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Background: Coronary artery disease (CAD) and severe aortic valve stenosis (AS) frequently coexist. While pre-transcatheter aortic valve replacement (TAVR) computed tomography angiography (CTA) allows to rule out obstructive CAD, interpreting hemodynamic significance of intermediate stenoses is challenging. This study investigates the incremental value of CT-derived fractional flow reserve (CT-FFR), quantitative coronary plaque characteristics (e.g., stenosis degree, plaque volume, and composition), and peri-coronary adipose tissue (PCAT) density to detect hemodynamically significant lesions among those with AS and CAD. Materials and methods: We included patients with severe AS and intermediate coronary lesions (20–80% diameter stenosis) who underwent pre-TAVR CTA and invasive coronary angiogram (ICA) with resting full-cycle ratio (RFR) assessment between 08/16 and 04/22. CTA image analysis included assessment of CT-FFR, quantitative coronary plaque analysis, and PCAT density. Coronary lesions with RFR ≤ 0.89 indicated hemodynamic significance as reference standard. Results: Overall, 87 patients (age 77.9 ± 7.4 years, 38% female) with 95 intermediate coronary artery lesions were included. CT-FFR showed good discriminatory capacity (area under receiver operator curve (AUC) = 0.89, 95% confidence interval (CI) 0.81–0.96, p < 0.001) to identify hemodynamically significant lesions, superior to anatomical assessment, plaque morphology, and PCAT density. Plaque composition and PCAT density did not differ between lesions with and without hemodynamic significance. Univariable and multivariable analyses revealed CT-FFR as the only predictor for functionally significant lesions (odds ratio 1.28 (95% CI 1.17–1.43), p < 0.001). Overall, CT-FFR ≤ 0.80 showed diagnostic accuracy, sensitivity, and specificity of 88.4% (95%CI 80.2–94.1), 78.5% (95%CI 63.2–89.7), and 96.2% (95%CI 87.0–99.5), respectively. Conclusion: CT-FFR was superior to CT anatomical, plaque morphology, and PCAT assessment to detect functionally significant stenoses in patients with severe AS. Clinical relevance statement: CT-derived fractional flow reserve in patients with severe aortic valve stenosis may be a useful tool for non-invasive hemodynamic assessment of intermediate coronary lesions, while CT anatomical, plaque morphology, and peri-coronary adipose tissue assessment have no incremental or additional benefit. These findings might help to reduce pre-transcatheter aortic valve replacement invasive coronary angiogram. Key Points: • Interpreting the hemodynamic significance of intermediate coronary stenoses is challenging in pre-transcatheter aortic valve replacement CT. • CT-derived fractional flow reserve (CT-FFR) has a good discriminatory capacity in the identification of hemodynamically significant coronary lesions. • CT-derived anatomical, plaque morphology, and peri-coronary adipose tissue assessment did not improve the diagnostic capability of CT-FFR in the hemodynamic assessment of intermediate coronary stenoses. [ABSTRACT FROM AUTHOR]

Some animal species shift their activity towards increased nocturnality in disturbed habitats to avoid predominantly diurnal humans. This may alter diel overlap among species, a precondition to most predation and competition interactions that structure food webs. Here, using camera trap data from 10 tropical forest landscapes, we find that hyperdiverse Southeast Asian wildlife communities shift their peak activity from early mornings in intact habitats towards dawn and dusk in disturbed habitats (increased crepuscularity). Our results indicate that anthropogenic disturbances drive opposing behavioural adaptations based on rarity, size and feeding guild, with more nocturnality among the 59 rarer specialists' species, more diurnality for medium-sized generalists, and less diurnality for larger hunted species. Species turnover also played a role in underpinning community- and guild-level responses, with disturbances associated with markedly more detections of diurnal generalists and their medium-sized diurnal predators. However, overlap among predator-prey or competitor guilds does not vary with disturbance, suggesting that net species interactions may be conserved. Prior studies showed that humans are causing species to become more active at night. Here the authors show that this trend is not consistent across hyperdiverse wildlife communities, as camera trap surveys in Southeast Asia show that responses depend on species traits and do not affect the temporal overlap of biotic interactions. [ABSTRACT FROM AUTHOR]

Objectives: Long-term treatment with nucleoside analog (NA) reduces the risks for decompensation and hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with compensated cirrhosis (CC). However, whether antiviral therapy has differential efficacy on the risks for decompensation and HCC is insufficiently elucidated. Therefore, we investigated the disease state transition, focusing on decompensation event-specific HCC risk in NA-treated CHB patients with CC. Methods: We prospectively followed up on 1163 NA-treated CHB patients with CC every six months for up to seven years. The cumulative incidence and risk of HCC were analyzed by the Kaplan–Meier method and competing risk model. The multistate model was used to estimate the transition probabilities to HCC from different disease states. Results: HCC predominated the first liver-related events, with a 5-year cumulative incidence of 9.0%, followed by decompensation (8.3%, including 7.9% nonbleeding decompensation and 2.4% variceal bleeding) and 0.2% death. The decompensation stage had a significantly higher 5-year cumulative HCC incidence than the CC stage (27.6% vs. 9.1%; HR = 2.42, 95% CI: 1.24, 4.71). Furthermore, nonbleeding decompensation events had a higher 5-year transition probability to HCC than bleeding (27.6% vs. 15.8%; HR = 2.69, 95% CI: 1.41, 4.17). Viral suppression modified the on-treatment transition risk to HCC (1-year: HR = 0.45, 95% CI: 0.28, 0.73; 3-year: HR = 0.23, 95% CI: 0.14, 0.38). An online calculator was developed to facilitate HCC risk stratification. Conclusions: In NA-treated CHB patients with compensated cirrhosis, the risk was higher for HCC than for decompensation; more importantly, different decompensation events conferred distinct HCC risks. [ABSTRACT FROM AUTHOR]

