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Abstract Remdesivir therapy has been declared as efficient in the early stages of Covid-19. Of the 339 patients (males 55.8%, age 71(59;77) years) with a detectable viral load, 140 were treated with remdesivir (of those 103 in the ICU and 57 immunosuppressed) and retrospectively compared with 199 patients (of those 82 in the ICU and 28 immunosuppressed) who were denied therapy due to advanced Covid-19. The viral load was estimated by detecting nucleocapsid antigen in serum (n = 155, median 217(28;1524)pg/ml), antigen in sputum (n = 18, COI 18(4.6;32)), nasopharyngeal antigen (n = 44, COI 17(8;35)) and the real-time PCR (n = 122, Ct 21(18;27)). After adjustment for confounders, patients on remdesivir had better 12-month survival (HR 0.66 (0.44;0.98), p = 0.039), particularly when admitted to the ICU (HR 0.49 (0.29;0.81), p = 0.006). For the immunocompromised patients, the difference did not reach statistical significance (HR 0.55 (0.18;1.69), p = 0.3). The other most significant confounders were age, ICU admission, mechanical ventilation, leukocyte/lymphocyte ratio, admission creatinine and immunosuppression. The impact of monoclonal antibodies or previous vaccinations was not significant. Despite frequent immune suppression including haemato-oncology diseases, lymphopenia, and higher inflammatory markers in the remdesivir group, the results support remdesivir administration with respect to widely available estimates of viral load in patients with high illness severity.

Abstract Background ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). Methods Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. Results Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6–1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1–10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. Conclusions Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer. Trial registration This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017–004166-10).

Purpose: To observe the impact of using scribes on documentation efficiency in ophthalmology clinics. Design: Single-center retrospective cohort study. Participants: A total of 29 997 outpatient visits conducted by 7 attending ophthalmologists between January 1, 2018, and December 31, 2019, were included in the study: 18 483 with a scribe present during the encounter and 11 514 without a scribe present. Methods: Use of a scribe. Main Outcome Measures: Total physician documentation time, physician documentation time during and after the visit, visit length, time to chart closure, note length, and percentage of note text edited by physician. Results: Total physician documentation time was significantly less when working with a scribe (mean ± standard deviation, 4.7 ± 2.9 minutes/note vs. 7.6 ± 3.8 minutes/note; P < 0.001), as was documentation time during the visit (2.8 ± 2.2 minutes/note vs. 5.9 ± 3.1 minutes/note; P < 0.001). Physicians also edited scribed notes less, deleting 1.9 ± 4.4% of scribes’ draft note text and adding 14.8 ± 11.4% of the final note text, compared with deleting 6.0 ± 9.1% (P < 0.001) of draft note text and adding 21.2 ± 15.3% (P < 0.001) of final note text when not working with a scribe. However, physician after-visit documentation time was significantly higher with a scribe for 3 of 7 physicians (P < 0.001). Scribe use was also associated with an office visit length increase of 2.9 minutes (P < 0.001) per patient and time to chart closure of 3.0 hours (P < 0.001), according to mixed-effects linear models. Conclusions: Scribe use was associated with increased documentation efficiency through lower total documentation time and less note editing by physicians. However, the use of a scribe was also associated with longer office visit lengths and time to chart closure. The variability in the impact of scribe use on different measures of documentation efficiency leaves unanswered questions about best practices for the implementation of scribes and warrants further study of effective scribe use.

Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematological cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class antibody drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leukemias and multiple myeloma by immunohistochemistry on tissue microarrays. Anti-tumor activity of MEN1309/OBT076 as single agent was then shown across 42 B-cell lymphoma cell lines with a median IC50 of 200 pM and induction of apoptosis in 25/42 (59.5%) of the cases. The activity appeared highly correlated with its target expression. After in vivo validation as the single agent, the antibody drug conjugate synergized with the BCL2 inhibitor venetoclax, and the anti-CD20 monoclonal antibody rituximab. The first-in-class antibody drug targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti-tumor activity in lymphoma, warranting further investigations as a single agent and in combination.

Aim. The CORD Study compared effectiveness and tolerability of losartan and ramipril in patients with arterial hypertension (AH).Material and methods. The study included two groups, A and B. In Group A (n=4016; mean age 62,6+11,6 years; 53,1% women), the patients with blood pressure (BP) 3 months were switched from ACE inhibitors to losartan. At baseline and 1, 3, 6, and 12 months later, BP, heart rate, and biochemical parameters were measured; general blood assay and electrocardiography (ECG) were also performed. In group B (n=3813; mean age 60,5+12,2 years; 50,5% women), the patients with BP >140/90 mm Hg and no previous ACE inhibitor or angiotensin receptor blocker (ARB) therapy were randomly administered either losartan (50 mg/d; n=1887) or ramipril (5 mg/d; n=1926).Results. Group A demonstrated a decrease in BP — from 147,4+14,8/87,7+9,3 to 139,7+11,8/83,0+9,3 mm Hg (p

Dysregulated cell-cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell-cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell-cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

Background: Glutathione S-transferases (GSTs) play important roles in protecting cells against oxidative stress and toxic chemicals. This study aimed to investigate the distribution of GSTM1, GSTT1, and GSTP1 variants and their roles in periodontitis susceptibility in a Caucasian population., Methods: We analyzed 406 participants, including 204 healthy controls and 203 periodontitis patients. A multiplex polymerase chain reaction (PCR) approach was used to analyze GSTM1 and GSTT1 loci. GSTP1 variants were detected by PCR-haplotyping method in a subgroup of participants (N = 350). Chi-square or Fisher´s exact tests were used to compare genotypic and allelic differences. The Bonferroni method was applied to correct for multiple comparisons (p corr )., Results: The GSTM1 genotype distribution did not differ significantly between controls and periodontitis patients (p = 0.44). Additionally, the wild/null genotypes of GSTT1, Ile105Val and Ala114Val frequencies of GSTP1 were not significantly different between the two groups after correction for multiple comparisons (p = 0.05, p = 0.55, p = 0.02, p corr >0.05, respectively). The GSTM1 and GSTP1 Ile105Val gene variants were similarly distributed between non-smokers and smokers in both groups (p = 0.38, p = 0.20, and p = 0.14, p = 0.35, respectively). However, the wild genotype of the GSTT1 and Ala114Ala variant of the GSTP1 genes were present more frequently in non-smoking periodontitis patients than in non-smoking controls (p = 0.03, p corr >0.05, and p = 0.009, p corr >0.05, respectively) although their frequencies did not differ between smoking periodontitis patients and smoking controls (p = 0.23, p = 0.68, respectively)., Conclusions: This study in a Czech Caucasian population did not confirm a highly significant association between GST gene variants and susceptibility to periodontitis, as previously reported by Arshad and colleagues in Pakistanis. However, a weak relationship between GSTT1 and GSTP1 rs1138272 polymorphisms and periodontitis in non-smokers was observed., (© 2024. The Author(s).)

The aim of this study was to determine the relationship between the presence of sella turcica bridging and palatal canine impaction (PCI) using several classification methods. In this retrospective study, lateral cephalometric radiographs of 120 subjects with PCI (43 males, 77 females; mean age 18.8 ± 7.8 years) and 120 controls (44 males, 76 females; mean age 18.1 ± 5.6 years) with complete permanent dentition were examined. The extent of sella turcica bridging was assessed using two different methods, and the types of complete sella turcica bridging were evaluated. The sella turcica dimensions were measured and analyzed using the t -test, and comparison of the presence of sella turcica bridging was performed using the two-tailed Fisher's exact test. The frequency of complete sella turcica bridging was significantly higher in subjects with PCI (18.3%) than in controls (8.3%, p = 0.023) but without significant differences in the occurrence of sella turcica bridging of Type A (ribbon-like fusion) and Type B (extension of clinoid processes). No significant differences in partial bridging were found between patients with PCI and controls according to both methods. The length and the anteroposterior diameter were significantly larger in subjects with PCI and no difference was observed between the groups in the sella turcica depth. Complete sella turcica bridging occurred significantly more frequently in subjects with PCI than in controls. However, the association between partial bridging and PCI was not confirmed, therefore, we do not recommend any classification of partial bridging for clinical practice., Competing Interests: The authors declare no conflict of interest., (©2023 The Author(s). Published by MRE Press.)

SARS-CoV-2 infection, which causes the respiratory disease COVID-19, has spread rapidly from Wuhan, China, since 2019, causing nearly 7 million deaths worldwide in three years. In addition to clinical risk factors such as diabetes, hypertension, and obesity, genetic variability is an important predictor of disease severity and susceptibility. We analyzed common polymorphisms within the LZTFL1 (rs11385942) and ABCA3 (rs13332514) genes in 519 SARS-CoV-2-positive subjects (164 asymptomatic, 246 symptomatic, and 109 hospitalized COVID-19 survivors) and a population-based control group (N?=?2,592; COVID-19 status unknown). Rare ABCA3 AA homozygotes (but not A allele carriers) may be at a significantly increased risk of SARS-CoV-2 infection [P?=?0.003; OR (95 % CI); 3.66 (1.47-9.15)]. We also observed a borderline significant difference in the genotype distribution of the LZTFL1 rs11385942 polymorphism (P?=?0.04) between the population sample and SARS-CoV-2-positive subjects. In agreement with previous studies, a nonsignificantly higher frequency of minor allele carriers was detected among hospitalized COVID-19 subjects. We conclude that a common polymorphism in the ABCA3 gene may be a significant predictor of susceptibility to SARS-CoV-2 infection.

Aim: Retrospective national sub-analysis of antidiabetic pharmacotherapy in patients with diabetes mellitus (DM) and heart failure (HF) based on data reported to the National Register of Paid Health Services in the Czech Republic between 2012-2018., Methodology and Results: In 2012, there were 75,022 patients with HF and DM (i.e. 42.5% of patients with HF), 6 years later 117,265 (i.e. 41.0% of HF patients in 2018). The most represented antidiabetic drug was metformin (45.6%). Of the insulins and analogues, glargine showed the largest positive trend (5.8% 2012; 14.8% 2018). Empagliflozin was the most prescribed SGLT-2 inhibitor (1.8% in 2018). A decrease in prescribing was observed for saxagliptin (0.5% 2012; 0.1% 2018) and for sulfonylurea derivates - gliclazide (13.0% 2012; 10.3% in 2018) and glimepiride (12.9% 2012; 9.0% 2018). Linagliptin was the most prescribed dipeptidyl peptidase inhibitor (0.7% 2012; 6.8% 2018)., Conclusion: In the Czech Republic, between 2012 and 2008, there was an increase in prevalence of patients with heart failure and concomitant diabetes mellitus, their proportion being similar. In correspondence with other registries, metformin was used mostly. A positive trend was observed in prescription of DDP-4 and SGLT-2 inhibitors, while there was a significant decrease in patients taking sulfonylureas., Competing Interests: The authors report no conflicts of interest in this work.

Background: Coronavirus disease (COVID-19), which is caused by the SARS-CoV-2 virus, has become a global pandemic. While susceptibility to COVID-19 is subject to several external factors, including hypertension, BMI, and the presence of diabetes, it is also genetically determined to a significant extent. Infectious agents require iron (Fe) for proper functioning. Carriers of mutations resulting in increased iron concentrations are understood to be at increased risk of COVID-19., Methods: We examined HFE genotypes associated with hereditary haemochromatosis (rs1800562 and rs1799945 SNPs) in 617 COVID-19 patients (166 asymptomatic, 246 symptomatic and 205 hospitalised survivors) and 2 559 population-based controls., Results: We found a higher frequency of the minor allele (Tyr282) of the rs1800562 polymorphism (P < 0.002) in patients compared to controls (8.5 % vs 5.5 %). Non-carriers of the minor allele were protected against SARS-Cov-2 infection (OR, 95 %CI; 0.59, 0.42-0.82). The frequency of minor allele carriers was almost identical across asymptomatic, symptomatic, and hospitalised survivors. The rs1799945 variant did not affect disease severity and its occurrence was almost identical in patients and controls (P between 0.58 and 0.84)., Conclusions: In conclusion, our results indicate that presence of the rs1800562 minor allele, which is associated with hereditary haemochromatosis (thus increased levels of plasma Fe), increases susceptibility to SARS-CoV-2., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Recurrent aphthous stomatitis is one of the most prevalent oral mucosal immunological diseases. A recent case-control study in the Egyptian population suggested that single nucleotide polymorphism Gly54Asp (rs1800450) of the mannose-binding lectin 2 gene might affect the mannose-binding lectin serum level and recurrent aphthous stomatitis development. The aim of this study was to determine the distribution of six functional mannose-binding lectin 2 gene polymorphisms and analyse their role in recurrent aphthous stomatitis susceptibility in the Czech population., Methods: The study included 227 subjects; 137 healthy people and 90 patients with recurrent aphthous stomatitis. Six mannose-binding lectin 2 gene polymorphisms (rs11003125, rs7096206, rs7095891, rs5030737, rs1800450, rs1800451) were analysed by the SNaPshot assay method, mannose-binding lectin serum levels were determined by enzyme-linked immunosorbent assay (ELISA) method in a subgroup of subjects (N = 87)., Results: No significant differences in mean of mannose-binding lectin serum levels between healthy controls and patients with recurrent aphthous stomatitis were observed (383 ng/ml ± 249 standard deviation (SD) vs. 316 ng/ml ± 177 SD in remission phase vs. 343 ng/ml ± 254 SD in active phase; p > 0.05), also the allele and genotype frequencies of the studied mannose-binding lectin 2 polymorphisms did not differ significantly between the two groups (p > 0.05, odds ratio (OR): 0.75-1.23). Moreover, the distribution of mannose-binding lectin 2 haplotypes and haplogenotypes was similar in the healthy subjects and patients with recurrent aphthous stomatitis (p > 0.05, OR: 0.75-1.23)., Conclusions: This study did not confirm the previously reported association of the mannose-binding lectin 2 Gly54Asp gene variant and low mannose-binding lectin serum level as the risk factors for susceptibility to recurrent aphthous stomatitis. In addition, no significant relationships between mannose-binding lectin 2 functional haplotypes or haplogenotypes and recurrent aphthous stomatitis were observed., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Heart failure (HF) patients are at higher risk of severe coronavirus disease 2019 (COVID-19). The Omicron variant has many novel mutations including those in the spike protein, leading to questions about vaccine effectiveness. The aim of this analysis was to evaluate the effectiveness of the COVID-19 vaccine with or without a booster (i.e., after the third dose) during the Omicron variant wave., Methods: Chronic heart failure patients in the Czech Republic were included in the analysis. COVID-19 infection was monitored from January 1st 2022 to March 31st 2022. The analysis was conducted on data collected in the National Health Information System. Vaccine effectiveness of vaccinated (with or without booster) vs. unvaccinated patients was analyzed for incidence of COVID-19, COVID-19-related hospitalizations, COVID-19 related intensive care unit admissions, and COVID-19 related mechanical ventilation/extracorporeal membrane oxygenation treatment., Findings: From a total 165,453 HF patients in the Czech Republic, 9,728 contracted COVID-19 (22.9% of them not vaccinated, 23.2% vaccinated and 53.8% vaccinated and boosted). Risk of intensive care unit (ICU) hospitalization was 7.6% in the unvaccinated group, 4.8% in the vaccinated group and 2.9% in the boosted group. The calculated effectiveness of the COVID-19 vaccine in prevention of ICU hospitalization in the vaccinated group was 41.9 and 76.6% in the boosted group., Interpretation: The results demonstrated moderate vaccine effectiveness in the prevention of severe COVID-19 in vaccinated but not boosted HF patients. Much stronger effectiveness was found in those who were vaccinated and boosted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Parenica, Benesova, Radvan, Sanca, Hlasensky, Lokaj, Ondrus, Helanova, Kala, Dusek and Jarkovsky.)

Severe Early Childhood Caries (sECC) is a multifactorial disease associated with the occurrence of specific oral microorganisms and other environmental, behavioral, and genetic factors. This study aimed to construct a multivariable model including the occurrence of Candida spp. and selected behavioral factors (length of breastfeeding, serving sweet beverages and beginning of brushing child's teeth) to determine their relationships to the occurrence of sECC. In this case-control study 164 children with sECC and 147 children without dental caries were included. MALDI-TOF MS and multiplex qPCR were used to identify Candida spp. and selected bacteria in dental plaque samples, respectively. A questionnaire on oral hygiene, diet, and children's health was filled in by the parents. The constructed multivariable logistic regression model showed an independent influence of the microbial and behavioral factors in sECC etiopathogenesis. The occurrence of C. albicans and C. dubliniensis was associated with higher odds of sECC development (odds ratio, OR: 9.62 and 16.93, respectively), together with breastfeeding of 6 months or less (OR: 2.71), exposure to sweet beverages (OR: 3.77), and starting to brush child's teeth after the 12 th month of age (OR: 4.10), all statistically significant ( p < 0.01). Considering the high occurrence of C. albicans and C. dubliniensis in dental plaque in children with sECC, we propose them as "keystone pathogens" and risk factors for sECC. The models showed that presence of specific species of Candida in dental plaque may be a better descriptor of sECC than the mentioned behavioral factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cvanova, Ruzicka, Kukletova, Lipovy, Gachova, Izakovicova Holla, Danek, Hola, Bartosova, Jarkovsky, Dusek and Borilova Linhartova.)

