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QRS complex shortening by cardiac resynchronization therapy (CRT) has been associated with improved outcomes.

We hypothesized that the absence of QRS duration (QRSd) prolongation by right ventricular mid-septal pacing (RVP) may indicate complete left bundle branch block (cLBBB).

We prospectively collected 12-lead surface electrocardiograms (ECGs) and intracardiac electrograms during CRT implant procedures. Digital recordings were edited and manually measured. The outcome measure was a change in QRSd induced by CRT (delta CRT). Several outcome predictors were investigated native QRSd, cLBBB (by using Strauss criteria), interval between the onset of the QRS complex and the local left ventricular electrogram (Q-LV), and a newly proposed index defined by the difference between RVP and native QRSd (delta RVP).

One hundred thirty-three consecutive patients were included in the study. Delta RVP was 27 ± 25 ms, and delta CRT was -14 ± 28 ms. Delta CRT correlated with native QRSd (r = -0.65), with the presence of ECG-based cLBBB (r = -0.40), with Q-LV (r = -0.68), and with delta RVP (r = 0.72) (P < .00001 for all correlations). In multivariable analysis, delta CRT was most strongly associated with delta RVP (P < .00001), followed by native QRSd and Q-LV, while ECG-based cLBBB became a nonsignificant factor.

Baseline QRSd, delta RVP, and LV electrical lead position (Q-LV) represent strong independent predictors of ECG response to CRT. The absence of QRSd prolongation by RVP may serve as an alternative and more specific marker of cLBBB. Delta RVP correlates strongly with the CRT effect on QRSd and outperforms the predictive value of ECG-based cLBBB.

Baseline QRSd, delta RVP, and LV electrical lead position (Q-LV) represent strong independent predictors of ECG response to CRT. The absence of QRSd prolongation by RVP may serve as an alternative and more specific marker of cLBBB. Delta RVP correlates strongly with the CRT effect on QRSd and outperforms the predictive value of ECG-based cLBBB.Transcriptomic analysis can provide insight as to how Staphylococcus aureus adapts to the environmental niche of periprosthetic joint infection (PJI), a challenging clinical infection. Here, in vivo RNA expression of eight S. aureus PJIs was compared with expression of the corresponding isolates in planktonic culture using a total RNA-sequencing approach. Expression varied among isolates, with a common trend showing increased expression of several ica-independent biofilm formation genes, including sdr, fnb, ebpS, and aaa; genes encoding enzymes and toxins, including coa, nuc, hlb, and hlgA/B/C; and genes facilitating acquisition of iron via the iron-binding molecule siderophore B (snb) and heme consumption protein (isd) pathways in PJI. Several antimicrobial resistance determinants were detected; although their presence correlated with phenotypic susceptibility of the associated isolates, no difference in expression between in vivo and in vitro conditions was identified.

The present study aimed to examine prospectively the occurrence of hypercalciuria and changes in bone metabolite markers in pediatric patients during immobilization.

In total, 13 children with an orthopedic disease requiring immobilization longer than two weeks were enrolled. Blood samples were collected after breakfast. Urine samples were collected at the second voiding after waking. The urine Ca/Cr ratio and various bone metabolite parameters were measured before, and every one to four weeks after, the start of immobilization.

The median patient age was 7 years with a range of 2 to 13 years. Orthopedic diseases in the patients were dislocated hip joint (N=7), slipped capital femoral epiphysis (N=2), etc. The urine Ca/Cr ratio increased significantly within a week after immobilization (p<0.01) and continued to increase for two more weeks. Once immobilization ended, the urine Ca/Cr ratio fell gradually and returned to the normal range about six weeks after mobility was achieved (p<0.01). Serum ALP and bone-specific ALP significantly decreased after immobilization began (p<0.01). After immobilization ended, the serum ALP returned to pre-immobilization levels in two to four weeks (p<0.01). Serum NTX did not change significantly during immobilization.

The urine Ca/Cr ratio immediately increased after immobilization. In contrast to adults, bone formation markers in children decreased during immobilization whereas bone resorption markers did not increase. This study is the first to examine bone metabolism markers in children during immobilization.

