Practical approach to the child presenting with acute generalised weakness.

Acute generalised muscle weakness in children is a paediatric emergency with a broad differential diagnosis. A careful history and neurologic examination guides timely investigation and management. We review some of the more common causes of acute generalised muscle weakness in children, highlighting key history and examination findings, along with an approach to lesion localisation to guide differential diagnosis and further investigation.

PHArmacy Students as Educators (PHASE): Implementation and evaluation of an educator's curriculum for pharmacy students.

BACKGROUND AND PURPOSE: Designed to address the Association of Faculties of Pharmacy of Canada's competency "teach pharmacy team members, the public, and other health care professionals," the PHArmacy Students as Educators (PHASE) program was developed by the institute's entry-to-practice doctor of pharmacy program. The program's objective was to support students in developing the necessary skills to fulfill their role as pharmacist-educators. EDUCATIONAL ACTIVITY AND SETTING: We performed a two-year pilot (2017-2019) of the PHASE program which consists of a large-group didactic session followed by an academic half-day (AHD) session. Evaluation was conducted using Likert-scale and qualitative student survey data collected pre- and post-sessions to determine: (1) how the PHASE program supported students as future educators, and (2) students' perceptions and experiences related to teaching and learning. FINDINGS: All students in the 2020 and 2021 graduating cohorts were included in the study following consent. We determined that while respondents agreed to the statement, "A role of a pharmacist includes being an educator" (93.7% and 98.2% for 2020 and 2021 cohorts) at baseline, the proportion of strongly agree responses increased following the didactic session (P < .005). Of note, average Likert-score for respondents' confidence in educating increased following the AHD session (P < .001). Qualitative analysis identified an increase in students' self-rated ability for determining learners' needs, developing and conducting educational sessions, and confidence related to educating others. SUMMARY: Overall, the PHASE program showed positive impact during the first two years of implementation and lessons learned from the pilot are discussed.

Strategies Proposed by Students and Pharmacists for Virtual Experiential Patient Care Practicums.

Background: The University of British Columbia (UBC) Pharmacists Clinic (the Clinic) is a pharmacist-led patient care clinic serving as a practice site for experiential education in a team-based primary care practice. Given the unprecedented circumstances surrounding COVID-19, some pharmacy practice sites have permanently transitioned select experiential education activities to a virtual format. Currently, there is limited literature on teaching practices that are conducive to students' success in a virtual environment. Objective: To determine the factors that enable successful development of a virtual patient care practicum experience at a university clinic from the perspectives of student pharmacists and practice educators. Methods: A qualitative research methodology was used to gain the perspectives of student pharmacists, who did not have experience with virtual practicums, and practice educators, who had some experience with virtual practicums at the time of the study. Separate focus group interviews were conducted using a semi-structured approach and consisted of questions aimed at gathering insight into participant perspectives on virtual practicums. The focus group sessions were audio recorded with participant consent and transcribed. A thematic analysis was conducted to analyze the data. Results: Three pharmacist practice educators and three student pharmacists participated in their respective focus groups. Six major themes were developed based on the data: (1) technology optimization, (2) patient care related activities, (3) student-practice educator relationship, (4) student skill development, (5) student support, and (6) in-person vs virtual practicum preferences. Proposed strategies to mitigate the limitations of virtual practicums included setting communication guidelines, arranging enriching learning opportunities, and having reliable internet connection. Conclusion: The participants in this study provided insight on factors to support successful development and delivery of a virtual patient care practicum. The results from this study can be applied to other health disciplines and their approach to virtual practicums during and following the COVID-19 pandemic.

Radiation Protection of the Child from Diagnostic Imaging.