Background: The real-world protection provided by SARS-CoV-2 messenger RNA (mRNA) vaccines to kidney transplant recipients (KTRs) remains uncertain., Objective: To study the association between mRNA vaccination and SARS-CoV-2 infection rate in KTRs., Design: Retrospective observational cohort study., Setting: The Czech Republic (17 February to 16 May 2021)., Patients: 2101 KTRs followed in the Department of Nephrology at the Institute for Clinical and Experimental Medicine., Measurements: Positive result for SARS-CoV-2 on polymerase chain reaction test and vaccination status of KTRs., Results: The incidence rate in the vaccinated group was 0.474 per 1000 person-days (33 cases in 69 672 days at risk). The incidence rate in the unvaccinated group was 1.370 per 1000 person-days (79 cases in 57 658 days at risk). The unadjusted incidence rate ratio (IRR; incidence rate of vaccinated/incidence rate of unvaccinated) for KTRs was 0.346 (95% CI, 0.227 to 0.514). The multivariable adjusted IRR for KTRs was 0.544 (CI, 0.324 to 0.876)., Limitation: Retrospective observational design, uneven follow-up of patient groups, and different exposition to SARS-CoV-2 stemming from strong temporal trends and differences in clinical and probably behavioral characteristics., Conclusion: Vaccination of KTRs is associated with lower risk for SARS-CoV-2 infection., Primary Funding Source: The Ministry of Health of the Czech Republic.

Objectives: To compare the performance of transvaginal and transabdominal ultrasound with that of the first-line staging method (contrast-enhanced computed tomography (CT)) and a novel technique, whole-body magnetic resonance imaging with diffusion-weighted sequence (WB-DWI/MRI), in the assessment of peritoneal involvement (carcinomatosis), lymph-node staging and prediction of non-resectability in patients with suspected ovarian cancer., Methods: Between March 2016 and October 2017, all consecutive patients with suspicion of ovarian cancer and surgery planned at a gynecological oncology center underwent preoperative staging and prediction of non-resectability with ultrasound, CT and WB-DWI/MRI. The evaluation followed a single, predefined protocol, assessing peritoneal spread at 19 sites and lymph-node metastasis at eight sites. The prediction of non-resectability was based on abdominal markers. Findings were compared to the reference standard (surgical findings and outcome and histopathological evaluation)., Results: Sixty-seven patients with confirmed ovarian cancer were analyzed. Among them, 51 (76%) had advanced-stage and 16 (24%) had early-stage ovarian cancer. Diagnostic laparoscopy only was performed in 16% (11/67) of the cases and laparotomy in 84% (56/67), with no residual disease at the end of surgery in 68% (38/56), residual disease ≤ 1 cm in 16% (9/56) and residual disease > 1 cm in 16% (9/56). Ultrasound and WB-DWI/MRI performed better than did CT in the assessment of overall peritoneal carcinomatosis (area under the receiver-operating-characteristics curve (AUC), 0.87, 0.86 and 0.77, respectively). Ultrasound was not inferior to CT (P = 0.002). For assessment of retroperitoneal lymph-node staging (AUC, 0.72-0.76) and prediction of non-resectability in the abdomen (AUC, 0.74-0.80), all three methods performed similarly. In general, ultrasound had higher or identical specificity to WB-DWI/MRI and CT at each of the 19 peritoneal sites evaluated, but lower or equal sensitivity in the abdomen. Compared with WB-DWI/MRI and CT, transvaginal ultrasound had higher accuracy (94% vs 91% and 85%, respectively) and sensitivity (94% vs 91% and 89%, respectively) in the detection of carcinomatosis in the pelvis. Better accuracy and sensitivity of ultrasound (93% and 100%) than WB-DWI/MRI (83% and 75%) and CT (84% and 88%) in the evaluation of deep rectosigmoid wall infiltration, in particular, supports the potential role of ultrasound in planning rectosigmoid resection. In contrast, for the bowel serosal and mesenterial assessment, abdominal ultrasound had the lowest accuracy (70%, 78% and 79%, respectively) and sensitivity (42%, 65% and 65%, respectively)., Conclusions: This is the first prospective study to document that, in experienced hands, ultrasound may be an alternative to WB-DWI/MRI and CT in ovarian cancer staging, including peritoneal and lymph-node evaluation and prediction of non-resectability based on abdominal markers of non-resectability. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Background: Evaluation of time trends is an integral part of a comprehensive analysis of cancer data. Our study aimed to assess trends in cancer incidence in the period 1977-2018 in the Czech Republic., Methods: Cancer data were obtained from the Czech National Cancer Registry. Incidence trends were evaluated using the joinpoint regression. The overall trend for the entire analysed period and the current trend for the last 10 years were determined using the average annual percentage change., Results: In the period 1977-2018, the age-standardised incidence (European standard) of malignant neoplasms excluding non-melanoma skin cancers increased from 518.2 to 681.9 cases per 100,000 population in men, and from 320.9 to 467.2 in women. The largest increase in trend in the analysed period was observed for melanoma, which showed an average annual increase of 4.0 % in men and 3.3 % in women. Over the last decade, a significant increase has been observed for head and neck cancer and oesophageal cancer, mainly in women. On the contrary, the largest decrease in trend in the analysed period was observed for stomach cancer, with an average decrease of 2.9 % in men and 2.8 % in women. Over the last 10 years, a highly significant decrease has also been observed for colorectal cancer: 3.2 % in men and 2.8 % in women. The largest difference in trend between the sexes was recorded in lung cancer: a steady decline of 1.3 % per year was observed for men, but an increase of 3.1 % per year was demonstrated for women. After the introduction of colorectal and cervical cancer screening programmes, a significant decrease of incidence rates for these diagnoses was observed., Conclusions: Knowledge of the current cancer burden in the population and its time trends will help to prioritise targets and future resource allocation to cancer control., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread from China in 2019/2020 to all continents. Significant geographical and ethnic differences were described, and host genetic background seems to be important for the resistance to and mortality of COVID-19. Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism (rs4646994) is one of the candidates with the potential to affect infection symptoms and mortality., Methods: In our study, we successfully genotyped 408 SARS-CoV-2-positive COVID-19 survivors (163 asymptomatic and 245 symptomatic) and compared them with a population-based DNA bank of 2,559 subjects., Results: The frequency of ACE I/I homozygotes was significantly increased in COVID-19 patients compared with that in controls (26.2% vs. 21.2%; P = 0.02; OR [95% CI] = 1.55 [1.17-2.05]. Importantly, however, the difference was driven just by the symptomatic subjects (29.0% vs. 21.2% of the I/I homozygotes; P = 0.002; OR [95% CI] = 1.78 [1.22-2.60]). The genotype distribution of the ACE genotypes was almost identical in population controls and asymptomatic SARS-CoV-2-positive patients (P = 0.76)., Conclusions: We conclude that ACE I/D polymorphism could have the potential to predict the severity of COVID-19, with I/I homozygotes being at increased risk of symptomatic COVID-19., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Numbers of patients who develop subsequent primary tumours have markedly increased recently. This study aimed to carry out a comprehensive analysis documenting the risk of incidence of subsequent haematological malignancies., Methods: The Czech National Cancer Registry was the main data source, containing records of 126,822 haematological malignancies diagnosed in the period 1977-2016. Subsequent haematological malignancies were identified according to IACR rules. Joinpoint regression was employed to assess the time trends. The risk of development of subsequent haematological malignancy was evaluated by the standardised incidence ratio. The Kaplan-Meier curves were used to assess the differences in survival., Results: Age-standardised incidence of subsequent haematological malignancies increased from 0.5 in 1977 to 9.1 in 2016. In 1992, there was a significant change in the trend: a sharp increase by 7.7 % annually was revealed thereafter. The risk of development of a haematological malignancy was approximately 1.5 times higher in persons with history of any cancer than in the general Czech population. Patients with haematological malignancies - mainly myelodysplastic syndromes, polycythaemia vera and non-Hodgkin lymphoma - were shown to be at the highest risk of developing a subsequent haematological malignancy. While the median survival following a first haematological malignancy was 2.3 years, it was only 1.1 years for subsequent haematological malignancies (p < 0.001)., Conclusions: Our study identified the highest-risk diagnoses in terms of development of subsequent haematological malignancy. The results might be useful to set up correctly follow-up procedures from which cancer patients could benefit., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease (COVID-19), has spread widely around the globe. Significant inter-individual differences have been observed during the course of the infection, which suggests that genetic susceptibility may be a contributing factor. CC chemokine receptor 5 (CCR5), which acts as a co-receptor for the entry of HIV-1 into cells, is promising candidate whose can have an influence on SARS-CoV-2 infection. A genetic mutation known as CCR5Delta32, consisting of a 32-nucleotide deletion, encodes a truncated protein that protects homozygous carriers of the deletion from HIV-1 infection. Similarly, inhibition of CCR5 seems to be protective against COVID-19. In our study, we successfully genotyped 416 first-wave SARS-CoV-2-positive infection survivors (164 asymptomatic and 252 symptomatic) for CCR5?32, comparing them with a population based sample of 2,404 subjects. We found the highest number (P=0.03) of CCR5Delta32 carriers in SARS-CoV-2-positive/COVID-19-asympto-matic subjects (23.8 %) and the lowest number in SARS-CoV-2-positive/COVID-19-symptomatic patients (16.7 %), with frequency in the control population in the middle (21.0 %). We conclude that the CCR5?32 I/D polymorphism may have the potential to predict the severity of SARS-CoV-2 infection.

