The cost-effectiveness of using a prognosis-tailored strategy model to triage couples with idiopathic infertility for assisted reproduction technology.

OBJECTIVES: To evaluate whether a prognosis-tailored triage of ART for couples with idiopathic infertility by using the Hunault prognostic model can decrease the cost of treatment without compromising the chance of live birth. STUDY DESIGN: This is a retrospective study conducted in an Australian fertility clinic. Couples seeking infertility consultation who were subsequently found to have idiopathic infertility after evaluation were included. We compared the costs per conception leading to live birth of the prognosis-tailored strategy with the immediate ART strategy, which generally reflects the current practice in Australian fertility clinics, over a 24-month period. In the prognosis-tailored strategy, for each couple, the prognosis for natural conception was assessed using the well-established Hunault model. Total cost of treatments were calculated as the sum of typical out-of-pocket and Australian Medicare cost (Australian national insurance scheme). RESULTS: We studied 261 couples. In the prognosis-tailored strategy, the total cost was $2,766,781 and the live birth rate was 63.9%. In contrast, the immediate ART strategy yielded a live birth rate of 64.4% with a total cost of $3,176,845. Implementing the prognosis-tailored strategy using the Hunault model saved $410,064 in total and $1,571 per couple. The incremental cost-effectiveness ratio (ICER) was $341,720 per live birth. CONCLUSION: In couples with idiopathic infertility, assessment of prognosis for natural conception using the Hunault model and delaying ART for 12 months in couples with favourable prognoses can considerably reduce costs without significantly compromising live birth rates.

The predictive value of anti-Müllerian hormone for natural conception leading to live birth in subfertile couples.

RESEARCH QUESTION: What is the predictive value of serum anti-Müllerian hormone (AMH) level for natural conception and its clinical effect on subfertile couples? DESIGN: A retrospective cohort of ovulatory women seeking fertility consultation in a private fertility clinic. Couples who had an immediate indication for IVF were excluded. All natural conceptions leading to live birth before the start of assisted reproductive technology were followed within 12 months of the initial consultation. A prediction model was developed by updating the Hunault model with serum AMH to predict the probabilities of achieving a natural conception leading to live birth. RESULTS: A total of 325 couples were included in the final analysis. The estimated cumulative proability of achieving natural conception leading to live birth within 12 months was 20.9% (95% CI 12.9% to 28.2%). The categorical net reclassification improvement of AMH is 7.6%. For couples with a predicted chance of natural conception changed from poor (<30%) by the reference model to good (≥30%) by the updated model, the cumulative natural conception rate leading to live birth was 52.0%. For couples who had predicted chance of natural conception changed from good to poor by the updated model, the rate was 18.9%. CONCLUSIONS: The addition of serum AMH to the routine fertility work-up may improve prognosis-based treatment policy and help to prevent unnecessary costs and stress for couples. Prospective validation of the updated model with AMH is required before clinical application.

Average lifespan shortened due to breast cancer in Australia, 1990-2015.

BACKGROUND: This short report aims to investigate changes in lifespan of Australian women with breast cancer using the novel average lifespan shortened (ALSS) measure METHODS: We obtained the mortality data of Australian women with breast cancer from the World Health Organization mortality database for the 1990-2015 period. We calculated the age-standardized rate (ASR) according to the World Standard Population. We estimated the ALSS as a ratio of years of life lost in relation to the expected lifespan to examine changes in lifespan of Australian women with breast cancer over the study period. RESULTS: Over a 25-year period, the ASR of breast cancer deaths decreased from 20.5 to 12.6 deaths per 100,000 women. We observed a decline in ALSS values from 24.0% of their lifespan in 1990 to 22.0% in 2015. CONCLUSION: The novel ALSS measure indicates an improvement of two percentage points in the lifespan of Australian women with breast cancer over the study.

Promoting Safety: Behavioural Emergency Response during the COVID-19 Pandemic.

