Penile squamous cell carcinoma (pSCC) is a rare tumour with a variable prognosis. More prognostic markers linked to mutational signatures and the tumour immune microenvironment are needed. A cohort made up of 165 invasive pSCC was retrospectively analysed using formalin-fixed, paraffin-embedded tumour tissue, focusing on tumour mutational burden (TMB), programmed death ligand 1 (PD-L1) expression, microsatellite instability (MSI), the number of tumour infiltrating lymphocytes (TILs) expressing cytotoxic T-lymphocyte-associated protein 4 (CTLA4), HPV status determined by p16 immunohistochemistry, and several traditional histopathological variables. High TMB (>10 mut/Mb) was associated with high PD-L1 expression (TPS 50-100%), and HPV-negative status. High PD-L1 expression was linked to HPV negativity, a high number of intratumoural CTLA4+ cells, and brisk lymphocytic infiltrate. High TMB was a significant predictor of shorter overall survival (OS) in both univariate and multivariate analysis when using a median cut-off value of 4.3 mut/Mb, but not when using an arbitrary cut-off of 10 mut/Mb. Low CTLA4+ cell infiltration at the tumour invasion front was a marker of shorter OS and cancer-specific survival in both univariate and multivariate analysis. PD-L1 expression had no significant impact on prognosis. Only two cases were MSI high. The results support the hypothesis of two aetiological pathways in pSCC cancerogenesis: (1) SCC linked to HPV infection characterised by low TMB, less common PD-L1 expression, and a lower number of TILs; and (2) SCC linked to chronic inflammation leading to a high number of acquired mutations (high TMB), HPV negativity, increased neoantigen production (i.e., PD-L1), and high immune cell infiltration.

• MeSH
• antigen CTLA-4 MeSH
• antigeny CD274 metabolismus   MeSH
• infekce papilomavirem * komplikace   MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory penisu * genetika   MeSH
• retrospektivní studie MeSH
• spinocelulární karcinom * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: To date there remains much ambiguity in the literature regarding the immunological interplay between SARS-CoV-2 and HIV and the true risk posed to coinfected individuals. There has been little conclusive data regarding the use of CD4 cell count and HIV viral load stratification as predictors of COVID-19 severity in this cohort. METHODS: We performed a retrospective, observational cohort study on people living with HIV (PLWH) who contracted COVID-19 in central and eastern Europe. We enrolled 536 patients from 16 countries using an online survey. We evaluated patient demographics, HIV characteristics and COVID-19 presentation and outcomes. Statistical analysis was performed using SPSS 20.1. RESULTS: The majority of the study cohort were male (76.4%) and 152 (28.3%) had a significant medical comorbidity. Median CD4 cell count at COVID-19 diagnosis was 605 cells/μL [interquartile range (IQR) 409-824]. The majority of patients on antiretroviral therapy (ART) were virally suppressed (92%). In univariate analysis, CD4 cell count <350 cells/μL was associated with higher rates of hospitalization (p < 0.0001) and respiratory failure (p < 0.0001). Univariate and multivariate analyses found that an undetectable HIV VL was associated with a lower rate of hospitalization (p < 0.0001), respiratory failure (p < 0.0001), ICU admission or death (p < 0.0001), and with a higher chance of full recovery (p < 0.0001). CONCLUSION: We can conclude that detectable HIV viral load was an independent risk factor for severe COVID-19 illness and can be used as a prognostic indicator in this cohort.

