Targeted Genome Mining Reveals the Psychrophilic Clostridium estertheticum Complex as a Potential Source for Novel Bacteriocins, Including Cesin A and Estercticin A

Antimicrobial resistance in pathogenic bacteria is considered a major public health issue necessitating the discovery of alternative antimicrobial compounds. In this regard, targeted genome mining in bacteria occupying under-explored ecological niches has the potential to reveal such compounds, including bacteriocins. In this study, we determined the bacteriocin biosynthetic potential of the psychrophilic Clostridium estertheticum complex (CEC) through a combination of genome mining and phenotypic screening assays. The genome mining was performed in 40 CEC genomes using antiSMASH. The production of bacteriocin-like compounds was phenotypically validated through agar well (primary screening) and disk diffusion (secondary screening) assays using cell free supernatants (CFS) and partially purified extracts, respectively. Stability of four selected CFS against proteolytic enzymes, temperature and pH was determined while one CFS was analyzed by HRMS and MS/MS to identify potential bacteriocins. Twenty novel bacteriocin biosynthetic gene clusters (BBGC), which were classified into eight (six lantibiotics and two sactipeptides) distinct groups, were discovered in 18 genomes belonging to C. estertheticum (n = 12), C. tagluense (n = 3) and genomospecies2 (n = 3). Primary screening linked six BBGC with narrow antimicrobial activity against closely related clostridia species. All four preselected CFS retained activity after exposure to different proteolytic, temperature and pH conditions. Secondary screening linked BBGC1 and BBGC7 encoding a lantibiotic and sactipeptide, respectively, with activity against Bacillus cereus while lantibiotic-encoding BBGC2 and BBGC3 were linked with activity against B. cereus, Staphylococcus aureus (methicillin-resistant), Escherichia coli and Pseudomonas aeruginosa. MS/MS analysis revealed that C. estertheticum CF004 produces cesin A, a short natural variant of nisin, and HRMS indicated the production of a novel sactipeptide named estercticin A. Therefore, we have shown the CEC, in particular C. estertheticum, is a source of novel and stable bacteriocins that have activities against clinically relevant pathogens.

Acceptability of extending HPV-based cervical screening intervals from 3 to 5 years: An interview study with women in England

Objectives: The introduction of primary HPV testing in the NHS Cervical Screening Programme in England means the screening interval for 25-49-year-olds can be extended from 3 to 5 years. We explored womens responses to the proposed interval extension. Methods: We conducted semi-structured phone/video interviews with 22 women aged 25-49 years. Participants were selected to vary in age, socioeconomics, and screening history. We explored attitudes to the current 3-year interval, then acceptability of a 5-year interval. Interviews were transcribed verbatim and analysed using Framework Analysis. Results: Attitudes to the current 3-year interval varied; some wanted more frequent screening, believing cancer develops quickly. Some participants worried about the proposed change; others trusted it was evidence-based. Frequent questions concerned the rationale and safety of longer intervals, speed of cancer development, the possibility of HPV being missed or cell changes occurring between screens. Many participants felt reassured when the interval change was explained alongside the move to HPV primary screening, of which most had previously been unaware. Conclusions: Communication of the interval change should be done in the context of broader information about HPV primary screening, emphasising that people who test negative for HPV are at lower risk of cell changes so can safely be screened every 5 years. The long time needed for HPV to develop into cervical cancer provides reassurance about safety, but it is important to be transparent that no screening test is perfect.

A Primary Screening Method for Liver Cancer in Chronic Hepatitis B Carriers: A Prospective Community-Based Cohort Study

BackgroundPatients with hepatitis B virus (HBV) were invited to receive ultrasound and alpha-protein examination directly in China. However, not all HBV carriers need to be subjected to further tests. This study aimed to develop a feasible primary screening method to narrow down potential high-risk individuals of liver cancer among populations with HBV.MethodsBased on a prospective community-based cohort, potential risk factors were selected as the predictors, including age, sex, smoking, alcohol consumption, diabetes, liver cancer family history, liver diseases in mothers, source of water, body mass index (BMI), and psychological trauma. Cox proportional regression model was applied to predict the 3-year absolute risk of liver cancer and derive risk scores. The area under receiver operating characteristic curve (AUROC) and calibration plot were used to assess the performance of the model. Bootstrap resampling was used for internal validation.ResultsAge, sex, BMI, alcohol consumption, liver diseases in mothers, and psychological trauma were independent risks of liver cancer. The 1- to 3-year AUROC of the prediction model was 71.15% (95% CI, 66.88–75.42), 71.16% (95% CI, 67.42–74.90), and 72.95% (95% CI, 64.20–81.70), respectively. The predicted risk was calibrated well with the observed liver cancer risk. Bootstrap resampling showed that C-index was 0.70 (0.67–0.74). A 32-point risk score was also developed and a score over 5 was identified for patients at extremely high risk.ConclusionsA user-friendly primary screening method was created that could estimate the 3-year absolute risk of liver cancer and identify extremely high-risk individuals among the population with HBV.

Understanding HPV and cervical screening

Cervical cancer is preventable and curable. Sarah Butler and Yvonne Wilkinson explain how the cervical screening programme has changed from a cytology based test to HPV primary screening Screening for human papillomavirus is now the primary test for cervical screening in England, Wales and Scotland. Cervical screening for those individuals with a cervix routinely occurs every 3 years for those aged 25–49 (24½ in England) and every 5 years for those aged 50–64. Over 99.7% of cervical cancers are caused by human papillomavirus. Cervical cancer is preventable and curable; primary HPV screening can detect early changes in cervical cells allowing for effective monitoring and treatment.