Background: Hyperdynamic circulation in portal hypertension (PHT) depends on central neural activation. However, the initiating mechanism that signals PHT to the central neural cardiovascular-regulatory centers remains unclear. We aimed to test the hypothesis that oxidative stress in the gut initiates the signal that activates central cardiovascular nuclei in portal hypertensive rats. Methods: Two groups of rats were used. One had portal hypertension produced by partial portal vein ligation, while controls underwent sham operation. Hemodynamics including portal pressure, cardiac output, mean arterial pressure (MAP) and peripheral vascular resistance were measured. Activation of central cardiovascular nuclei was determined by immunohistochemical Fos expression in the paraventricular nucleus (PVN) of the hypothalamus. Myeloperoxidase activity, an oxidative stress marker, was measured in the jejunum. Hydrogen peroxide, the antioxidant N-acetyl-cysteine (NAC) or saline controls were administered for 12–14 days by gavage or osmotic minipumps placed in the peritoneal cavity. Results: Compared with controls, PHT rats showed increased cardiac output (54.2 ± 9.5 vs 33.6 ± 2.4 ml/min/100 g BW, p < 0.01), decreased MAP (96.2 ± 6.4 mmHg vs 103.2 ± 7.8, p < 0.01) and systemic vascular resistance (1.84 ± 0.28 vs 3.14 ± 0.19 mmHg/min/ml/100 g BW, p < 0.01). PHT rats had increased jejunal myeloperoxidase and PVN Fos expression. NAC treatment eliminated the hyperdynamic circulation, decreased jejunal myeloperoxidase and PVN Fos expression in PHT rats, but had no effect on sham controls. H2O2 significantly increased PVN Fos expression and decreased MAP. Conclusion: These results indicate that in PHT, mesenteric oxidative stress is the initial signal that activates chemoreceptors and triggers hyperdynamic circulation by central neural cardiovascular-regulatory centers. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPARγ expression was mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. PpargΔHep increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPARγ expression. Our study shows that hepatocyte PPARγ expression is associated with NASH in mice and humans. In male mice, hepatocyte PPARγ negatively regulates methionine metabolism and contributes to the progression of fibrosis. [ABSTRACT FROM AUTHOR]

Introduction: Routine screening plays a critical role in the diagnosis of hepatocellular carcinoma (HCC), but not all patients undergo consistent surveillance. This study aims to evaluate surveillance patterns and their association with diagnosis stage and survival among Medicare patients at risk for HCC. Patients and Methods: Patients with HCC and guideline-based screening eligibility who underwent imaging with ultrasound or abdominal magnetic resonance imaging (MRI) in the 2 years prior to diagnosis were identified from SEER-Medicare (2008–2015). Three surveillance cohorts were created: diagnostic (imaging only within 3 months prior), intermittent (imaging only once within 2 years prior, excluding diagnostic), and routine (at least two imaging encounters within 2 years prior, excluding diagnostic). Multivariable logistic regression was used to predict early-stage diagnosis (stage I–II), and 5-year survival was evaluated using the accelerated failure time method with Weibull distribution. Results: Among 2261 eligible patients, 26.1% were classified as diagnostic, 15.8% as intermittent, and 58.1% as routine surveillance. The median age was 74 years (IQR 70–78 years). The majority of patients had a preexisting cirrhosis diagnosis (81.5%). Routine and intermittent, compared with diagnostic, surveillance were predictive of early-stage disease (routine: OR 2.05, 95% CI 1.64–2.56; intermittent: OR 1.43, 95% CI 1.07–1.90). Patients who underwent routine surveillance had significantly lower risk of mortality (HR 0.84, 95% CI 0.75–0.94) compared with the diagnostic group. Conclusions: A large proportion of screening-eligible patients do not undergo routine surveillance, which is associated with late-stage diagnosis and higher risk of mortality. These findings demonstrate the impact of timely and consistent healthcare access and can guide interventions for promoting surveillance among these patients. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to compare hemodynamic characteristics of different self-expanding (SE) and balloon-expandable (BE) transcatheter heart valves (THV) in relation to native aortic annulus anatomy. Background: A patient centered THV selection becomes increasingly important as indications for transcatheter aortic valve replacement (TAVR) are extended towards lower risk populations. Methods: Hemodynamic parameters including mean gradient (MG), effective orifice area (EOA), Doppler velocity index (DVI), degree of paravalvular regurgitation (PVR) and patient-prosthesis mismatch (PPM) were compared by valve type, label size and in relation to quintiles of native aortic annulus area. Results: 2609 patients were treated at 3 centers in Germany with SAPIEN 3 (n = 1146), ACURATE Neo (n = 649), Evolut R (n = 546) or Evolut Pro (n = 268) THV. SE THVs provided superior hemodynamics in terms of larger EOA, higher DVI and lower MG compared to BE THV, especially in patients with small aortic annuli. Severe PPM was less frequent in SE treated patients. The rate of PVR ≥ moderate was comparable for SE and BE devices in smaller annular dimensions, but remarkably lower for BE TAVR in large aortic annular dimensions (> 547.64 mm2) (2% BE THV vs. > 10% for SE THV; p < 0.001). Conclusions: Patients with small aortic annular dimensions may benefit hemodynamically from SE THV. With increasing annulus size, BE THV may have advantages since PVR ≥ moderate occurs less frequently. [ABSTRACT FROM AUTHOR]

