Organoid cultures derived from patients with advanced prostate cancer.

The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D organoid system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss. Whole-exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as in DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies.

Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer.

BACKGROUND: In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival. METHODS: We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability). RESULTS: A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67). CONCLUSIONS: Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.).

Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).

Catalytic Activity of the Archetype from Group 4 of the FTR-like Ferredoxin:Thioredoxin Reductase Family Is Regulated by Unique S = 7/2 and S = 1/2 [4Fe-4S] Clusters.

Thioredoxin reductases (TrxR) activate thioredoxins (Trx) that regulate the activity of diverse target proteins essential to prokaryotic and eukaryotic life. However, very little is understood of TrxR/Trx systems and redox control in methanogenic microbes from the domain Archaea (methanogens), for which genomes are abundant with annotations for ferredoxin:thioredoxin reductases [Fdx/thioredoxin reductase (FTR)] from group 4 of the widespread FTR-like family. Only two from the FTR-like family are characterized: the plant-type FTR from group 1 and FDR from group 6. Herein, the group 4 archetype (AFTR) from Methanosarcina acetivorans was characterized to advance understanding of the family and TrxR/Trx systems in methanogens. The modeled structure of AFTR, together with EPR and Mössbauer spectroscopies, supports a catalytic mechanism similar to plant-type FTR and FDR, albeit with important exceptions. EPR spectroscopy of reduced AFTR identified a transient [4Fe-4S]1+ cluster exhibiting a mixture of S = 7/2 and typical S = 1/2 signals, although rare for proteins containing [4Fe-4S] clusters, it is most likely the on-pathway intermediate in the disulfide reduction. Furthermore, an active site histidine equivalent to residues essential for the activity of plant-type FTR and FDR was found dispensable for AFTR. Finally, a unique thioredoxin system was reconstituted from AFTR, ferredoxin, and Trx2 from M. acetivorans, for which specialized target proteins were identified that are essential for growth and other diverse metabolisms.

Synaptic Plasticity and Cognitive Ability in Experimental Adult-Onset Hypothyroidism.

Adult-onset hypothyroidism impairs normal brain function. Research on animal models of hypothyroidism has revealed critical information on how deficiency of thyroid hormones impacts the electrophysiological and molecular functions of the brain, which leads to the well known cognitive impairment in untreated hypothyroid patients. Currently, such information can only be obtained from experiments on animal models of hypothyroidism. This review summarizes important research findings that pertain to understanding the clinical cognitive consequences of hypothyroidism, which will provide a better guiding path for therapy of hypothyroidism. SIGNIFICANCE STATEMENT: Cognitive impairment occurs during adult-onset hypothyroidism in both humans and animal models. Findings from animal studies validate clinical findings showing impaired long-term potentiation, decreased CaMKII, and increased calcineurin. Such findings can only be gleaned from animal experiments to show how hypothyroidism produces clinical symptoms.

Identification and characterization of the low molecular mass ferredoxins involved in central metabolism in Heliomicrobium modesticaldum.

The homodimeric Type I reaction center (RC) from Heliomicrobium modesticaldum lacks the PsaC subunit found in Photosystem I and instead uses the interpolypeptide [4Fe-4S] cluster FX as the terminal electron acceptor. Our goal was to identify which of the small mobile dicluster ferredoxins encoded by the H. modesticaldum genome are capable of accepting electrons from the heliobacterial RC (HbRC) and pyruvate:ferredoxin oxidoreductase (PFOR), a key metabolic enzyme. Analysis of the genome revealed seven candidates: HM1_1462 (PshB1), HM1_1461 (PshB2), HM1_2505 (Fdx3), HM1_0869 (FdxB), HM1_1043, HM1_0357, and HM1_2767. Heterologous expression in Escherichia coli and studies using time-resolved optical spectroscopy revealed that only PshB1, PshB2, and Fdx3 are capable of accepting electrons from the HbRC and PFOR. Modeling studies using AlphaFold show that only PshB1, PshB2, and Fdx3 should be capable of docking on PFOR at a positively charged patch that overlays a surface-proximal [4Fe-4S] cluster. Proteomic analysis of wild-type and gene deletion strains ΔpshB1, ΔpshB2, ΔpshB1pshB2, and Δfdx3 grown under nitrogen-replete conditions revealed that Fdx3 is undetectable in the wild-type, ΔpshB1, and Δfdx3 strains, but it is present in the ΔpshB2 and ΔpshB1pshB2 strains, implying that Fdx3 may substitute for PshB2. When grown under nitrogen-deplete conditions, Fdx3 is present in the wild-type and all deletion strains except for Δfdx3. None of the knockout strains demonstrated significant impairment during chemotrophic dark growth on pyruvate, photoheterotrophic light growth on pyruvate, or phototrophic growth on acetate+CO2, indicating a high degree of redundancy among these three electron transfer proteins. Loss of both PshB1 and PshB2, but not FdxB, resulted in poor growth under N2-fixing conditions.

