Proton pump inhibitors and the risk of acquiring a penicillin allergy label.

The negative consequences of having a penicillin allergy label are well established. Penicillin allergy de-labelling improves healthcare outcomes; however, less attention is paid to modifying risk factors leading to penicillin allergy development. In this propensity score-matched retrospective cohort study, we used a de-identified population-based database (TriNetX Research Network) and examined the 30-day risk of acquiring a penicillin allergy label in patients using proton pump inhibitors (PPIs). We demonstrated a higher risk of acquiring a penicillin allergy label among PPI users compared to controls.

Guideline No. 423: Female Genital Cosmetic Surgery and Procedures.

OBJECTIVE: To provide Canadian surgeons and other providers who offer female genital cosmetic surgery (FGCS) and procedures, and their referring practitioners, with evidence-based direction in response to increasing requests for, and availability of, vaginal and vulvar surgeries and procedures that fall outside the traditional realm of medically indicated reconstructions. TARGET POPULATION: Women of all ages seeking FGCS or procedures. BENEFITS, HARMS, AND COSTS: Health care providers play an important role in educating women about their anatomy and helping them appreciate individual variations. Most women requesting FGCS and procedures have normal genitalia, and up to 87% are reassured by counselling. At this time, due to lack of rigorous clinical or scientific evidence of short- and long-term efficacy and safety, FGCS and procedures for non-medical indications cannot be supported. FGCS and procedures are typically provided in the private sector, where costs are borne by the patient. EVIDENCE: Literature was retrieved through searches of MEDLINE, Scopus, and The Cochrane Library using appropriate controlled vocabulary and keywords. The selected search terms represented keywords for FGCS (labiaplasty, surgery, vaginal laser therapy, laser vaginal tightening, vaginal laser, vaginal rejuvenation, vaginal relaxation syndrome, hymenoplasty, vaginal cosmetic procedures) combined with female genital counselling, consent, satisfaction, follow-up, adolescent, and body dysmorphic or body dysmorphia. The search was restricted to publications after 2012 in order to update the literature since the previous guideline on this topic. Results were restricted to systematic reviews, randomized controlled trials, and observational studies. Studies were restricted to those involving humans, and no language restrictions were applied. The search was completed on May 20, 2020, and updated on November 10, 2020. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). INTENDED AUDIENCE: Gynaecologists, primary care providers, surgeons performing FGCS and/or procedures.

Directive clinique no 423 : Interventions chirurgicales et thérapeutiques esthétiques génitales féminines.

OBJECTIF: Fournir aux chirurgiens et autres fournisseurs de soins canadiens qui réalisent des interventions chirurgicales ou thérapeutiques esthétiques génitales féminines, et tout praticien demandeur, des directives fondées sur des données probantes en réponse à l'augmentation des demandes et de la disponibilité des interventions chirurgicales et thérapeutiques vaginales et vulvaires sortant du cadre traditionnel de la reconstruction avec indication médicale. POPULATION CIBLE: Les femmes de tous âges qui consultent pour subir une intervention chirurgicale ou thérapeutique esthétique génitale. BéNéFICES, RISQUES ET COûTS: Les professionnels de la santé qui prodiguent des soins aux femmes jouent un rôle important en renseignant les femmes sur leur anatomie et en les aidant à prendre conscience des variations individuelles. La plupart des femmes qui demandent une intervention chirurgicale ou thérapeutique esthétique génitale féminine ont des organes génitaux normaux, et jusqu'à 87 % d'entre elles sont rassurées par des conseils. À l'heure actuelle, étant donné le manque de données probantes cliniques et scientifiques rigoureuses sur l'efficacité et l'innocuité à court et à long terme, il n'y a aucune base pour se prononcer en faveur des interventions chirurgicales ou thérapeutiques esthétiques génitales féminines sans indication médicale. Les interventions chirurgicales ou thérapeutiques esthétiques génitales féminines sont généralement réalisées dans le secteur privé, où les coûts sont assumés par la patiente. DONNéES PROBANTES: La littérature publiée a été rassemblée par des recherches dans les bases de données Medline, Scopus et Cochrane Library au moyen de termes et mots clés pertinents et validés. Les termes de recherche sélectionnés se composaient de mots clés sur les interventions chirurgicales ou thérapeutiques esthétiques génitales féminines (labiaplasty, surgery, vaginal laser therapy, laser vaginal tightening, vaginal laser, vaginal rejuvenation, vaginal relaxation syndrome, hymenoplasty, vaginal cosmetic procedures) combinés à female genital counselling, consent, satisfaction, follow-up, adolescent et body dysmorphic or body dysmorphia. La recherche a été limitée aux articles publiés après 2012 afin de mettre à jour la documentation depuis la dernière directive à ce sujet. Les résultats ont été restreints aux revues systématiques, aux essais cliniques randomisés et aux études observationnelles. Les études ont été limitées à celles menées chez l'humain seulement, et aucune restriction linguistique n'a été appliquée. La recherche a été effectuée le 20 mai 2020 et mise à jour le 10 novembre 2020. MéTHODES DE VALIDATION: Les auteures ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique d'évaluation, de développement et d'évaluation (GRADE). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et faibles). PROFESSIONNELS CONCERNéS: Gynécologues, fournisseurs de soins primaires, chirurgiens réalisant des interventions chirurgicales et/ou thérapeutiques esthétiques génitales féminines. RECOMMANDATIONS.

