cohorts from 37 schools in four U.S. communities to replicate the four subgroups and evaluate measurement invariance of latent class indicators across cohort, sex, race‐ethnicity, and study site. Results replicated the four‐class solution and illustrated that sociodemographic differences in subgroup membership were less evident after accounting for differential item functioning. [ABSTRACT FROM AUTHOR]

Introduction. The quadriceps femoris consists of four muscles: the rectus femoris, vastus medialis, vastus intermedius, and vastus lateralis. However, the effect of additional quadriceps femoris heads on the vasti muscles and patellar ligaments is unknown. The aims of the present study are to determine the relationship between additional quadriceps femoris heads and the vasti muscles and patellar ligaments and to review the morphology of the vastus lateralis, vastus medialis, and vastus intermedius. Materials and Methods. One hundred and six lower limbs (34 male and 19 female cadavers) fixed in 10% formalin were examined. Results. On all lower extremities, the vastus lateralis consisted of superficial, intermediate, and deep layers. The vastus medialis, on the other hand, consisted of only the longus and obliquus layers. The quadriceps head had one or more supplementary heads in 106 dissected limbs from 68 cadavers (64.1%). The distal portion of the patella was wider in lower limbs without supplementary heads than in type IA but narrower than in type IIIA. In general, the distal portion of the patella was narrower in specimens with a supplementary head than in those without (19.03 SD 3.18 mm vs. 20.58 SD 2.95 mm, p = 0.03817). Other patellar ligament dimensions did not differ significantly. Conclusion. The quadriceps femoris muscle is characterized by high morphological variability. Occurrence of extra heads is at the level of 64.1%. The vastus lateralis consists of three parts (superficial, intermediate, and deep), and vastus medialis consists of two (longus and oblique). [ABSTRACT FROM AUTHOR]

Experimental analyses of posttraumatic knee arthrofibrosis utilize a rabbit model as a gold standard. However, a rodent model of arthrofibrosis offers many advantages including reduced cost and comparison with other models of organ fibrosis. This study aimed to characterize the biomechanical, histological, and molecular features of a novel posttraumatic model of arthrofibrosis in rats. Forty eight rats were divided into two equal groups. An immobilization procedure was performed on the right hind limbs of experimental rats. One group was immobilized for 4 weeks and the other for 8 weeks. Both groups were remobilized for 4 weeks. Limbs were studied biomechanically via assessment of torque versus degree of extension, histologically via whole knee specimen, and molecularly via gene expression of posterior capsular tissues. Significant differences were observed between experimental and control limbs at 4 N‐cm of torque in the 4‐week (knee extension: 115° ± 8° vs. 169° ± 17°, respectively; p = 0.007) and 8‐week immobilization groups (knee extension: 99° ± 12° vs. 174° ± 9°, respectively; p = 0.008). Histologically, in each group experimental limbs demonstrated increased posterior capsular thickness and total area of tissue when compared to control limbs (p < 0.05). Gene expression values evaluated in each group were comparable. This study presents a novel rat model of arthrofibrosis with severe and persistent knee contractures demonstrated biomechanically and histologically. Statement of clinical significance: Arthrofibrosis is a common complication following contemporary total knee arthroplasties. The proposed model is reproducible, cost‐effective, and can be employed for translational investigations studying the pathogenesis of arthrofibrosis and efficacy of neoadjuvant pharmacologic agents. [ABSTRACT FROM AUTHOR]

Objective: A group of genes have been reported to be associated with myopathies with tubular aggregates (TAs). Many cases with TAs still lack of genetic clarification. This study aims to explore the genetic background of cases with TAs in order to improve our knowledge of the pathogenesis of these rare pathological structures. Methods: Thirty‐three patients including two family members with biopsy confirmed TAs were collected. Whole‐exome sequencing was performed on 31 unrelated index patients and a candidate gene search strategy was conducted. The identified variants were confirmed by Sanger sequencing. The wild‐type and the mutant p.Ala11Thr of ALG14 were transfected into human embryonic kidney 293 cells (HEK293), and western blot analysis was performed to quantify protein expression levels. Results: Eleven index cases (33%) were found to have pathogenic variant or likely pathogenic variants in STIM1, ORAI1, PGAM2, SCN4A, CASQ1 and ALG14. Among them, the c.764A>T (p.Glu255Val) in STIM1 and the c.1333G>C (p.Val445Leu) in SCN4A were novel. Western blot analysis showed that the expression of ALG14 protein was severely reduced in the mutant ALG14 HEK293 cells (p.Ala11Thr) compared with wild type. The ALG14 variants might be associated with TAs in patients with complex multisystem disorders. Interpretation: This study expands the phenotypic and genotypic spectrums of myopathies with TAs. Our findings further confirm previous hypothesis that genes related with calcium signalling pathway and N‐linked glycosylation pathway are the main genetic causes of myopathies with TAs. [ABSTRACT FROM AUTHOR]

Background. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ended in 2002, but it is important to study its long-term outcomes during the posttrial period by incorporating posttrial antihypertensive medication uses in the analysis. Purposes. The primary aim is to explore the patterns of antihypertensive medication use during the posttrial period from Medicare Part-D data over the 11-year period from 2007 to 2017. The secondary aim is to examine the potential effects of these posttrial antihypertensive medications on the observed mortality and morbidity benefits. Methods. This is a posttrial passive follow-up study of ALLHAT participants in 567 US centers in 1994–1998 with the last date of active in-trial follow-up on March 31, 2002, by linking with their Medicare and National Death Index data through 2017 among 8,007 subjects receiving antihypertensive drugs (3,637 for chlorthalidone, 2,189 for amlodipine, and 2,181 for lisinopril). Outcomes included posttrial antihypertensive drug use, all-cause mortality, and cardiovascular disease (CVD) mortality. Results. Of 8007 subjects, 3,637 participants were initially randomized to diuretic (chlorthalidone). The majority (67.9%) of them still received diuretics in 2007, and 52.7%, 47.2%, and 44.0% received β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers (CCBs), respectively. Compared to participants who received diuretic-based antihypertensives, those who received CCB had a nonsignificantly higher risk of all-cause mortality (1.17, 0.99–1.37), whereas those who received ACE/ARB (angiotensin receptor blockers) had a significantly higher risk of all-cause mortality (1.26, 1.09–1.45). For the combined fatal or nonfatal hospitalized events, the risk of CVD was significantly higher in patients receiving CCB (1.30, 1.04–1.61) and ACE/ARB (1.49, 1.22–1.81) as compared to patients receiving diuretics. Conclusion. After the conclusion of the ALLHAT, almost all patients switched to combination antihypertensive therapies, independently by the original drug class, and the combination therapies (mostly based on diuretics) reduced the incidence of major cardiovascular outcomes and mortality. [ABSTRACT FROM AUTHOR]

Neurodegenerative movement disorders (NMDs) are age‐dependent disorders that are characterised by the degeneration and loss of neurons, typically accompanied by pathological accumulation of different protein aggregates in the brain, which lead to motor symptoms. NMDs include Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and Huntington's disease, among others. Epigenetic modifications are responsible for functional gene regulation during development, adult life and ageing and have progressively been implicated in complex diseases such as cancer and more recently in neurodegenerative diseases, such as NMDs. DNA methylation is by far the most widely studied epigenetic modification and consists of the reversible addition of a methyl group to the DNA without changing the DNA sequence. Although this research field is still in its infancy in relation to NMDs, an increasing number of studies point towards a role for DNA methylation in disease processes. This review addresses recent advances in epigenetic and epigenomic research in NMDs, with a focus on human brain DNA methylation studies. We discuss the current understanding of the DNA methylation changes underlying these disorders, the potential for use of these DNA modifications in peripheral tissues as biomarkers in early disease detection, classification and progression as well as a promising role in future disease management and therapy. [ABSTRACT FROM AUTHOR]