Plain language summary of the FOENIX-CCA2 study: futibatinib for people with advanced bile duct cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life. WHAT WERE THE RESULTS?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib. WHAT DO THE RESULTS MEAN?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles address: 1- The use of AI in fetal echocardiography, 2- The role of Apixaban in thromboembolism prevention in pediatric congenital heart disease, 3- Cardiovascular events in childhood cancer survivors, and lastly 4- the new consensus statement on cardiac catheterization for pediatrics and adults with congenital heart disease.

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review, we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles address (1) A new index for prenatal diagnosis of total anomalous pulmonary venous return, (2) Outcomes of patients with Tetralogy of Fallot after pulmonary valve replacement (PVR), and (3) Short-term outcomes of the self expanding Harmony valve for transcatheter PVR.

Performance of two laser motion modes versus conventional orthodontic ceramic brackets debonding technique on enamel surface topography.

The risk of enamel deterioration that frequently coexists with debonding of orthodontic teeth brackets elevates the mandate for finding an optimum approach for debonding them without harmful effects. This in-vitro study is intended to compare the effects of two different laser modes (scanning and circular) and a conventional method on the enamel surface after debonding orthodontic brackets. 66 extracted premolars were assigned into 3 groups. After that, light-cure composite resin was used to attach the ceramic brackets to the teeth. Amongst the test groups, Group I: specimens that were debonded using conventional debonding using pliers; Group 2: specimens that were debonded using Er, Cr: YSGG laser applications using the circular motion method; and Group 3: specimens that were debonded using Er, Cr: YSGG laser applications using the scanning motion method. Adhesive Remnant Index (ARI) assessment, intra-pulpal temperature increase, enamel surface roughness after polishing, and assessment of the microstructure of enamel were carried out with scanning electron microscopy. The gathered information was examined statistically. The conventional debonding method had a significantly higher proportion of adhesive remnant index (ARI) scores of 2 and 3 in comparison to the circular (p < .004) and scanning laser groups (p < .001). There was no significant difference in ARI scores between the circular and scanning laser groups (p > .05). Moreover, the circular and scanning laser debonding methods resulted in a significantly higher proportion of Enamel Surface Roughness (ESR) scores of 0 and a lower proportion of ESR scores of 3 compared to the conventional technique group (p < .001). However, there was no significant difference in ESR scores between the circular and scanning laser methods (p = .945). Lastly, the average intra-pulpal temperature was significantly higher in the circular laser group (1.9 ± 0.5 ) compared to the scanning laser group (0.9 ± 0.2) with p < .001. Er, Cr: YSGG laser irradiation is a tool that shows promise for debonding ceramic brackets with minimal harm to the enamel surface. The scanning laser technique is more desirable due to the lower intra-pulpal temperature increase.

Menopausal hormone therapy and risk of venous thromboembolism: The story so far.