• MeSH
• COVID-19 * epidemiologie   komplikace   MeSH
• HIV infekce * komplikace   farmakoterapie   epidemiologie   MeSH
• lidé MeSH
• počet CD4 lymfocytů MeSH
• respirační insuficience * MeSH
• retrospektivní studie MeSH
• SARS-CoV-2 MeSH
• testování na COVID-19 MeSH
• virová nálož MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Geografické názvy
• východní Evropa MeSH

High-risk human papillomaviruses (HPVs) cause various cancers. While type-specific prophylactic vaccines are available, additional anti-viral strategies are highly desirable. Initial HPV cell entry involves receptor-switching induced by structural capsid modifications. These modifications are initiated by interactions with cellular heparan sulphates (HS), however, their molecular nature and functional consequences remain elusive. Combining virological assays with hydrogen/deuterium exchange mass spectrometry, and atomic force microscopy, we investigate the effect of capsid-HS binding and structural activation. We show how HS-induced structural activation requires a minimal HS-chain length and simultaneous engagement of several binding sites by a single HS molecule. This engagement introduces a pincer-like force that stabilizes the capsid in a conformation with extended capsomer linkers. It results in capsid enlargement and softening, thereby likely facilitating L1 proteolytic cleavage and subsequent L2-externalization, as needed for cell entry. Our data supports the further devising of prophylactic strategies against HPV infections.

• MeSH
• heparitinsulfát * metabolismus   chemie   MeSH
• infekce papilomavirem virologie   MeSH
• internalizace viru * MeSH
• kapsida * metabolismus   chemie   MeSH
• lidé MeSH
• lidské papilomaviry MeSH
• lidský papilomavirus 16 metabolismus   fyziologie   MeSH
• mikroskopie atomárních sil * MeSH
• Papillomaviridae fyziologie   MeSH
• polysacharidy metabolismus   chemie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• virové plášťové proteiny * metabolismus   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: To evaluate the efficacy and tolerability of a single dose of oral cefixime 800 mg plus oral doxycycline 100 mg twice a day for 7 days, compared with a recommended single dose of ceftriaxone plus single dose of oral azithromycin, for treatment of uncomplicated urogenital, rectal, or pharyngeal gonorrhoea. METHODS: A noninferiority, open-label, multicentre randomized controlled trial was conducted in Prague, Czech Republic. Some 161 patients, 18-65 years of age diagnosed with uncomplicated urogenital, rectal, or pharyngeal gonorrhoea by nucleic acid amplification test (NAAT) were randomized to treatment with single dose of cefixime 800 mg plus doxycycline 100 mg twice a day for 1 week or a single dose of ceftriaxone 1 g intramuscularly plus single dose of azithromycin 2 g. The primary outcome was the number of participants with negative culture and NAAT at 1 week and 3 weeks, respectively, after treatment initiation. RESULTS: In all, 161 patients were randomized and 152 were included in per-protocol analyses. All 76 (100%; 95% CI, 0.95-1.00) patients treated with ceftriaxone plus azithromycin achieved negative cultures and NAAT after treatment. In the cefixime plus doxycycline arm at week 1, culture was negative in all 76 (100%) patients; at week 3, culture was negative in 70 of the 76 patients (92%; 95% CI, 0.84-0.97) and NAAT negative in 66 of the 76 patients (87%; 95% CI, 0.77-0.94). At week 3, culture and NAAT were negative in 65 of the 76 patients (86%; 95% CI, 0.76-0.93). Per-protocol risk difference was 14.5%; 95% CI, 6.56-22.38. All treatment failures observed in the cefixime arm were pharyngeal gonorrhoea cases. DISCUSSION: The combination of cefixime and doxycycline did not achieve noninferiority to ceftriaxone and azithromycin for treatment of gonorrhoea when including pharyngeal gonorrhoea. It did, however, show high efficacy for urogenital and rectal gonorrhoea.

• MeSH
• antibakteriální látky terapeutické užití   MeSH
• azithromycin terapeutické užití   MeSH
• cefixim terapeutické užití   MeSH
• ceftriaxon * MeSH
• dospělí MeSH
• doxycyklin terapeutické užití   MeSH
• gonorea * farmakoterapie   mikrobiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• Neisseria gonorrhoeae MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• hodnocení ekvivalence MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