During the ongoing COVID-19 pandemic, patients with and without pre-existing mental health diagnoses will either be admitted to the hospital as patients under investigation for COVID-19 or patients positive for COVID-19. A safe and timely response is required for patients exhibiting escalating behaviours (e.g., responsive, agitated and/or aggressive behaviours) to prevent harm to the patient, nearby patients and staff. In this paper, we report on a new protocol that has been implemented throughout our institution to address Code White calls for escalating behaviours during the COVID-19 pandemic. This procedure uses a least restraint-based philosophy for the management of an escalating situation, involves the use of an interprofessional team of healthcare providers (including mental health clinicians) and security team members and accounts for the need for personal protective equipment. We believe that other hospitals could benefit from knowing about this approach as a strategy to improve patient care and diminish disease transmission.

Evaluation of the expression levels of BRAFV600E mRNA in primary tumors of thyroid cancer using an ultrasensitive mutation assay.

BACKGROUND: The BRAFV600E gene encodes for the mutant BRAFV600E protein, which triggers downstream oncogenic signaling in thyroid cancer. Since most currently available methods have focused on detecting BRAFV600E mutations in tumor DNA, there is limited information about the level of BRAFV600E mRNA in primary tumors of thyroid cancer, and the diagnostic relevance of these RNA mutations is not known. METHODS: Sixty-two patients with thyroid cancer and non-malignant thyroid disease were included in the study. Armed with an ultrasensitive technique for mRNA-based mutation analysis based on a two step RT-qPCR method, we analysed the expression levels of the mutated BRAFV600E mRNA in formalin-fixed paraffin-embedded samples of thyroid tissues. Sanger sequencing for detection of BRAFV600E DNA was performed in parallel for comparison and normalization of BRAFV600E mRNA expression levels. RESULTS: The mRNA-based mutation detection assay enables detection of the BRAFV600E mRNA transcripts in a 10,000-fold excess of wildtype BRAF counterparts. While BRAFV600E mutations could be detected by Sanger sequencing in 13 out of 32 malignant thyroid cancer FFPE tissue samples, the mRNA-based assay detected mutations in additionally 5 cases, improving the detection rate from 40.6 to 56.3%. Furthermore, we observed a surprisingly large, 3-log variability, in the expression level of the BRAFV600E mRNA in FFPE samples of thyroid cancer tissue. CONCLUSIONS: The expression levels of BRAFV600E mRNA was characterized in the primary tumors of thyroid cancer using an ultrasensitive mRNA-based mutation assay. Our data inspires further studies on the prognostic and diagnostic relevance of the BRAFV600E mRNA levels as a molecular biomarker for the diagnosis and monitoring of various genetic and malignant diseases.

No Tissue Expression of KRAS or BRAF Mutations in 61 Adult Patients Treated for Esophageal Atresia in Early Childhood.

BACKGROUND: Previous studies have reported an association among esophageal atresia (EA), Barrett's esophagus, and esophageal adenocarcinoma later in life. OBJECTIVE: The objective of the article is to evaluate KRAS and BRAF mutations as potential genetic markers for early detection of malignant transformation, we used an ultrasensitive technique to detect tissue expression of KRAS and BRAF mutations in endoscopic biopsies from 61 adult patients under follow-up after treatment for EA. MATERIALS AND METHODS: RNA was extracted from 112 fresh-frozen endoscopic tissue biopsies from 61 adult patients treated for EA in early childhood. RNA was reverse transcribed using the extendable blocking probe reverse transcription method. KRAS codons 12 and 13, as well as BRAF mutations were detected by quantitative polymerase chain reaction. RESULTS: No mutations of KRAS codon 12, KRAS codon 13, or BRAF were found in 112 endoscopic biopsy samples from 61 patients. CONCLUSION: Despite the presence of histological findings indicating long-standing gastroesophageal reflux in 25%, as well as symptomatic gastroesophageal reflux in more than 40%, there was no detectable tissue expression of KRAS or BRAF mutations in this cohort of patients.

MAPK inhibitors induce serine peptidase inhibitor Kazal type 1 (SPINK1) secretion in BRAF V600E-mutant colorectal adenocarcinoma.