The urine Ca/Cr ratio immediately increased after immobilization. In contrast to adults, bone formation markers in children decreased during immobilization whereas bone resorption markers did not increase. This study is the first to examine bone metabolism markers in children during immobilization.The pyrethroid deltamethrin and the macrocyclic lactone emamectin benzoate (EMB) are used to treat infestations of farmed salmon by parasitic salmon lice, Lepeophtheirus salmonis. While the efficacy of both compounds against Atlantic populations of the parasite has decreased as a result of the evolution of resistance, the molecular mechanisms of drug resistance in L. salmonis are currently not fully understood. The functionally diverse carboxylesterases (CaE) family includes members involved in pesticide resistance phenotypes of terrestrial arthropods. The present study had the objective to characterize the CaE family in L. salmonis and assess its role in drug resistance. Cyclopamine datasheet L. salmonis CaE homologues were identified by homology searches in the parasite's transcriptome and genome. The transcript expression of CaEs predicted to be catalytically competent was studied using quantitative reverse-transcription PCR in drug susceptible and multi-resistant L. salmonis. The above strategy led to the identification of 21 CaEs genes/pseudogenes. Phylogenetic analyses assigned 13 CaEs to clades involved in neurodevelopmental signaling and cell adhesion, while three sequences were predicted to encode secreted enzymes. Ten CaEs were identified as being potentially catalytically competent. Transcript expression of acetylcholinesterase (ace1b) was significantly increased in multi-resistant lice compared to drug-susceptible L. salmonis, with transcript abundance further increased in preadult-II females following EMB exposure. In summary, results from the present study demonstrate that L. salmonis possesses fewer CaE gene family members than most arthropods characterized so far. Drug resistance in L. salmonis was associated with overexpression of ace1b.Podophyllotoxin (PPT) has been reported to have many pharmacological activities, especially its anti-tumor effects. To improve the cytotoxicity and selective effect of PPT, in this study, we have designed and synthesized 20 ester derivatives by introducing Boc-amino acids or organic acids at the C-4 position of PPT. The cytotoxicity of these compounds was evaluated with PC-3M, HemECs, A549, MCF-7 and HepG2 cells. We observed that the proliferation of PC-3M cells was inhibited by all 20 ester derivatives in the largest degree, comparing to the other cell lines. Comparing to PPT (IC50 = 234.90 ± 20.7 nM), eight derivatives had better performance in inhabiting proliferation of PC-3M cells, six of them belong to Boc-amino acid ester derivatives, and the derivative named V-05 (IC50 = 1.28 ± 0.1 nM) had the strongest inhibitation effect. Changes in cell proliferation and apoptotic signaling pathways were studied by DAPI staining, colony formation assay, migration assay, flow cytometry and western blot analysis. We found that V-05 were able to inhibit PC-3M cells proliferation and migration, and induced apoptosis by downregualting p-PI3K, p-Akt and Bcl-2, and upregulating Cleaved caspase-3 and Bax. Our research provides the first insight for the application of PPT derivatives in PC-3M cells, which may offer information to the effective medicine development for human prostate cancer treatment.We have previously reported the development of indole-based CNS-active antivirals for the treatment of neurotropic alphavirus infection, but further optimization is impeded by a lack of knowledge of the molecular target and binding site. Herein we describe the design, synthesis and evaluation of a series of conformationally restricted analogues with the dual objectives of improving potency/selectivity and identifying the most bioactive conformation. Although this campaign was only modestly successful at improving potency, the sharply defined SAR of the rigid analogs enabled the definition of a three-dimensional pharmacophore, which we believe will be of value in further analog design and virtual screening for alternative antiviral leads.7-Dehydrocholesterol reductase (DHCR7) catalyses the final step of cholesterol biosynthesis in the Kandutsch-Russel pathway, the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. 7DHC can be acted on by a range of other enzymes including CYP27A1 and CYP11A1, as well as by UVB radiation, producing a number of derivatives including hydroxy-metabolites, some of which retain the C7-C8 double bond and are biologically active. These metabolites include lumisterol (L3) which is a stereoisomer of 7DHC produced in the skin by UVB radiation of 7DHC, as well as vitamin D3. The aim of this study was to test whether these metabolites could act as substrates or inhibitors of DHCR7 in rat liver microsomes. To initially screen the ability of these metabolites to interact with the active site of DHCR7, their ability to inhibit the conversion of ergosterol to brassicasterol was measured. Sterols that significantly inhibited this reaction included 7DHC (as expected), 20S(OH)7DHC, 27(OH)DHC, 8DHC, 20S(OH)L3 and 22(OH)L3 but not 7-dehydropregnenolone (7DHP), 25(OH)7DHC, L3 or vitamin D3 and its hydroxyderivatives. Sterols that inhibited ergosterol reduction were directly tested as substrates for DHCR7. 20S(OH)7DHC, 27(OH)DHC and 7-dehydrodesmosterol were confirmed to be substrates, giving the expected product with the C7-C8 double bond removed. No products were observed from 8DHC or 20S(OH)L3 indicating that these sterols are inhibitors and not substrates of DHCR7. The resistance of lumisterol and 7DHP to reduction by DHCR7 in cells will permit other enzymes to metabolise these sterols to their active forms retaining the C7-C8 double bond, conferring specificity to their biological actions.

There is controversy regarding the use of older grafts for liver transplantation (LT) in HCV-infected patients, but the introduction of direct-acting antivirals (DAA) can radically change that debate.

The aim of this retrospective cohort study was to evaluate outcomes of the use of liver grafts from donors older than 70 years in recipients with HCV infection who underwent pre- or post-LT treatment with DAA. We compared two groups of patients who underwent LT using livers >70 years; the groups were defined according to antiviral therapy non-DAA therapy group (n=62; LT between May 1996 and December 2013), and DAA therapy group (n=31; LT between January 2014 and December 2019).

Thirty (96.8%) patients of DAA therapy and nine (14.5%) of non-DAA therapy (21 patients underwent complete therapy with interferon-ribavirin) achieved sustained viral response (SVR). One, 3-, and 5-year patient survival were 83.9%, 67.7%, and 56.5% in the non-DAA group vs 93.5%, 88.4%, and 88.4% in the DAA group (P=0.04); the 1-, 3-, and 5-year graft survival were 77.