Ciele: Cieľom pilotného projektu bolo zvýšiť testovanie ako aj prepojenie so zdravotnou starostlivosťou o novodiagnostikované osoby s infekciou HIV/HCV/syfilisu a tiež zlepšiť zber a prenos údajov pomocou štandardných nástrojov zberu údajov z komunitných centier poskytujúcich dobrovoľné poradenstvo a testovanie (CBVCT) do národného epidemiologického a monitorovacieho systému. Metódy: Integrované dobrovoľné anonymné testovanie z krvi na HIV, HCV a syfilis bolo realizované pomocou rýchlych testov v období 6 mesiacov (03/2019 až 8/2019). Účastníkom s reaktívnymi výsledkami sa odporučilo, aby navštívili špecialistu za účelom potvrdenia diagnózy a nasadenia terapie. Výsledky: Otestovaných bolo 675 klientov na HIV, 410 na HCV a 457 na syfilis. Medián veku účastníkov sa pohyboval od 24 do 35,6 (IQR:24), 75,3 % z nich bolo mužov, 23,7 % žien a 0,6 % transrodových ľudí. Z hľadiska rizika akvírovania testovaných infekcii 48,9 % zo 675 klientov boli muži majúci styk s mužmi (MSM), 0,3 % osoby pracujúce v sex-biznise (SW), 9,0 % injekční užívatelia drog (PWID), 2,4 % migranti (Mi) a 8,3 % klientov uvádzalo kombináciu týchto rizík. Pilotný projekt odhalil infekciu HIV u 0,4 %, HCV u 2,4 % a T. pallidum u 1,8 % klientov. Len 2 klienti, s potvrdenou HIV infekciou boli prepojení s následnou zdravotnou starostlivosťou. Najvyššia prevalencia HIV bola zistená u MSM/Mi (4,2 %), HCV u PWID (30,8 %) a syfilisu u SW/PWID (7,1 %). Bezkondómový styk so SW, PWID, MSM a HIV pozitívnymi za posledných 12 mesiacov uviedlo 5/92, 41/82, 3/78 a 0/88 odpovedajúcich klientov. Výsledky štúdie boli zahrnuté do ročnej národnej epidemiologickej správy. Záver: Pilotný projekt odhalil potrebu podpory integrovaného testovania v CBVCT, prekonania prekážok pri potvrdzujúcom testovaní a prepojení so zdravotnou starostlivosťou ako aj potrebu integrácie základných údajov v rámci monitorovania a hodnotenia (M&E) testovania v CBVCT do národných systémov surveillance na Slovensku.

Aim: Aim of the pilot was to increase HIV/HCV/syphilis testing and linkage to care of newly diagnosed persons, improve data collection and transfer using standard data collection tools in CBVCT services. Methods: Integrated anonymous voluntary testing from blood for HIV, HCV and syphilis was realised using rapid tests in the period of 6 months (03/2019–08/2019). Participants with reactive results were advised to see a specialist for confirmatory testing and/or treatment. Results: A total of 675 clients were tested for HIV, 410 for HCV, and 457 for syphilis. Participants’ median age ranged from 24 to 35.6 (IQR: 24), 75.3% of them were men, 23.7% were women, and 0.6% identified as transgender. In terms of groups at risk 48.9 % of 675 clients were men who have sex with men (MSM), 0.3 % sex workers (SW), 9.0 % people who inject drugs (PWID), 2.4 % migrants (Mi) and the rest of clients (8.3 %) belonged to groups at combined risk. Pilot revealed HIV, HCV and T. pallidum infections in 0.4 %, 2.4 % and 1.8 % of clients, respectively. Just 2 clients, confirmed HIV-positive, were linked to care. The highest prevalence of HIV (4.2 %), HCV (30.8 %) and syphilis (7.1 %) was found among MSM/Mi, PWID and SW/PWID, respectively. Condomless intercourse with SW, PWID, MSM and HIV-positive person in the last 12 months was reported by 5/92, 41/82, 3/78 and 0/88 of responding clients, respectively. Core indicators were included in the yearly national epidemiological report. Conclusions: Pilot revealed the need to support integrated CBVCT to overcome barriers in confirmatory testing and linkage to care and to integrate core data of monitoring and evaluation (M&E) testing framework at CBVCT services into a national surveillance and M&E systems in Slovakia.