Objective: Periinterventional stroke is one of the most feared potential complication, among patients treated with transcatheter aortic valve implantation (TAVI). The purpose of this review was to investigate the incidence of cerebrovascular events and the influence of postinterventional neurologic check-up in patients undergoing TAVI. Methods: A systematic review and meta-analysis were conducted according to the PRISMA guideline. Three separate electronic searches of the public domains Medline and Clinicaltrials.gov were performed to identify the 30-day incidence of stroke within randomized controlled trials (RCTs) and registries for patients undergoing a TAVI procedure. A meta-analysis was conducted to evaluate the 30-day incidence of stroke within RCTs. Furthermore, we pooled the RCTs in which a scheduled neurological check-up was conducted or not to investigate the effect of this intervention. Results: Twenty-three studies including 399,491 TAVI patients were included, 6370 from RCTs, 833 from cerebral-embolic protection device RCTs and 392,288 were adopted from registries. The mean 30-day incidence of stroke among all reviewed studies was 2.33%. In RCTs evaluating TAVI the pooled stroke incidence was 3.86%, among RCTs focused CEP the incidence was 6.36% and in registries the incidence was 2.29%. Ten RCTs conducted scheduled neurological check-ups, the incidence in these was 4.03% and among the remaining RCTs it was 2.47%. In the meta-analysis, the pooled 30-day stroke incidence was 3.61% (95% CI 2.57–4.79%). Conclusion: This systematic review demonstrates that the stroke incidences following TAVI differ strongly according to the study design and neurological follow-up. Intense neurological testing increases the incidence of a stroke after TAVI. [ABSTRACT FROM AUTHOR]

In many childhood-onset genetic epilepsies, seizures are accompanied by neurobehavioral impairments and motor disability. In the Stargazer mutant mouse, genetic disruptions of Cacng2 result in absence-like spike-wave seizures, cerebellar gait ataxia and vestibular dysfunction, which limit traditional approaches to behavioral phenotyping. Here, we combine videotracking and instrumented home-cage monitoring to resolve the neurobehavioral facets of the murine Stargazer syndrome. We find that despite their gait ataxia, stargazer mutants display horizontal hyperactivity and variable rates of repetitive circling behavior. While feeding rhythms, circadian or ultradian oscillations in activity are unchanged, mutants exhibit fragmented bouts of behaviorally defined "sleep", atypical licking dynamics and lowered sucrose preference. Mutants also display an attenuated response to visual and auditory home-cage perturbations, together with profound reductions in voluntary wheel-running. Our results reveal that the seizures and ataxia of Stargazer mutants occur in the context of a more pervasive behavioral syndrome with elements of encephalopathy, repetitive behavior and anhedonia. These findings expand our understanding of the function of Cacng2. [ABSTRACT FROM AUTHOR]

Cirrhotic cardiomyopathy (CCM) is a recognized complication of cirrhosis and is associated with poor outcomes, especially under challenges such as surgery/liver transplantation. However, the mechanism is not clear, and the treatment is not specific. The present study aimed to evaluate the role of anti-β1-adrenergic receptor antibodies (anti-β1-AR) in CCM. We enrolled 3 groups: healthy controls, cirrhotic patients without CCM, and patients with CCM. We found that the anti-β1-AR levels in the CCM group were significantly higher than that in the non-CCM group; anti-β1-AR was positively correlated to NT-proBNP, negatively correlated to left ventricular ejection fraction, fractional shortening ((r = − 0.466, P < 0.05), and the ratio of peak early (E wave) and atrial (A wave) flow velocities (E/A (r = − 0.475, P < 0.05) in CCM patients. Anti-β1-AR is a useful predictive biomarker for the presence of CCM and eventually may also have therapeutic implications. Clinical Trials Registration: Chinese Clinical Trials No. ChiCTR 2,000,037,730 [ABSTRACT FROM AUTHOR]