Cost assessment of allergy procedures to improve high-value care implementation.

Background: Oral challenges and desensitizations are regularly performed by allergy/immunology physicians. However, there is limited research that has evaluated their cost-effectiveness and overall health-care-related value. Objective: The objective was to analyze the costs of oral challenges and desensitizations by clinician type (including allergy/immunology physicians, other physicians, and certified registered nurse practitioners [CRNP] and physician assistants [PA]), and by geographic distribution in the United States. Methods: By using a de-identified commercial database of medical encounters, we identified all claims for outpatient oral challenges and desensitizations in 2017 and grouped them separately by clinician type and by U.S. Census region. We used analysis of variance to test for cost differences between these two groupings. Results: Allergy/immunology physicians performed the majority of oral challenges (74.36%) with a mean cost of $161, significantly less than that of other physicians ($280). Allergy/immunology physicians also performed the majority of desensitizations (84.48%) with a mean cost of $335, significantly higher than that of CRNPs/PAs ($280); other physicians were reimbursed significantly more than both groups ($410). By geographic region, the mean costs of oral challenges in the Northeast ($212) and the West ($210) were significantly higher than those of other regions, whereas the mean cost of desensitizations was significantly highest in the West ($381). Conclusion: Allergy/immunology physicians and CRNPs/PAs cost the least with respect to oral challenges, whereas CRNPs/PAs cost the least with respect to desensitizations. The Northeast and the West regions provided the highest cost for oral challenges, whereas the West was most expensive in terms of desensitizations. Further knowledge and examination of these reimbursement patterns are crucial in understanding their relative value and the impact on delivery of high-value care.

Pegylated Liposomal Doxorubicin Is an Active Agent for Chemotherapy-Resistant Choriocarcinoma: A Report of Two Cases.

BACKGROUND: Despite advances in chemotherapy, radiation, surgery, and supportive treatments, a significant proportion of high-risk metastatic gestational trophoblastic disease patients develop resistant disease and die. Of those cured, protracted treatments can lead to long-term morbidity or later toxicity and death. Here we describe 2 patients with brain metastases who failed multiple lines of standard chemotherapy and radiation but had complete response to pegylated liposomal doxorubicin (PLD). CASE 1: A 35-year-old woman presented with choriocarcinoma in the brain, lungs, and subcutaneous tissues 11 months after full-term delivery. Her FIGO risk score was 14. Over 3 years she was treated with EMA-CO, EMA-CE, Taxol, gemcitabine, brain radiation, and excisional craniotomy for recurrent choriocarcinoma. She showed complete response of choriocarcinoma brain metastases following 2 cycles of PLD. She was choriocarcinoma free until her death 9 months later from acute myelogenous leukemia. CASE 2: A 52-year-old multigravid woman presented with choriocarcinoma 3 years following miscarriage. Her FIGO score was 16. Over 18 months she was treated with EMA-CO, TP/TE and IT MTX, and radiation. Her disease proved resistant and midbrain tumor unresectable. She showed complete response to PLD following 3 cycles but ultimately died from neurologic complications. CONCLUSION: PLD is an active agent in the treatment of high-risk choriocarcinoma.