Aims: Multiple system atrophy (MSA) is a fatal neurodegenerative disease. Similar to Parkinson's disease (PD), MSA is an α‐synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α‐synuclein (SNCA) in oligodendrocytes. We previously identified consistent changes in myelin‐associated oligodendrocyte basic protein (MOBP) and huntingtin interacting protein 1 (HIP1) DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation. Methods: We investigated the relationship between MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays. Results: We found decreased MOBP mRNA levels significantly correlated with increased DNA methylation in MSA. For HIP1, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington's disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with SNCA. Conclusions: This study supports a role for DNA methylation in downregulation of MOBP mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA. [ABSTRACT FROM AUTHOR]

Aims: Risk stratification in acute heart failure (HF) patients can help to decide therapies and time for discharge. The potential of growth differentiation factor 15 (GDF‐15) in HF has been previously shown. We aimed to study the importance of GDF‐15‐level variations in acute HF patients. Methods and results: We retrospectively evaluated a cohort of patients hospitalized due to acute HF. GDF‐15 was measured both at admission and on the discharge day. Patients were followed‐up during a 3 year period. The endpoint under analysis was all‐cause mortality. GDF‐15 variation is equal to [(admission GDF‐15 − discharge GDF‐15)∕admission GDF‐15] × 100. Variation was categorized in levels of increase or decrease of GDF‐15. Patients were cross‐classified according to admission and discharge GDF‐15 cut‐off points. A Cox regression analysis was used to assess the prognostic impact of GDF‐15 variation and the impact of both admission and discharge GDF‐15 according to the cross‐classification. We studied a group of 249 patients with high co‐morbidity burden. Eighty‐one patients died at 1 year and 147 within 3 years. There was a modest decrease in GDF‐15 during hospitalization from a median value of 4087 to 3671 ng/mL (P = 0.02). No association existed between GDF‐15 variation and mortality. In multivariate analysis, patients with admission GDF‐15 ≥ 3500 ng/mL and discharge GDF‐15 ≥ 3000 ng/mL had a significantly higher 1 year death risk when compared with the remaining—hazard ratio = 2.59 (95% confidence interval: 1.41–4.76)—and a 3 year 1.76 (95% confidence interval: 1.08–2.87) higher death risk compared with those with both values below the cut‐off. Conclusions: Growth differentiation factor 15 decreased during an acute HF hospitalization, but its variation had no prognostic implications. The knowledge of both admission and discharge GDF‐15 added meaningful information to patients' risk stratification. [ABSTRACT FROM AUTHOR]