Use of Baricitinib in Treatment of COVID-19: A Systematic Review

Objectives To assess the role of baricitinib alone or in combination with other therapies as a treatment for patients with COVID-19. Methods Systematic literature search was conducted in the WHO COVID-19 Coronavirus disease database to find clinical studies on use of baricitinib for treatment of COVID-19 between December 1st 2019 and September 30th 2021. Two independent set of reviewers identified the eligible studies fulfilling the inclusion criteria, and relevant data was extracted and a qualitative synthesis of evidence performed. The risk of bias was evaluated with validated tools. Results A total of 267 articles were found to be eligible after primary screening of title and abstracts. Following assessment of full texts, 19 studies were finally included for this systematic review, out of which 16 are observational, and 3 are interventional studies. Collating the results from these observational and interventional studies, baricitinib used as add on to standard therapy, either alone or in combination with other drugs, was found to have favourable outcomes in moderate to severe hospitalised patients with COVID-19. Furthermore, ongoing trials indicate that drug is being extensively studied across the world for its safety and efficacy in COVID-19. Conclusion Baricitinib significantly improves clinical outcomes in hospitalized patients with COVID-19 pneumonia and further evidence may establish the drug as a standard treatment among such patients. Keywords: Baricitinib, JAK kinase inhibitor, SARS-Cov-2, COVID-19, Clinical outcome, Mortality

Detection and Outcome of Endocervical Atypia in Cytology in Primary HPV Screening Programme

Most endocervical adenocarcinomas (EAC) are associated with high-risk HPV (hrHPV) infection, with HPV genotypes 16, 18 and 45 accounting for >90% of the cases. Among endocervical glandular lesions, screening with hrHPV test has previously shown to predict the outcome better than cytology, although around one-fifth of the EAC remain negative both in hrHPV testing and cytology. The study consists of two consecutive HPV-primary screening rounds, conducted in 2012–2015 and 2017–2020. Of the 87 women aged 35 to 60 years of age diagnosed with Atypical endocervical cells, NOS or Atypical endocervical cells, favor neoplastic cytology during the first screening round, 63 (72.4%) were hrHPV positive and 24 (27.6%) were hrHPV negative. Among hrHPV positive patients, three EAC, two adenocarcinomas in situ (AIS), one AIS + high-grade intraepithelial lesion (HSIL) and 13 HSIL were found. Of the histologically verified lesions, 68.4% (13/19) were purely of squamous origin. All the EAC and AIS were HPV16 or HPV 18 positive. No high-grade histological lesions were found among the hrHPV negative patients with cytological glandular atypia. A later database search revealed one HPV-negative, gastric-type mucinous EAC that was missed by the HPV primary screening.

The value of computer aided detection system for mammography in the fatty breast: the results of the single-centered, prospective, randomized clinical trial

Aim. To assess the reasonability to use CAD added to mammography with subsequent targeted ultrasound (US) of CAD markings in patients with low-density (ACR A-В) breasts.Materials and methods. In the prospective study we included 2326 women with low breast density. They were randomized for CAD (MammCheck II of our own design) checking with subsequent targeted US (MMG + CAD group) or without CAD (MMG only group). After the initial screening we performed the 3-year follow-up phase.Results. Totally, during the primary screening in the MMG only group we found 77 breast cancers (BCs) (28,57% of them sized less than 1 cm), in the MMG + CAD group – 69 BCs (36,23% of them sized less than 1 cm), р > 0.05. The suspicious lesion was identified only during the targeted US of the CAD marking in 4 of 25 women in the MMG + CAD group, and all these BCs were below 1 cm in size. During the subsequent follow-up in the MMG only group we found 5 additional BCs, with no such cases in the MMG + CAD group (p < 0.05). Three of these five BCs were retrospectively marked by CAD. The only visible BC that was not marked by CAD was 3 mm in size.Discussion. The overall false positive marking rate was 0.31 и 0.28 per film-screen and digital image, respectively (р > 0.05).Conclusion. The CAD usage added to mammography with subsequent targeted US of markings in patients with low-density (ACR A-В) breast is reasonable due to the significant decrease of the BC rate diagnosed during the 3-year follow-up. This combination detected 77 of the 77 (100.00%) BCs compared to 69 of 74 (93.24%) BCs when only mammography used.

Targeted Secondary Screening for Congenital Hypothyroidism in High-Risk Neonates: A 9 Year Review in a Large California Health Care System

Secondary screening for missed congenital hypothyroidism (CH) has been introduced sporadically, but its necessity and optimal strategy have not been recognized. We hypothesized that a simple clinical protocol (performed by a medical group without a governmental mandate) targeting infants at high risk for missed CH can identify cases. We performed a 9-year retrospective review of 338,478 neonates within a California health plan following the introduction of thyrotropin (TSH) secondary screening for neonates at high risk for missed CH due to very-low-birthweight (VLBW), hospitalized congenital heart disease (CHD), and same-sex multiples (SSM). Screening performance by day 60 of life was 95% successful for VLBW and >50% for CHD and SSM, leading to an additional 35% CH treated cases despite re-testing only 1.7% of the cohort. Infants with VLBW or CHD were 33 times more likely (190 times more likely for CHD with Down Syndrome) to receive treatment for CH than random infants diagnosed by primary screening (p < 0.001), and 92% of these infants were not found by primary newborn screening. Currently, permanent disease has been documented in 84% of CH by primary screening compared to 27% by secondary screening (p < 0.001). This targeted secondary screening program identifies and treats additional CH cases after TSH-only newborn screening.