Menopausal hormone therapy (MHT) is known to increase the risk of venous thromboembolism (VTE), which includes deep vein thrombosis, pulmonary embolism, and less frequently cerebral vein thrombosis, but the absolute risk for a given patient is very low. After starting MHT, the risk of VTE seems to be at its highest, declining to the non-HRT user baseline level of risk after stopping. Whether estrogen-only or estrogen-progestin HRT combination is linked to a similar risk of VTE is unclear from the available evidence. The aim of this study is to evaluate the risks of developing VTE in relation to different types as well as different modes of administration of MHT through a database search including PubMed, MEDLINE, Google Scholar, Cochrane Library, and others in order to provide the women carers with the up-to-date and evidence-based guidelines and recommendations while counseling the post-menopausal women enquiring on use of hormonal therapies either to alleviate the menopausal symptoms or to prevent the long-term sequelae of estrogen deficiency.

On sait que l'hormonothérapie ménopausique (MHT) augmente le risque de thromboembolie veineuse (TEV), qui comprend la thrombose veineuse profonde, l'embolie pulmonaire et, moins fréquemment, la thrombose veineuse cérébrale, mais le risque absolu pour un patient donné est très faible. Après le début du MHT, le risque de TEV semble être à son plus haut niveau, diminuant jusqu'au niveau de risque de base des non-utilisatrices de THS après l'arrêt. Les preuves disponibles ne permettent pas de savoir si un THS à base d'œstrogène seul ou d'association œstroprogestative est lié à un risque similaire de TEV. Le but de cette étude est d'évaluer les risques de développer une TEV par rapport à différents types ainsi qu'à différents modes d'administration du MHT grâce à une recherche dans des bases de données comprenant PubMed, MEDLINE, Google Scholar, Cochrane Library et autres afin de fournir aux femmes les soignants avec les lignes directrices et recommandations à jour et fondées sur des preuves tout en conseillant les femmes ménopausées qui se renseignent sur l'utilisation de thérapies hormonales, soit pour soulager les symptômes de la ménopause, soit pour prévenir les séquelles à long terme d'une carence en œstrogènes.

The effect of aging on the translucency of contemporary zirconia generations: in-vitro study.

BACKGROUND: The translucency of different zirconia generations at each time point after thermocycling aging is still lacking. METHODS: Four zirconia materials were used with a total of 60 samples produced from monolithic third generation (5Y) 5 mol% yttria-stabilized zirconia polycrystalline ceramic and fourth generation zirconia (4Y) 4 mol% yttria-stabilized zirconia polycrystalline ceramic, represented by [group1:[CM-5Y] Ceramill Zolid fx (3rd generation zirconia) (Amann Girrbach, Koblach, Austria), group 2:[CM-4Y] Ceramill Zolid HT + (4th generation zirconia) (Amann Girrbach, Koblach, Austria), group 3:[CC-5Y] Cercon XT/ML (Dentsply Sirona, Germany) (3rd generation), and group 4:[CC-4Y] Cercon HT/ML (Dentsply Sirona, Germany) (4th generation)]. The L*a*b* figures were measured by using a spectrophotometer at baseline and after 10,000, 30,000, and 50,000 cycles of thermocycling. At each interval, the translucency of the samples was estimated by using the translucency formula CIEDE2000. The Scheffe post-hoc compared differences among each of the four materials. The Repeated measures ANOVA tested the differences between the materials at each of the different thermocycling intervals (p < .001). Data analyses were evaluated at a significance level of p < .05 (CI 95%). RESULTS: Two-way ANOVA revealed that at baseline the third and fourth generation's zirconia showed statistically significant differences in translucency (P < .001). Translucency values at baseline and after thermocycling exhibited statistically significant changes (p = .003). At each of the time interval; CM-4Y had the highest translucency values followed by CM-5Y, CC-4Y and CC-5Y had the least translucency values. CONCLUSIONS: The third and fourth generations of zirconia displayed different translucencies. Thermocycling affected the translucency of both third and fourth generations of zirconia. At each of the time intervals group 2:[CM-4Y] had the highest TP followed by group1:[CM-5Y], while, group 3:[CC-5Y] and group 4:[CC-4Y] had the least TP.

A Strategy for the Formal C-N Cross-Coupling of Tertiary Amines.