Introduction: Over-expression of common inflammatory mediators in the metabolic syndrome (MetS) and in rheumatoid arthritis (RA) may lead to mutually adverse outcomes. Aim: We investigate the prevalence of MetS in a multi-ethnic population of RA patients and its effect on clinical and patient-reported outcomes. Method: Six hundred sixty RA (561 women) patients from a public-sector specialist clinic in a hospital in Singapore were assessed for MetS according to the 2009 Joint Consensus (JC) and the 2004 National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definitions. Univariable and multivariable regression modelling were used to investigate the associations between patients' demographics with MetS and MetS with RA outcomes. Results: The prevalence of MetS in our RA cohort was 49.4% and 44.9% according to the JC and NCEP ATP III definitions, respectively. The diagnosis of MetS was largely due to hypertriglyceridemia, hypertension, and obesity. MetS was associated with older age (OR 1.06 [95% CI 1.04–1.08]), Malay ethnicity (OR 1.78 [95% CI 1.02–3.09]), or Indian ethnicity (OR 3.07 [95% CI 1.68–5.59]). No significant associations between MetS and RA outcomes were observed. RA patients with MetS are more likely to suffer from stroke and ischemic heart disease. Conclusion: The prevalence of MetS in RA patients in Singapore was almost double that in the general population. MetS does not adversely affect RA outcomes but raises the risks of stroke and heart disease. RA patients, especially those older and of Indian and Malay ethnicities, should be routinely screened for MetS. Any MetS-defining condition should be actively controlled. Key Points • Approximately half of the RA sample from the Singapore RA population can be diagnosed with MetS. • Older patients, and patients of Malay and Indian ethnicities have higher odds of MetS. • MetS does not adversely affect RA outcomes but raises the risks of stroke and heart disease. [ABSTRACT FROM AUTHOR]

I argue that high level causal relationships are often more fundamental than low level causal relationships. My argument is based on some general principles governing when one causal relationship will metaphysically ground another—a phenomenon I term derivative causation. These principles are in turn based partly on our intuitive judgments concerning derivative causation in a series of representative examples, and partly on some powerful theoretical considerations in their favour. I show how these principles entail that low level causation can derive from high level causation, and in particular that neural causation can derive from mental causation. I then draw out several important consequences of this result. Most immediate among these are the implications the result has for aspirations to reduce high level causation to its low level counterpart. But the result also bears on the possibility of downward causation, the relationship between counterfactuals and causation, and the idea—familiar from both the literature on the exclusion problem and the literature on proportionality constraints on causation—that causal relationships at different levels compete for their existence. [ABSTRACT FROM AUTHOR]

Minutiae used in most fingerprint recognition devices is robust to presentation attack, but generates a high false match rate. Thus, it is applied along with orientation map or skeleton images. There has been plenty of research on security vulnerability of minutiae, whereas few research has been conducted on orientation map or skeleton images. This study analyzes vulnerability of presentation attack for skeleton images. For this purpose, it proposes a new algorithm of recovering fingerprints with the use of machine learning and skeleton image features of fingerprints. In the proposed method, we suggest the new machine learning Pix2Pix model to generate more natural images. The suggested model is developed in the way of adding a latent vector to the conventional image-to-image translation model Pix2Pix. In the experiment, fingerprints were recovered with the use of the proposed Pix2Pix model, and it was found that a fingerprint recognition device which recognized the recovered fingerprints had a high success rate of recognition. Therefore, it was proved that a fingerprint recognition device using skeleton images as well was vulnerable to presentation attack. It is expected that the algorithm proposed in this study will be very useful to many different application areas related to image processing, including biometrics, fingerprint recognition and recovery, and image surveillance. [ABSTRACT FROM AUTHOR]

Cortico-striatal projections are critical components of forebrain circuitry that regulate motivated behaviors. To enable the study of the human cortico-striatal pathway and how its dysfunction leads to neuropsychiatric disease, we developed a method to convert human pluripotent stem cells into region-specific brain organoids that resemble the developing human striatum and include electrically active medium spiny neurons. We then assembled these organoids with cerebral cortical organoids in three-dimensional cultures to form cortico-striatal assembloids. Using viral tracing and functional assays in intact or sliced assembloids, we show that cortical neurons send axonal projections into striatal organoids and form synaptic connections. Medium spiny neurons mature electrophysiologically following assembly and display calcium activity after optogenetic stimulation of cortical neurons. Moreover, we derive cortico-striatal assembloids from patients with a neurodevelopmental disorder caused by a deletion on chromosome 22q13.3 and capture disease-associated defects in calcium activity, showing that this approach will allow investigation of the development and functional assembly of cortico-striatal connectivity using patient-derived cells. Organoids representing the human striatum are generated and used to build circuits in cortico-striatal assembloids. [ABSTRACT FROM AUTHOR]

