Scar heterogeneity on cardiovascular magnetic resonance as a predictor of appropriate implantable cardioverter defibrillator therapy

Background: Despite the survival benefit of implantable-cardioverter-defibrillators (ICDs), the vast majority of patients receiving an ICD for primary prevention do not receive ICD therapy. We sought to assess the role of heterogeneous scar area (HSA) identified by late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) in predicting appropriate ICD therapy for primary prevention of sudden cardiac death (SCD). Methods: From September 2003 to March 2011, all patients who underwent primary prevention ICD implantation and had a pre-implantation LGE-CMR were identified. Scar size was determined using thresholds of 4 and 6 standard deviations (SD) above remote normal myocardium; HSA was defined using 3 different criteria; as the region between 2 SD and 4 SD (HSA2-4SD), between 2SD and 6SD (HSA2-6SD), and between 4SD and 6SD (HSA4-6SD). The end-point was appropriate ICD therapy. Results: Out of 40 total patients followed for 25 ± 24 months, 7 had appropriate ICD therapy. Scar size measured by different thresholds was similar in ICD therapy and non-ICD therapy groups (P = NS for all). However, HSA2-4SD and HSA4-6SD were significantly larger in the ICD therapy group (P = 0.001 and P = 0.03, respectively). In multivariable model HSA2-4SD was the only significant independent predictor of ICD therapy (HR = 1.08, 95%CI: 1.00-1.16, P = 0.04). Kaplan-Meier analysis showed that patients with greater HSA2-4SD had a lower survival free of appropriate ICD therapy (P = 0.026). Conclusions: In primary prevention ICD implantation, LGE-CMR HSA identifies patients with appropriate ICD therapy. If confirmed in larger series, HSA can be used for risk stratification in primary prevention of SCD

Inhibitory role of peroxisome proliferator-activated receptor gamma in hepatocarcinogenesis in mice and in vitro

Although peroxisome proliferator-activated receptor gamma (PPARγ) agonist have been shown to inhibit hepatocellular carcinoma (HCC) development, the role of PPARγ in hepatocarcinogenesis remains unclear. We investigated the therapeutic efficacy of PPAR

Emricasan (IDN-6556) Lowers Portal Pressure in Patients with Compensated Cirrhosis and Severe Portal Hypertension

Caspases play a central role in apoptosis, inflammation and fibrosis. They produce hemodynamically-active, pro-inflammatory microparticles that cause intrahepatic inflammation, vasoconstriction and extrahepatic splanchnic vasodilation. Emricasan is a pan-caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open-label study enrolled 23 subjects with compensated cirrhosis and PH (HVPG >5 mmHg). Emricasan 25 mg BID was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings.Median age was 59 (range 49-80); 70% were male. Cirrhosis etiologies were NASH and HCV. Subjects were Child class A (87%) with median MELD score of 8 (range 6-15). Twelve had severe PH (HVPG?12mmHg). Overall, there was no significant change in HVPG after emricasan (mean [SD] -1.1[4.57] mmHg). HVPG decreased significantly (mean [SD] -3.7[4.05] mmHg; p=0.003) in those with severe PH. 4/12 had a ?20% decrease; 8/12 had a ?10% decrease; and 2/12 HVPG decreased below 12mmHg. There were no significant changes in blood pressure or heart rate. AST/ALT decreased significantly in the entire group and in severe PH. Serum cCK18 and caspase-3/7 decreased significantly. Emricasan was well-tolerated. One subject discontinued for non-serious adverse events.Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH. An effect upon portal venous inflow is likely and concomitant decreases in AST/ALT suggest an intrahepatic anti-inflammatory effect

Validation of the GALS musculoskeletal screening exam for use in primary care: a pilot study

<p>Abstract</p> <p>Background</p> <p>As the proportion of the Canadian population ≥65 grows, so too does the prevalence of musculoskeletal (MSK) conditions. Approximately 20% of visits to family physicians occur as a result of MSK complaints. The GALS (Gait, Arms, Legs, and Spine) screening examination was developed to assist in the detection of MSK abnormalities. Although MSK exams are primarily performed by rheumatologists or other MSK specialists, expanding their use in primary health care may improve the detection of MSK conditions allowing for earlier treatment. The primary goal of this study was to evaluate the use of the GALS locomotor screen in primary care by comparing the results of assessments of family physicians with those of rheumatologists. The secondary goal was to examine the incidence of MSK disorders and assess the frequency with which new diagnoses not previously documented in patients' charts were identified.</p> <p>Methods</p> <p>Patients ≥65 years old recruited from an academic family health centre were examined by a rheumatologist and a family physician who recorded the appearance of each participant's gait and the appearance and movement of the arms, legs and spine by deeming them normal or abnormal. GALS scores were compared between physicians with the proportion of observed (P_obs), positive (P_pos) and negative (P_neg) agreement being the primary outcomes. Kappa statistics were also calculated. Descriptive statistics were used to describe the number of "new" diagnoses by comparing rheumatologists' findings with each patient's family practice chart.</p> <p>Results</p> <p>A total of 99 patients consented to participate (92 with previously diagnosed MSK conditions). Results showed reasonable agreement between family physicians and rheumatologists; P_obs= 0.698, P_pos= 0.614 and P_neg= 0.752. The coefficient of agreement (estimated Kappa) was 0.3675 for the composite GALS score. For individual components of the GALS exam, the highest agreement between family physicians and rheumatologists was in the assessment of gait and arm movement.</p> <p>Conclusion</p> <p>Previously reported increases in undiagnosed signs and symptoms of musculoskeletal conditions have highlighted the need for a simple yet sensitive screening exam for the identification of musculoskeletal abnormalities. Results of this study suggest that family physicians can efficiently use the GALS examination in the assessment of populations with a high proportion of musculoskeletal issues.</p