We report a strategy for the C-N cross-coupling of tertiary amines via the in situ generation and displacement of N-acyl ammonium species. Specifically, treatment of diverse tertiary amines with TFAA or choroformates in the presence of NaI leads to the efficient generation of alkyl iodides, which can be engaged directly in Ni-catalyzed cross-couplings. The protocol is applicable to acyclic and cyclic systems, including highly hindered variants. Applications to the late-stage modification of complex heterocycles are presented.

Review of cardiac safety in onasemnogene abeparvovec gene replacement therapy: translation from preclinical to clinical findings.

Human gene replacement therapies such as onasemnogene abeparvovec (OA) use recombinant adeno-associated virus (rAAV) vectors to treat monogenic disorders. The heart and liver are known target organs of toxicity in animals; with cardiac and hepatic monitoring recommended in humans after OA dosing. This manuscript provides a comprehensive description of cardiac data from preclinical studies and clinical sources including clinical trials, managed access programs and the post-marketing setting following intravenous OA administration through 23 May 2022. Single dose mouse GLP-Toxicology studies revealed dose-dependent cardiac findings including thrombi, myocardial inflammation and degeneration/regeneration, which were associated with early mortality (4-7 weeks) in the high dose groups. No such findings were documented in non-human primates (NHP) after 6 weeks or 6 months post-dose. No electrocardiogram or echocardiogram abnormalities were noted in NHP or humans. After OA dosing, some patients developed isolated elevations in troponin without associated signs/symptoms; the reported cardiac adverse events in patients were considered of secondary etiology (e.g. respiratory dysfunction or sepsis leading to cardiac events). Clinical data indicate cardiac toxicity observed in mice does not translate to humans. Cardiac abnormalities have been associated with SMA. Healthcare professionals should use medical judgment when evaluating the etiology and assessment of cardiac events post OA dosing so as to consider all possibilities and manage the patient accordingly.

A phase Ib/II study of galunisertib in combination with nivolumab in solid tumors and non-small cell lung cancer.

BACKGROUND: In this phase Ib/II open-label study, tumor immune suppression was targeted in patients with advanced refractory solid tumors and patients with recurrent/refractory non-small cell lung cancer (NSCLC) using galunisertib with nivolumab. METHODS: Eligible patients were ≥ 18 years old, had an Eastern Cooperative Oncology Group performance status ≤ 1, and were treatment-naive for anti-programmed cell death-1, its ligand, or transforming growth factor ß receptor 1 kinase inhibitors. Phase Ib was an open-label, dose-escalation assessment of the safety and tolerability of galunisertib with nivolumab in patients with advanced refractory solid tumors. Phase II evaluated the safety of galunisertib with nivolumab in NSCLC patients who had received prior platinum-based treatment but were immuno-oncology agent-naive. RESULTS: This trial was conducted between October 2015 and August 2020. No dose-limiting toxicities were observed in phase I. In the phase II NSCLC cohort (n = 25), patients received 150 mg twice daily galunisertib (14 days on/14 days off dosing schedule for all phases) plus nivolumab at 3 mg/kg (intravenously every 2 weeks). In this phase, the most frequent treatment-related adverse events (AEs) were pruritus (n = 9, 36%), fatigue (n = 8, 32%), and decreased appetite (n = 7, 28%). No grade 4 or 5 treatment-related AEs were observed. Six (24%) patients had confirmed partial response (PR) and 4 (16%) had stable disease; 1 additional patient had confirmed PR after initial pseudo-progression. The median duration of response was 7.43 months (95% confidence interval [CI]: 3.75, NR). Among the 7 responders, including the delayed responder, 1 had high PD-L1 expression (≥ 50%). The median progression-free survival was 5.26 months (95% CI: 1.77, 9.20) and the median overall survival was 11.99 months (95% CI: 8.15, NR). Interferon gamma response genes were induced post-treatment and cell adhesion genes were repressed, although the association of these observations with tumor response and clinical outcomes was not statistically powered due to limited samples available. CONCLUSIONS: The study met its primary endpoint as galunisertib combined with nivolumab was well tolerated. Preliminary efficacy was observed in a subset of patients in the Phase 2 NSCLC cohort. TRIAL REGISTRATION: Trial registered with ClinicalTrials.gov (NCT02423343; 22.04.2015).