Objective: Voiding dysfunctions represent a leading morbidity after radical hysterectomy performed in patients with early-stage cervical cancer. The aim of this study was to perform ad hoc analysis of factors influencing voiding recovery in SENTIX (SENTinel lymph node biopsy in cervIX cancer) trial., Methods: The SENTIX trial (47 sites, 18 countries) is a prospective study on sentinel lymph node biopsy without pelvic lymphadenectomy in patients with early-stage cervical cancer. Overall, the data of 300 patients were analysed. Voiding recovery was defined as the number of days from surgery to bladder catheter/epicystostomy removal or to post-voiding urine residuum ≤50 mL., Results: The median voiding recovery time was three days (5th-95th percentile: 0-21): 235 (78.3%) patients recovered in <7 days and 293 (97.7%) in <30 days. Only seven (2.3%) patients recovered after >30 days. In the multivariate analysis, only previous pregnancy (p = 0.033) and type of parametrectomy (p < 0.001) significantly influenced voiding recovery >7 days post-surgery. Type-B parametrectomy was associated with a higher risk of delayed voiding recovery than type-C1 (OR = 4.69; p = 0.023 vs. OR = 3.62; p = 0.052, respectively), followed by type-C2 (OR = 5.84; p = 0.011). Both previous pregnancy and type C2 parametrectomy independently prolonged time to voiding recovery by two days., Conclusions: Time to voiding recovery is significantly related to previous pregnancy and type of parametrectomy but it is not influenced by surgical approach (open vs minimally invasive), age, or BMI. Type B parametrectomy, without direct visualisation of nerves, was associated with longer recovery than nerve-sparing type C1. Importantly, voiding dysfunctions after radical surgery are temporary, and the majority of the patients recover in less than 30 days, including patients after C2 parametrectomy., Competing Interests: Conflict of interest statement Authors do not have any conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Central neuropathic extremity pain (CNEP) is the most frequent type of pain in multiple sclerosis (MS). The aim of the present study was to evaluate sensory and pain modulation profiles in MS patients with CNEP., Methods: In a single-centre observational study, a group of 56 CNEP MS patients was compared with 63 pain-free MS patients and with a sex- and age-adjusted control group. Standardized quantitative sensory testing (QST) and dynamic QST (dQST) protocols comprising temporal summation and conditioned pain modulation tests were used to compare sensory profiles., Results: Loss-type QST abnormalities in both thermal and mechanical QST modalities prevailed in both MS subgroups and correlated significantly with higher degree of disability expressed as Expanded Disability Status Scale (EDSS). Comparison of sensory phenotypes disclosed a higher frequency of the 'sensory loss' prototypic sensory phenotype in the CNEP subgroup (30%) compared with pain-free MS patients (6%; p = .003)., Conclusion: The role of aging process and higher lesion load in the spinothalamocortical pathway might be possible explanation for pain development in this particular 'deafferentation' subtype of central neuropathic pain in MS. We were unable to support the role of central sensitization or endogenous facilitatory and inhibitory mechanisms in the development of CNEP in MS., Significance: This article presents higher prevalence of the 'sensory loss' prototypic sensory phenotype in multiple sclerosis patients with central extremity neuropathic pain compared to pain-free patients. Higher degree of disability underlines the possible role of higher lesion load in the somatosensory pathways in this particular 'deafferentation' type of central neuropathic pain., (© 2020 European Pain Federation - EFIC®.)

Background: The latest European heart failure guidelines define patients as those with reduced (HFrEF), mid-range, and preserved (HFpEF) left ventricular ejection fraction (LVEF; <40%, 40%-49%, and ≥50%, respectively). We investigated the causes of rehospitalizations/deaths in our institution's heart failure patients and focused on differences in the clinical presentation, risk profile, and long-term outcomes between the HFrEF and HFpEF groups in a real-life scenario., Methods and Results: We followed 1274 patients discharged from heart failure hospitalization in 2 centres. The mean patient age was 75.9 years, and men and women were represented equally. During the minimal follow-up of 2 years, 57% of patients were hospitalised for any cause, 24.9% for decompensated heart failure, and 43.3% for any cardiovascular cause. A total of 36.1% of patients died, either with prior (11.8%) or without prior (24.3%) heart failure rehospitalization. Heart failure was also the most frequent cause of cardiovascular hospitalization, followed by gastrointestinal problems, infections, and tumours for noncardiovascular hospitalizations. Patients with HFrEF had different baseline characteristics and risk profiles, experienced more hospitalizations for acute heart failure (28.6% vs 20.2%, P=0.012), and had higher cardiovascular mortality (82.4% vs 63.5%, P<0.001) when compared with HFpEF patients. Overall mortality and rehospitalization rates were similar., Conclusion: Within 2 years, half of the patients died and/or were hospitalised for acute decompensation of heart failure, and only one-third of the patients survived without any hospitalization. HFrEF and HFpEF patients were confirmed to be different entities with diverse characteristics, risk profiles, and cardiovascular event rates.

Objectives: COVID-19 might either be entirely asymptomatic or manifest itself with a large variability of disease severity. It is beneficial to identify early patients with a high risk of severe course. The aim of the analysis was to develop a prognostic model for the prediction of the severe course of acute respiratory infection., Design: A population-based study., Setting: Czech Republic., Participants: The first 7455 consecutive patients with COVID-19 who were identified by reverse transcription-PCR testing from 1 March 2020 to 17 May 2020., Primary Outcome: Severe course of COVID-19., Result: Of a total 6.2% of patients developed a severe course of COVID-19. Age, male sex, chronic kidney disease, chronic obstructive pulmonary disease, recent history of cancer, chronic heart failure, acid-related disorders treated with proton-pump inhibitors and diabetes mellitus were found to be independent negative prognostic factors (Area under the ROC Curve (AUC) was 0.893). The results were visualised by risk heat maps, and we called this diagram a 'covidogram'. Acid-related disorders treated with proton-pump inhibitors might represent a negative prognostic factor., Conclusion: We developed a very simple prediction model called 'covidogram', which is based on elementary independent variables (age, male sex and the presence of several chronic diseases) and represents a tool that makes it possible to identify-with a high reliability-patients who are at risk of a severe course of COVID-19. Obtained results open clinically relevant question about the role of acid-related disorders treated by proton-pump inhibitors as predictor for severe course of COVID-19., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The knowledge of cancer burden in the population, its time trends and the possibility of international comparison is an important starting point for cancer control programmes. Our study aimed to evaluate trends in childhood cancer epidemiology of patients aged 0-14 years in the period 1994-2016 in the Czech Republic., Methods: Data on childhood cancers have been obtained from the Czech National Cancer Registry. These data were validated using the clinical database of childhood cancer patients and combined with data from death certificates. Incidence and mortality trends were assessed by the joinpoint regression method. The life tables method was used to calculate the overall age-standardised five-year survival., Results: The incidence trend was stable; the age-standardised (world) cancer incidence - ASR (W) - was 173.7 per 1 million children in the period 1994-2016. However, there was apparent significant decrease in mortality: ASR (W) dropped from 58.1 per 1 million children in 1994 to 21.4 per 1 million children in 2016. The overall five-year survival increased over time by 10 %. Statistically significant improvements in survival were observed in patients with lymphoid leukaemia, astrocytomas, neuroblastomas, osteosarcomas and rhabdomyosarcomas., Conclusion: Such a relevant increase in survival rates, and therefore also a decrease in mortality rates in the Czech Republic, is most likely due to improvements in diagnostic and treatment methods since the 1990s, which were facilitated by the concentration of childhood cancer patients in children's cancer centres., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Triple-positive breast cancer (TPBC), i.e. HER2-positive (HER2+) and hormone receptors-positive breast cancer, is a specific subgroup of breast cancers. TPBC biology is characterized by strong mutual interactions between signaling pathways stimulated by estrogens and HER2 amplification. The present study aims to carry out a population-based analysis of treatment outcomes in a cohort of hormone receptor (HR) positive and negative breast cancer patients who were treated with anti-HER2 therapy in the Czech Republic. The BREAST research database was used as the data source for this retrospective analysis. The database covers approximately 95% of breast cancer patients treated with targeted therapies in the Czech Republic. The analysis included 6,122 HER2-positive patients. The patients were divided into two groups, based on estrogen receptor (ER) or progesterone receptor (PR) positivity: hormone receptor negative (HR-) patients had both ER- and PR-negative tumors (n=2,518), unlike positive (HR+) patients (n=3,604). HR+ patients were more often diagnosed premenopausal at the time of diagnosis, presented more often at stage I or II and their tumors were less commonly poorly differentiated. The overall survival (OS) was significantly higher in subgroups of HR+ patients according to treatment setting. When evaluated by stages, significantly higher OS was observed in HR+ patients diagnosed at stages II, III, and IV and regardless of tumor grade.