Background: Despite all efforts, mortality of out of hospital cardiac arrest (OHCA) remains high. Patients with OHCA due to a primary shockable rhythm typically have a better prognosis. However, outcome worsens if return of spontaneous circulation (ROSC) cannot be achieved quickly. There is insufficient evidence for maximum duration of resuscitation in these patients and it is unclear, which patients profit from transport under ongoing CPR. Objective: Investigate predictors for favourable neurologic outcome in OHCA patients with presumed cardiac cause due to refractory shockable rhythm (rSR). Methods: Retrospective analysis of OHCA patients that presented to a tertiary hospital due to a rSR. Results: One hundred seventy-five OHCA patients with presumed cardiac cause due to rSR were included. Overall hospital mortality was 50% and 83% of initial survivors were discharged with a good neurologic outcome [cerebral performance category (CPC) 1–2]. In patients with a time from cardiac arrest to ROSC of > 45 min, 18% survived to CPC 1–2. Independent predictors for good neurologic outcome were age, lower no-flow time and lower serum lactate levels at hospital arrival. Conclusion: In an urban setting, a significant proportion of OHCA patients with rSR can survive to a good neurologic outcome, despite very long time to ROSC. [ABSTRACT FROM AUTHOR]

In the progression of cancer, cells acquire genetic mutations that cause uncontrolled growth. Over time, the primary tumour may undergo additional mutations that allow for the cancerous cells to spread throughout the body as metastases. Since metastatic development typically results in markedly worse patient outcomes, research into the identity and function of metastasis-associated biomarkers could eventually translate into clinical diagnostics or novel therapeutics. Although the general processes underpinning metastatic progression are understood, no clear cross-cancer biomarker profile has emerged. However, the literature suggests that some microRNAs (miRNAs) may play an important role in the metastatic progression of several cancer types. Using a subset of The Cancer Genome Atlas (TCGA) data, we performed an integrated analysis of mRNA and miRNA expression with paired metastatic and primary tumour samples to interrogate how the miRNA–mRNA regulatory axis influences metastatic progression. From this, we successfully built mRNA- and miRNA-specific classifiers that can discriminate pairs of metastatic and primary samples across 11 cancer types. In addition, we identified a number of miRNAs whose metastasis-associated dysregulation could predict mRNA metastasis-associated dysregulation. Among the most predictive miRNAs, we found several previously implicated in cancer progression, including miR-301b, miR-1296, and miR-423. Taken together, our results suggest that metastatic samples have a common cross-cancer signature when compared with their primary tumour pair, and that these miRNA biomarkers can be used to predict metastatic status as well as mRNA expression. [ABSTRACT FROM AUTHOR]

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Purpose of Review: In this review, we will assess what is currently known about Candida biofilms, its epidemiology and impact on clinical practice, and the biology underlying biofilm-related antifungal drug resistance. We also review potential antifungal lock therapies and discuss what avenues are available for future discoveries for the prevention and eradication of fungal biofilms. Recent Findings: There is a multitude of in vitro tests of agents against Candida biofilms, but many of these studies have not demonstrated their utility against other Candida species and/or their efficacy in in vivo systems. This makes it particularly difficult to translate these findings for use in the clinical setting. Summary: Research has helped us to understand the complexity of biofilms and its inherent antifungal resistance. The extracellular matrix remains a significant barrier for most antifungal therapy, and thus it stands to reason that agents directed at disrupting this protective barrier could be useful in antifungal lock therapies. [ABSTRACT FROM AUTHOR]

Background: Estimating the quantitative effect of transcatheter mitral valve repair on functional parameters and quality of life is important for individual treatment decision-making. Methods: We combined data from a prospective monocentric cohort study ( N = 215) with data from a systematic literature review (PubMed search term 'mitraclip', till 30.04.2016) on patients undergoing MitraClip with at least mortality after discharge reported as an outcome. Effects on functional parameters were reported as range of mean change. Results: 36 observational studies and 1 randomized controlled trial were identified. Due to substantial heterogeneity of effect estimates ( I -heterogeneity >75%) and inadequate quality of studies with a lack of comparison group in 97.4% and lack of an independent assessment of outcomes in 86.8%, no pooled estimates were calculated. All studies reported improvements of mean New York Heart Association (NYHA) class (0.5-1.9 classes), Short-Form (SF)-12/36 scores (4.4-9.2 for physical component score, 2.6-8.9 for mental component score), 6-min walk distance [(6MWD) 2-336 m] and Minnesota Living with Heart failure questionnaire (MLWHFQ) score (−7 to −18 points), with improvements regarded as clinically relevant in 20 of 29 studies for NYHA class, in all of 7 studies for SF12/36, in 9 of 15 studies for 6MWD and in all of 8 studies for MLWHFQ. Conclusion: MitraClip therapy provides improvements in physical capacity, physical and mental functioning and disease-specific quality of life in the majority of patients. However, more comparative and high-quality studies are required for understanding the heterogeneity of results, which is crucial for optimal patient selection. [ABSTRACT FROM AUTHOR]