Body weight loss as a prognostic and predictive factor in previously treated patients with metastatic gastric cancer: post hoc analyses of the randomized phase III TAGS trial.

BACKGROUND: Body weight loss (BWL) is a negative prognostic factor in metastatic gastric or gastroesophageal junction cancer (mGC/GEJC). In the phase III TAGS study, trifluridine/tipiracil improved survival versus placebo in third- or later-line mGC/GEJC. These retrospective analyses examined the association of early BWL with survival outcomes in TAGS. METHODS: Efficacy and safety were assessed in patients who experienced < 3% or ≥ 3% BWL from treatment start until day 1 of cycle 2 (early BWL). The effect of early BWL on overall survival (OS) was assessed by univariate and multivariate analyses. RESULTS: Body weight data were available for 451 of 507 (89%) patients in TAGS. In the trifluridine/tipiracil and placebo arms, respectively, 74% (224/304) and 65% (95/147) experienced < 3% BWL, whereas 26% (80/304) and 35% (52/147) experienced ≥ 3% BWL at cycle 1 end. Median OS was longer in < 3% BWL versus ≥ 3% BWL subgroups (6.5 vs 4.9 months for trifluridine/tipiracil; 6.0 vs 2.5 months for placebo). In univariate analyses, an unadjusted HR of 0.58 (95% CI, 0.46-0.73) for the < 3% vs ≥ 3% BWL subgroup indicated a strong prognostic effect of early BWL. Multivariate analyses confirmed early BWL as both prognostic (P < 0.0001) and predictive (interaction P = 0.0003) for OS. Similar results were obtained for progression-free survival. Any-cause grade ≥ 3 adverse events were reported in 77% and 82% of trifluridine/tipiracil-treated and 45% and 67% of placebo-treated patients with < 3% and ≥ 3% BWL, respectively. CONCLUSIONS: In TAGS, early BWL was a strong negative prognostic factor for OS in patients with mGC/GEJC receiving third- or later-line treatment.

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review, we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. This review includes (1) Fetal diagnosis, associated anomalies, and factors affecting outcomes in fetal congenitally corrected transposition of the great arteries (ccTGA), (2) The impact of Fontan-associated liver disease on heart and heart/liver transplant, (3) 1-year outcomes of the Harmony transcatheter pulmonary valve, (4) Risk factors associated with major adverse cardiac events in patients with pulmonary atresia and intact ventricular septum undergoing intervention, and (5) Benefits of pulmonary valve replacement in tetralogy of Fallot patients.

Influences of glycine supplementation during vitrification on the developmental potential of vitrified/warmed immature dromedary camel oocytes.

Oocytes experience detrimental osmotic stress during vitrification and warming procedures because of the osmolality imbalance between the vitrification-warming fluids and the intracellular environment. Cellular osmotic homeostasis can be preserved by glycine, a powerful osmolyte with antioxidant properties. We aimed to examine the influences of supplementing glycine to the vitrification solutions (VS) on the developmental potential of vitrified/warmed immature dromedary camel oocytes following IVM/IVF and in vitro embryo culture (IVC). Cumulus oocyte complexes (COCs) were collected from dromedary camel ovaries and randomly allocated into two groups namely control (oocytes subjected directly to IVM) and vitrified (COCs were vitrified into VS supplemented with 0.0, 0.5, 1.0 or 2.0 mM glycine). For vitrification, COCs were equilibrated for 3 min in 12.5% ethylene glycol; EG plus 12.5% dimethyl sulfoxide; DMS and then they were vitrified for 60 s in VS composed of 25% EG + 25% DMSO using solid surface vitrification (SSV). Warming of vitrified oocytes was conducted in decreasing concentrations of trehalose solution. Following vitrification and warming, the morphologically viable oocytes were subjected to IVM for 36 h. Matured oocytes were then fertilized in vitro by epididymal spermatozoa and cultured for seven days. The results showed that the percentage of viable oocytes assessed by trypan blue stain was significantly higher (p ≤ .05) in the 1.0 mM glycine-supplemented group than 0.0- and 2.0-mM glycine-supplemented ones (90.0 % vs. 80.0% and 76.6%, respectively). However, no significant difference was observed between 0.5 mM glycine and other vitrified groups. Nuclear maturation rates, cleavage (48-h post-insemination; pi) and blastocyst rate (7-days pi) were significantly lower in vitrified groups than control ones (p ≤ .05). Among vitrified groups, these parameters were the highest in the 1.0 mM glycine-supplemented group. Taken together, supplementation of vitrification solutions with 1.0 mM glycine could enhance the developmental potential of vitrified/warmed immature dromedary camel oocytes.