Background/aim: The study aimed to evaluate differences in the overall survival of HER2+ breast cancer patients treated with regard to their hormone receptors negativity or positivity. We evaluated a cohort of patients treated with trastuzumab in the Czech Republic., Patients and Methods: The present study is a retrospective analysis of patients whose data were recorded in a nationwide non-interventional, post-authorisation database BREAST. After propensity score matching of data, the cohort included 4,532 patients., Results: A significant difference in overall survival (OS) of the entire cohort was found between patients with and without hormone dependence. The OS was significantly higher in the group of patients with hormone receptor-positive (HR+) tumours in the following cohorts: patients treated with neoadjuvant therapy, patients with advanced disease, G2 tumours, stage III and IV and in patients with stage II and III of G2 tumours., Conclusion: Increased OS rates were found in several subgroups of patients with HR+/HER2+ tumours compared to those with HR-/HER2+ tumours. Better outcomes of HR+/HER2+ patients were only observed in the first four/five years of follow-up, and the differences disappeared over time., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Noninvasive fetal RHD genotyping is an important tool for predicting RhD incompatibility between a pregnant woman and a fetus. This study aimed to assess a methodological approach other than the commonly used one for noninvasive fetal RHD genotyping on a representative set of RhD-negative pregnant women. The methodology must be accurate, reliable, and broadly available for implementation into routine clinical practice. A total of 337 RhD-negative pregnant women from the Czech Republic region were tested in this study. The fetal RHD genotype was assessed using two methods: real-time PCR and endpoint quantitative fluorescent (QF) PCR. We used exon-7-specific primers from the RHD gene, along with internal controls. Plasma samples were analyzed and measured in four/two parallel reactions to determine the accuracy of the RHD genotyping. The RHD genotype was verified using DNA analysis from a newborn buccal swab. Both methods showed an excellent ability to predict the RHD genotype. Real-time PCR achieved its greatest accuracy of 98.6% (97.1% sensitivity and 100% specificity (95% CI)) if all four PCRs were positive/negative. The QF PCR method also achieved its greatest accuracy of 99.4% (100% sensitivity and 98.6% specificity (95% CI)) if all the measurements were positive/negative. Both real-time PCR and QF PCR were reliable methods for precisely assessing the fetal RHD allele from the plasma of RhD-negative pregnant women.

Background: Heart rate (HR) at admission in patients with acute heart failure (AHF) has been shown to be an important risk marker of in-hospital mortality. However, its relation with mid and long-term prognosis as well as the impact of Ejection Fraction (EF) is unknown. Our objective was to study the relationship between long-term survival and HR at admission depending on EF in a cohort of patients hospitalized for AHF., Methods: We analyzed the data of 2335 patients in sinus rhythm hospitalized for AHF from AHEAD registry. Patients with cardiogenic shock and AHF from surgical or non-cardiac etiology were excluded., Results: Survival rates at 6 and 12 months were 84.8% and 78% respectively. Increased age, decreased diastolic BP, lack of PCI during hospitalization, increased creatinine level and increased HR (with different cut-offs according to EF categories) were found as predictors whatever the EF at 6 and 12 months. Optimal prognostic cut-offs of heart rate were identified for Heart Failure with reduced EF at 100 bpm, for Heart Failure with mid-range EF at 90 bpm and for Heart Failure with preserved EF at 80 bpm for both 6 and 12 months., Conclusion: Our study suggests that HR at admission appears to be an independent prognostic parameter in AHF patients in sinus rhythm irrespective of EF and can be used to classify patients according to the severity of the disease., Competing Interests: Declaration of conflict of interest The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. BT and FF are employees of Institut de Recherches Internationales Servier (IRIS). All authors declare no potential conflict of interest related to this article., (Copyright © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Some muscular dystrophies may have a negative impact on fertility. A decreased ovarian reserve is 1 of the factors assumed to be involved in fertility impairment. AMH (anti-Müllerian hormone) is currently considered the best measure of ovarian reserve.A total of 21 females with myotonic dystrophy type 1 (MD1), 25 females with myotonic dystrophy type 2 (MD2), 12 females with facioscapulohumeral muscular dystrophy (FSHD), 12 female carriers of Duchenne muscular dystrophy mutations (cDMD) and 86 age-matched healthy controls of reproductive age (range 18 - 44 years) were included in this case control study. An enzymatically amplified 2-site immunoassay was used to measure serum AMH level.The MD1 group shows a significant decrease of AMH values (median 0.7 ng/mL; range 0 - 4.9 ng/mL) compared with age-matched healthy controls (P < .01). AMH levels were similar between patients and controls in terms of females with MD2 (P = .98), FSHD (P = .55) and cDMD (P = .60).This study suggests decreased ovarian reserve in women with MD1, but not in MD2, FSHD and cDMD.