Summary: Background: Variants in multiple genetic loci modify the risk of non‐alcoholic fatty liver disease (NAFLD) and cirrhosis but there are limited data on the quantitative impact of variant copies on liver fibrosis. Aim: To investigate the effect of PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 genotype on liver fibrosis assessed by magnetic resonance elastography (MRE), a reproducible, accurate, continuous biomarker of liver fibrosis. Methods: This is a cross‐sectional analysis derived from a well‐characterised cohort at risk for NAFLD who underwent genotyping and MRE assessment. Liver stiffness (LS) was estimated using MRE and advanced fibrosis was defined as liver stiffness ≥3.63 kilopascals (kPa). Univariable and multivariable linear and logistic regression analysis, were used to assess the association between genotype and MRE. Results: Two hundred sixty‐four patients (63% women) with a mean age 53 (±17) years, and 31% Hispanic ethnicity with genotyping and MRE were included. The odds of advanced fibrosis were 3.1 (95% CI: 1.1‐8.9, P = 0.04) for CG and 6.5 (95% CI: 2.2‐18.9, P < 0.01) for GG compared to CC PNPLA3 genotype. Each PNPLA3 risk variant copy was associated with 0.40 kPa (95% CI: 0.19‐0.61, P < 0.01) increase in LS on MRE in analysis adjusted for age, sex and BMI and there was significant genotype‐age interaction (P < 0.01). Conversely, the protective TA allele in HSD17B13 was associated with a −0.41 kPa (95% CI: −0.76 to −0.05, P = 0.03) decrease in liver stiffness on MRE multivariable analysis. Conclusion: Knowledge of PNPLA3 and HSD17B13 genotype may assist in the non‐invasive risk stratification of NAFLD with closer monitoring recommended for those with high genetic risk. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, which includes frontotemporal dementia and progressive supranuclear palsy. About 90% of the FTLD cases show either TDP‐43 or tau pathology (FTLD‐TDP or FTLD‐tau, respectively). Though aberrant brain DNA methylation has consistently been associated with Alzheimer's disease and other neurodegenerative diseases, studies on FTLD are scarce. The main goal of this study was to investigate DNA methylation variation in FTLD bulk brain tissue and brain‐derived nuclei. Methods: We used bulk frontal cortex genome‐wide DNA methylation profiles (Illumina 450K or EPIC microarrays) from three FTLD cohorts (N = 228). To identify unique and shared differentially methylated loci across FTLD subgroups/subtypes, we performed cohort‐specific epigenome‐wide association studies (EWAS) followed by a meta‐analysis. Additionally, we used weighted gene correlation network analysis to identify co‐methylation signatures associated with FTLD, FTLD pathological subtypes, and other disease‐related traits. To identify disturbed cell‐types and biological processes within disease associated signatures, we then carried out cell‐type and functional enrichment analyses. We also generated and have ongoing analysis of DNA methylation profiles (EPIC microarrays) of neuronal (NeuN+) and glial nuclei (NeuN‐) from FTLD‐TDP cases and controls (N = 40). Wherever possible, we also integrated additional DNA methylation, and gene and protein expression datasets. Results: In bulk tissue, the EWAS meta‐analysis identified four shared differentially methylated loci in FTLD, including hypomethylation in OTUD4, a gene we found to be upregulated (mRNA and protein) in FTLD. Two of the four meta‐analysis hits (mapping to OTUD4 and CEBPZ), were found to be co‐methylated within signatures strongly associated with FTLD. Disease‐associated signatures implicate transcription regulation, the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling, and specific brain cell‐types, including pyramidal neurons and oligodendrocytes, in FTLD. Preliminary analysis of the neuronal and glial datasets also revealed FTLD‐associated DNA methylation signatures, which will further inform on cell‐type‐specific changes in FTLD. Conclusions: Our findings identified novel FTLD‐associated loci, including OTUD4, and point to DNA methylation as an important mechanism in the dysregulation of biological processes relevant to the FTLD pathogenesis, such as RNA/stress granule formation. [ABSTRACT FROM AUTHOR]