Effect of mouth rinses on the stainability of monolithic lithium disilicate glass-ceramics with different surface treatments: An in vitro study.

STATEMENT OF PROBLEM: Mouth rinses have been reported to cause tooth surface discoloration. However, information regarding their effect on the stainability of monolithic glass-ceramics with different surface treatments is lacking. PURPOSE: The purpose of this in vitro study was to assess the effect of mouth rinses on the color change of milled and pressed monolithic lithium disilicate glass-ceramics with different surface treatments. MATERIAL AND METHODS: Fifty-six Ø12×1.5-mm disk specimens were fabricated using 2 different processing techniques: milling and pressing. Each group was subdivided into 2 subgroups according to surface treatments: glazed and polished. Specimens were then immersed in 2 different types of mouth rinse (n=7): chlorhexidine (CHX) and Listerine (LST). Color parameters were assessed using a digital spectrophotometer. Color difference (ΔE00) was calculated and compared with perceptibility (ΔE00=0.8) and acceptability (ΔE00=1.8) thresholds. The data were analyzed using ANOVA and Tukey post hoc tests (α=.05). RESULTS: The color difference (ΔE00) was significantly affected by the type of processing technique, surface treatment, and mouth rinse (P<.001) and their interaction (P=.008). All ΔE00 values were below the selected clinical acceptability threshold (ΔE00=1.8). Milled groups (ΔE00=1.13) showed greater discoloration than pressed groups (ΔE00=0.86). Glazed specimens (ΔE00=0.70) were more resistant to discoloration than polished specimens (ΔE00=1.28) and immersion in CHX (ΔE00=1.09) led to more discoloration than immersion in LST (ΔE00=0.89). CONCLUSIONS: The color of milled and pressed monolithic lithium disilicate glass-ceramics with different surface treatments was affected by using CHX and LST mouth rinses. Glazed lithium disilicate glass-ceramics showed less staining compared with those that were polished. Specimens immersed in CHX showed more discoloration than those immersed in LST.

Physical-Layer Security in Power-Domain NOMA Based on Different Chaotic Maps.

Nonorthogonal multiple access (NOMA) is a relevant technology for realizing the primary goals of next-generation wireless networks, such as high connectivity and stability. Because a rising number of users are becoming connected, user data security has become a critical issue. Many chaotic communication systems have been established to address this important issue via exhibition of affordable physical-layer-security solutions. In this study, we propose a chaotic downlink NOMA (C-DL-NOMA) system over the additive white Gaussian noise and Rayleigh-fading channels to enhance the security of the DL-NOMA system. The proposed algorithm is based on a coherent analog modulation technique that combines various chaotic maps for chaotic masking of encrypted data. On the transmitter, chaotic encryption was used for transmitted data with fixed power-allocation-level control, whereas on the receiver, successive interference-cancellation demodulation was utilized to detect multiple users, after which chaotic decryption was performed. Simulation results were evaluated based on security analyses, such as statistical analysis (histogram and correlation analyses and information entropy), bit-error-rate performance, and achievable-data-rate performance. According to these security analyses and numerical results, the proposed C-DL-NOMA system outperformed traditional unencrypted NOMA systems.