Background: The need for radical surgery followed by adjuvant chemoradiation may be reduced by abandoning radical surgery in patients in whom lymph node involvement is detected intra-operatively., Objectives: To analyze, in a retrospective cohort study, the efficacy of the algorithm using intra-operative pathological assessment of sentinel lymph nodes., Methods: A retrospective single-institution study was carried out, which analyzed data from all consecutive patients with cervical cancer who were referred for primary surgical treatment between May 2005 and December 2015. Inclusion criteria were as follows: (1) TNM stage T1a1 with lymphovascular space invasion, T1a2, T1b, T2a, and selected T2b with incipient parametrial invasion; (2) adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma; (3) no evidence of enlarged suspicious nodes or distant metastases on pre-operative imaging; (4) primary surgery with curative intent; (5) successful detection of sentinel lymph node, at least, unilaterally. All patients had at least one sentinel lymph node detected and submitted for frozen section evaluation. When sentinel lymph node involvement was detected intra-operatively, the cervical procedure was abandoned and the patient was referred for definitive chemoradiation. Radical surgery was completed in patients with intra-operative negative sentinel lymph nodes. The reliability of intra-operative sentinel lymph node assessment was evaluated by calculating the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio., Results: The study included a total of 309 patients. Sentinel lymph nodes were detected bilaterally in 86% of the patients. Lymph node positivity was detected intra-operatively in 18 (6%) patients in whom the cervical procedure was abandoned. Adjuvant radiotherapy after completed radical surgery was given to 29 (9%) patients, including 20 patients with macrometastases (8) or micrometastases (12) reported from the final histology, eight patients with positive parametria (all ≤3 mm), and one patient with a positive vaginal resection margin. The sensitivity, specificity, positive predictive value, and negative predictive value for the intra-operative detection of lymph node positivity (macrometastases or micrometastases) was 47% (95% CI 31% to 64%), 100%, 100%, and 93% (95% CI 90% to 96%), respectively. A total of 18 (6%) patients were spared combined treatment owing to the intra-operative sentinel lymph node triage; 29 patients (9%) received combined treatment with both radical surgery and adjuvant radiotherapy CONCLUSIONS: Of 47 patients with high-risk prognostic risk factors (lymph node, parametria, or surgical margin involvement), combined treatment was successfully avoided in 18 (38%). Despite an effort to triage the patients intra-operatively, 9% received a combination of cervical procedure and adjuvant chemoradiation, mostly owing to the low sensitivity of the frozen section in the detection of micrometastases and macrometastases., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The data on the prognostic significance of low volume metastases in lymph nodes (LN) are inconsistent. The aim of this study was to retrospectively analyze the outcome of a large group of patients treated with sentinel lymph node (SLN) biopsy at a single referral center. Patients with cervical cancer, stage T1a-T2b, common tumor types, negative LN on preoperative staging, treated by primary surgery between 01/2007 and 12/2016, with at least unilateral SLN detection were included. Patients with abandoned radical surgery due to intraoperative SLN positivity detected by frozen section were excluded. All SLNs were postoperatively processed by an intensive protocol for pathological ultrastaging. Altogether, 226 patients were analyzed. Positive LN were detected in 38 (17%) cases; macrometastases (MAC), micrometastases (MIC), isolated tumor cells (ITC) in 14, 16, and 8 patients. With the median follow-up of 65 months, 22 recurrences occurred. Disease-free survival (DFS) reached 90% in the whole group, 93% in LN-negative cases, 89% in cases with MAC, 69% with MIC, and 87% with ITC. The presence of MIC in SLN was associated with significantly decreased DFS and OS. Patients with MIC and MAC should be managed similarly, and SLN ultrastaging should become an integral part of the management of patients with early-stage cervical cancer.

Background: The development of recurrent aphthous stomatitis (RAS), inflammatory disease of oral mucosa, is influenced by both environmental and genetic factors. The aim of this study was to investigate polymorphisms located in seven genes coding different types of matrix metalloproteinases (MMPs)-collagenases (MMP1, MMP8, and MMP13), gelatinases (MMP2 and MMP9), stromelysin (MMP3), and membrane-type metalloproteinase (MMP16) in patients with RAS and healthy controls., Methods: Totally, 223 subjects were included in this case-control study and their detailed anamnestic, clinical, and laboratory parameters were recorded. Seventy-seven patients with RAS and 146 controls were genotyped for seventeen polymorphisms in the MMPs genes using the real-time polymerase chain reaction (PCR) or PCR with restriction analysis., Results: Allele, genotype, and haplotype frequencies of the studied polymorphisms between RAS patients and controls were similar, except for allele distributions of MMP1 rs1144393, MMP9 rs3918242, and MMP16 rs10429371, which were different between patients with RAS and healthy controls (P = .023, P = .049 and P = .025, all P corr  > 0.05, respectively). Moreover, the comparison of genotype frequencies (TT vs CC + CT) of the MMP16 rs10429371 variant showed a marginally significant difference between RAS patients and controls (P = .05, P corr  > 0.05, OR = 1.68, 95% CI = 0.95-2.98)., Conclusions: No significant relationship between investigated polymorphisms in seven MMPs genes and RAS development in the Czech population was observed in this study., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The management of patients with intraoperative detection of lymph node involvement remains controversial. The most significant aspect is the decision regarding the completion of the cervical procedure, such as hysterectomy, radical hysterectomy, or a fertility sparing procedure., Primary Objective: The primary objective of the ABandoning RAd hyst in cerviX cancer (ABRAX) trial is to determine whether the completion of the cervical procedure (ie, radical hysterectomy) improves oncological outcome in patients with intraoperatively detected lymph node involvement before they are referred for definitive chemoradiation., Study Hypothesis: We hypothesize that, in patients with intraoperative lymph node involvement, completion of radical hysterectomy or other cervical procedure does not improve the oncological outcome of definitive chemoradiation., Trial Design: The ABRAX trial is a multicenter, retrospective, cohort study. Patients with negative lymph nodes in clinical staging, in whom lymph node involvement is detected intraoperatively, are included. Completion or abandonment of the planned cervical procedure stratifies the cohort into two subgroups in which oncological outcome and morbidity will be compared., Major Inclusion/exclusion Criteria: Patients with early stage (pT1a-pT2b) cervical cancer, who did not have positive lymph nodes on preoperative imaging, who were scheduled for primary surgical treatment, and in whom metastatic involvement of pelvic lymph node was found during surgery either as a grossly (macroscopically) involved or on intraoperative pathology assessment will be enrolled. Patients can be included irrespective of surgical approach (minimal invasive surgery or laparotomy) and type of cervical procedure performed (hysterectomy, radical hysterectomy, or a fertility sparing procedure)., Primary Endpoint: The primary endpoint of this retrospective study is a progression free survival in two subgroups with abandoned or completed cervical procedure followed by definitive chemoradiation in both groups., Sample Size: The assumed sample size is 718 patients (in total for both groups)., Estimated Dates for Completing Accrual and Presenting Results: Estimated end of data collection: December 2019; estimated date of presenting results: Q2/3 2020., Trial Registration: Clinicaltrials.gov: NCT04037124., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The stability of fusion was evaluated by its breakage when interocular blur differences were presented under vergence demand to healthy subjects. We presumed that these blur differences cause suppression of the more blurred image (interocular blur suppression, IOBS), disrupt binocular fusion and suppressed eye leaves its forced vergent position. During dichoptic presentation of static grayscale images of natural scenes, the luminance contrast (mode B) or higher-spatial frequency content (mode C) or luminance contrast plus higher-spatial frequency content (mode A) were stepwise reduced in the image presented to the non-dominant eye. We studied the effect of these types of blur on fusion stability at various levels of the vergence demand. During the divergence demand, the fusion was disrupted with approximately half blur than during convergence. Various modes of blur influenced fusion differently. The mode C (isolated reduction of higher-spatial frequency content) violated fusion under the lowest vergence demand significantly more than either isolated or combined reduction of luminance contrast (mode B and A). According to our results, the image´s details (i.e. higher-spatial frequency content) protects binocular fusion from disruption by the lowest vergence demand.

Background: Our study aimed to evaluate incidence and mortality trends for childhood and adolescent cancers in the period 1994-2016 in the Czech Republic., Material and Methods: Data on childhood cancers, which are recorded in the Czech National Cancer Registry, were validated using a clinical database of childhood cancer patients and combined with data from the National Register of Hospitalised Patients and with data from death certificates. These validated data were used to establish cancer incidence. Data from death certificates were used to evaluate long-term trends in mortality. Incidence and mortality trends were assessed by the average annual percentage change., Results: The age-standardised incidence trend for childhood cancers (i.e. those diagnosed in patients aged 0-19 years) showed a statistically significant slight long-term increase in the number of new cases, +0.5% annually on average (p &lt; 0.01), more specifically an increase of +0.6% in girls and a statistically insignificant decrease of 0.1% in boys. In children aged 0-14 years, other malignant epithelial neoplasms and malignant melanomas showed the largest statistically significant average annual increase in incidence (+4.9%; p &lt; 0.01), followed by central nervous system neoplasms (+1.3%; p &lt; 0.05). Lymphomas, by contrast, showed a statistically significant average annual decrease in incidence in children aged 0-14 years (2.1%; p &lt; 0.01). In adolescents aged 15-19 years, other malignant epithelial neoplasms and malignant melanomas also showed a statistically significant average annual increase in incidence (+5.2%; p &lt; 0.01), followed by central nervous system neoplasms (+1.5%; p &lt; 0.05). Mortality trends showed a statistically significant long-term decrease: on average, 5.1% annually in children aged 0-14 years (p &lt; 0.01), and 3.7% annually in adolescents aged 15-19 years (p &lt; 0.01)., Conclusion: Available data make it possible to analyse long-term trends in childhood cancer incidence and mortality.

