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Objective: The aim was to evaluate the effect of activated bleaching agents on the nanoceramic composite resins based on microhardness and surface roughness measurements. Methods: Opalescence Boost (Ultradent Products, USA) and Whiteness HP Blue Calcium (FGM Dental Products, Brazil) bleaching agents and a nanoceramic composite resin Ceram.X® SphereTEC™ One (DENTSPLY, Germany) were used in the study. Fifty composite samples in disc form (8x2mm) were prepared. The samples were polished with discs (Sof-Lex, 3M Dental Products, St.Paul, USA) and incubated in the dark in distilled water. Samples were divided into 5 main groups (n=10). Control group (C), Opalescence Boost/ without light (OB), Opalescence Boost/ with light (OBL), Whiteness HP Blue/ without light (WB), and Whiteness HP Blue/ with light (WBL). Surface roughness (Ra) and Vickers microhardness (VHN) measurements were conducted after the bleaching process. Statistical analyses were performed using the Kruskal Wallis – H test and the Mann Whitney – U test; a p value of < 0.05 was considered statistically significant. Result: The VHN was significantly different among groups in terms of the application of bleaching agents and light (p = 0.008). The Ra was not significantly different among groups with respect to the application of bleaching agents or lighting conditions (p = 0.144). Conclusion: Within the conditions of this study, after bleaching procedure the microhardness values of the nanoceramic composite increased, however bleaching did not show any effect on surface roughness.

BACKGROUND/AIMS: There is a pressing need for new therapies for the most aggressive subtype of breast cancer, triple-negative breast cancer (TNBC). Tenascin-C (TN-C) codes for a tumor microenvironment-specific protein, which promotes apoptosis evasion and cell proliferation. The aim of this study was to knock down TN-C by using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system to induce cancer cell apoptosis and stunt cell proliferation, laying the grounds for a new gene therapy approach in TNBC.MATERIALS and METHODS: The human TNBC cell line, MDA-MB-231 cells were transfected by TN-C-specific CRISPR/Cas9 plasmids. TN-C messenger RNA levels were assessed by real-time polymerase chain reaction to determine the knock-down efficiency. Two days after the transfection, the percentage of apoptotic cells and the proportion of cells in cell cycle phases were compared between the treatment and the control groups using flow cytometry. The resultant change in cell proliferation due to the knock-down was determined by MTT assay. RESULTS: Transfection with the TN-C CRISPR/Cas9 plasmid reduced TN-C levels in the cells by approximately 49% relative to the scrambled -control CRISPR/Cas9 transfected cells. This TN-C downregulation increased the percentage of cells in apoptosis and induced G1-phase arrest. The combined effect of apoptosis and cell cycle arrest led to a significant decrease in the number of cancer cells in the treatment group.CONCLUSION: Our successful preliminary study of a potential TNBC gene therapy based on TN-C genome editing by the CRISPR/Cas9 system led to significant decrease in TNBC cell numbers and it justifies the testing of this system in more advanced preclinical studies.

The vascular endothelium is one of the main targets of oxidative stress which plays an important role in the pathophysiology of vascular damage. Recent studies show that vitamin D can positively regulate endothelial functions in various chronic diseases and in cases of increased oxidative stress. In our study, we investigated the restorative and protective potentials of paricalcitol which is frequently used in patients with chronic renal failure, a vitamin D analogue, in human umbilical vein endothelial cells (HUVEC) before and after H2O2-induced oxidative stress. Paricalcitol treatment after the oxidative stress induced by H2O2 increased cell viability in endothelial cells depending on the dose that was used. While paricalcitol (500 nM) decreased caspase-3 activity and mitochondrial membrane potential loss, it increased nitric oxide (NO) production and reduced glutathione (GSH) levels. Paricalcitol treatment before oxidative stress increased cell viability. It increased NO production and mitochondrial membrane potential while significantly reducing caspase-3 activity. While paricalcitol caused a significant inhibition of protein disulfide isomerase (PDI) reductase activity in healthy endothelial cells, it did not cause a significant change on the PDI reductase activity under oxidative stress conditions. Present study showed that paricalcitol has restorative and protective effects on endothelial cells against oxidative injury, but these effects occur at high concentrations of paricalcitol.

Objective: This study aims to determine the clinical leadership levels of nurse managers and related factors Methods: This descriptive study was conducted on 109 nurse managers working at six hospitals – including four public hospitals, one private hospital, and one university hospital. The data was collected using Clinical Leadership Scale (CLS) including their personal and demographic information, as well as their clinical leadership traits. Results: The participants had a total mean score of 2.72±0.19 on clinical leadership scale. The mean scores of the improving services subscale were higher in female nurse managers than those of male counterparts. Participants who formally studied on management earned higher mean scores for the overall CLS and its setting direction subscale than those who did not. Likewise, the participants who formally studied on leadership earned higher mean scores for the overall CLS and its personal qualities subscale than those who did not. These findings were statistically significant (p

Objective: In-stent restenosis (ISR) is the narrowing of a stented coronary artery lesion. A considerable number of patients undergoing percutaneous coronary intervention (PCI) are affected by ISR. The predominant mechanism in the development of ISR is an inflammatory response to vessel wall injury during PCI. Vitamin D is reported to have anti-inflammatory properties, so it may also be related with ISR. Therefore, in this study the relationship between vitamin D receptor (VDR), vitamin D binding protein (VDBP) gene variations and ISR were investigated.Methods: Fifty-eight ISR patients who have chest pain, underwent angiography and were found to have restenosis in the previously inserted stent were included in the patient group and thirty-five patients who have chest pain and were not found to have restenosis in their previous stent in coronary angiography were included in the control group. rs7041 and rs4588 variations in VDBP; rs1544410 and rs2228570 variations in VDR were investigated by real-time polymerase chain reaction (RT-PCR).Results were evaluated statistically. Results: The CC genotype of rs2228570 variation of VDR and the CA genotype of rs4588 variation of VDBP were found statistically high in patient group. rs7041 variation was found statistically high in patients who had myocardial infarction history before stent implantation. Additionally, it was demonstrated that vitamin D deficiency (vitamin D level