• MeSH
• anonymní testování * MeSH
• hepatitida C diagnóza   epidemiologie   MeSH
• HIV infekce diagnóza   epidemiologie   MeSH
• integrované poskytování zdravotní péče metody   MeSH
• lidé MeSH
• ochrana veřejného zdraví metody   MeSH
• sexuálně přenosné nemoci * diagnóza   epidemiologie   MeSH
• sexuální a genderové menšiny MeSH
• služby preventivní péče metody   MeSH
• syfilis diagnóza   epidemiologie   MeSH
• uživatelé drog * MeSH
• Check Tag
• lidé MeSH
• Geografické názvy
• Slovenská republika MeSH

• MeSH
• HIV infekce komplikace   MeSH
• infekce dýchací soustavy etiologie   imunologie   klasifikace   komplikace   MeSH
• lidé MeSH
• oportunní infekce * etiologie   imunologie   klasifikace   komplikace   MeSH
• pneumocystová pneumonie diagnóza   etiologie   farmakoterapie   patologie   MeSH
• respirační syncytiální viry patogenita   MeSH
• transplantace plic škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

INTRODUCTION: HIV replication leads to a change in lymphocyte phenotypes that impairs immune protection against opportunistic infections. We examined current HIV replication as an independent risk factor for tuberculosis (TB). METHODS: We included people living with HIV from 25 European cohorts 1983-2015. Individuals <16 years or with previous TB were excluded. Person-time was calculated from enrolment (baseline) to the date of TB diagnosis or last follow-up information. We used adjusted Poisson regression and general additive regression models. RESULTS: We included 272,548 people with a median follow-up of 5.9 years (interquartile range [IQR] 2.3-10.9). At baseline, the median CD4 cell count was 355 cells/μL (IQR 193-540) and the median HIV-RNA level 22,000 copies/mL (IQR 1,300-103,000). During 1,923,441 person-years of follow-up, 5,956 (2.2%) people developed TB. Overall, TB incidence was 3.1 per 1,000 person-years (95% confidence interval [CI] 3.02-3.18) and was four times higher in patients with HIV-RNA levels of 10,000 compared with levels <400 copies/mL in any CD4 stratum. CD4 and HIV-RNA time-updated analyses showed that the association between HIV-RNA and TB incidence was independent of CD4. The TB incidence rate ratio for people born in TB-endemic countries compared with those born in Europe was 1.8 (95% CI 1.5-2.2). CONCLUSIONS: Our results indicate that ongoing HIV replication (suboptimal HIV control) is an important risk factor for TB, independent of CD4 count. Those at highest risk of TB are people from TB-endemic countries. Close monitoring and TB preventive therapy for people with suboptimal HIV control is important.

• MeSH
• dospělí MeSH
• HIV infekce * epidemiologie   imunologie   komplikace   MeSH
• incidence MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• počet CD4 lymfocytů MeSH
• replikace viru MeSH
• rizikové faktory MeSH
• RNA virová MeSH
• tuberkulóza * epidemiologie   imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH

• MeSH
• AIDS epidemiologie   MeSH
• HIV infekce * epidemiologie   MeSH
• hlášení nemocí MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• tabulky MeSH
• Geografické názvy
• Česká republika MeSH

• MeSH
• AIDS * epidemiologie   přenos   MeSH
• HIV infekce * epidemiologie   přenos   MeSH
• hlášení nemocí normy   MeSH
• incidence MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• tabulky MeSH
• Geografické názvy
• Česká republika MeSH

• MeSH
• AIDS epidemiologie   přenos   MeSH
• HIV infekce * epidemiologie   přenos   MeSH
• hlášení nemocí normy   MeSH
• kontrola infekčních nemocí normy   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• tabulky MeSH
• Geografické názvy
• Česká republika MeSH