HPV8-induced STAT3 activation led keratinocyte stem cell expansion in human actinic keratoses.

Despite epidermal turnover, the skin is host to a complex array of microbes including viruses, such as the human papillomavirus (HPV), which must infect and manipulate skin keratinocyte stem cells (KSC) to survive. This crosstalk between the virome and KSC populations remains largely unknown. Here, we investigated the effect of HPV8 on KSCs using various mouse models. We observed that the HPV8 early region gene E6 specifically caused Lrig1+ hair follicle junctional zone KSC proliferation and expansion, which would facilitate viral transmission. Within Lrig1+ KSCs specifically, HPV8 E6 bound intracellular p300 to phosphorylate the STAT3 transcriptional regulatory node. This induces ΔNp63 expression, resulting in KSC expansion into the overlying epidermis. HPV8 was associated with 70% of human actinic keratoses (AK). Together these results define the "hit and run" mechanism for HPV8 in human actinic keratosis as an expansion of KSCs, which lacks melanosome protection and is thus susceptible to sun-light-induced malignant transformation.

Evidence-guided approach to portfolio-guided teaching and assessing communications, ethics and professionalism for medical students and physicians: a systematic scoping review.

OBJECTIVES: Guiding the development of longitudinal competencies in communication, ethics and professionalism underlines the role of portfolios to capture and evaluate the multiple multisource appraisals and direct personalised support to clinicians. However, a common approach to these combined portfolios continues to elude medical practice. A systematic scoping review is proposed to map portfolio use in training and assessments of ethics, communication and professionalism competencies particularly in its inculcation of new values, beliefs and principles changes attitudes, thinking and practice while nurturing professional identity formation. It is posited that effective structuring of portfolios can promote self-directed learning, personalised assessment and appropriate support of professional identity formation. DESIGN: Krishna's Systematic Evidence-Based Approach (SEBA) is employed to guide this systematic scoping review of portfolio use in communication, ethics and professionalism training and assessment. DATA SOURCES: PubMed, Embase, PsycINFO, ERIC, Scopus and Google Scholar databases. ELIGIBILITY CRITERIA: Articles published between 1 January 2000 and 31 December 2020 were included. DATA EXTRACTION AND SYNTHESIS: The included articles are concurrently content and thematically analysed using the split approach. Overlapping categories and themes identified are combined using the jigsaw perspective. The themes/categories are compared with the summaries of the included articles in the funnelling process to ensure their accuracy. The domains identified form the framework for the discussion. RESULTS: 12 300 abstracts were reviewed, 946 full-text articles were evaluated and 82 articles were analysed, and the four domains identified were indications, content, design, and strengths and limitations. CONCLUSIONS: This review reveals that when using a consistent framework, accepted endpoints and outcome measures, longitudinal multisource, multimodal assessment data fashions professional and personal development and enhances identity construction. Future studies into effective assessment tools and support mechanisms are required if portfolio use is to be maximised.

Portfolio use in postgraduate medical education: a systematic scoping review.

BACKGROUND: Portfolios are increasingly commonplace in postgraduate medical education. However, poor understanding of and variations in their content, quality, and structure have hindered their use across different settings, thus dampening their efficacy. METHODS: This systematic scoping review on portfolios in postgraduate medical education utilized Krishna's Systematic Evidence Based Approach (SEBA). Braun and Clarke's thematic analysis and Hsieh and Shannon's directed content analysis were independently used to evaluate the data. RESULTS: In total, 12 313 abstracts were obtained, and 76 full-text articles included. Six key themes/categories were identified: (i) portfolio definitions and functions, (ii) platforms, (iii) design, (iv) implementation, (v) use in assessments, and (vi) evaluations of their usage. CONCLUSIONS: Portfolios allow for better appreciation and assessments of knowledge, skills, and attitudes in time-, learner-, and context-specific competencies through the establishment of smaller micro-competencies and micro-credentialling. Organized into three broad stages-development, implementation, and improvement-a six-step framework for optimizing and instituting portfolios in postgraduate medical education is offered.

Medical Student Portfolios: A Systematic Scoping Review.