The magnitude of the 2022 multi-country monkeypox virus (MPXV) outbreak has surpassed any preceding outbreak. It is unclear whether asymptomatic or otherwise undiagnosed infections are fuelling this epidemic. In this study, we aimed to assess whether undiagnosed infections occurred among men attending a Belgian sexual health clinic in May 2022. We retrospectively screened 224 samples collected for gonorrhea and chlamydia testing using an MPXV PCR assay and identified MPXV-DNA-positive samples from four men. At the time of sampling, one man had a painful rash, and three men had reported no symptoms. Upon clinical examination 21-37 days later, these three men were free of clinical signs, and they reported not having experienced any symptoms. Serology confirmed MPXV exposure in all three men, and MPXV was cultured from two cases. These findings show that certain cases of monkeypox remain undiagnosed and suggest that testing and quarantining of individuals reporting symptoms may not suffice to contain the outbreak. Findings of unrecognized or asymptomatic monkeypox virus (MPXV) infections with replication-competent virus in humans suggest that a lack of recognized, clinical symptoms could play a role in virus transmission and the magnitude of the 2022 MPXV outbreak.

Since the introduction of live-attenuated rotavirus vaccines in Belgium in 2006, surveillance has routinely detected rotavirus vaccine-derived strains. However, their genomic landscape and potential role in gastroenteritis have not been thoroughly investigated. We compared VP7 and VP4 nucleotide sequences obtained from rotavirus surveillance with the Rotarix vaccine sequence. As a result, we identified 80 vaccine-derived strains in 5125 rotavirus-positive infants with gastroenteritis from 2007 to 2018. Using both viral metagenomics and reverse transcription qPCR, we evaluated the vaccine strains and screened for co-infecting enteropathogens. Among the 45 patients with known vaccination status, 39 were vaccinated and 87% received the vaccine less than a month before the gastroenteritis episode. Reconstruction of 30 near complete vaccine-derived genomes revealed 0-11 mutations per genome, with 88% of them being non-synonymous. This, in combination with several shared amino acid changes among strains, pointed at selection of minor variant(s) present in the vaccine. We also found that some of these substitutions were true revertants (e.g., F167L on VP4, and I45T on NSP4). Finally, co-infections with known (e.g., Clostridioides difficile and norovirus) and divergent or emerging (e.g., human parechovirus A1, salivirus A2) pathogens were detected, and we estimated that 35% of the infants likely had gastroenteritis due to a 'non-rotavirus' cause. Conversely, we could not rule out the vaccine-derived gastroenteritis in over half of the cases. Continued studies inspecting reversion to pathogenicity should monitor the long-time safety of live-attenuated rotavirus vaccines. All in all, the complementary approach with NGS and qPCR provided a better understanding of rotavirus vaccine strain evolution in the Belgian population and epidemiology of co-infecting enteropathogens in suspected rotavirus vaccine-derived gastroenteritis cases. ispartof: VACCINE vol:40 issue:35 pages:5114-5125 ispartof: location:Netherlands status: published

The effect of Astragalus membranaceus on Caenorhabditis elegans was assessed in this experiment. Parkinson’s Disease directly causes dopamine depletion and other related symptoms. Astragalus contains complex carbohydrates linked to dopamine neuron protection, which could be used to treat Parkinson’s. In this experiment, C.elegans inflicted with Parkinson’s were treated with different concentrations of Astragalus. C.elegans are free-living nematodes that can be genetically engineered to model or stimulate various diseases caused by genetics, Parkinson’s being one of them. The concentrations of astragalus solution were 2 mg/mL, 4 mg/mL, and 8 mg/mL, which were added to the agar that the C.elegans inhabited. Mechanosensory tests included tap reflex and gentle and harsh touch assessment. M9 Buffer was used to inhibit the egg-laying behaviors of C.elegans, and the thrashing rate was assessed for each group. The results indicate that 4 mg/mL is the optimal concentration to treat disease-inflicted C.elegans and had with consistently highest scores out of the 3 trials. The 4 mg/mL group constantly had the highest tap reflex, gentle, and harsh touch scores that were similar or greater than the wild-type control group. Additionally, the 2 mg/mL also had high scores in trials 2 and 3 in both the gentle and harsh touch assessments. No definite conclusions can be determined from thrashing rate data. The results imply that lower and intermediate concentrations of Astragalus may treat the symptoms of Parkinson’s Disease.

Background: The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines. Methods: A core protocol approach will be used, allowing multiple vaccine candidates to be tested against controls. The primary objective of the trial will be to evaluate the effect of each vaccine on the rate of virologically confirmed Marburg virus disease, although Marburg infection assessed via seroconversion could be the primary objective in some cases. The overall trial design will be a mixture of individually and cluster-randomized designs, with individual randomization done whenever possible. Clusters will consist of either contacts and contacts of contacts of index cases, that is, ring vaccination, or other transmission units. Results: The primary efficacy endpoint will be analysed as a time-to-event outcome. A vaccine will be considered successful if its estimated efficacy is greater than 50% and has sufficient precision to rule out that true efficacy is less than 30%. This will require approximately 150 total endpoints, that is, cases of confirmed Marburg virus disease, per vaccine/comparator combination. Interim analyses will be conducted after 50 and after 100 events. Statistical analysis of the trial will be blended across the different types of designs. Under the assumption of a 6-month attack rate of 1% of the participants in the placebo arm for both the individually and cluster-randomized populations, the most likely sample size is about 20,000 participants per arm. Conclusion: This event-driven design takes into the account the potentially sporadic spread of Marburg virus. The proposed trial design may be applicable for other pathogens against which effective vaccines are not yet available.