Objectives: Research across many fields of medicine now points towards the clinical advantages of combining regenerative procedures with platelet-rich fibrin (PRF). This systematic review aimed to gather the extensive number of articles published to date on PRF in the dental field to better understand the clinical procedures where PRF may be utilized to enhance tissue/bone formation. Materials and methods: Manuscripts were searched systematically until May 2016 and separated into the following categories: intrabony and furcation defect regeneration, extraction socket management, sinus lifting procedures, gingival recession treatment, and guided bone regeneration (GBR) including horizontal/vertical bone augmentation procedures. Only human randomized clinical trials were included for assessment. Results: In total, 35 articles were selected and divided accordingly (kappa = 0.94). Overall, the use of PRF has been most investigated in periodontology for the treatment of periodontal intrabony defects and gingival recessions where the majority of studies have demonstrated favorable results in soft tissue management and repair. Little to no randomized clinical trials were found for extraction socket management although PRF has been shown to significantly decrease by tenfold dry sockets of third molars. Very little to no data was available directly investigating the effects of PRF on new bone formation in GBR, horizontal/vertical bone augmentation procedures, treatment of peri-implantitis, and sinus lifting procedures. Conclusions: Much investigation now supports the use of PRF for periodontal and soft tissue repair. Despite this, there remains a lack of well-conducted studies demonstrating convincingly the role of PRF during hard tissue bone regeneration. Future human randomized clinical studies evaluating the use of PRF on bone formation thus remain necessary. Clinical relevance: PRF was shown to improve soft tissue generation and limit dimensional changes post-extraction, with little available data to date supporting its use in GBR. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The pathogenic mechanisms of demyelinating CMT remain unclear, and no effective therapy currently exists for this disease. The discovery that mutations in different genes can cause a similar phenotype of demyelinating peripheral neuropathy raises the possibility that there may be convergent mechanisms leading to demyelinating CMT pathogenesis. Increasing evidence indicates that ErbB receptor-mediated signaling plays a major role in the control of Schwann cell-axon communication and myelination in the peripheral nervous system. Recent studies reveal that several demyelinating CMT-linked proteins are novel regulators of endocytic trafficking and/or phosphoinositide metabolism that may affect ErbB receptor signaling. Emerging data have begun to suggest that dysregulation of ErbB receptor trafficking and signaling in Schwann cells may represent a common pathogenic mechanism in multiple subtypes of demyelinating CMT. In this review, we focus on the roles of ErbB receptor trafficking and signaling in regulation of peripheral nerve myelination and discuss the emerging evidence supporting the potential involvement of altered ErbB receptor trafficking and signaling in demyelinating CMT pathogenesis and the possibility of modulating these trafficking and signaling processes for treating demyelinating peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The main objective of this study was to investigate whether maternal adiponectin regulates fetal growth through the endocrine system in the fetal compartment. Methods: Adiponectin knockout ( Adipoq ) mice and in vivo adenovirus-mediated reconstitution were used to study the regulatory effect of maternal adiponectin on fetal growth. Primary human trophoblast cells were treated with adiponectin and a specific peroxisome proliferator-activated receptor α (PPARα) agonist or antagonist to study the underlying mechanism through which adiponectin regulates fetal growth. Results: The body weight of fetuses from Adipoq dams was significantly greater than that of wild-type dams at both embryonic day (E)14.5 and E18.5. Adenoviral vector-mediated maternal adiponectin reconstitution attenuated the increased fetal body weight induced by maternal adiponectin deficiency. Significantly increased blood glucose, triacylglycerol and NEFA levels were observed in Adipoq dams, suggesting that nutrient supply contributes to maternal adiponectin-regulated fetal growth. Although fetal blood IGF-1 concentrations were comparable in fetuses from Adipoq and wild-type dams, remarkably low levels of IGF-binding protein 1 (IGFBP-1) were observed in the serum of fetuses from Adipoq dams. IGFBP-1 was identified in the trophoblast cells of human and mouse placentas. Maternal fasting robustly increased IGFBP-1 levels in mouse placentas, while reducing fetal weight. Significantly low IGFBP-1 levels were found in placentas of Adipoq dams. Adiponectin treatment increased IGFBP-1 levels in primary cultured human trophoblast cells, while the PPARα antagonist, MK886, abolished this stimulatory effect. Conclusions/interpretation: These results indicate that, in addition to nutrient supply, maternal adiponectin inhibits fetal growth by increasing IGFBP-1 expression in trophoblast cells. [ABSTRACT FROM AUTHOR]

The exocyst is an octameric complex that orchestrates the docking and tethering of vesicles to the plasma membrane during exocytosis and is fundamental for key biological processes including growth and establishment of cell polarity. Although components of the exocyst are well conserved among fungi, the specific functions of each component of the exocyst complex unique to Candida albicans biology and pathogenesis are not fully understood. This commentary describes recent findings regarding the role of exocyst subunits Sec6 and Sec15 in C. albicans filamentation and virulence. [ABSTRACT FROM AUTHOR]