In recent years due to the technological advances in imaging techniques, which have undoubtedly improved diagnostic accuracy and resulted in improved patient care, the utilization of ionizing radiation in diagnostic imaging has significantly increased. Computed tomography is the major contributor to the radiation burden, but fluoroscopy continues to be a mainstay in paediatric radiology. The rise in the use of ionizing radiation is of particular concern with regard to the paediatric population, as they are up to 10 times more sensitive to the effects of radiation than adults, due to their increased tissue radiosensitivity, increased cumulative lifetime radiation dose and longer lifetime in which to manifest the effects. This article will review the estimated radiation risk to the child from diagnostic imaging and summarise the various methods through which both the paediatrician and radiologist can practice the ALARA (As Low As Reasonably Achievable) principle, which underpins the safe practice of radiology. Emphasis is on the justification for an examination, i.e. weighing of benefits versus radiation risk, on the appropriate utilization of other, non-ionizing imaging modalities such as ultrasound and magnetic resonance imaging, and on optimisation of a clinically indicated examination. It is essential that the paediatrician and radiologist work together in this decision making process for the mutual benefit of the patient. The appropriate practical application of ALARA in the workplace is crucial to the radiation safety of our paediatric patients.

HPV 16 E2 binding sites 1 and 2 become more methylated than E2 binding site 4 during cervical carcinogenesis.

E2 protein binding to the four E2 binding sites (E2BSs) at the long control region of Human Papillomavirus (HPV) 16/18 genome may exert either transcriptional activation/repression on E6 and E7 oncoproteins. Methylation status at the E2BSs may affect the relative binding of E2 protein to them. In this study, methylation percentage at E2BS 1, 2 (promoter-proximal), and 4 (promoter-distal) were assessed by pyrosequencing and compared among HPV 16/18-positive cervical cancer, high-grade, and low-grade Cervical Intraepithelial Neoplasia, Atypical Squamous Cells of Undetermined Significance, and normal cervical epithelium. HPV 16 E2BS1&2 were more methylated than HPV 16 E2BS4 in cervical cancer whereas in cervical premalignant lesions and normal epithelium, HPV 16 E2BS1&2 were less methylated than HPV 16 E2BS4. HPV 18 E2BS1&2 remained more methylated than E2BS4 in all histological groups. HPV 16 E2BS1&2 methylation increased from high-grade lesions to cervical cancer (P < 0.001). HPV 16 E2BS4 methylation increased from low-grade to high-grade premalignant lesions (P = 0.041). Both HPV 18 E2BS1&2 and E2BS4 methylation increased from low-grade to high-grade Cervical Intraepithelial Neoplasia (P = 0.019 and 0.001 respectively) and further increased form high-grade lesions to cervical cancer (P < 0.001 and 0.005 respectively). Conclusively, HPV 16 E2BS1&2 (for transcriptional repression of E6/E7 oncoproteins) became more heavily methylated than E2BS4 (for transcriptional activation of E6/E7) in cervical cancer, favouring the differential binding of E2 protein to E2BS4. Increasing methylation at HPV 16/18 E2BSs are potentially useful adjunctive molecular markers for predicting progression from low-grade to high-grade cervical premalignant lesions and from high-grade lesions to cervical cancer.

Prevalence and risk factors of Human Papillomavirus (HPV) infection in southern Chinese women - a population-based study.

BACKGROUND: Persistent high-risk type Human papillomavirus (HPV) infection is recognized as a necessary cause of cervical cancer. This study aimed to compare the HPV prevalence and risk factors between women residing in Hong Kong (HK) and Guangzhou (GZ) region of China. METHODOLOGY/PRINCIPAL FINDINGS: A total of 1,570 and 1,369 women were recruited from HK and GZ, respectively. The cytology samples were collected and tested for HPV infection. The overall and type-specific HPV prevalence and the potential risk factors for acquisition of HPV infection were studied. Women with normal cytology in the GZ cohort had significantly higher HPV prevalence (10%) than those in the HK cohort (6.2%, p<0.001). The patterns of the age-specific HPV prevalence were also different between the two cohorts. In the HK cohort, women at the age of 20-29 years old had the highest prevalence and a second peak was observed in the age of ≥ 60 years old. In the GZ cohort, the highest HPV prevalence was also observed in 20-29 years old but declined as the age increased and a second peak was not seen. HPV16 and HPV52 were the most common high-risk types found in the HK and GZ cohorts, respectively. Age was the most consistently observed independent risk factor for HPV infection in the HK, while the number of sexual partners had association in the GZ cohort. CONCLUSIONS/SIGNIFICANCE: Our study provides the current status and the epidemiological characteristics of HPV prevalence in Southern Chinese women. The results strongly suggested that population education and the effective cervical cancer screening would be vital in the prevention of cervical cancer.