Summary: Background: Magnetic resonance elastography (MRE) is a reliable non‐invasive alternative to liver biopsy for assessing liver fibrosis. There are limited data regarding an association between liver fibrosis by MRE and risk of cardiovascular disease (CVD). Aim: To investigate the association of high‐risk CVD phenotype determined by coronary artery calcification (CAC) with liver fibrosis by MRE in patients with non‐alcoholic fatty liver disease (NAFLD). Method: This was a cross‐sectional analysis of well‐characterised, prospective cohorts including 105 patients with NAFLD (MR imaging‐derived proton density fat fraction ≥ 5%) with contemporaneous cardiac computed tomography (CT) and MRE. Patients were assessed using MRE for liver stiffness, and cardiac CT for the presence of CAC (defined as coronary artery calcium score > 0). Odds of presence of CAC were analysed using logistic regression analysis. Results: The average age and body mass index were 54.9 years and 32.9 kg/m2 respectively. In this cohort, 49.5% of patients had CAC and 35.2% had significant liver fibrosis (defined as MRE ≥2.97 kPa). Compared to patients without CAC, those with CAC were older (50.0 [39.0‐59.0] vs 63.0 [55.5‐67.5], P < 0.001) and had higher Framingham risk score (FRS, 1.0 [0.5‐3.5] vs 6.0 [2.0‐12.0], P < 0.001). In multivariable‐adjusted analysis, liver stiffness as a continuous trait on MRE was independently associated with the presence of CAC in a sex and age‐adjusted model (adjusted odd ratios [aOR] = 2.23, 95% confidence interval [CI] = 1.31‐4.34, P = 0.007) as well as in a FRS‐adjusted model (aOR = 2.16, 95% CI = 1.29‐4.09, P = 0.008). When analysed as a dichotomous trait, significant fibrosis (MRE‐stiffness ≥2.97 kPa) remained independently associated with the presence of CAC in both FRS‐adjusted model and sex and age‐adjusted model (aOR = 3.21‐3.53, P = 0.013‐0.017). In addition, CAC was more prevalent in patients with significant fibrosis than those without as determined by MRE (67.6% vs 39.7%, P = 0.012). Conclusion: Liver stiffness determined by MRE is an independent predictor for the presence of CAC in patients with NAFLD. Patients with NAFLD and significant fibrosis by MRE should be considered for further cardiovascular risk assessment, regardless of their FRS. [ABSTRACT FROM AUTHOR]

Paraganglioma is a catecholamine-secreting tumor (CST) in extra-adrenal autonomic ganglia and a rare cause of hypertension during pregnancy. If not properly treated, it can lead to disastrous outcomes for both the mother and fetus. This report describes the successful anesthetic management of a paraganglioma diagnosed during pregnancy. A pregnant woman, with 32 weeks of gestational age, presented with severe paroxysmal hypertension, refractory to methyldopa and nifedipine at maximum dosages, headache, sweating, and palpitations. Diagnostic work-up was positive for elevated serum and urinary normetanephrines, and magnetic resonance showed a solid nodule above the hilum of the right kidney, suggestive of paraganglioma. Optimal alpha-blockade was achieved with doxazosin, and given the advanced gestational age, tumor resection was postponed until after delivery. Cesarean delivery was scheduled at 34 weeks, under combined spinal-epidural anesthesia and continuous blood pressure monitoring. Antihypertensive drugs were prepared for immediate administration as needed. Intraoperative and postoperative periods went uneventfully for both the mother and newborn, both under intensive care observation for 24 h. [ABSTRACT FROM AUTHOR]

Hydroxychloroquine sulfate (HCQ) is being scrutinized for repositioning in the treatment and prevention of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. This antimalarial drug is also chronically used to treat patients with autoimmune diseases. By analyzing the Portuguese anonymized data on private and public based medical prescriptions we have identified all cases chronically receiving HCQ for the management of diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases. Additionally, we have detected all laboratory confirmed cases of SARS‐CoV‐2 infection and all laboratory confirmed negative cases in the Portuguese population (mandatorily registered in a centrally managed database). Cross linking the two sets of data has allowed us to compare the proportion of HCQ chronic treatment (at least 2 grams per month) in laboratory confirmed cases of SARS‐CoV‐2 infection with laboratory confirmed negative cases. Out of 26 815 SARS‐CoV‐2 positive patients, 77 (0.29%) were chronically treated with HCQ, while 1215 (0.36%) out of 333 489 negative patients were receiving it chronically (P =.04). After adjustment for age, sex, and chronic treatment with corticosteroids and/or immunosuppressants, the odds ratio of SARS‐CoV‐2 infection for chronic treatment with HCQ has been 0.51 (0.37‐0.70). Our data suggest that chronic treatment with HCQ confer protection against SARS‐CoV‐2 infection. Highlights: Patients under chronic treatment with hydroxychloroquine have lesser incidence of CoVID‐19. [ABSTRACT FROM AUTHOR]