Phenomenon: Medical Student Portfolios (MSP)s allow medical students to reflect and better appreciate their clinical, research and academic experiences which promotes their individual personal and professional development. However, differences in adoption rate, content design and practice setting create significant variability in their employ. With MSPs increasingly used to evaluate professional competencies and the student's professional identity formation (PIF), this has become an area of concern. Approach: We adopt Krishna's Systematic Evidence-Based Approach to carry out a Systematic Scoping Review (SSR in SEBA) on MSPs. The structured search process of six databases, concurrent use of thematic and content analysis in the Split Approach and comparisons of the themes and categories with the tabulated summaries of included articles in the Jigsaw Perspective and Funnelling Process offers enhanced transparency and reproducibility to this review. Findings: The research team retrieved 14501 abstracts, reviewed 779 full-text articles and included 96 articles. Similarities between the themes, categories and tabulated summaries allowed the identification of the following funnelled domains: Purpose of MSPs, Content and structure of MSPs, Strengths and limitations of MSPs, Methods to improve MSPs, and Use of E-portfolios. Insights: Variability in the employ of MSPs arise as a result of a failure to recognise its different roles and uses. Here we propose additional roles of MSPs, in particular, building on a consistent set of content materials and assessments of milestones called micro-competencies. Whislt generalised micro-competencies assess achievement of general milestones expected of all medical students, personalised micro-competencies record attainment of particular skills, knowledge and attitudes balanced against the medical student's abilities, context and needs. This combination of micro-competencies in a consistent framework promises a holistic, authentic and longitudinal perspective of the medical student's development and maturing PIF.

Usefulness of supplementary ultrasound surveillance in the detection of a second breast cancer in patients with ductal carcinoma in situ.

INTRODUCTION: Supplementary ultrasound surveillance in breast cancer patients can detect additional cancers but is associated with unnecessary biopsies and follow-ups. We aim to determine, in patients with ductal carcinoma in situ (DCIS), the prevalence and factors associated with second breast cancers and the usefulness of supplementary ultrasound surveillance. This is the first study which focused on the usefulness of ultrasound surveillance in DCIS patients. METHODS: DCIS patients were retrospectively analyzed to determine the prevalence and factors associated with second breast cancers. The prevalence of patients with benign biopsies, additional ultrasound follow-ups and second breast cancers, resulting from ultrasound surveillance, were calculated. RESULTS: Three hundred and thirty- two patients were included. 25 (7.5%) patients developed second breast cancers after a mean follow-up of 77.7 months. Breast conservation (P= .0218), involved margins after lumpectomy (P = .0003) and shortened hormonal therapy (P= 0.0369) were associated with second cancers. Of the 314 patients who had ultrasound surveillance, ipsilateral, and contralateral ultrasounds yielded 1.7%/1.3% cancer detection, 5.8%/6.7% benign biopsies and 10.4%/15.3% additional follow-ups. Patients with involved margins after lumpectomy have ipsilateral cancer detection, benign biopsies and additional follow-ups of 4.5%, 4.5%, and 9.1% respectively. A total of 85.4% patients had mammographically dense breasts. CONCLUSION: In DCIS patients, the rate of second breast cancers was 7.5%. Breast conservation, involved margins after lumpectomy and shortened hormonal therapy were associated with second cancers. Patients with involved margins after lumpectomy have the highest cancer detection rate and minimal unnecessary biopsies and follow-ups. Hence, ipsilateral breast ultrasound surveillance could be personalized for this high-risk group with mammographically dense breasts.

A Systematic Scoping Review on Portfolios of Medical Educators.

BACKGROUND: Heralded as a teaching, assessment and reflective tool, and increasingly as a longitudinal and holistic perspective of the educator's development, medical educator's portfolios (MEP)s are increasingly employed to evaluate progress, assess for promotions and career switches, used as a reflective tool and as a means of curating educational activities. However, despite its blossoming role, there is significant dissonance in the content and structure of MEPs. As such, a systematic scoping review (SSR) is proposed to identify what is known of MEPs and its contents. METHODS: Krishna's Systematic Evidenced Based Approach (SEBA) was adopted to structure this SSR in SEBA of MEPs. SEBA's constructivist approach and relativist lens allow data from a variety of sources to be considered to paint a holistic picture of available information on MEPs. RESULTS: From the 12 360 abstracts reviewed, 768 full text articles were evaluated, and 79 articles were included. Concurrent thematic and content analysis revealed similar themes and categories including: (1) Definition and Functions of MEPs, (2) Implementing and Assessing MEPs, (3) Strengths and limitations of MEPs and (4) electronic MEPs. DISCUSSION: This SSR in SEBA proffers a novel 5-staged evidence-based approach to constructing MEPs which allows for consistent application and assessment of MEPs. This 5-stage approach pivots on assessing and verifying the achievement of developmental milestones or 'micro-competencies' that facilitate micro-credentialling and effective evaluation of a medical educator's development and entrust-ability. This allows MEPs to be used as a reflective and collaborative tool and a basis for career planning.