Evaluation of a newly developed GenoArray human papillomavirus (HPV) genotyping assay and comparison with the Roche Linear Array HPV genotyping assay.

Persistent infection with high-risk types of human papillomavirus (HPV) is a necessary step in the development of cervical cancer. The incorporation of HPV detection into cervical screening programs may improve the ability to identify women at risk of cervical cancer. We recently evaluated the performance characteristics of a newly developed HPV detection assay, the GenoArray (GA) genotyping assay, for the detection of HPV infections by comparing it with the commercial Roche Linear Array (LA) HPV genotyping assay. The GA assay has an analytical sensitivity for the detection of HPV types 16 (HPV-16) and HPV-18 of as few as 10 to 50 copies, and its reproducibility is adequate. The GA and LA assays showed no significant difference in the rates of detection of genotypes detected by both HPV genotyping assays and oncogenic genotypes, and the interassay agreement was excellent. The GA and LA assays revealed either concordant or compatible genotyping results for 97.5% of the samples and discordant results for only eight (2.5%) samples. Compatible results were also observed for the detection of single or multiple HPV infections and the detection of most of the genotypes. The GA assay also demonstrated good clinical performance characteristics when the comparisons were carried out with clinical subgroups of samples from patients with normal cytologies, low-grade or high-grade squamous intraepithelial lesions, and cancers. Therefore, the GA assay appears to be highly sensitive and specific for the genotyping of HPV. It has the advantage that it specifically detects HPV-52, which overcomes a limitation of the LA assay, and hence, it has potential value for use for genotyping, especially in regions where HPV-52 has a high prevalence.

Extrarenal rhabdoid tumours outside the central nervous system in infancy.

BACKGROUND: Malignant rhabdoid tumours (RT) are increasingly recognized in young children, probably as a consequence of advances in accurate histological diagnosis rather than a true increase in frequency. Although typically presenting as renal tumours in infancy, extrarenal tumours outside the central nervous system (CNS) in children less than 12 months of age are now well recognized, but previous literature on their imaging features is very limited. OBJECTIVE: To demonstrate the imaging features of extrarenal RTs outside the CNS. MATERIALS AND METHODS: A retrospective database review was made from 1989 to 2007 of patients diagnosed with extrarenal RT in infancy, i.e. below 12 months of age. RESULTS: There were nine patients (six boys and three girls). The age at presentation varied from 1 to 11 months (average 6 months). Tumours were located in the thorax/mediastinum (n=3), liver (n=3), neck (n=1), shoulder (n=1) and axilla (n=1). The imaging modalities used included US (n=8), CT (n=7) and MRI (n=6). Bone scan was positive in one patient, while metastases at the time of diagnosis occurred in four patients. On MRI the tumours tended to show nonspecific hypointensity on T1-W images and heterogeneous hyperintensity on T2-W images, with heterogeneous enhancement. CONCLUSION: This is the largest radiological series of extrarenal RTs outside the CNS in infancy. In our series no imaging features were found specific to the diagnosis. A tendency towards large size and mediastinal/paravertebral location were noted. A hypodense solid component on CT and a heterogeneous hyperintensity on T2-W MR images suggest that this tumour should be considered in the routine differential diagnosis of soft-tissue tumours in infancy, in addition to rhabdomyosarcoma.

Embryonal rhabdomyosarcoma of the omentum: two cases occurring in children.

Rhabdomyosarcoma is a soft-tissue malignancy that represents approximately 4-8% of all solid tumours in children and commonly arises from the head and neck and genitourinary system. Intraperitoneal rhabdomyosarcoma, in particular with omental involvement, has been rarely reported in the literature. Furthermore, reports of omental rhabdomyosarcoma of embryonal origin do not exist, to our knowledge. We report two cases of omental embryonal rhabdomyosarcoma affecting children and illustrate the imaging characteristics of this rare tumour.

Distribution of six oncogenic types of human papillomavirus and type 16 integration analysis in Chinese women with cervical precancerous lesions and carcinomas.

OBJECTIVES: The prevalent genotypes of human papillomavirus (HPV) infection and the significance of HPV16 integration in cervical precancerous lesions and cancer of Chinese women were investigated. METHODS: HPV genotyping and HPV16 integration status were studied on 100 normal cervical cytology, 90 low-grade (LSIL) and 99 high-grade squamous intraepithelial lesions (HSIL), as well as 96 cervical cancer biopsies using DNA sequencing and quantitative real-time PCR. RESULTS: HPV were detected in 12.0% of normal cytology, 93.3% of LSIL, 90.9% of HSIL and 89.6% of cervical cancer samples. High-risk HPV16, 18, 58, 52, 33 and 31 were the 6 major HPV types observed, composing 45.6, 82.8 and 85.4% of HPV infections in LSIL, HSIL and cervical cancers, respectively, with a significant rising trend in increasing disease severity (p = 0.002). While HPV16 and HPV18 were most commonly found in cervical cancer, HPV58 was prevalently observed in cervical precancerous lesions, and its frequency decreased with increased disease severity. Among HPV16-positive patients, 40.0% of LSIL, 88.9% of HSIL and 86.4% of cancer cases had HPV16 integration. The frequency of the integrated form of HPV16 significantly increased with the severity of the disease. CONCLUSIONS: Our results demonstrated that high-risk HPV infection and viral DNA integration were in progressive frequency from low-grade cervical precancerous lesions to cancer. HPV16 integration status had the potential to be a marker for cancer risk assessment of cervical precancerous lesions.

Promoter methylation of death-associated protein kinase and its role in irradiation response in cervical cancer.

This study was aimed at investigating the death-associated protein kinase (DAPK) promoter methylation and its clinical relevance in cervical cancer. The DAPK promoter methylation was detected by methylation-specific PCR (MSP) and correlated with DAPK mRNA and protein expression. The effect of DAPK expression on the radiosensitivity of the cervical cancer cell line was assessed by overexpressing DAPK in the radioresistant cell line SiHa. DAPK hypermethylation was found in 56.08% of the cervical cancer samples and was associated with the tumor histological cell type of squamous cell carcinoma (p=0.002) and advanced tumor stage (p=0.005). Subsequently, DAPK protein expression was found to significantly decrease in cervical cancer samples when compared to normal tissues. The DAPK mRNA and protein expression levels were absent or remarkably reduced in SiHa and HeLa in which the DAPK promoter was hypermethylated. The expression levels of DAPK could be restored after demethylation treatment with 5-aza-2'-deoxycytidine. Overexpressing DAPK in vitro had no significant influence to the survival of the radioresistant SiHa cell after being challenged by irradiation. Our findings suggest that DAPK might not directly be responsible for the cellular radiosensitivity, however, DAPK hypermethylation appeared to be of prognostic significance in the advanced stages of cervical cancer.

Imaging features of von Hippel-Lindau disease.

von Hippel-Lindau (VHL) disease is a rare, autosomal dominantly inherited multisystem disorder characterized by development of a variety of benign and malignant tumors. The spectrum of clinical manifestations of the disease is broad and includes retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renal cysts and tumors, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas. The most common causes of death in VHL disease patients are renal cell carcinoma and neurologic complications from cerebellar hemangioblastomas. The various manifestations can be demonstrated with different imaging modalities such as ultrasonography, computed tomography, magnetic resonance imaging, and nuclear medicine. Although genetic testing is available, the manifestations of the syndrome are protean; therefore, imaging plays a key role in identification of abnormalities and subsequent follow-up of lesions. It is also used for screening of asymptomatic gene carriers and their long-term surveillance. Screening is important because the lesions in VHL disease are treatable; thus, early detection allows use of more conservative therapy and may enhance the patient's length and quality of life. A multidisciplinary team approach is important in screening for VHL disease.

Enhancement of the radiosensitivity of cervical cancer cells by overexpressing p73alpha.

Radiation therapy is the most effective therapy for cervical cancer in advanced stages. p53 plays a critical role in the cellular response to radiation-induced DNA damage. However, p53 function is often impaired in the presence of the oncoprotein E6 from human papillomavirus, which is often associated with the development of cervical cancer. p73, a p53 family member, is highly similar to p53, but is resistant to the degradation by human papillomavirus E6. In this study, we investigated the role of p73alpha in relation to cellular radiosensitivity in the p53-impaired cervical cancer cells. Radiosensitivity and irradiation-induced apoptotic cell death were examined in the exogenous overexpressed p73alpha- and p53-impaired cells. Our results showed that the endogenous p73alpha expressed only in the radiosensitive cervical cancer C4-1 cells, but not in the radioresistant SiHa, Caski, and HeLa cells. Overexpression of exogenous p73alpha by transfection in the radioresistant cells resulted in a significant increase of cellular sensitivity to radiation. Enhanced radiosensitivity in p73alpha-transfected cells was attributed by increase of cellular apoptosis. Coactivation of p21 was also observed in the p73alpha-transfected cells upon radiation treatment. In summary, our findings suggested that p73alpha is an important determinant of cellular radiosensitivity in the p53-impaired cervical cancer cells.

p73 expression is associated with the cellular radiosensitivity in cervical cancer after radiotherapy.

Apoptosis is one of the causes of cell death in cervical cancer following radiotherapy. By studying the gene expression profile with cDNA apoptotic array, the p73 gene was found overexpressed in radiosensitive cervical cancers when compared with radioresistant ones. To investigate the role of the p73 gene in relation to clinical assessment of radiosensitivity in cervical cancer based on the findings of residual tumor cells in cervical biopsies after completion of radiotherapy, we studied the protein expression of p73 in 59 cervical cancers after radiotherapy and 68 normal cervices using immunohistochemistry. The expression of p73 was found to be significantly increased in cancer samples and, more importantly, in those samples sensitive to radiotherapy (P < 0.001). The overexpression of p73 actually predicted a better prognosis in cervical cancer patients (P < 0.001). To investigate the possible involvement of p73 downstream genes, the protein expressions of p21 and Bax were studied. The expression of p21, but not Bax, was found to be positively correlated with the expression of p73 (P = 0.001). Furthermore, the epigenetic regulation of p73 expression via DNA methylation was also investigated in 103 cervical cancers and 124 normals. Hypermethylation of p73 gene was observed in 38.8% of cervical cancers, and it was significantly associated with reduced or absent p73 expression (P < 0.001). Reactivation of p73 expression in two cervical cancer cell lines by demethylation treatment supported the role of methylation in the regulation of p73 expression. Our findings suggested that p73 expression was related to the radiosensitivity of cervical cancer cells and may play an important role in the regulation of cellular radiosensitivity.

Coagulopathy as a presenting feature of Wilms tumour.

UNLABELLED: Wilms' tumour (nephroblastoma) is the most common intrarenal malignancy of childhood. The most common presentation is of an asymptomatic abdominal mass (more than 80%), usually discovered incidentally. Abdominal pain occurs in 30% to 40% of patients, and hypertension, frank haematuria and fever are found in 5% to 30%. A lesser known presentation of Wilms' tumour is that of acquired von Willebrand syndrome (AVWS). This has a well recognised association with malignancies, most commonly with monoclonal gammopathies, lymphoproliferative and myeloproliferative disorders, and less commonly with solid tumours. In this article we report two cases of AVWS in patients with Wilms' tumour, the discovery of which led to a retrospective study to determine the incidence of acquired von Willebrand syndrome and coagulopathy in general in association with Wilms' tumour. We reviewed the case notes of 65 children diagnosed with Wilms' tumour between 1996 and 2001 and referred to a haematology/oncology unit within a tertiary referral centre. We observed an incidence of abnormal clotting in 16/65 and AVWS in 2/65. Treatment of the coagulation abnormalities in these two patients was with fresh frozen plasma for both and also von Willebrand factor concentrate for one. In both cases resolution of the coagulation abnormalities occurred upon treatment of the tumour. CONCLUSION: we emphasise the importance of a routine coagulation screen in every patient who presents with a possible Wilms' tumour.