Self‐compacting concrete (SCC) is a concrete that does not require vibration for casting and consolidation. It is able to flow under its own weight, completely filling the formwork and achieving full consolidation, even in the presence of congested reinforcement. SCC possesses special technical features and properties that recommend its application in a considerable amount of applications. Nevertheless, an inadequate behavior of the material at early ages has been observed in some situations, due to shrinkage. Shrinkage has a significant importance in the design, construction and in‐service performance of concrete structures. The regulatory requirements were derived from experience with traditional concrete, which is not always suitable for SCC. In addition, the option of using new materials, such as binders with large amount of pozzolanic or latent hydraulic additions, strongly limits the validity of existing rules. In order to contribute for a better understanding of the major drawback of this material—its high potential shrinkage, experimental research was carried out using different commercial shrinkage‐compensating products. This study focuses on the use of a shrinkage reducing admixture and an expansive agent. The results obtained demonstrate the efficiency of the individual or combined use of these products and allowed identifying three different strategies to control the shrinkage, with distinct levels of efficiency. [ABSTRACT FROM AUTHOR]

The processes of urban regeneration of long‐disinvested inner‐city neighbourhoods today happening in many European cities sometimes dramatically transform residents' traditional uses of their public places. Focusing on a neighbourhood renowned for its traditional public place sociability – Mouraria, in Lisbon – this study explored the psychosocial processes that may shape the maintenance of that sociability in the face of increasing social diversification and small‐scale gentrification brought about by a mixed/bottom‐up regeneration plan. A questionnaire survey (n = 201) with two types of residents ("traditional residents" and "new gentrifiers") indicated that: (a) both types report using Mouraria's public places for socializing, although traditional residents do so to a greater degree; (b) perceived cultural continuity of the neighbourhood is positively related to public place sociability for both groups; and (c) this relationship is mediated by both place identification and place knowledge; but (d) it is not moderated by type of resident. By implication, we argue that regenerated inner‐city neighbourhoods may remain as places of lively public sociability and companionship if residents are able to forge and/or retain a sense of identification with, and intimate knowledge of, the neighbourhood, and view it as maintaining continuity with the past. [ABSTRACT FROM AUTHOR]

Background: There is lack of data on the association between infective endocarditis (IE) and outcomes of mortality and complications in stroke. We aimed to compare characteristics and outcomes of stroke patients with and without IE. Methods: We retrospectively examined the above association using data obtained from an insurance database which covers ~75% of the Thai population. All hospitalised strokes between 8 January 2003 and 31 December 2013 were included in the current study. Characteristics and outcomes were compared between stroke patients with or without IE, and then between two main stroke types. Multiple logistic regression models including propensity score‐matched analyses were constructed to assess study outcomes controlling for age, sex, stroke type and comorbidities. Results: A total of 590 115 stroke patients (mean (SD) age = 64.2 ± 13.7 years; ischaemic = 51.7%; haemorrhagic = 32.6%; undetermined = 15.7%) were included, of whom 2129 (0.36%) had stroke associated with IE. After adjustment, we found that IE was significantly associated with the following complications: arrhythmias (adjusted odds ratio (95% CI) 6.94 (6.29‐7.66)), sepsis (1.24 (1.01‐1.52)), pneumonia (1.34 (1.17‐1.53)), respiratory failure (1.43 (1.24‐1.66)) and in‐hospital mortality (1.29 (1.13‐1.47)) (P for all <.001). Patients with haemorrhagic stroke with IE had poorer outcomes for in‐hospital mortality and respiratory failure compared with their counterparts with ischaemic stroke. Propensity score‐matched analysis showed similar results. Conclusions: Our results suggest that stroke patients with IE differ from that of the general stroke population and these patients have worse outcomes. Future studies are needed to determine the best treatment strategies for stroke patients with IE. [ABSTRACT FROM AUTHOR]