The mitogen-activated protein kinase (MAPK) pathway plays a central role in colorectal cancers (CRC). In particular, BRAF V600E-mutant tumors, which represent around 10% of CRCs, are refractory to current therapies. Overexpression and secretion of serine peptidase inhibitor Kazal type 1 (SPINK1) are observed in around 50% of CRCs, and its serum level can be used as a biomarker for poor prognosis. Utilizing a recently developed extendable blocking probe assay, we analyzed the BRAF mutation status in a CRC patient cohort (N = 571) using tissue-derived RNA as the starting material. From the same RNA samples, we measured the relative SPINK1 expression levels using a quantitative real-time PCR method. Expression of mutant BRAF V600E correlated with poor prognosis, as did low expression of SPINK1 mRNA. Further, BRAF V600E correlated negatively with SPINK1 levels. In order to investigate the effect of MAPK pathway-targeted therapies on SPINK1 secretion, we conducted in vitro studies using both wild-type and V600E CRC cell lines. BRAF inhibitor vemurafenib, and subsequent MAPK pathway inhibitors trametinib and SCH772984, significantly increased SPINK1 secretion in V600E CRC cell lines Colo205 and HT-29 with a concomitant decrease in trypsin-1 and -2 secretion. Notably, no SPINK1 increase or trypsin-1 decrease was observed in BRAF wild-type CRC cell line Caco-2 in response to MAPK pathway inhibitors. In further mechanistic studies, we observed that only trametinib was able to diminish completely both MEK and ERK phosphorylation in the V600E CRC cells. Furthermore, the key regulator of integrated stress response, activating transcription factor 4 (ATF-4), was downregulated both at mRNA and at protein level in response to trametinib treatment. In conclusion, these data suggest that sustained inhibition of not only MAPK pathway activation, but also ATF-4 and trypsin, might be beneficial in the therapy of BRAF V600E-mutant CRC and that SPINK1 levels may serve as an indicator of therapy response.

The psychiatry-integrated nurse practitioner role in hemodialysis: An opportunity to provide nurse practitioner care between the interface of psychiatry and hemodialysis.

The mental health of patients living with end-stage kidney disease (ESKD) is an important aspect of their care. According to national survey data, depressive disorders affect about 9% of the North American population (Kessler, Chiu, Demler, Merikangas, & Walters, 2005). A review of psychological distress and depression across the spectrum of chronic kidney disease indicates that the prevalence of depression in ESKD is reported to be about four times that of the general population and it is associated with adverse outcomes including low quality-of-life ratings, graft failure, and death after renal transplantation (Zalai, Szeifert, & Novak, 2012). At St. Michael's Hospital (SMH), patients on hemodialysis (HD) requiring psychiatry consultation had traditionally been referred to a dedicated outpatient psychiatrist. This presented challenges around access to psychiatry assessment and follow-up, as patients were reluctant to attend appointments outside of HD visits. The team recognized these challenges and addressed them through the introduction of the Medical Psychiatry NP (MP NP) role, as the point-of-care consultant in HD.

Comparison Between a Typical Undergraduate Psychiatry Program in China and Canada--an Approach to Inform Psychiatry Education Reform in China.

OBJECTIVE: Psychiatry as a field and undergraduate psychiatry education (UPE) specifically have historically been in the periphery of medicine in China, unlike the relatively central role they occupy in the West. During the current economic reform, Chinese undergraduate medical education (UME) is undergoing significant changes and standardization under the auspices of the national accreditation body. A comparative study, using Bereday's comparative education methodology and Feldmann's evaluative criteria as theoretical frameworks, to gain understanding of the differences and similarities between China and the West in terms of UPE can contribute to the UME reform, and specifically UPE development in China, and promote cross-cultural understanding. METHOD: The authors employed multi-sourced information to perform a comparative study of UPE, using the University of Toronto as a representative of the western model and Guangxi Medical University, a typical program in China, as the Chinese counterpart. RESULTS: Key contrasts are numerous; highlights include the difference in age and level of education of the entrants to medical school, centrally vs. locally developed UPE curriculum, level of integration with the rest of medical education, visibility within the medical school, adequacy of teaching resources, amount of clinical learning experience, opportunity for supervision and mentoring, and methods of student assessment. CONCLUSIONS: Examination of the existing, multi-sourced information reveals some fundamental differences in the current UPE between the representative Chinese and western programs, reflecting historical, political, cultural, and socioeconomic circumstances of the respective settings. The current analyses show some areas worthy of further exploration to inform Chinese UPE reform. The current research is a practical beginning to the development of a deeper collaborative dialogue about psychiatry and its educational underpinnings between China and the West.

