The effects of age on functional connectivity (FC) of intrinsic connectivity networks (ICNs) have largely been derived from cross-sectional studies. Far less is known about longitudinal changes in FC ...and how they relate to ageing-related cognitive decline. We evaluated intra- and inter-network FC in 78 healthy older adults two or three times over a period of 4years. Using linear mixed modeling we found progressive loss of functional specialization with ageing, evidenced by a decline in intra-network FC within the executive control (ECN) and default mode networks (DMN). In contrast, longitudinal inter-network FC between ECN and DMN showed a u-shaped trajectory whereby functional segregation between these two networks initially increased over time and later decreased as participants aged. The rate of loss in functional segregation between ECN and DMN was associated with ageing-related decline in processing speed. The observed longitudinal FC changes and their associations with processing speed remained after correcting for longitudinal reduction in gray matter volume. These findings help connect ageing-related changes in FC with ageing-related decline in cognitive performance and underscore the value of collecting concurrent longitudinal imaging and behavioral data.
•Longitudinal ageing decline in functional specialization of the default mode (DMN) and executive control networks (ECN).•Functional connectivity between ECN and DMN showed a u-shaped trajectory.•ECN–DMN functional segregation initially increased and later decreased with ageing.•Decline in ECN–DMN functional segregation associated with rate of decline in processing speed.•These results remained after correcting for ageing-related loss of gray matter volume.
Direct-acting antiviral (DAA) therapy is used in patients with HCV-related decompensated cirrhosis with the expectation of improving hepatic function. However, little is known about the long-term ...hepatic benefit of successful antiviral treatment.
Patients with advanced/decompensated cirrhosis (model for end-stage liver disease MELD ≥10), in whom NS5A-containing DAA therapy was initiated prior to September 2018, were included (from the HCV-TARGET cohort). Treatment outcomes and the impact of treatment on short-term and long-term hepatic function were examined.
A total of 642 patients were analyzed. The mean age was 60 years, 68% were male. The median baseline MELD was 12 (range 10–39) and 64% had prior decompensation. Among patients with available virologic outcomes, 90.5% achieved a sustained virologic response at 12 weeks (SVR12). Eighty (24%) patients achieved a clinically significant decrease in MELD by ≥3 points during short-term follow-up (9–26 weeks after the end of treatment). However, in long-term follow-up (median of 4 years after treatment), mean changes in MELD (−0.30 points), total bilirubin (+0.23 mg/dl) and albumin (+0.36 g/dl) were marginal. Fifty-one patients died and 22 underwent liver transplant. In long-term follow-up, a clinically meaningful decrease in MELD of ≥3 occurred in 29% and a final MELD score of <10 was achieved in 25%.
In a large real-world experience of patients with advanced/decompensated HCV-related cirrhosis treated with DAAs, there were only marginal improvements in MELD, total bilirubin, or albumin at long-term follow-up (after achieving SVR12). These patients may remain at high risk of decompensation and must continue to be closely monitored.
NCT01474811.
Hepatitis C virus infection can now be cured with medications, even in patients who have advanced scarring of the liver (cirrhosis). In this study, we evaluated whether liver function improves or deteriorates in the long-term, following successful treatment of hepatitis C in patients with cirrhosis. We found that overall liver function was relatively stable with only 29% of patients achieving a clinically meaningful improvement in liver function, and we therefore believe that these patients require ongoing monitoring.
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•SVR was achieved in 90.5% of patients with advanced/decompensated cirrhosis treated with direct-acting antivirals.•In long-term (>4 years) follow-up, overall mean changes in MELD, total bilirubin and albumin were marginal.•A clinically meaningful decrease in MELD of ≥3 occurred in 29% and a final MELD score of <10 was achieved in 25%.•Patients with advanced/decompensated liver disease should continue to be monitored following SVR.
Chronic hepatitis C virus infection is well-recognized as a common blood-borne infection with global public health impact affecting 3 to 5 million persons in the United States and more than 170 ...million persons worldwide. Chronic hepatitis C virus infection is associated with significant morbidity and mortality due to complications of liver cirrhosis and hepatocellular carcinoma. Current therapies with all-oral direct-acting antiviral agents are associated with high rates of sustained virologic response (SVR), generally exceeding 90%. SVR is associated with a reduced risk of liver cirrhosis, hepatic decompensation, need for liver transplantation, and both liver-related and all-cause mortality. However, a subset of patients who achieve SVR will remain at long-term risk for progression to cirrhosis, liver failure, hepatocellular carcinoma, and liver-related mortality. Limited evidence is available to guide clinicians on which post-SVR patients should be monitored vs discharged, how to monitor and with which tests, how frequently should monitoring occur, and for how long. In this clinical practice update, available evidence and expert opinion are used to generate best practice recommendations on the care of patients with chronic hepatitis C virus who have achieved SVR.