Obesity is considered an important global public health challenge, and its prevalence is rapidly increasing in children. We investigated in this study if the upper-normal TSH level may be associated with metabolic syndrome parameters, including obesity, high blood pressure, and dyslipidemia and changes in insulin sensitivity in overweight and obese children. We also investigated whether there is a relationship between BMI and these parameters. This prospective case-control study comprised 145 participants (74 females, 71 males) aged 5–18 years. Participants were divided into three groups according to their BMI z-score, as overweight, obese and control. The control group included 35 age and sex-matched healthy subjects. Thyroid stimulating hormone levels of control, overweight and obese groups were 2.14 ± 1.27, 2.97 ± 1.26 and 3.13 ± 1.11, respectively (p

Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This finding raises basic questions about their metabolic origin, their contribution to disease pathogenesis, and the utility of targeting the underlying enzymatic machinery for treatment of cardiometabolic disorders. Here, we outline the development of a potent N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. We demonstrate that this compound reduces the ceramide synthase 2 mRNA level and that this translates into efficient lowering of protein expression and activity as well as Cer d18:1/24:1 and Cer d18:1/24:0 levels in liver. Intriguingly, we discover that the hepatocyte-specific antisense oligonucleotide also triggers a parallel modulation of blood plasma ceramides, revealing that the biomarkers predictive of cardiovascular death are governed by ceramide biosynthesis in hepatocytes. Our work showcases a generic therapeutic framework for targeting components of the ceramide enzymatic machinery to disentangle their roles in disease causality and to explore their utility for treatment of cardiometabolic disorders. ispartof: MOLECULAR THERAPY vol:30 issue:4 pages:1661-1674 ispartof: location:United States status: published

Objective: This phenomenologic study aims to investigate the difficulties experienced by a group of nursing students during the pandemia process thoroughly and to explain coping strategies. Methods: This research was carried out using the phenomenological method, which is one of the qualitative research methods, to examine the views of nursing students on their pandemic experiences and their coping strategies “Information Form” and “Questionnaire Form” were sent to the students online, and forms that were filled out completely and sent back were included in the content analysis. Results: Participants mean age was 21.19±1.06. Of the participants, 77.00% were female, 34.4% stated that they live in a metropolis during the pandemia process, while 83.6% mentioned that they were with their family, 31.1% did not leave their homes unless it is necessary. As a result of data analysis, the main themes of difficulties/stressors, stress/anxiety increasing factors, and coping strategies were reached. Conclusion: Student nurses experience more than one difficulty regarding the pandemia process; some students state that the pandemia process has changed their perception of their profession, and they mostly use positive methods to cope with these difficulties.

Background. Doctors have higher rates of mental illness and suicide than the general population worldwide. Suicides of doctors are known to be underreported in developing countries. To the best of our knowledge, there are no studies investigating suicides among medical students and doctors in Turkey.Objectives. To investigate the characteristics of suicides in medical school students and doctors in Turkey.Materials and methods. In this retrospective study, newspaper websites and Google search engine were searched for information on medical school student and doctor suicides in Turkey between 2011 and 2021. Cases of suicide attempt, parasuicide or deliberate self-harm were not included in the study.Results. Sixty-one suicides were reported between 2011-2021. There was a male predominance (45 (73.8%)), and more than half of the suicides (32 (52.5%)) occurred among specialist doctors. Self poisoning, jumping from heights and firearms were the most common methods of suicide (18 (29.5%), 17 (27.9%) and 15 (24.6%), respectively). Cardiovascular surgery, family medicine, gynecology, and obstetrics specialties had the highest numbers of suicide deaths. Depression/mental illness was the most common speculated etiology. These results show that suicides among medical students and doctors in Turkey have characteristics that differ from both suicided among the general population in Turkey and doctor suicides in other countries.Conclusions. In this study, we identified the suicidal characteristics of medical students and doctors in Turkey for the first time. The results help us to better understand this understudied topic and provide an avenue for future studies. The data also indicate that it is important to monitor the individual and systemic difficulties experienced by doctors, starting from the medical education stage, and to provide individual and environmental support to help decrease the risk of suicide.

Objective: This study was carried out to evaluate the relationship between the nutritional status, anthropometric measurements and dietary inflammatory index (DII) of professional football players exposed to long-term intense exercise. Method: Twenty-one professional male football players with a mean age of 26.00±5.69 years playing in the same club participated in the study. The nutritional status of the football players was evaluated with 3-day food consumption record (2 days of training and 1 match day). DII scores were calculated using data on 34 nutrient/nutritional ingredients obtained from the food consumption records. Body fat percentage in the anthropometric evaluations were determined by caliper and skinfold thicknesses. Results: The median DII scores of the football players were found as – 3.42 (-9.95 – 0.95), and their nutritional intake were found to be antiinflammatory. When the relationship between the DII scores of the football players and their anthropometric measurements was examined, a positive and significant correlation (R: .476; p: .029) was found between their DII score and their abdominal adiposity. However, there was no significant correlation (p> .05) between the DII scores and the other anthropometric measurements. In addition, there was a significant negative correlation (R: – .468; p: .032) between fiber consumption and abdominal adiposity, and a significant positive correlation between carbohydrate and fat consumption and body weight (respectively R= .730 p= .000; R= .526 p= .014). Conclusion: It has been revealed that the football players participating in our study generally have an anti-inflammatory diet. It was also found that abdominal adiposity was higher in the football players with high DII scores.

Objective: Insomnia is an important health problem affecting physical, spiritual and social well-being of individuals negatively and it should be early diagnosed as well. The purpose is to appraise the psychometric features of the Turkish version of the Bergen Insomnia Scale (BIS) for adults. Methods: A total of 495 adults were included in the methodological study in Turkey. Turkish form of BIS was designed within the scope of study conducted in adolescent sample. Construct validity was appraised with exploratory, confirmatory factor analysis, convergent and discriminant validity. Internal-consistency and test-retest analysis were used for reliability. Results: According to results of explanatory, confirmatory factor analysis; it was identified that BIS showed a two-factor structure as daytime symptoms (α=.85) and nocturnal symptoms (α=.80). Item-total correlations were found as ≥.59 and test-retest correlation as .83. Conclusions: The Turkish version of the Bergen Insomnia Scale for adults was assessed as valid and reliable.

Objective: School nursing education has not been standardized in Turkey so that it was decided the Delphi technique would be used to develop a curriculum for a program of education in school nursing. Methods: The data were collected from the expert panel via the Delphi technique by means of e-mail. Data were collected in three consecutive Delphi rounds. The population of the study comprised academic nurses and school nurses working in the area of school nursing in Turkey. A total of 83 experts were invited to participate in the study. The data were evaluated in terms of Quartile 1, Quartile 3, medians, interquartile ranges. Interquartile range refers to the difference between Quartile 3 and 1. Consensus was considered as less than the interquartile range of 1.2. Results: At the end of Round-1, 177 learning outcomes, nine main topics, 262 sub-topics were obtained. At the end of Round-2, 167 learning outcomes, nine main and 255 sub-topics were gathered, while at the end of Round-3, agreement was reached regarding nine main topics, 255 sub-topics, 167 learning outcomes, thus ending the Delphi rounds. Conclusions: The curriculum on which agreement was reached will be treated as a guide to school nursing education and contribute to the standardization of this instruction.

CTGrepeat expansion (CTGexp) is associated with aberrant alternate splicing that contributes to cardiac dysfunction in myotonic dystrophy type 1 (DM1). Excision of thisCTGexprepeat using CRISPR-Cas resulted in the disappearance of punctate ribonuclear foci in cardiomyocyte-like cells derived from DM1-induced pluripotent stem cells (iPSCs). This was associated with correction of the underlying spliceopathy as determined byRNA sequencingand alternate splicing analysis. Certain genes were of particular interest due to their role in cardiac development, maturation, and function (TPM4,CYP2J2,DMD,MBNL3,CACNA1H,ROCK2,ACTB) or their association with splicing (SMN2,GCFC2,MBNL3). Moreover, while comparing isogenic CRISPR-Cas9-corrected versus non-corrected DM1 cardiomyocytes, a prominent difference in the splicing pattern for a number of candidate genes was apparent pertaining to genes that are associated with cardiac function (TNNT,TNNT2,TTN,TPM1,SYNE1,CACNA1A,MTMR1,NEBL,TPM1),cellular signaling(NCOR2,CLIP1,LRRFIP2,CLASP1,CAMK2G), and other DM1-related genes (i.e.,NUMA1,MBNL2,LDB3) in addition to the disease-causingDMPKgene itself. Subsequent validation using a selected gene subset, includingMBNL1,MBNL2,INSR,ADD3, andCRTC2, further confirmed correction of the spliceopathy followingCTGexprepeat excision. To our knowledge, the present study provides the first comprehensive unbiased transcriptome-wide analysis of the differential splicing landscape in DM1 patient-derived cardiac cells after excision of theCTGexprepeat using CRISPR-Cas9, showing reversal of the abnormal cardiac spliceopathy in DM1.

Introduction Among the various types of progressive fibrosing interstitial lung diseases (PF-ILDs), substantial survival data exist for idiopathic pulmonary fibrosis (IPF) but not for other types. This hinders evidence-based decisions about treatment and management, as well as the economic modelling needed to justify research into new treatments and reimbursement approvals. Given the clinical similarities between IPF and other PF-ILDs, we reasoned that patient survival data from four major IPF trials could be used to estimate long-term survival in other PF-ILDs. Methods We used propensity score matching to match patients with IPF taking either nintedanib or placebo in the TOMORROW, INPULSIS-1, INPULSIS-2 and INPULSIS-ON trials to patients with PF-ILDs other than IPF in the INBUILD trial. Seven models were fitted to the survival data for the matched patients with IPF, and the three best-fitting models were used to generate informative priors in a Bayesian framework to extrapolate patient survival of the INBUILD population. Results After propensity score matching, the analysis included data from 1099 patients with IPF (640 nintedanib patients; 459 placebo patients) and 654 patients with other PF-ILDs (326 nintedanib patients; 328 placebo patients). Gamma, log-logistic and Weibull models best fit the survival of the matched patients with IPF. All three models led to consistent Bayesian estimates of survival for the matched patients with other PF-ILDs, with median rates of overall survival ranging from 6.34 to 6.50 years after starting nintedanib. The corresponding control group survival estimates were 3.42 to 3.76 years. Conclusion We provide the first estimates of long-term overall survival for patients with PF-ILDs other than IPF, and our analysis suggests that nintedanib may prolong their survival. Our Bayesian approach to estimating survival of one disease based on clinical trial data from a similar disease may help inform economic modelling of rare, orphan and newly defined disorders.

INTRODUCTION: Apalutamide and darolutamide are next-generation androgen receptor inhibitors that have demonstrated superior efficacy compared to placebo in men with non-metastatic castration-resistant prostate cancer (nmCRPC) receiving androgen deprivation therapy (ADT). In the absence of head-to-head studies, the present study sought to indirectly compare the efficacy and tolerability between these two treatments. METHODS: This anchored matching-adjusted indirect comparison (MAIC) used patient-level data from the phase 3, randomized, controlled SPARTAN study (apalutamide + ADT), weighted to match aggregate published data from the ARAMIS study (darolutamide + ADT) for clinically relevant baseline measures. Hazard ratios (HR) and 95% credible intervals (CrI) were estimated for efficacy endpoints: metastasis-free survival (MFS), prostate-specific antigen (PSA) progression, progression-free survival (PFS), and overall survival (OS). Odds ratios were estimated for tolerability outcomes: adverse events and serious adverse events. RESULTS: Before weighting, baseline characteristics from SPARTAN versus ARAMIS were different for median PSA (7.8 vs. 9.2 ng/mL), Eastern Cooperative Oncology Group performance status of 1 (23% vs. 31%), use of bone-targeted agents (10% vs. 4%), median time from initial diagnosis (94.9 vs. 85.4 months), and proportion of patients from North America (35% vs. 12%) and Europe (50% vs. 64%). After matching (n = 455), our analysis demonstrated that apalutamide + ADT had a Bayesian probability of being more effective than darolutamide + ADT for MFS [98.3%; HR 0.70 (95% CrI 0.51, 0.98)], PSA progression [~ 100%; HR 0.46 (95% CrI 0.33, 0.64)], and PFS [93.2%; HR 0.79 (95% CrI 0.59, 1.08)]. Results for OS and tolerability were similar between apalutamide + ADT and darolutamide + ADT. CONCLUSION: This anchored MAIC analysis of pivotal phase 3 studies in patients with nmCRPC suggests that apalutamide + ADT is more effective than darolutamide + ADT for MFS, progression-free survival (PFS), and prostate-specific antigen (PSA) progression, with a similar OS benefit and tolerability profile. TRIAL REGISTRATION: ARAMIS ClinicalTrials.gov number: NCT02200614; SPARTAN ClinicalTrials.gov number: NCT01946204. ispartof: ADVANCES IN THERAPY vol:39 issue:1 pages:518-531 ispartof: location:United States status: published

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is rarely fatal in children and young people (CYP

COVID-19 symptoms and mortality are largely due to its devastating effects in the lungs. The disease is caused by the SARS (Severe Acute Respiratory Syndrome)-CoV-2 coronavirus, which requires host cell proteins such as ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) for infection of lung epithelia. The expression and function of the steroid hormone receptor family is important in many aspects that impact on COVID-19 effects in the lung – notably lung development and function, the immune system, and expression of TMPRSS2 and ACE2. This review provides a brief summary of current knowledge on the roles of the steroid hormone receptors [androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), mineralocorticoid receptor (MR) and oestrogen receptor (ER)] in the lung, their effects on host cell proteins that facilitate SARS-CoV-2 uptake, and provides a snapshot of current clinical trials investigating the use of steroid receptor (SR) ligands to treat COVID-19.

Background A “mismatch” sequence of less prenatal weight gain and more postnatal weight gain may lead to ectopic lipid accumulation, and trigger the development of early adrenarche/pubarche and the activation of the gonadotropic axis resulting in early puberty and ending up in full-blown adolescent polycystic ovary syndrome (PCOS). In the present study, we assess whether a low-dose combination of generics that collectively reduce ectopic fat through different pathways can slow down the accelerated maturation in “mismatch” girls with early puberty. Methods Randomized, placebo-controlled, multicenter, phase 2a, study in 64 girls [age, 8.0–9.3 years; birthweight (BW) for gestational age in lower tertile (−1.96< Z-score Z-score < +1.96) and early progressive puberty (Tanner B2 at 7.7–9.0 years)]. Pharmacological intervention will be with a half-dose version of SPIOMET (mini-spiomet), a combination that reverts the PCOS phenotype in “mismatch” adolescents; mini-spiomet will contain spironolactone (25 mg/day, to raise brown adipose tissue activity), pioglitazone (3.75 mg/day, to raise adiponectin and insulin sensitivity), and metformin (425 mg/day, to raise AMPK activity and GDF15). Recruitment: 1 year; double-blind treatment: 1 year; open follow-up: 1 year; analyses and reporting: 1 year. Interventions: randomization (1:1) for placebo vs mini-spiomet. Primary outcome: annualized bone age advancement (0–1 year) by BoneXpert; secondary outcomes: insulin, IGF-I, high-molecular-weight adiponectin (HMW-adip), sex hormone binding globulin (SHBG), ultra-sensitive C-reactive protein (usCRP), androgens, luteinizing hormone (LH), follicle-stimulating hormone (FSH), oestradiol, growth-and-differentiation factor 15 (GDF15), C-X-C motif chemokine ligand-14 (CXCL14), safety parameters, and quantification of hepato-visceral fat. Discussion The present study, if successful, may provide a first proof of the concept that the rapid maturation of girls with an upward mismatch between pre- and post-natal weight gain can be slowed down with a fixed low-dose combination of old and safe generics jointly targeting a reduction of ectopic fat without necessarily lowering body weight. Trial registration EudraCT 2021-006766-21. Registered on May 30, 2022.

We showed that the chemokine receptor C-X-C Motif Chemokine Receptor 2 (CXCR2) is essential for cartilage homeostasis. Here, we reveal that the CXCR2 ligand granulocyte chemotactic protein 2 (GCP-2) was expressed, during embryonic development, within the prospective permanent articular cartilage, but not in the epiphyseal cartilage destined to be replaced by bone. GCP-2 expression was retained in adult articular cartilage. GCP-2 loss-of-function inhibited extracellular matrix production. GCP-2 treatment promoted chondrogenesis in vitro and in human cartilage organoids implanted in nude mice in vivo. To exploit the chondrogenic activity of GCP-2, we disrupted its chemotactic activity, by mutagenizing a glycosaminoglycan binding sequence, which we hypothesized to be required for the formation of a GCP-2 haptotactic gradient on endothelia. This mutated version (GCP-2-T) had reduced capacity to induce transendothelial migration in vitro and in vivo, without affecting downstream receptor signaling through AKT, and chondrogenic activity. Intra-articular adenoviral overexpression of GCP-2-T, but not wild-type GCP-2, reduced pain and cartilage loss in instability-induced osteoarthritis in mice. We suggest that GCP-2-T may be used for disease modification in osteoarthritis. ispartof: EMBO MOLECULAR MEDICINE vol:15 issue:1 ispartof: location:England status: published

Background: Multiple COVID-19 vaccines have now been licensed for human use, with other candidate vaccines in different stages of development. Effective and safe vaccines against COVID-19 have been essential in achieving global reductions in severe disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), but multiple factors, including vaccine supply and vaccine confidence, continue to impact global uptake of COVID-19 vaccines. In this study, we explore determinants of COVID-19 vaccina-tion intent across17 countries worldwide.Methods: In this large-scale multi-country study, we explored intent to accept a COVID-19 vaccine and the socio-demographic and emotional determinants of uptake for 17 countries and over 19,000 individ-uals surveyed in June and July 2020 via nationally representative samples. We used Bayesian ordinal logistic regressions to probe the relationship between intent to accept a COVID-19 vaccine and individ-uals' socio-demographic status, their confidence in COVID-19 vaccines, and their recent emotional status. Gibbs sampling was used for Bayesian model inference, with 95% Bayesian highest posterior density intervals used to capture uncertainty.Findings: Intent to accept a COVID-19 vaccine was found to be highest in India, where 77.8% (95% HPD, 75.5 to 80.0%) of respondents strongly agreeing that they would take a new COVID-19 vaccine if it were available. The Democratic Republic of Congo (15.5%, 12.2 to 18.6%) and France (26.4%, 23.7 to 29.2%) had the lowest share of respondents who strongly agreed that they would accept a COVID-19. Confidence in the safety, importance, and effectiveness of COVID-19 vaccines are the most widely informative determi-nants of vaccination intent. Socio-demographic and emotional determinants played a lesser role, with being male and having higher education associated with increased uptake intent in five countries and being fearful of catching COVID-19 also a strong determinant of uptake intent.Interpretation: Barriers to COVID-19 vaccine acceptance are found to be country and context dependent. These findings highlight the importance of regular monitoring of COVID-19 vaccine confidence to identify groups less likely to vaccinate.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines. ispartof: JOURNAL OF EXPERIMENTAL MEDICINE vol:220 issue:1 ispartof: location:United States status: published

We previously reported the multi-system sequelae of fetal growth restriction, induced by placental underperfusion, in near-term born rabbits, in the immediate neonatal period and up to pre-adolescence. Herein, we describe the pulmonary and neurodevelopmental consequences of FGR in rabbits born preterm. We hypothesize that FGR has an additional detrimental effect on prematurity in both pulmonary function and neurodevelopment. FGR was induced at gestational day (GD) 25 by placental underperfusion, accomplished by partial uteroplacental vessel ligation in one uterine horn. Rabbits were delivered by cesarean section at GD 29, and placentas were harvested for histology. Neonates underwent neurobehavioral or pulmonary functional assessment at postnatal day 1, followed by brain or lung harvesting, respectively. The neurodevelopmental assessment included neurobehavioral testing and multiregional quantification of cell density and apoptosis in the brain. Lung assessment included functional testing, alveolar morphometry, and airway histology. FGR was associated with higher perinatal mortality, lower birth and placental weight, and a similar brain-to-body weight ratio compared to controls. Placental underperfusion decreased labyrinth and junction zone volumes in FGR placentas. FGR impaired pulmonary function, depicted by higher parenchymal resistance, damping, and elastance. Alveolar morphometry and airway smooth muscle content were comparable between groups. Neurobehavioral tests showed motoric and sensorial impairment in FGR rabbits. In FGR brains, cell density was globally reduced, with higher apoptosis in selected areas. In conclusion, in preterm-born rabbits, placental underperfusion leads to higher mortality, FGR, and impaired lung and brain development in early assessment. This study complements previous findings of placental, pulmonary, and neurodevelopmental impairment in near-term born rabbits in this model. ispartof: BIOMEDICINES vol:11 issue:1 ispartof: location:Switzerland status: published

Young children aged 6−59 months are recommended as one of the priority groups for seasonal influenza vaccination in China. This study assessed influenza vaccination coverage and the factors associated with vaccination uptake among children in three Chinese provinces. In September 2021, 2081 caregivers with children

The uptake of non-EPI vaccines, such as influenza and pneumonia vaccines, are very low in China compared to other countries. In China, immunization services are provided by dedicated vaccination service providers (VSPs), and their recommendation is the key to improve vaccine uptake. This study explores VSP recommendation practices for non-EPI vaccines from a socio-ecological perspective. A mixed-methods study, combining a questionnaire survey and key informant interviews, was conducted in Anhui, Shaanxi, and Guangdong provinces. 555 VSPs completed the valid questionnaire, and 49 VSPs participated in in-depth interviews. Among the surveyed VSPs, 51.54% stated that they always or often recommended non-EPI vaccines in work, and the remaining half reported that they sometimes or never recommended non-EPI vaccines. Most VSPs interviewed communicated about non-EPI vaccines with the public in an informed style, not a presumptive one, and provided the public with all the decision-making latitude. The infrequent recommendation of non-EPI vaccines was widely prevalent among Chinese VSPs regardless of their individual characteristics, and was mainly driven by the interpersonal relationship, institutional arrangement, and public policy. Firstly, the VSPs were concerned about conflicts arising from the recommendation of self-paid vaccines and the risk of adverse reactions following vaccination. Secondly, high workloads left them insufficient time to communicate about non-EPI vaccines. Thirdly, there was no performance assessment or financial incentive for VSPs to recommend non-EPI vaccination, and their main responsibility was around EPI vaccination. Therefore, multi-level socio-ecological systems around non-EPI vaccination should be improved to optimize the communication between VSPs and the public, which include a better system of legal redress to resolve potential misunderstandings between the VSPs and the public, more effective workload management through whole-process health information system and strengthening public health workforce, and the introduction of performance assessment and appropriate incentives on non-EPI vaccination. ispartof: VACCINES vol:10 issue:12 ispartof: location:Switzerland status: published

Objective: To investigate the effect of a novel mineral containing toothpaste in comparison to a fluoride toothpaste in children with white spot lesions. Method: The clinical study was conducted from 2016 to 2018 at Marmara University Department of Pediatric Dentistry Clinic after approval from the ethics review committee of Yeditepe University, Istanbul, Turkey, and comprised children of either gender aged 4-5 years having white spot lesions. They were randomly allocated into two groups. The FT ( Fluoridated Toothpaste ) group was given a 500ppm fluoridated toothpaste, while the Mineral Containing Toothpaste (MCT) group was given toothpaste containing calcium glycerophosphate, magnesium chloride, and 12% xylitol. The white spot lesions were examined using Laser Fluorescence (LF) at baseline and after a month of usage. The two readings were compared. Stimulated saliva was collected for measuring the salivary potential of hydrogen, buffering capacity, and streptococcus mutans. Data was analysed using SPSS 19. Results: Of the 26 children, 10(38%) were girls and 16(62%) were boys. The overall mean age was 4.77+/-0.54 years. There were 13(50%) subjects in each of the two groups. Of the 381 measurements done, 198(52%) were in the MCT group and 183(48%) in the FT group. LF scores decreased in both the groups (p=0.001). The remineralising potential was not significantly different (p=0.866), while salivary buffering capacity and potential of hydrogen increased in both the groups but the change was not significant (p>0.05). The number of children positive for streptococcus mutans decreased in both the groups (p>0.05). ---Continue

Objective: Adrenergic receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and adrenergic neurons in the central nervous system. The rs1800544 polymorphism in 3’-untranslated region of ADRA2A is caused by C-1291>G nucleotide change. In this study, we aimed to analyze the rs1800544 distribution in kickboxing players. Methods: A total of 12 male players and 101 sedentary individuals (as a control group) participated in the study. Following DNA isolation, rs1800544 polymorphism of ADRA2A was determined by real-time polymerase chain reaction (Rt-PCR). Statistical analysis was carried out by chi-square test. Results: CC, CG and GG genotypes and percentages for rs1800544 polymorphism were analyzed as 5 (41,7%), 4 (33,3%) and 3 (25%), respectively. C allele was counted as 14 (58,3%) and G allele as 10 (41,7%). In the control group CC, CG and GG were found as 34 (33,6%), 53 (52,5%), 14(13,9%), respectively. C allele was counted as 121 (60%) and G allele as 81 (40%). When we compare athletes and controls in the terms of genotypes, we detected no statistically significant difference (p>0,3940). For the allele comparison, we detected no significant difference between groups (p>0,0871). Conclusion: Determination of gene combinations in Turkish athletes is of great importance for carrying out of these studies. Therefore, we aimed to determine the distribution of the alleles related with athletic performance on successful athletes. In our cohort, CC genotype was more frequently found, and C allele was also higher in players. We think that the effect of ADR2A2 gene on athletic performance might be determined more clearly by the fact that this study is an example of similar studies involving higher numbers of subjects.

Objective: Health literacy is designated as a “Social Barrier” to accessing health services. The aim of the study was to determine the access status of the parents of mentally disabled individuals to health services according to their health literacy levels. Methods: The universe of this descriptive study consisted of the parents of individuals with intellectual disability (N:118). The data collection instruments used in the study were the Health Literacy Scale for Turkey-32 and an Access to Health Services Assessment Questionnaire. Ethics Committee permission and approvals were obtained. Results: A statistically significant difference was found between the caregivers’ health literacy levels and their knowledge of how to benefit from health services, their ability to understand the information given to them by health personnel, their ability to correctly communicate their needs, their access to health services and to adequate information, their ability to understand the information gathered and to obtain an appointment from health institutions, their tendency to give up due to the difficulties they faced in procuring an appointment, and their physically being unable to reach health services (p

Objective: The aim of the study was to evaluate the possible protective effects of alpha-lipoic acid (α-LA), donepezil and memantine combined therapy in the scopolamine-induced amnesia rat model. Objective: The aim of the study was to evaluate the possible protective effect of donepezil, memantine and alpha-lipoic acid (α-LA) combined therapy in the scopolamine-induced amnesia rat model. Methods: In this study, the effect of combined therapy used in the treatment of scopolamine-induced amnesia on behavioural parameters was evaluated using Y-maze and new object recognition (NOR) test. In addition, muscarinic acetylcholine receptor subtype M1, N-methyl-D-aspartate receptor NR2B subunit, brain-derived neurotrophic factor (BDNF) and mitochondrial apoptosis-related proteins [B-cell lymphoma-2 (Bcl-2) / Bcl-2 associated X (Bax) ratio, caspase (casp) -3, and -9] expression levels were evaluated using the western blot method in the frontal cortex and hippocampus regions. Results: The main findings of this study demonstrated that in scopolamine-induced amnesia rats, cognitive dysfunction determined by both the Y-maze and the NOR test were reversed with the combined treatment of memantine, donepezil and α-LA. According to immunoblotting results in both brain regions, scopolamine-induced decreased M1, BDNF, Bcl-2 / Bax ratio and increased NR2B, casp-3 and -9 expression levels were found to be reversed to almost control values with combined treatment. Conclusion: Consistent with the literature, our study results suggest that the positive contribution of α-LA to the combined treatment of donepezil and memantine, which is used in the routine treatment of neurodegenerative diseases, may be a treatment option in the future. Results: The main findings of this study demonstrated that in scopolamine-induced amnesia rats, cognitive dysfunction determined by both the Y-maze and the NORT test were reversed with the combined treatment of memantine, donepezil and α-LA. In addition, decreased BDNF, M1, bcl-2/bax ratio and increased NR2B, caspase-3 and caspase-9 expression levels due to scopolamine in both regions were improved with α-LA, donepezil and memantine combined therapy. Conclusion: The results of our study and other study results in the literature suggest that α-LA may be a future treatment option due to its positive contribution to the effects of other drugs used in the routine treatment of neurodegenerative diseases.

Self-amplifying mRNA (saRNA) represents a promising platform for nucleic acid delivery of vaccine immunogens. Unlike plasmid DNA, saRNA does not require entry into the nucleus of target cells for expression, having the capacity to drive higher protein expression compared to mRNA as it replicates within the cytoplasm. In this study, we examined the potential of stabilized native-like HIV-1 Envelope glycoprotein (Env) trimers to elicit immune responses when delivered by saRNA polyplexes (PLXs), assembled with linear polyethylenimine. We showed that Venezuelan equine encephalitis virus (VEEV) saRNA induces a stronger humoral immune response to the encoded transgene compared to Semliki Forest virus saRNA. Moreover, we characterized the immunogenicity of the soluble and membrane-bound ConSOSL.UFO Env design in mice and showed a faster humoral kinetic and an immunoglobulin G (IgG)2a skew using a membrane-bound design. The immune response generated by PLX VEEV saRNA encoding the membrane-bound Env was then evaluated in larger animal models including macaques, in which low doses induced high IgG responses. Our data demonstrated that the VEEV saRNA PLX nanoparticle formulation represents a suitable platform for the delivery of stabilized HIV-1 Env and has the potential to be used in a variety of vaccine regimens., Graphical abstract, Aldon, McKay, and colleagues evaluated the potential of formulated VEEV and SFV self-amplifying mRNA (saRNA) for the delivery of HIV-1 Env stabilized trimers. The authors demonstrate great potential for PEI-polyplex formulated VEEV-saRNA platform, which elicits strong humoral responses at low doses in non-human primates.

Background Congenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most common CDG is phosphomannomutase 2 (PMM2)-CDG which often has a severe clinical presentation and life-limiting consequences. There are no approved therapies for this condition. Also, there are no validated disease-specific quality of life (QoL) scales to assess the heterogeneous clinical burden of PMM2-CDG which presents a challenge for the assessment of the disease severity and the impact of a certain treatment on the course of the disease. Aim and methods This study aimed to identify the most impactful clinical signs and symptoms of PMM2-CDG, and specific patient and observer reported outcome measures (PROMs and ObsROMs, respectively) that can adequately measure such impact on patients’ QoL. The most burdensome signs and symptoms were identified through input from the CDG community using a survey targeting PMM2-CDG families and experts, followed by family interviews to understand the real burden of these symptoms in daily life. The list of signs and symptoms was then verified and refined by patient representatives and medical experts in the field. Finally, a literature search for PROMs and ObsROMs used in other rare or common diseases with similar signs and symptoms to those of PMM2-CDG was performed. Results Twenty-four signs/symptoms were identified as the most impactful throughout PMM2-CDG patients’ lifetime. We found 239 articles that included tools to measure those community-selected PMM2-CDG symptoms. Among them, we identified 80 QoL scales that address those signs and symptoms and, subsequently, their psychometric quality was analysed. These scales could be applied directly to the PMM2-CDG population or adapted to create the first PMM2-CDG-specific QoL questionnaire. Conclusion Identifying the impactful clinical manifestations of PMM2-CDG, along with the collection of PROMs/ObsROMs assessing QoL using a creative and community-centric methodology are the first step towards the development of a new, tailored, and specific PMM2-CDG QoL questionnaire. These findings can be used to fill a gap in PMM2-CDG clinical development. Importantly, this methodology is transferable to other CDG and rare diseases with multiple signs and symptoms.

Background Catechol-O-methyltransferase (COMT) has been shown to influence clinical pain, descending modulation, and exercise-induced symptom worsening. COMT regulates nociceptive processing and inflammation, key pathophysiological features of Chronic Fatigue Syndrome and Fibromyalgia (CFS/FM). We aimed to determine the interactions between genetic and epigenetic mechanisms regulating COMT and its influence on inflammatory markers and symptoms in patients with CFS/FM. Methods. A case-control study with repeated-measures design was used to reduce the chance of false positive and increase the power of our findings. Fifty-four participants (28 patients with CFS/FM and 26 controls) were assessed twice within 4 days. The assessment included clinical questionnaires, neurophysiological assessment (pain thresholds, temporal summation, and conditioned pain modulation), and blood withdrawal in order to assess rs4818, rs4633, and rs4680 COMT polymorphisms and perform haplotype estimation, DNA methylation in the COMT gene (both MB-COMT and S-COMT promoters), and cytokine expression (TNF-α, IFN-γ, IL-6, and TGF-β). Results. COMT haplotypes were associated with DNA methylation in the S-COMT promoter, TGF-β expression, and symptoms. However, this was not specific for one condition. Significant between-group differences were found for increased DNA methylation in the MB-COMT promoter and decreased IFN-γ expression in patients. Discussion Our results are consistent with basic and clinical research, providing interesting insights into genetic-epigenetic regulatory mechanisms. MB-COMT DNA methylation might be an independent factor contributing to the pathophysiology of CFS/FM. Further research on DNA methylation in complex conditions such as CFS/FM is warranted. We recommend future research to employ a repeated-measure design to control for biomarkers variability and within-subject changes.

Background Treatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone. Methods Opiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of ‘dose-limiting toxicity’ (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO2, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodically for 5 h after dosing. Discussion Study outcomes will determine what dose of baclofen is safe to prescribe to those receiving methadone, to inform a subsequent proof-of-concept trial of the efficacy baclofen to facilitate opiate detoxification. To proceed, the minimum acceptable dose is 30 mg of baclofen in patients receiving ≤ 60 mg/day methadone based on the clinical experience of baclofen’s use in alcoholism and guidelines for the management of opiate dependence. Trial registration Clinicaltrials.gov NCT05161351. Registered on 16 December 2021.

Objective: To assess the changes in children’s oral health-related quality of life following the treatment of severely affected molar-incisor hypomineralisation with Glass Hybrid Restorative System (GH) after selective caries removal. Method: The observational cross-sectional study was conducted at the Marmara University, School of Dentistry, Department of Pediatric Dentistry. Children aged 11–14 years (n = 55) who were diagnosed with MIH and had finished their dental treatment from November 2018 to December 2019, were included. The children’s MIH-affected teeth were treated with GH after SCR. Participants answered the Child Perceptions Questionnaire (CPQ) prior to their dental treatment and 6 months after the treatment. Results: Of the fifty-five patients, 40 patients (24 girls-16 boys) completed baseline and follow-up data. The mean age of the children was 11.85 (±1.02) years. The overall CPQ score ranged from 3–83 (average 33.27 ± 16.46) at baseline and 0–61 (average 11.67 ± 11.21) at follow up. The emotional well-being among children was the highest score at baseline. A significant decrease (p < 0.001) in the mean values was observed for both the overall CPQ scores and for the scores of the oral symptoms, functional limitations, and social-emotional well-being limitation. All subdomains showed large effect sizes and oral symptom limitation domain presented the greatest effect. Wilcoxon Rank test was used to determine the statistical significance of the changes and the magnitude of change was determined by calculating and classifying the effect size. Conclusion: Restorative treatment with GH following selective caries removal positively influenced the oral health-related quality of life of children with severe molar-incisor hypomineralisation. Key Words: Health-related quality of life, Dental enamel hypoplasia, Questionnaires, Child, Oral health.

BACKGROUND: Hepatic metastasis is the primary and direct cause of death in individuals with colorectal cancer (CRC) attribute to lack of effective therapeutic targets. The present study aimed to identify potential druggable candidate targets for patients with liver metastatic CRC. METHODS: The transcriptional profiles of super-enhancers (SEs) in primary and liver metastatic CRC were evaluated in publicly accessible CRC datasets. Immunohistochemistry of human CRC tissues was conducted to determine the expression level of CDK12. Cellular proliferation, survival and stemness were examined upon CDK12 inhibition by shCDK12 or a selective CDK12 inhibitor named SR-4835 with multiple in vitro and in vivo assays. RNA sequencing and bioinformatics analyses were carried out to investigate the mechanisms of CDK12 inhibition in CRC cells. RESULTS: We identified CDK12 as a driver gene for direct hepatic metastasis in CRC. Suppression of CDK12 led to robust inhibition of proliferation, survival and stemness. Mechanistically, CDK12 intervention preferentially repressed the transcription of SE-associated genes. Integration of the SE landscape and RNA sequencing, BCL2L1 and CCDC137 were identified as SE-associated oncogenic genes to strengthen the abilities of cellular survival, proliferation and stemness, eventually increasing liver metastasis of CRC. CONCLUSIONS: Our data highlight the potential of CDK12 and SE-associated oncogenic transcripts as therapeutic targets for patients with liver metastatic CRC. ispartof: CLINICAL AND TRANSLATIONAL MEDICINE vol:12 issue:10 ispartof: location:United States status: published