Feasibility of a paediatric radiology escape room for undergraduate education.

OBJECTIVES: To develop a paediatric radiology themed escape room session for undergraduate education and secondly, to determine participant satisfaction and improvement in knowledge. METHODS: A paediatric radiology escape room with accompanying tutorial was developed around key learning objectives set within the RCR and ESR undergraduate curriculum. Students were recruited from two different universities and undertook the escape room themed teaching. An 8-question single best answer (SBA) test was completed before, immediately after and at 2 weeks post-teaching to determine participant improvement and retention of knowledge. The general feedback was also collected. RESULTS: The escape room sessions were held three times, for 19 students (6-7 students per session). All groups completed the escape room in ≤ 20 min. Students enjoyed the experience, assigning an average satisfaction score of 9.4/10 (range 7-10). The majority (17/19, 89.5%) preferred this method of teaching to a lecture-based tutorial alone, although all said they found the tutorial component useful. For the SBA test, there was an average increase in 3.6 marks (range 1-6 marks) per participant between before and after the escape room. This improved knowledge was mostly sustained after 2 weeks, with an average increase of 3.4 marks difference (range 1 to 6) per participant compared to before the teaching. CONCLUSIONS: A paediatric radiology themed escape room is a feasible teaching method, enjoyed by participants and associated with an increase in radiological knowledge. Further work with larger sample size and direct comparison with other traditional teaching methods is required.

Computed tomography of the head for adult patients with minor head injury: are clinical decision rules a necessary evil?

INTRODUCTION: This study aimed to evaluate compliance with and performance of the Canadian Computed Tomography Head Rule (CCHR), and its applicability to the Singapore adult population with minor head injury. METHODS: We conducted a retrospective study over six months of consecutive patients who presented to the adult emergency department (ED) with minor head injury. Data on predictor variables indicated in the CCHR was collected and compliance with the CCHR was assessed by comparing the recommendations for head computed tomography (CT) to its actual usage. RESULTS: In total, 349 patients satisfied the inclusion criteria. Common mechanisms of injury were falls (59.3%), motor vehicle crashes (16.9%) and assault (12.0%). 249 (71.3%) patients underwent head CT, yielding 42 (12.0%) clinically significant findings. 1 (0.3%) patient required neurosurgical intervention. According to the CCHR, head CT was recommended for 209 (59.9%) patients. Compliance with the CCHR was 71.3%. Among the noncompliant group, head CT was overperformed for 20.1% and underperformed for 8.6% of patients. Multivariate logistic regression analysis revealed that absence of retrograde amnesia (odds ratio [OR] 4.1, 95% confidence interval [CI] 1.8-9.7) was associated with noncompliance to the CCHR. Factors associated with underperformance were absence of motor vehicle crashes as a mechanism of injury (OR 6.6, 95% CI 1.2-36.3) and absence of headache (OR 10.8, 95% CI 1.3-87.4). CONCLUSION: Compliance with the CCHR for adult patients with minor head injury remains low in the ED. A qualitative review of physicians' practices and patients' preferences may be carried out to evaluate reasons for noncompliance.

Protective role of adenylate cyclase in the context of a live pertussis vaccine candidate.

Despite high vaccination coverage, pertussis remains an important respiratory infectious disease and the least-controlled vaccine-preventable infectious disease in children. Natural infection with Bordetella pertussis is known to induce strong and long-lasting immunity that wanes later than vaccine-mediated immunity. Therefore, a live attenuated B. pertussis vaccine, named BPZE1, has been developed and has recently completed a phase I clinical trial in adult human volunteers. In this study, we investigated the contribution of adenylate cyclase (CyaA) in BPZE1-mediated protection against pertussis. A CyaA-deficient BPZE1 mutant was thus constructed. Absence of CyaA did not compromise the adherence properties of the bacteria onto mammalian cells. However, the CyaA-deficient mutant displayed a slight impairment in the ability to survive within macrophages compared to the parental BPZE1 strain. In vivo, whereas the protective efficacy of the CyaA-deficient mutant was comparable to the parental strain at a vaccine dose of 5 × 10(5) colony forming units (CFU), it was significantly impaired at a vaccine dose of 5 × 10(3) CFU. This impairment correlated with impaired lung colonization ability, and impaired IFN-γ production in the animal immunized with the CyaA-deficient BPZE1 mutant while the pertussis-specific antibody profile and Th17 response were comparable to those observed in BPZE1-immunized mice. Our findings thus support a role of CyaA in BPZE1-mediated protection through induction of cellular mediated immunity.