Evidence of a novel role for Pygopus in rRNA transcription.

Increased protein synthesis during cell proliferation is accompanied by a compensatory increase in efficient ribosome production, but the mechanisms by which cells adapt to this requirement are not fully understood. In the present study, we demonstrate evidence that Pygo (Pygopus), a protein originally identified as a core component of the Wnt-ß-catenin transcription complex is also involved in rRNA transcription during cancer cell growth. Pygo was detected in the nucleoli of several transformed cell lines and was associated with treacle and UBF (upstream binding factor), proteins that are essential for ribosome biogenesis in development and cancer. Pygo was also detected at the ribosomal gene promoter along with core components of the rDNA (ribosomal DNA) transcription complex. RNAi (RNA interference)-mediated depletion of hPygo2 (human Pygo 2) reduced histone H4 acetylation at the rDNA promoter, down-regulated rRNA production, and induced growth arrest in both p53-positive and -negative cells. In p53-positive cells, hPygo2 knockdown triggered the ribosomal stress pathway, culminating in p53-dependent growth arrest at G1-phase of the cell cycle. The results of the present study suggest a novel involvement of Pygo in the promotion of rRNA transcription in cancer cells.

Invasive cervical cancer incidence and mortality among canadian women aged 15 to 29 and the impact of screening.

OBJECTIVE: The utility of screening young women for cervical cancer is questionable given the likelihood of pre-cancer regression and the potential harm of the intervention. Our objective was to determine the incidence and mortality rates of invasive cervical cancer (ICC) in women aged 15 to 29 years and to assess changes in rates since the uptake of screening. METHODS: The incidence of ICC cases from 1970 to 2007 was obtained from records in the Canadian Cancer Registry and from the National Cancer Incidence Reporting System. Mortality rates in women with ICC for the same time period were obtained from the Canadian Vital Statistics Death Database. Data were classified by age group and year at diagnosis or death, assessed at five-year intervals. The incidence was further analyzed according to histology. RESULTS: ICC among 15- to 19-year-olds is rare and has remained relatively constant from 1970-1974 to 2005-2007. From 1975-1979 to 2005-2007, the incidence in 20- to 24-year-olds declined from 3.2 to 1.2 per 100 000. From 1980-1984 to 2005-2007, the incidence in 25- to 29-year-olds declined from 11.1 to 6.3 per 100 000. Deaths among 15- to 19-year-olds and 20- to 24-year-olds are rare, but in 25- to 29-year-olds mortality declined from 0.9 to 0.5 per 100 000 between 1975-1979 and 2005-2007. Among 20- to 24-year-olds, rates of all cervical cancers and squamous cell carcinomas declined, while adenocarcinomas and unknown types were rare. In 25- to 29-year-olds there was a decline in all cervical cancers and squamous cell cancers and an apparent increase in adenocarcinoma. CONCLUSIONS: ICC in adolescents is rare and does not justify population-based screening. Screening appears to have affected the incidence of ICC in 20- to 24-year olds and incidence and mortality from ICC in 25- to 29-year-olds.

A health economic model to estimate the costs and benefits of an mRNA vs DNA high-risk HPV assay in a hypothetical HPV primary screening algorithm in Ontario, Canada.

This study models the impact of using two different types of high-risk (HR) human papillomavirus (HPV) tests: mRNA (Aptima) and DNA (Hybrid Capture 2) as part of a hypothetical primary HPV screening program in Ontario, Canada. Outcomes were the costs of the screening program, and number of colposcopies, HPV tests and cytology tests. Results were estimated for one cohort going through the screening algorithm. A decision tree model was adapted from a published UK study, with inputs drawn from published Canadian data for the probabilities through the model, costs, demographic, and screening data from Ontario. Sensitivity and scenario analyses explored uncertainty in the model inputs and assumptions. Results indicated that screening using an mRNA test could yield cost savings of CAD $4,007,266 (95% credibility interval [CI]: -7,866,251 - 8,035) compared to using a DNA test, with 10,639 (95% CI: 10,170 - 11,094) fewer women undergoing unnecessary colposcopies, and reductions in unnecessary HR-HPV and cytology tests. The HR-HPV test comprised the largest percentage of the costs saved, and the probability of being HPV positive in the first year had the biggest impact on results. These results indicate that the choice of HR-HPV test is important when implementing a primary HPV screening program to avoid unnecessary resource use and cost, which will benefit both women and healthcare providers.