Background: Hyperuricemia is associated with a poorer prognosis in heart failure (HF) patients. Benefits of hyperuricemia treatment with allopurinol have not yet been confirmed in clinical practice. The aim of our work was to assess the benefit of allopurinol treatment in a large cohort of HF patients., Methods: The prospective acute heart failure registry (AHEAD) was used to select 3160 hospitalized patients with a known level of uric acid (UA) who were discharged in a stable condition. Hyperuricemia was defined as UA ≥500 μmoL/L and/or allopurinol treatment at admission. The patients were classified into three groups: without hyperuricemia, with treated hyperuricemia, and with untreated hyperuricemia at discharge. Two- and five-year all-cause mortality were defined as endpoints. Patients without hyperuricemia, unlike those with hyperuricemia, had a higher left ventricular ejection fraction, a better renal function, and higher hemoglobin levels, had less frequently diabetes mellitus and atrial fibrillation, and showed better tolerance to treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and/or beta-blockers., Results: In a primary analysis, the patients without hyperuricemia had the highest survival rate. After using the propensity score to set up comparable groups, the patients without hyperuricemia had a similar 5-year survival rate as those with untreated hyperuricemia (42.0% vs 39.7%, P = 0.362) whereas those with treated hyperuricemia had a poorer prognosis (32.4% survival rate, P = 0.006 vs non-hyperuricemia group and P = 0.073 vs untreated group)., Conclusion: Hyperuricemia was associated with an unfavorable cardiovascular risk profile in HF patients. Treatment with low doses of allopurinol did not improve the prognosis of HF patients., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Objective: The human papillomavirus (HPV) can cause premalignant and malignant tumors in the anogenital and oropharyngeal regions. The aim of this study was to describe the association in the prevalence of cervical, anal, and oral HPV infections in high-risk patients with biopsy-confirmed high-grade cervical lesion compared to low-risk women., Study Design: A total of 718 immunocompetent women were enrolled in the study. The high-risk (HR) group consisted of 473 patients with biopsy-confirmed high-grade cervical lesion while the low-risk (LR) group consisted of other 245 women. All participants completed an anonymous self-administered questionnaire and were subjected to cervical, anal, and oral HPV genotyping using the Linear array HPV test., Results: A total of 81.4% women were infected in the cervix, 43.3% in the anus, and 2.7% in the oral cavity in the HR group in comparison with only 26.9%, 24.5%, and 1.4% in the low-risk LR group, respectively. The cervical and anal HPV infections were much more frequent in the HR patients (p < 0.001); the difference in the oral HPV prevalence was not significant (p = 0.511) between groups. Concurrent cervical-anal infection was observed in 39.3% of HR women and in 8.3% of the LR patients (p < 0.001) and it significantly increased with the grade of cervical lesion (p trend <0.001). The higher prevalence of concurrent cervical-oral, anal-oral, and cervical-anal-oral infections in HR women was statistically not significant according to the generally small oral HPV prevalence., Conclusions: All HPV infections occurred more often in HR than in LR women but not all results were statistically significant. The genotype HPV 16 was found in approximately half of all infections at all sites.

Objectives: To assess the survival of patients who have received an operation for recurrent cervical and endometrial cancer and to determine prognostic variables for improved oncologic outcome., Methods: A retrospective multicenter analysis of the medical records of 518 patients with cervical (N = 288) or endometrial cancer (N = 230) who underwent surgery for disease recurrence and who had completed at least 1 year of follow-up., Results: The median survival reached 57 months for patients with cervical cancer and 113 months for patients with endometrial cancer after surgical treatment of recurrence (p = 0.036). Histological sub-type had a significant impact on overall survival, with the best outcome in endometrial endometrioid cancer (121 months), followed by cervical squamous cell carcinoma, cervical adenocarcinoma, or other types of endometrial cancer (81 vs 35 vs 35 months; p <0.001). The site of recurrence did not significantly influence survival in cervical or in endometrial cancer. Cancer stage at first diagnosis, tumor grade, lymph node status at recurrence, progression-free interval after first diagnosis, and free resection margins were associated with improved overall survival on univariate analysis. On multivariate analysis, the stage at first diagnosis and resection margins were significant independent predictive parameters of an improved oncologic outcome., Conclusion: Long-term survival can be achieved via secondary cytoreductive surgery in selected patients with recurrent cervical and endometrial cancer. An excellent outcome is possible even if the recurrence site is located in the lymph nodes. The possibility of achieving complete resection should be the main criterion for patient selection., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Specific variants in genes that encode adipokines and their mRNA and protein expression were previously studied in type 2 diabetes mellitus (T2DM) and obesity, and similar studies have been performed for chronic periodontitis (CP). The aim of this case-control study was to investigate the possible impacts of adiponectin (ADIPOQ), leptin (LEP) and its receptor (LEPR), and resistin (RETN) on the etiopathogenesis of CP. Examinations were performed on 118 non-periodontitis healthy subjects (healthy controls, HC), 205 healthy individuals with CP (H + CP) and 86 type 2 diabetes patients with CP (T2DM + CP). Variants within the ADIPOQ (rs2241766, rs1501299), LEP (rs13228377, rs2167270), LEP receptor (rs1805096), and RETN (rs1862513) genes were determined by qPCR. In addition, the plasma levels of ADIPOQ, LEP, and RETN were analysed by ELISA for 80 individuals. The genotype frequencies of the SNP ADIPOQ +45G/T (rs2241766) differed between the HC and H + CP groups (p=0.03, pcorr>0.05), and carriers of the TT genotype had a lower risk of developing CP compared to carriers of the GG or TG genotypes (p<0.01, pcorr>0.05). However, there were no significant differences in the plasma levels of ADIPOQ, LEP or RETN between the study groups (p > 0.05). Plasma levels of the adipokines were also independent of the gene profiles (p > 0.05). Adipokine plasma levels did not change in patients with H + CP/T2DM + CP compared to HC, but we did identify a specific polymorphism in the ADIPOQ gene that was associated with CP. Although the ADIPOQ +45G/T (rs2241766) gene variant may be a candidate biomarker for CP, further research is required in larger populations with different ethnic backgrounds before any final conclusions can be drawn about the role of this gene in CP.

Background: Oral diseases, such as early childhood caries (ECC), have a complex etiology with common, behaviour-related risk factors. Appropriately targeted behavioural intervention using effective tools can help to eliminate risk behaviour leading to ECC. The aim of this study was to ascertain which visual stimuli with a supporting text evoke the strongest emotional response in infants' mothers and, therefore, are suitable candidates for inclusion in behavioural interventions within the prevention of ECC., Methods: Thirty-nine mothers of one-year-old children who filled out an originally designed electronic questionnaire, containing 20 visual stimuli with accompanying texts related to dental caries (10/10 with positive/negative intended emotional response), were included in this cross-sectional study. The emotional impact of each stimulus in the mothers was evaluated using the Self-Assessment Manikin (SAM) technique, which represents three emotional dimensions: valence, arousal, and dominance., Results: Each of the stimuli was assessed by the mothers of infants based on its emotional impact. The real emotional response (evaluated according to the median of valence) was in line with the primarily intended response in 90% of cases (p < 0.05). The text with a warning evoked a greater emotional response (evaluated according to the median of arousal) in mothers than only the informative instruction (p < 0.05). The relationship between arousal and valence (r = - 0.99; p < 0.05) indicates that the more aversive stimuli raise higher arousal. The significant correlation between valence and dominance shows that the more positive the stimuli, the higher feeling of control over the evoked emotion the mothers have (r = 0.83; p < 0.05), and, on the contrary, the lowest control over emotion is correlated with higher arousal (r = - 0.85; p < 0.05). Generally, mothers rated themselves as in high control of their emotions over the individual stimuli., Conclusions: This pilot study proved that negative pictorial and text warnings about the risks of developing caries had the potential to evoke strong emotional responses in the mothers of infants. We identified three visual stimuli that could be included in future extensive motivation material in an attempt to affect the preventive behaviour of mothers, and thus the oral health of their infants.

Objectives: Assessment of neuropathic pain in chronic low back syndromes is important. However, there is currently no gold standard for its diagnosis. The aim of this observational cross-sectional study was to assess the neuropathic component of pain in various chronic low back pain syndromes using a range of diagnostic tests., Materials and Methods: Included in this study were 63 patients with chronic axial low back pain (ALBP), 48 patients with chronic radicular syndromes (CRS) comprising 23 with discogenic compression (CDRS) and 25 with lumbar spinal stenosis (LSS), and 74 controls. PainDETECT questionnaire (PDQ), quantitative sensory testing (QST), and skin biopsy with evaluation of intraepidermal nerve fiber density (IENFD) were used to assess the neuropathic pain component., Results: Positive PDQ (≥19) was obtained more frequently in patients with CDRS and LSS (26.1% and 12.0%, respectively) compared with patients with ALBP (1.6%, P<0.001). The proportion of patients with sensory loss confirmed by QST was lowest in the ALBP subgroup (23.8%) compared with CDRS (47.8%), and LSS (68.0%) subgroups (P<0.001). A reduction in IENFD was disclosed in a proportion of up to 52.0% of affected roots in patients with CRS., Discussion: Neuropathic pain is quite frequent in CRS, and QST reveals sensory loss as a frequent abnormality in patients with CRS. Using a cut-off value of 19, PDQ identified a neuropathic component in a relatively low proportion of patients with CRS. CRS may be associated with a reduction in IENFD.