Extendable blocking probe in reverse transcription for analysis of RNA variants with superior selectivity.

Here we provide the first strategy to use a competitive Extendable Blocking Probe (ExBP) for allele-specific priming with superior selectivity at the stage of reverse transcription. In order to analyze highly similar RNA variants, a reverse-transcriptase primer whose sequence matches a specific variant selectively primes only that variant, whereas mismatch priming to the alternative variant is suppressed by virtue of hybridization and subsequent extension of the perfectly matched ExBP on that alternative variant template to form a cDNA-RNA hybrid. This hybrid will render the alternative RNA template unavailable for mismatch priming initiated by the specific primer in a hot-start protocol of reverse transcription when the temperature decreases to a level where such mismatch priming could occur. The ExBP-based reverse transcription assay detected BRAF and KRAS mutations in at least 1000-fold excess of wild-type RNA and detection was linear over a 4-log dynamic range. This novel strategy not only reveals the presence or absence of rare mutations with an exceptionally high selectivity, but also provides a convenient tool for accurate determination of RNA variants in different settings, such as quantification of allele-specific expression.

Psychiatry clerkship core curriculum renewal: assessing the shift to larger-group learning.

BACKGROUND/OBJECTIVE: A curriculum renewal of the third-year psychiatry clerkship rotation at University of Toronto Medical School resulted in a shift from case-based, small-group teaching at multiple teaching sites to the delivery of core material in a larger-group format. The authors examine the effects of this change in curriculum delivery. METHOD: Student examination performance and student evaluations of the clerkship rotation and teaching were compared for the years before and after adoption of the updated, larger-group format curriculum. RESULTS: Student examination performance was unchanged, comparing those who participated in small-group seminars versus those receiving larger-group core teaching. Student evaluations of the curriculum as a whole and of the core teaching were also unchanged, other than more negative evaluation of the course organization in the year immediately after implementation of the new curriculum. CONCLUSIONS: Delivering core curriculum in larger- versus smaller-group format did not have any discernible effect on student psychiatry clerkship performance, and overall student assessment of the rotation remained largely positive. The involvement of highly-rated teachers and the higher number of uninterrupted clinical days may balance out with the trend for students to generally prefer small-group to larger-group learning. Ongoing evaluation and refinement of the psychiatry clerkship experience and core curriculum will be crucial to continued assurance of a high-quality learning experience for our medical students.

Teaching to Teach in Toronto.

OBJECTIVE: The training objectives for postgraduate education in the United States and Canada both state that teaching skills should be formally developed during training. This article reviews the development of the Teaching-to-Teach program at the University of Toronto Department of Psychiatry, the current curriculum, evaluation, and future directions of the program. The authors highlight some of the challenges encountered and discuss ideas for implementation of similar programs in diverse training settings. METHODS: A Teaching-to-Teach curriculum was developed with separate tracks for junior and senior residents. Topics covered include one-to-one teaching, the one-minute clinical preceptor model, challenging teaching scenarios, and providing effective feedback. RESULTS: In 2007, 100% of residents who responded to an evaluation questionnaire agreed or strongly agreed that the topics covered were relevant, and in 2008, 92% of respondents agreed that topics were relevant. In 2007, all respondents agreed or strongly agreed that they felt more prepared to teach. In 2008, 85% of respondents felt more prepared to teach. In 2007, all respondents felt that the amount of teaching was good or too little, but in 2008, 46% of respondents felt there was too much teaching. CONCLUSION: The large size of the University of Toronto psychiatry program may make this curriculum difficult to generalize to smaller training sites. The use of online modules, collaboration between programs, or individual teaching electives may be other ways of implementing a teaching to teach program. Overall, our curriculum was well-received by trainees and they felt better prepared to take on the role of teacher after participating.