Attenuated Bordetella pertussis BPZE1 as a live vehicle for heterologous vaccine antigens delivery through the nasal route.

Whereas the great majority of the current vaccines are delivered through the parenteral route, mucosal administration has been increasingly considered for controlling infection and preventing disease. Mucosal vaccination can trigger both humoral and cell-mediated protection, not only at the targeted mucosal surface, but also systemically. In this regard, nasal vaccination has shown great potential. The live attenuated strain of Bordetella pertussis, BPZE1, is particularly attractive and promising as a nasal vaccine delivery vector of heterologous antigen vaccine candidates. BPZE1 was originally developed as a live nasal pertussis vaccine candidate, and is currently undergoing phase I clinical trial in human (http://www.child-innovac.org). Highly adapted to the human respiratory tract and offering several potential protein carriers for presentation of the heterologous antigen vaccine candidates, BPZE1 represents an appealing platform for the development of live recombinant vaccines delivered via the nasal route that would confer simultaneous protection against pertussis and the targeted infectious disease(s).

Development of live attenuated Bordetella pertussis strains expressing the universal influenza vaccine candidate M2e.

The attenuated Bordetella pertussis BPZE1 vaccine strain represents an attractive platform for the delivery of heterologous vaccine candidates via the nasal route. The filamentous hemagglutinin (FHA) has been used to secrete or expose the foreign antigens at the bacterial surface. In this study, one, two and three copies of the Cys-containing ectodomain of matrix protein 2 (M2e) from influenza A virus were genetically fused to full length FHA and expressed in BPZE1. The secretion efficacy of the FHA-(M2e)(1,2,3) chimera in the extracellular milieu and the ability of the recombinant bacteria to colonize the mouse lungs inversely correlated with the number of M2e copies fused to FHA. Nevertheless FHA-(M2e)(3)-producing bacteria (BPLR3) triggered the highest systemic anti-M2e antibody response upon nasal administration to BALB/c mice. Nasal immunization with BPLR3 bacteria resulted in a significant reduction in the viral loads upon challenge with H1N1/PR8 influenza A virus, but did not improve the survival rate compared to BPZE1-immunized mice. Furthermore, since previous work reported that disulfide bond formation in Cys-containing passenger antigens affects the secretion efficacy of the FHA chimera, the dsbA gene encoding a periplasmic disulfide isomerase was deleted in the FHA-(M2e)(3)-producing strain. Despite improving significantly the secretion efficacy of the FHA-(M2e)(3) chimera, the dsbA deletion did not result in higher anti-M2e antibody titers in mice, due to impaired bacterial fitness and colonization ability.

Attenuated Bordetella pertussis protects against highly pathogenic influenza A viruses by dampening the cytokine storm.

The threat of a pandemic spread of highly virulent influenza A viruses currently represents a top global public health problem. Mass vaccination remains the most effective way to combat influenza virus. However, current vaccination strategies face the challenge to meet the demands in a pandemic situation. In a mouse model of severe influenza virus-induced pneumonitis, we observed that prior nasal administration of an attenuated strain of Bordetella pertussis (BPZE1) provided effective and sustained protection against lethal challenge with two different influenza A virus subtypes. In contrast to most cross-protective effects reported so far, the protective window offered upon nasal treatment with BPZE1 lasted up to at least 12 weeks, suggesting a unique mechanism(s) involved in the protection. No significant differences in viral loads were observed between BPZE1-treated and control mice, indicating that the cross-protective mechanism(s) does not directly target the viral particles and/or infected cells. This was further confirmed by the absence of cross-reactive antibodies and T cells in serum transfer and in vitro restimulation experiments, respectively. Instead, compared to infected control mice, BPZE1-treated animals displayed markedly reduced lung inflammation and tissue damage, decreased neutrophil infiltration, and strong suppression of the production of major proinflammatory mediators in their bronchoalveolar fluids (BALFs). Our findings thus indicate that protection against influenza virus-induced severe pneumonitis can be achieved through attenuation of exaggerated cytokine-mediated inflammation. Furthermore, nasal treatment with live attenuated B. pertussis offers a potential alternative to conventional approaches in the fight against one of the most frightening current global public health threats.