Background: Plasma cell leukemia (PCL) is a rare but most aggressive form of monoclonal gammopathies. PCL is characterized by the presence of clonal plasma cells in peripheral blood. There are two forms of PCL - primary which presents de novo in patients with no evidence of previous multiple myeloma and secondary which is a leukemic transformation of relapsed or refractory dis-ease in patients with previously recognized multiple myeloma., Materials and Methods: This is the first study to provide information on PCL epidemiology in the Czech population us-ing The Czech National Cancer Registry (CNCR) as the basic source of data for the population-based evaluation of PCL epidemiology., Results: Accord-ing to CNCR data, there were on average six newly dia-gnosed cases of PCL and four deaths caused by PCL each year in the Czech Republic in the period 2000-&#8202;2015. PCL incidence in the Czech Republic was reported at 0.57 per million in 2000-&#8202;2015. We suppose that most reported cases of PCL are primary PCL because secondary PCL is a relapse of a previously reported myeloma and, in most cases, is not coded as an independent dia-gnosis in the CNCR., Conclusion: Data from registries such as the CNCR can provide useful information on epidemiology of various dis-eases. These data, however, have several limitations, such as dia-gnostic criteria and proper cod-ing of not only the dis-ease itself, but also its various forms. These limitations have to be taken into account dur-ing the process of results interpretation. Key words plasma cell leukemia -&#8202; epidemiology -&#8202; Czech National Cancer Registry (CNCR) -&#8202; Czech Republic.

Purpose: Although inhibitors of vascular endothelial growth factor and inhibitors of epidermal growth factor receptor (EGFRi) are commonly used for the treatment of metastatic colorectal cancer (mCRC), the optimal sequencing of these agents is currently unclear., Methods: A national registry of targeted therapies was used to analyze baseline characteristics and outcomes of patients with mCRC and wild-type KRAS exon 2 status who received bevacizumab and EGFRi (cetuximab or panitumumab) as a part of first- and second-line treatment in either sequence., Results: The cohort included 490 patients (181 patients treated with first-line EGFRi and second-line bevacizumab and 309 patients treated with first-line bevacizumab and second-line EGFRi). Median overall survival (OS) from the initiation on first-line therapy was similar for patients treated with either sequence, reaching 31.8 (95% CI 27.5-36.1) vs 31.4 months (95% CI 27.8-35.0) for EGFRi → bevacizumab vs bevacizumab → EGFRi cohort, respectively. Time from first-line initiation to progression on the second-line therapy [progression-free survival (PFS)] was 21.1 (95% CI 19.3-23.0) vs 19.3 months (95% CI 17.3-21.3) for bevacizumab → EGFRi vs EGFRi → bevacizumab cohort, respectively ( P =0.016)., Conclusion: This retrospective analysis of real-world data of patients with wild-type KRAS exon 2 mCRC showed no differences in OS between cohorts treated with bevacizumab → EGFRi vs the reverse sequence while combined PFS favored the bevacizumab → EGFRi sequence., Competing Interests: Disclosure TB, OF, and BM have received research funding, travel grants, and honoraria from Roche, Merck, and Amgen. AP has received honoraria and travel grants from Roche and Amgen. IK has received speakers’ honoraria from Roche, Merck, and Amgen. JF has received lecture honoraria and travel grants from Roche, Merck, Pfizer, Novartis, and Amgen. The authors declare no other conflicts of interest in this work.

Genetic factors, especially those related to immune system functioning, have been intensively studied to determine their role in the development of recurrent aphthous stomatitis (RAS). The aim of the present study was to analyze gene variability in interleukin (IL)2, IL4 (and its receptor α, IL4Rα), IL10, and IL13, which were selected based on literature review and/or their functional relevance, in Czech patients with RAS and in healthy controls. In total, 252 subjects (178 controls and 74 patients with RAS) were enrolled in this case-control study, and their detailed anamnestic, clinical, and laboratory data were obtained. Nine polymorphisms in the genes encoding interleukins were determined using PCR techniques. There were no significant differences in allele or genotype frequencies of the IL2, IL4, IL4Rα, IL10, and IL13 polymorphisms rs2069762/rs2069763, rs2243250/rs79071878, rs1801275, rs1800896, and rs1800925, respectively, between controls and patients with RAS. The minority alleles rs1800871 and rs1800872, which encode variants of IL10, were associated with a statistically significantly higher risk of RAS, as confirmed by the results of genotype and haplotype analyses. We suggest that variability in the IL10 gene may play an important role in the development of RAS in the Czech population., (© 2018 Eur J Oral Sci.)

Background: The addition of monoclonal antibodies targeting the epidermal growth factor receptor (anti-EGFR Abs) to chemotherapy for metastatic colorectal carcinoma (mCRC) is commonly delayed in the real-world clinical practice, usually because of late RAS testing results., Objective: To determine whether delayed addition of anti-EGFR mAbs up to the fourth cycle of backbone chemotherapy adversely affected outcomes of mCRC patients treated with first-line regimens., Patients and Methods: Clinical data of patients with histologically verified, RAS wild-type mCRC treated with first-line systemic therapy regimens containing anti-EGFR mAbs were retrospectively analysed from a national database. Patients were divided into three groups according to the timing of anti-EGFR mAbs addition to the chemotherapy backbone. Cohort A (n = 401) included patients in whom anti-EGFR mAbs were added to chemotherapy from the first cycle, cohort B (n = 71) patients with anti-EGFR mAbs added to chemotherapy from the second cycle, and cohort C (n = 101) patients who had anti-EGFR mAbs added to chemotherapy from the third or fourth cycle., Results: Three hundred and thirty-six (58.6%) patients received panitumumab and 237 (41.4%) patients received cetuximab. The median progression-free survival (PFS) of the whole cohort was 12.2 months (95% confidence interval [CI] 10.9-13.5), and the median overall survival (OS) was 33.5 months (95% CI 27.6-39.4). The median PFS and OS for patients treated with anti-EGFR mAbs added to chemotherapy were 12.9 (95% CI 11.5-14.3) and 30.6 months (95% CI 25.2-36.1) for cohort A, 9.7 (95% CI 9.1-10.3) and not reached for cohort B, compared to 11.5 (95% CI 9.8-13.2) and 37.9 months (95% CI 28.6-47.3) for cohort C, respectively., Conclusions: Delayed addition of anti-EGFR mAbs to first-line chemotherapy was not associated with inferior survival or response rates.

Objectives: The role of adjuvant radiotherapy for lymph node-negative stage IB patients with tumor-related negative prognostic factors is not uniformly accepted. It is advocated based on the GOG 92 trial, which was initiated in 1989. The aim of the current study is to report the oncological outcome of "intermediate risk" patients treated by tailored surgery without adjuvant radiotherapy. Data from two institutions that refer these patients for adjuvant radiotherapy served as a control group., Methods: Included were patients with stage IB cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy, who had negative pelvic lymph nodes but a combination of negative prognostic factors adopted from the GOG 92 trial. Data were obtained from prospectively collected databases of three institutions. Radical surgery was a single-treatment modality in one of them and in the remaining two institutes it was followed by adjuvant chemoradiation., Results: In 127 patients who received only radical surgery, with a median follow-up of 6.1 years, the local recurrence rate was 1.6% (2 cases), and total recurrence was 6.3% (8 cases). Disease-specific survival at 5 years was 95.7% (91.9%; 99.4%) and 91% (83.7%; 98.3%) at 10 years. The only significant factor for disease-specific survival was tumor size ≥4 cm (P = 0.032). The recurrence rate, local control or overall survival did not differ from the control group. Adjuvant radiotherapy was not a significant prognostic factor within the whole cohort., Conclusions: An excellent oncological outcome, especially local control, can be achieved by both radical surgery or combined treatment in stage IB lymph node-negative cervical cancer patients with negative prognostic factors. The substantially better outcome than in the GOG 92 trial can be attributed to more accurate pre-operative and pathological staging and an improvement in surgical techniques., (Copyright © 2018 Elsevier Inc. All rights reserved.)