shows a strict host tropism for reticulocytes. We identified transferrin receptor 1 (TfR1) as the receptor for
reticulocyte-binding protein 2b (PvRBP2b). We determined the structure of the N-terminal ...domain of PvRBP2b involved in red blood cell binding, elucidating the molecular basis for TfR1 recognition. We validated TfR1 as the biological target of PvRBP2b engagement by means of TfR1 expression knockdown analysis. TfR1 mutant cells deficient in PvRBP2b binding were refractory to invasion of
but not to invasion of
Using Brazilian and Thai clinical isolates, we show that PvRBP2b monoclonal antibodies that inhibit reticulocyte binding also block
entry into reticulocytes. These data show that TfR1-PvRBP2b invasion pathway is critical for the recognition of reticulocytes during
invasion.
Atrial fibrillation (AF), with its significant associated morbidity and mortality contributes to significant healthcare utilisation and expenditure. Given its progressively rising incidence, ...strategies to limit AF development and progression are urgently needed. Lifestyle modification is a potentially potent but underutilised weapon against the AF epidemic. The purpose of this article is to review the role of lifestyle factors as risk factors for AF, outline potential mechanisms of pathogenesis and examine the available evidence for lifestyle intervention in primary and secondary AF prevention. It will also highlight the need for investment by physicians, researchers, health services and governments in order to facilitate delivery of the comprehensive, multidisciplinary AF care that is required to manage this complex and multifactorial disease.
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•Lifestyle modification is key to reducing AF incidence, burden and progression.•Targets include weight loss, exercise, alcohol abstinence and smoking cessation.•Collaboration at every level of healthcare is needed to improve AF care delivery.
Managing peri-mitral flutter Lim, Michael W; Kistler, Peter M
Journal of cardiovascular electrophysiology,
10/2023, Letnik:
34, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The exponential rise in the incidence of peri-mitral flutter has paralleled the increasing use of more extensive atrial substrate ablation for atrial fibrillation (AF). Given the relative paucity of ...randomized evidence to support its role in AF management, mitral isthmus ablation should largely be reserved for patients with peri-mitral flutter. Catheter ablation for peri-mitral flutter is challenging due to complex anatomic relationships. The aim of this report is to review the anatomic considerations and approaches to catheter ablation for peri-mitral flutter.
The multifunctional protein cytochrome c (cyt c) plays key roles in electron transport and apoptosis, switching function by modulating bonding between a heme iron and the sulfur in a methionine ...residue. This Fe–S(Met) bond is too weak to persist in the absence of protein constraints. We ruptured the bond in ferrous cyt c using an optical laser pulse and monitored the bond reformation within the protein active site using ultrafast x-ray pulses from an x-ray free-electron laser, determining that the Fe–S(Met) bond enthalpy is ~4 kcal/mol stronger than in the absence of protein constraints. The 4 kcal/mol is comparable with calculations of stabilization effects in other systems, demonstrating how biological systems use an entatic state for modest yet accessible energetics to modulate chemical function.
Sleep deprivation (SD) consistently degrades performance in tasks requiring sustained attention, resulting in slower and more variable response times that worsen with time-on-task. Loss of motivation ...to exert effort may exacerbate performance degradation during SD. To test this, we evaluated sustained performance on a vigilance task, combining this with an effort-based decision-making task and pupillometry. Vigilance was tested at rest and after sleep deprivation, under different incentive conditions (1, 5 or 15 cents for fast responses). Subsequently, preference measures were collected from an effort-discounting task, in which a commensurate reward was offered for maintaining attentional performance for different durations (1, 5, 10, 20 or 30 min). Vigilance was impaired during SD, in a manner modulated by reward value. Preference metrics showed that the value of available rewards was discounted by task duration, an effect compounded by SD. Pupillometry revealed that arousal was modulated during SD in a value-based manner, and moment-to-moment fluctuations in pupil diameter were directly predictive of performance. Together, these data demonstrate that attentional performance can be interpreted within a value-based effort allocation framework, such that the perceived cost of attentional effort increases after sleep deprivation.
•Sleep deprivation (SD) affects attentional performance by reducing cognitive resources.•Decline in motivation after SD may reduce the effort allocated to task performance.•We combined performance, pupillometric and preference metrics to study effort allocation.•All metrics showed a shift towards more selective allocation of attentional effort after SD.•Exerting effort thus appears to be more costly after SD.
Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity ...in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underlie clonal transcriptomic, epigenomic, and histopathologic signatures in meningioma. Stereotactic co-registration of sample coordinates to preoperative magnetic resonance images further suggest that high apparent diffusion coefficient (ADC) distinguishes meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we develop a human cerebral organoid model of meningioma and validate the high ADC marker genes CDH2 and PTPRZ1 as potential targets for meningioma therapy using live imaging, single cell RNA sequencing, CRISPR interference, and pharmacology.
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