A full year of aerosol size distribution data from the central Arctic under an extreme positive Arctic Oscillation : insights from the Multidisciplinarydrifting Observatory for the Study of Arctic Climate (MOSAiC) expedition

The Arctic environment is rapidly changing due to accelerated warming in the region. The warming trend is driving a decline in sea ice extent, which thereby enhances feedback loops in the surface energy budget in the Arctic. Arctic aerosols play an important role in the radiative balance and hence the climate response in the region, yet direct observations of aerosols over the Arctic Ocean are limited. In this study, we investigate the annual cycle in the aerosol particle number size distribution (PNSD), particle number concentration (PNC), and black carbon (BC) mass concentration in the central Arctic during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition. This is the first continuous, year-long data set of aerosol PNSD ever collected over the sea ice in the central Arctic Ocean. We use a k-means cluster analysis, FLEXPART simulations, and inverse modeling to evaluate seasonal patterns and the influence of different source regions on the Arctic aerosol population. Furthermore, we compare the aerosol observations to land-based sites across the Arctic, using both long-term measurements and observations during the year of the MOSAiC expedition (2019-2020), to investigate interannual variability and to give context to the aerosol characteristics from within the central Arctic. Our analysis identifies that, overall, the central Arctic exhibits typical seasonal patterns of aerosols, including anthropogenic influence from Arctic haze in winter and secondary aerosol processes in summer. The seasonal pattern corresponds to the global radiation, surface air temperature, and timing of sea ice melting/freezing, which drive changes in transport patterns and secondary aerosol processes. In winter, the Norilsk region in Russia/Siberia was the dominant source of Arctic haze signals in the PNSD and BC observations, which contributed to higher accumulation-mode PNC and BC mass concentrations in the central Arctic than at land-based observatories. We also show that the wintertime Arctic Oscillation (AO) phenomenon, which was reported to achieve a record-breaking positive phase during January-March 2020, explains the unusual timing and magnitude of Arctic haze across the Arctic region compared to longer-term observations. In summer, the aerosol PNCs of the nucleation and Aitken modes are enhanced; however, concentrations were notably lower in the central Arctic over the ice pack than at land-based sites further south. The analysis presented herein provides a current snapshot of Arctic aerosol processes in an environment that is characterized by rapid changes, which will be crucial for improving climate model predictions, understanding linkages between different environmental processes, and investigating the impacts of climate change in future Arctic aerosol studies.Peer reviewe

Identification of Human Papillomavirus Type 58 Lineages and the Distribution Worldwide

Background. Human papillomavirus type 58 (HPV-58) accounts for a much higher proportion of cervical cancers in East Asia than other types. A classification system of HPV-58, which is essential for molecular epidemiological study, is lacking. Methods and results. This study analyzed the sequences of 401 isolates collected from 15 countries and cities. The 268 unique concatenated E6-E7-E2-E5-L1-LCR sequences that comprised 57% of the whole HPV-58 genome showed 4 distinct clusters. L1 and LCR produced tree topologies that best resembled the concatenated sequences and thus are the most appropriate surrogate regions for lineage classification. Moreover, short fragments from L1 (nucleotides 6014–6539) and LCR (nucleotides 7257–7429 and 7540–52) were found to contain sequence signatures informative for lineage identification. Lineage A was the most prevalent lineage across all regions. Lineage C was more frequent in Africa than elsewhere, whereas lineage D was more prevalent in Africa than in Asia. Among lineage A variants, sublineage A2 dominated in Africa, the Americas, and Europe, but not in Asia. Sublineage A1, which represents the prototype that originated from a patient with cancer, was rare worldwide except in Asia. Conclusions. HPV-58 can be classified into 4 lineages that show some degree of ethnogeographic predilection in distribution. The evolutionary, epidemiological, and pathological characteristics of these lineages warrant further study

In Vivo Outer Hair Cell Length Changes Expose the Active Process in the Cochlea

BACKGROUND: Mammalian hearing is refined by amplification of the sound-evoked vibration of the cochlear partition. This amplification is at least partly due to forces produced by protein motors residing in the cylindrical body of the outer hair cell. To transmit power to the cochlear partition, it is required that the outer hair cells dynamically change their length, in addition to generating force. These length changes, which have not previously been measured in vivo, must be correctly timed with the acoustic stimulus to produce amplification. METHODOLOGY/PRINCIPAL FINDINGS: Using in vivo optical coherence tomography, we demonstrate that outer hair cells in living guinea pigs have length changes with unexpected timing and magnitudes that depend on the stimulus level in the sensitive cochlea. CONCLUSIONS/SIGNIFICANCE: The level-dependent length change is a necessary condition for directly validating that power is expended by the active process presumed to underlie normal hearing

Modeling Spinal Muscular Atrophy in Drosophila

Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets

Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most com- mon chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA 21 that directly contribute to cognitive de fi cits remain incompletely understood. Here, we found that the HSA21- encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued de fi cits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes