Appropriateness of aspirin use among diabetic patients in primary prevention of atherosclerotic cardiovascular diseases: an analysis of the ASSOS study.

OBJECTIVE: Aspirin is an essential drug in the prevention of atherosclerotic cardiovascular disease (ASCVD). It is ultimately indicated in a patient with ASCVD. However, its role is debated in primary prevention. We aimed to investigate the appropriateness of aspirin use in diabetic patients according to recommendations of recent guidelines. PATIENTS AND METHODS: ASSOS was a multicenter observational study investigating aspirin use in cardiology outpatient clinics. We evaluated aspirin use in diabetic patients in primary prevention from the ASSOS study. We also assessed the appropriate use of aspirin according to the European Society of Cardiology (ESC), American College of Cardiology/American Heart Association (ACC/AHA), American Diabetes Association (ADA), Consensus Statement of Endocrinology, Cardiology, and Nephrology (ENCARNE), and the United States Preventive Services Task Force (USPTF). RESULTS: A total of 5,007 patients of whom 1,537 had type 2 diabetes mellitus (DM) were included in the study. 1,132 of the total participants used aspirin for primary prevention; 313 of them had type 2 DM. Only 248 (76.7%), 132 (40.8%), and 128 (39.6%) diabetic patients indicated aspirin use according to the ESC/INCARNE, ACC/AHA, and ADA/USPTF guidelines, respectively. CONCLUSIONS: Inappropriate aspirin use was common among diabetic patients, according to clinical practice guideline recommendations. In addition, the differences between the indications for the use of aspirin in diabetic patients according to the guidelines were remarkable. Guidelines that minimize these differences are needed for clinicians, and compliance with these guidelines in clinical practice could reduce inappropriate aspirin use.

Determination of candidate genes involved in schizophrenia using the whole-exome sequencing.

OBJECTIVES: We used the whole-exome sequencing to evaluate several genes suspected of being involved in the pathogenesis of schizophrenia. METHODS: The study sample was composed of two families. In the first family, two siblings had schizophrenia, and the parents were healthy. In the second family, two siblings had schizophrenia, while the other sibling and the parents did not. RESULTS: Indels were detected in some genes, including SPON1, GRIA3, SMAD5, PCLO, KMT2C, SRD5A2, SEMA3B, NCOR2, GPHB5, FAM174B, CLTCL1, and TMEM216. The insertion of three nucleotides (TGA) was detected in the sequence of the PCLO gene. The mutation resulted in the insertion of aspartic acid (Asp, D) in the amino acid sequence of the PCLO protein. Indels detected in SPON1, GRIA3, SMAD5, KMT2C, SRD5A2, SEMA3B, GPHB5, CLTCL1, and TMEM216 were shown to be frameshifting. Bioinformatics analysis showed that the indels in SPON1, GRIA3, SMAD5, KMT2C, SRD5A2, SEMA3B, NCOR2, GPHB5, FAM174B, CLTCL1, and TMEM216 had a damaging effect, while the indel in PCLO had a non-damaging effect on protein function. CONCLUSION: To the best of our knowledge, no previous studies have examined the relationship between the pathogenesis of schizophrenia and the gene mutations identified in this study (Tab. 1, Ref, 42).

Current studies of immunotherapy in head and neck cancer.

BACKGROUND: Recently, enormous progress in cancer therapy has been achieved by the use of immune checkpoint inhibitors. Activating the body's own immune system has added a novel and powerful therapeutic option for the treatment of melanoma and lung cancer. Furthermore, the potential use of immunotherapy is being extensively explored also in other malignancies. OBJECTIVE OF REVIEW: This review summarises current clinical studies using immune checkpoint modulators for the treatment of head and neck cancer (HNSCC). TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: A PubMed search from 2010 onwards was performed for the use of immune checkpoint inhibitors in clinical trials of HNSCC. An equivalent search was performed at clinicaltrials.gov. Additionally, the abstracts from the annual meetings of the ASCO, ESMO and AACR were screened. RESULTS: A total of 45 relevant studies using immune checkpoint inhibitors in HNSCC were identified. In the majority of these studies, antagonistic antibodies targeting the immune checkpoint receptors PD-1 are used either solely or combined, mostly with other immunomodulatory antibodies, such as inhibitors of CTLA-4. Most studies are still recruiting patients (26/45). In the primary setting, we identified 16 studies using checkpoint inhibition as neoadjuvant/adjuvant modality for treatment with curative intent. The response rate upon treatment with PD-1 antagonists in relation to the PD-L1 status is being investigated in 12 trials. Novel immune checkpoint modulators combined with the inhibition of the PD-1/PD-L1 axis or CTLA-4 have been set up in six trials. So far, only four studies that use immune checkpoint inhibition in HNSCC have presented results and all of these explored the inhibition of the PD-1/PD-L1 axis. The studies demonstrated overall response rates (ORR) in the range of 20%. These preliminary data suggest that a PD-L1 expression ≥1% is associated with a higher response rate compared to a PD-L1 expression ≤1%. The anti-PD-1-antibody pembrolizumab extended the duration of response in recurrent and/or metastatic (R/M) HNSCC (by approximately 53 weeks) in a phase Ib study. Therefore, pembrolizumab was granted accelerated approval for the treatment of platinum refractory R/M HNSCC by the FDA. CONCLUSION: Numerous clinical trials are addressing the suitability and efficacy of immune checkpoint modulators in HNSCC with the predominant targets being the established immune checkpoint receptors PD-1/PD-L1 and CTLA-4. Recently, presented results have shown a survival benefit, a favourable safety profile and an extended duration of response in favour of using immune checkpoint modulation in R/M HNSCC.

Real-life use of digoxin in patients with non-valvular atrial fibrillation: data from the RAMSES study.

WHAT IS KNOWN AND OBJECTIVE: Although inappropriate use of digoxin has been described in various populations, a real-world evaluation of patterns of digoxin prescription has not been well studied in patients with atrial fibrillation (AF). The aim of this study was to identify prevalence, indications and appropriateness of digoxin use in the general population of patients with non-valvular AF (NVAF) in Turkey. METHODS: We included and classified patients from the RAMSES (ReAl-life Multicentre Survey Evaluating Stroke prevention strategies in Turkey) study, a prospective registry including 6273 patients with NVAF, on the basis of digoxin use. After excluding the data of 73 patients whose medical history about digoxin use or left ventricle function was absent, 6200 patients were included for the final analysis. Digoxin use was considered inappropriate if patients did not have left ventricular systolic dysfunction or symptomatic heart failure (HF). RESULTS AND DISCUSSION: Digoxin was used in 1274 (20·5%) patients. Patients treated with digoxin were older (71·4 ± 9·8 years vs. 69·2 ± 10·9 years, P < 0·001), more likely to be female (58·8% vs. 55·9%, P = 0·019) and had more common comorbidities such as HF (40·2% vs. 17·4%), diabetes (26·4% vs. 21·1%), coronary artery disease (35·3 vs. 27·6%) and persistent/permanent AF (93·4% vs. 78·4%; P < 0·001 for each comparison). Of the 1274 patients, the indication of digoxin use was considered inappropriate in 762 (59·8%). WHAT IS NEW AND CONCLUSION: Our findings show that nearly one-fifth of the patients with NVAF were on digoxin therapy and nearly 60% of these patients were receiving digoxin with inappropriate indications in a real-world setting.

Prognostic value of transthoracic echocardiography and biomarkers of cardiac dysfunction in community-acquired pneumonia.

The aim of this study was to determine the prognostic role of echocardiography and compare with admission N-terminal proB-type natriuretic peptide (NT-proBNP) levels in adult patients with community-acquired pneumonia (CAP). Consecutive adult patients hospitalized with CAP were prospectively enrolled and followed-up until hospital discharge or death. Echocardiography was performed within the first 48 hours. Complicated hospitalization (CH) was defined as intensive care unit admission, need for mechanical ventilation or in-hospital mortality. This study was registered with ClinicalTrials.gov, number NCT02441855. A total of 15 CH (13.5%) occurred among 111 patients with CAP. CAP patients with a CH compared with those without CH had significantly higher NT-proBNP values (1267.4±1146.1 vs. 305.6±545.7 pg/mL, p <0.001) and troponin I (23.8±24.3 vs. 10.3±6.3 ng/mL, p 0.02) but had lower left ventricle ejection fraction (52.7±8.7 vs. 60.5±6.7%, p <0.001) and tricuspid annular plane systolic excursion (TAPSE), which is a measure of right ventricular systolic function (17.1±4.4 vs. 21.8±4 mm; p 0.001). Patients with elevation of NT-proBNP and decreased TAPSE at presentation had a significantly higher probability of CH (60%) than patients with either elevated NT-proBNP or decreased TAPSE (40%). Patients with neither elevated NT-proBNP nor decreased TAPSE had a 0% probability of CH. This is the first study to demonstrate that decreased right ventricular systolic function is associated with increased rates of adverse events in patients with CAP.

Impact of QRS morphology on heart rate turbulence and heart rate variability after cardiac resynchronization therapy in patients with heart failure.

OBJECTIVE: Impairment of heart rate turbulence (HRT) and heart rate variability (HRV) are associated with poor prognosis in chronic heart failure (CHF). Although previous studies have demonstrated that patients with a left bundle branch block (LBBB) have a better outcome with cardiac resynchronization therapy (CRT), the effect of QRS morphology on HRV and HRT is not known. We aimed to evaluate the effect of QRS morphology on HRV and HRT after CRT implantation in patients with CHF. PATIENTS AND METHODS: Patients who had been implanted a CRT device with cardioversion-defibrillation feature were included to the study. Forty-three patients with LBBB (group 1) were compared with 21 patients without LBBB (group 2). HRV and HRT parameters were compared before and one month after CRT implantation. RESULTS: We compared the echocardiographic and electrocardiographic changes in both groups after CRT. Cardiac output (CO) was found to be significantly much more increased in group 1 (1.1 ± 0.4 vs. 0.6 ± 0.4, p = 0.001). Similarly, except SDNN and LF, all HRT and HRV parameters were significantly changed in the patients with LBBB (TO 1.4 ± 0.3 vs. 1.2 ± 0.2, p = 0.001; TS -1.8 ± 0.7 vs. -0.9 ± 0.7, p = 0.001; RMSSD -15.7 ± 9.9 vs. -6.3 ± 6.2, p = 0.001; PNN50 -7.0 ± 4.6 vs. -1.7 ± 1.1, p = 0.001; HF -13.3 ± 6.7 vs. -4.3 ± 3.5, p = 0.001; LF/HF 1.9 ± 0.4 vs. 1.5 ± 0.2, p = 0.001) compared to those without LBBB. Lineer regression analysis showed that the CO (ß = 0.2, t = 2.8, p = 0.007) and QRS configuration (ß = 0.6, t = 0.5, p = 0.001) were independent parameters affecting TO. CONCLUSIONS: HRV and HRT are improved after CRT but these improvements are more remarkable in patients with LBBB. CO, QRS configuration (but not duration) were two independent parameters affecting TO, LF and LF/HF ratio after CRT.

The efficacy of an enuresis alarm in monosymptomatic nocturnal enuresis.

INTRODUCTION: Monosymptomatic nocturnal enuresis (MNE) is a frequent problem in children older than five years of age. Of the various treatment options, the enuresis alarm has been widely advocated for treating nocturnal enuresis. This study was designed to evaluate the success rates of the enuretic alarm device in patients with MNE. METHODS: 40 patients who had significant MNE (three or more wet nights per week) were included. They used an enuretic alarm for 12 weeks initially. If a relapse was observed, reusage of the device was provided. A success criterion was defined as "14 consecutive dry nights" and a relapse criterion was "more than one wet night a week". RESULTS: The patients' mean age was 8.1 (range 6-16) years and the mean follow-up time was 10.2 (range 6-19) months. 27 patients became dry at night at the end of three months. In the follow-up period, a relapse was observed in 66.7 percent of the initial responders. For recovery, 14 patients started to reuse the device, and seven of them responded positively. At the end of the treatment, a total of 13 of the patients had benefited from the enuretic alarm. CONCLUSION: During the follow-up, the enuretic alarm device provided acceptable initial and long-term complete dryness in patients with primary nocturnal enuresis. Without the need for expensive pharmacological intervention, the alarm treatment is an effective choice for children with nocturnal enuresis.

Telomerase is not an epidermal stem cell marker and is downregulated by calcium.

The ribonucleoprotein complex telomerase, which was found to be active in germ line, immortal, and tumor cells, and in cells from continuously renewing normal tissues such as epidermis or bone marrow, is thought to be correlated with an indefinite life span. Therefore, it has been postulated that in the normal tissues, telomerase activity may be restricted to stem cells, the possible precursors of tumor cells. Here, we demonstrate that a 56% enriched population of epidermal stem cells exhibited less telomerase activity than the more actively proliferating transit amplifying cells, which are destined to differentiate after a finite number of cell divisions. Thus telomerase is not a stem cell marker. In human epidermis we found a heterogeneous expression of the telomerase RNA component (hTR) within the basal layer, with clusters of hTR-positive cells showing variable activities. Histone-3 expressing S-phase basal cells were distributed evenly, illustrating that hTR upregulation may not strictly be correlated with proliferation. We further show for human epidermal cells that differentiation-dependent downregulation of telomerase correlates with Ca++-induced cell differentiation and that increasing the amount of Ca++ but not Mg++ or Zn++ reduced telomerase activity in a dose-dependent manner in a cell-free system (differentiation-independent). Furthermore, addition of ethyleneglycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid completely reversed this Ca++-induced inhibition. These data indicate that Ca++ is not only an important regulator of epidermal differentiation but also a key regulator of telomerase.

Sense and antisense transcripts of human papillomavirus type 16 in cervical cancers.

Human papillomavirus type 16 (HPV-16) transcription was analysed in one squamous cervical carcinoma by cDNA cloning and DNA sequencing, and in eight additional squamous cervical carcinomas and 11 precancerous lesions by RNA-RNA in situ hybridization. The nucleotide sequences of the cDNA clones revealed structures of early HPV-16 mRNAs (E6*-E7-E1 E4-E5) in agreement with data reported for other premalignant and malignant tumours. cDNA clones possibly representing viral RNA of antisense orientation were also detected. These RNAs included sequences of the upstream regulatory region, part of the early and the late region of the genome. In three of eight squamous cervical carcinomas examined by in situ hybridization, signals specific for viral antisense RNA were also found. The antisense RNAs had a predominantly nuclear localization. Viral antisense RNA could not be detected in any of 11 HPV-16-positive premalignant lesions. The expression of HPV antisense RNA is likely to be linked to viral integration into the host genome. The possible effects of viral antisense transcription with regard to tumour progression remain to be determined.