Screening for the prevention and early detection of cervical cancer: protocol for systematic reviews to inform Canadian recommendations.

PURPOSE: To inform recommendations by the Canadian Task Force on Preventive Health Care on screening in primary care for the prevention and early detection of cervical cancer by systematically reviewing evidence of (a) effectiveness; (b) test accuracy; (c) individuals' values and preferences; and (d) strategies aimed at improving screening rates. METHODS: De novo reviews will be conducted to evaluate effectiveness and to assess values and preferences. For test accuracy and strategies to improve screening rates, we will integrate studies from existing systematic reviews with search updates to the present. Two Cochrane reviews will provide evidence of adverse pregnancy outcomes from the conservative management of cervical intraepithelial neoplasia. We will search Medline, Embase, and Cochrane Central (except for individuals' values and preferences, where Medline, Scopus, and EconLit will be searched) via peer-reviewed search strategies and the reference lists of included studies and reviews. We will search ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. Two reviewers will screen potentially eligible studies and agree on those to include. Data will be extracted by one reviewer with verification by another. Two reviewers will independently assess risk of bias and reach consensus. Where possible and suitable, we will pool studies via meta-analysis. We will compare accuracy data per outcome and per comparison using the Rutter and Gatsonis hierarchical summary receiver operating characteristic model and report relative sensitivities and specificities. Findings on values and preferences will be synthesized using a narrative synthesis approach and thematic analysis, depending on study designs. Two reviewers will appraise the certainty of evidence for all outcomes using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and come to consensus. DISCUSSION: The publication of guidance on screening in primary care for the prevention and early detection of cervical cancer by the Task Force in 2013 focused on cytology. Since 2013, new studies using human papillomavirus tests for cervical screening have been published that will improve our understanding of screening in primary care settings. This review will inform updated recommendations based on currently available studies and address key evidence gaps noted in our previous review.

Augmentation of Myc-Dependent Mitotic Gene Expression by the Pygopus2 Chromatin Effector.

Mitotic segregation of chromosomes requires precise coordination of many factors, yet evidence is lacking as to how genes encoding these elements are transcriptionally controlled. Here, we found that the Pygopus (Pygo)2 chromatin effector is indispensable for expression of the MYC-dependent genes that regulate cancer cell division. Depletion of Pygo2 arrested SKOV-3 cells at metaphase, which resulted from the failure of chromosomes to capture spindle microtubules, a critical step for chromosomal biorientation and segregation. This observation was consistent with global chromatin association findings in HeLa S3 cells, revealing the enrichment of Pygo2 and MYC at promoters of biorientation and segmentation genes, at which Pygo2 maintained histone H3K27 acetylation. Immunoprecipitation and proximity ligation assays demonstrated MYC and Pygo2 interacting in nuclei, corroborated in a heterologous MYC-driven prostate cancer model that was distinct from Wnt/ß-catenin signaling. Our evidence supports a role for Pygo2 as an essential component of MYC oncogenic activity required for mitosis.

PYGOPUS2 expression in prostatic adenocarcinoma is a potential risk stratification marker for PSA progression following radical prostatectomy.

AIMS: Prostate cancer (PrCa) is the most frequently diagnosed non-cutaneous cancer in men. Without clear pathological indicators of disease trajectory at diagnosis, management of PrCa is challenging, given its wide-ranging manifestation from indolent to highly aggressive disease. This study examines the role in PrCa of the Pygopus (PYGO)2 chromatin effector protein as a risk stratification marker in PrCa. METHODS: RNA expression was performed in PrCa cell lines using Northern and RT-PCR analyses. Protein levels were assessed using immunoblot and immunofluorescence. Immunohistochemistry was performed on tissue microarrays constructed from radical prostatectomies with 5-year patient follow-up data including Gleason score tumour staging, margin and lymph node involvement and prostate serum antigen (PSA) levels. Biochemical recurrence (BR) was defined as a postoperative PSA level of >0.2 nL. Univariate and multivariate analyses were performed using SAS and Kaplan-Meier curves using graphPad (Prism). RESULTS: In vitro depletion of PYGO2 by RNAi in both androgen receptor positive and negative PrCa cell lines attenuated growth and reduced Ki67 and 47S rRNA expression, while PYGO2 protein was localised to the nuclei of tumours as determined by immunohistochemistry. High expression levels of PYGO2 in tumours (n=156) were correlated with BR identified as PSA progression, after 7-year follow-up independent of other traditional risk factors. Most importantly, high PYGO2 levels in intermediate grade tumours suggested increased risk of recurrence over those with negative or weak expression. CONCLUSION: Our data suggest that elevated PYGO2 expression in primary prostate adenocarcinoma is a potential risk factor for BR.

Requirement of Pygopus 2 in breast cancer.

The development of novel therapeutic strategies for breast cancer requires the identification of molecular targets involved in malignancy. Human Pygopus (Pygo)-1 and -2 are recently discovered components of the Wnt signaling pathway required for beta-Catenin/Tcf dependent transcription in embryos and colorectal cancer cells, but the role of these proteins in malignant cell growth and survival has not yet been determined. We report the expression and requirement for proliferation of hPygo2 in breast cancer cells. hPygo2 protein was overexpressed in malignant breast tumors and in the nuclei of five breast cancer cell lines, but was not expressed in the nuclei of non-malignant breast cells. Phosphorothioated antisense oligonucleotides were used to specifically knockdown expression hPygo2 in Mcf-7 and MDA-MB-468 cell lines. hPygo2 was required for the growth, in tissue culture and anchorage-independent assays, of both cell lines and for the expression of the Wnt target gene Cyclin D1. We conclude that hPygo2 is highly expressed in, and required for the growth of breast carcinoma cells.

Selective estrogen receptor modulators and betulinic acid act synergistically to target ERα and SP1 transcription factor dependent Pygopus expression in breast cancer.

AIMS: Estrogen and progesterone hormone receptor (ER and PR) expression in invasive breast cancer predicts response to hormone disruptive therapy. Pygopus2 (hPYGO2) encodes a chromatin remodelling protein important for breast cancer growth and cell cycle progression. The aims of this study were to determine the mechanism of expression of hPYGO2 in breast cancer and to examine how this expression is affected therapeutically. METHODS: hPYGO2 and ER protein expression was examined in a breast tumour microarray by immunohistochemistry. hPYGO2 RNA and protein expression was examined in ER+ and ER- breast cancer cell lines in the presence of selective estrogen hormone receptor modulator drugs and the specificity protein-1 (SP1) inhibitor, betulinic acid (BA). The effects of these drugs on the ability for ER and SP1 to bind the hPYGO2 promoter and affect cell cycle progression were studied using chromatin immunoprecipitation assays. RESULTS: hPYGO2 was expressed in seven of eight lines and in nuclei of 98% of 65 breast tumours, including 3 Ductal carcinoma in situ and 62 invasive specimens representing ER-negative (22%) and ER-positive (78%) cases. Treatment with either 4-Hydroxytamoxifen (OHT) or fulvestrant reduced hPYGO2 mRNA 10-fold and protein 5-10-fold within 4 h. Promoter analysis indicated an ER/SP1 binding site at nt -225 to -531 of hPYGO2. SP1 RNA interference and BA reduced hPYGO2 protein and RNA expression by fivefold in both ER- and ER+ cells. Further attenuation was achieved by combining BA and 4-OHT resulting in eightfold reduction in cell growth. CONCLUSIONS: Our findings reveal a mechanistic link between hormone signalling and the growth transcriptional programme. The activation of its expression by ERα and/or SP1 suggests hPYGO2 as a theranostic target for hormone therapy responsive and refractory breast cancer.