Responses are faster and more accurate when they are spatially compatible with a stimulus than when they are incompatible (the stimulus-response compatibility (SRC) effect). In studies using two-dimensional (2-D) stimulus and response sets in which stimuli and responses have both vertical (top-bottom) and horizontal (right-left) spatial relations, SRC effects are generally larger along the horizontal dimension, an effect called right-left prevalence. Several accounts have been posited to explain this asymmetry, including frames of reference to the body and spatio-anatomical constraints. We propose a new account of the right-left prevalence effect in which prevalence effects are largely determined by the spatial alignment between elements on the stimulus display and response locations on the control panel-the control-display alignment (CDA). For example, when responses are aligned below a display, 2-D stimulus and response sets share a common vertical midline that emphasizes a right-left distinction. When responses are to the right or left of the display, the shared midline is horizontal, emphasizing the top-bottom distinction and should instead lead to top-bottom prevalence effects. Participants completed two-choice, 2-D SRC tasks in four control-display configurations with a response panel centered above, below, left, and right of a projected display. As hypothesized, right-left prevalence was elicited using vertical CDA and top-bottom prevalence was elicited using horizontal CDA. The findings demonstrate that CDA largely determines prevalence effects and should be taken into account when using multidimensional stimulus and response sets. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis B (CHB) is a major public health concern, particularly in endemic areas like Asia-Pacific. Sustained virologic suppression correlates with regression of histologic fibrosis and cirrhosis. Aim: This study evaluated efficacy and safety of tenofovir disoproxil fumarate (TDF) in Asian patients through 240 weeks of treatment. Methods: Post hoc analysis of the Asian subpopulation from two phase 3 clinical studies was performed. Following a 48-week randomized, double-blind evaluation of once-daily TDF versus once-daily adefovir dipivoxil, open-label TDF for up to 240 weeks was evaluated. Patients with both baseline and week 240 liver biopsies were evaluated for histologic changes. Results: At baseline, 189/641 (29 %) patients randomized were Asian. Sixty-eight percent of Asian patients were male; 50 % were hepatitis B e antigen (HBeAg)-positive. At week 240, similar proportions of Asian (88 %) and non-Asian (87 %) patients demonstrated improvement in liver histology, and 19/22 (86 %) Asian patients with baseline cirrhosis were no longer cirrhotic. By modified intent-to-treat analysis, 74 % of Asian patients and 76 % of non-Asian patients had HBV DNA <400 copies/mL at the end of week 240 ( P = 0.602). No differences were seen in HBeAg loss or seroconversion in Asian versus non-Asian patients. No Asian patient experienced hepatitis B surface antigen loss. Safety and tolerability of TDF through week 240, including changes in renal function and in hip/spine bone mineral density (from weeks 192 to 240), were comparable between Asian and non-Asian patients. Conclusions: Long-term virologic and histologic efficacy and safety of TDF are comparable in Asian and non-Asian CHB patients. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Rituximab, an anti-CD20 monoclonal antibody that selectively depletes B cells, has shown promise in autoantibody-associated, immune-mediated disorders. As ursodeoxycholic acid (UDCA) is not successful in all patients with primary biliary cirrhosis (PBC), additional treatment options are necessary. The objective of this study was to assess the safety and efficacy of rituximab in patients with PBC refractory to UDCA.METHODS:Fourteen PBC patients refractory to UDCA received two rituximab infusions (1,000 mg) 2 weeks apart. The primary efficacy outcome was normalization and/or 25% improvement in serum alkaline phosphatase (ALP) concentration at 6 months.RESULTS:The median age was 53 years, and 92% were female and antimitochondrial antibody (AMA) positive. The median UDCA dosage was 15.3 mg/kg/day (interquartile range 14.5-17.8). Although rituximab was well tolerated, one patient withdrew due to an asthma exacerbation during the first infusion. Effective B-cell depletion was observed in the remaining 13 patients, including three that developed human anti-chimeric antibodies. ALP normalization and/or ≥25% improvement was observed in three patients (23%) at 6, 12, and 18 months. Significant reductions in median ALP (from 259 U/l at baseline to 213 U/l at 6 months; median decrease 16%), and serum IgM and AMA levels were observed at 6 months. Although fatigue was stable, pruritus improved in 60% of patients at 12 months (vs. 8% with worsening pruritus).CONCLUSIONS:Selective B-cell depletion with rituximab was safe and associated with a significant decrease in autoantibody production, but had limited biochemical efficacy in PBC patients with an incomplete response to UDCA. [ABSTRACT FROM AUTHOR]

Portal vein thrombosis (PVT) can contribute to significant morbidity and mortality; in patients with cirrhosis, this can make transplant more technically challenging. Additionally, the clot may extend further into the mesenteric and splenic veins, and disturbance of the hepatic blood flow may lead to faster progression of the cirrhosis. Development of PVT is associated with local risk factors, and many patients have associated systemic prothrombotic factors. Anticoagulation in noncirrhotic patients should be initiated at diagnosis, using low-molecular-weight heparin overlapping with vitamin K antagonists. Cirrhotic patients with PVT should be screened for varices and then anticoagulated with low-molecular-weight heparin for at least a 6-month period. All patients should be assessed for triggering factors and tumors, as well as systemic prothrombotic factors. Newer evidence suggests that prophylactic anticoagulation in patients with cirrhosis may have a role in clinical management with decreased incidence of PVT and improved survival; further study is needed. [ABSTRACT FROM AUTHOR]

Patients with burn injuries are at high risk of developing invasive fungal infections leading to increased morbidity and mortality. Burn patients undergo major physiologic changes, which produce significant alterations in the pharmacokinetics and pharmacodynamics of antimicrobial agents. These changes result from the breakdown of the body's natural barriers to infection and the systemic responses that subsequently ensue after burn injury, including systemic inflammatory responses, third spacing, and development of a hypermetabolic state. Severe burn injuries often lead to larger volumes of distribution and increased drug clearance. Limited data are available to guide the clinician in optimizing the dosing regimen of antifungals in patients with burn injuries. We present a review of antifungal pharmacokinetics and describe how these properties can be used to design rational therapeutic regimens tailored to the pharmacodynamic alterations characteristic of burn patients. [ABSTRACT FROM AUTHOR]

Heart failure is one of the most common medical diseases—almost every third 55-year-old person in the Western world is going to develop heart failure in his or her life. The development of heart failure is associated with pivotal restructuring of the β-adrenergic system. The β-adrenoceptor antagonists have emerged to be an essential part of the therapy of chronic heart failure. Three different β-adrenoceptors could be identified and characterized so far. The β1-adrenoceptors are being down-regulated, while the β3-adrenoceptors are being up-regulated. The mechanisms that are responsible for the positive impact of β-adrenoceptor antagonists are not completely understood up to now. Therefore, it is necessary to point out the crucial role of the β-adrenergic system for the regulation of the cardiovascular system and the pathogenesis of heart failure. In the recent couple of years, numerous transgenic mouse models have proven to be helpful to gain a better understanding of the function and the relevance of these receptors. This review gives an overview of the pathophysiological relevance of the β-adrenergic system for heart failure and outlines the most important insights concerning heart function, which could be derived from genetically changed mice with chronic deficiency and overexpression of the β-adrenoceptor. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The epidemiology of primary sclerosing cholangitis (PSC) has been incompletely assessed by population-based studies. We therefore conducted a population-based study to determine: (a) incidence rates of large and small duct PSC in adults and children, (b) the risk of inflammatory bowel disease on developing PSC, and (c) patterns of clinical presentation with the advent of magnetic resonance cholangiopancreatography (MRCP). METHODS: All residents of the Calgary Health Region diagnosed with PSC between 2000 and 2005 were identified by medical records, endoscopic, diagnostic imaging, and pathology databases. Demographic and clinical information were obtained. Incidence rates were determined and risks associated with PSC were reported as rate ratios (RR) with 95% confidence intervals (CI). RESULTS: Forty-nine PSC patients were identified for an age- and gender-adjusted annual incidence rate of 0.92 cases per 100,000 person-years. The incidence of small duct PSC was 0.15/100,000. In children the incidence rate was 0.23/100,000 compared with 1.11/100,000 in adults. PSC risk was similar in Crohn's disease (CD; RR 220.0, 95% CI 132.4–343.7) and ulcerative colitis (UC; RR 212.4, 95% CI 116.1–356.5). Autoimmune hepatitis overlap was noted in 10% of cases. MRCP diagnosed large duct PSC in one-third of cases. Delay in diagnosis was common (median 8.4 months). A minority had complications at diagnosis: cholangitis (6.1%), pancreatitis (4.1%), and cirrhosis (4.1%). CONCLUSIONS: Pediatric cases and small duct PSC are less common than adult large duct PSC. Surprisingly, the risk of developing PSC in UC and CD was similar. Autoimmune hepatitis overlap was noted in a significant minority of cases. [ABSTRACT FROM AUTHOR]

BACKGROUND: Octreotide and terlipressin are widely used in acute variceal hemorrhage to reduce the bleeding rate. They purportedly act by mesenteric arterial vasoconstriction, thus reducing portal venous flow (PVF) and portal pressure. Little is known about the immediate-early hemodynamic effects of these drugs.AIM: To compare the acute hemodynamic effects of octreotide and terlipressin in patients with cirrhosis.PATIENTS: Forty-two cirrhotic patients with a history of variceal bleeding were randomized to receive either octreotide 100μg intravenous bolus followed by a continuous infusion at 250μg/h (n= 21), or terlipressin 2 mg intravenous bolus (n= 21).METHODS: Mean arterial pressure (MAP), heart rate (HR), hepatic venous pressure gradient (HVPG), and PVF, assessed by duplex Doppler ultrasonography, were measured before and at 1, 5, 10, 15, 20, and 25 min after the start of drug administration.RESULTS: Octreotide markedly decreased HVPG (−44.5± 17.8%) and PVF (−30.6± 13.6%) compared to the baseline at 1 min (p<0.05). Thereafter, both variables rapidly returned toward the baseline, and by 5 min, no significant differences in HVPG (−7.1± 28.9%) and PVF (10.2± 26.2%) were noted. A similar transient effect on MAP and HR was observed. Terlipressin significantly decreased HVPG (−18.3± 11.9%) and PVF (−32.6± 10.5%) at 1 min (p<0.05) and sustained these effects at all time points. The effects on arterial pressure and HR were also sustained.CONCLUSIONS: Octreotide only transiently reduced portal pressure and flow, whereas the effects of terlipressin were sustained. These results suggest that terlipressin may have more sustained hemodynamic effects in patients with bleeding varices.(Am J Gastroenterol 2005;100:1–5) [ABSTRACT FROM AUTHOR]