Attribution of neuropsychiatric symptoms and prioritisation of evidence in the diagnosis of neuropsychiatric lupus: mixed methods analysis of patient and clinician perspectives from the international INSPIRE study.

OBJECTIVE: Neuropsychiatric lupus (NPSLE) is challenging to diagnose. Many neuropsychiatric symptoms, such as headache and hallucinations, cannot be verified by tests or clinician assessment. We investigated prioritisations of methods for diagnosing NPSLE and attributional views. METHODS: Thematic and comparative analyses were used to investigate how clinicians prioritise sources of evidence from a 13-item list, and explore discordances in clinician and patient perspectives on attribution. RESULTS: We identified high levels of variability and uncertainty in clinicians' assessments of neuropsychiatric symptoms in SLE patients. In attributional decisions, clinicians (surveys n = 400, interviews n = 50) ranked clinicians' assessments above diagnostic tests (many of which they reported were often unenlightening in NPSLE). Clinicians ranked patient opinion of disease activity last, and 46% of patients reported never/rarely having been asked if their SLE was flaring, despite experienced patients often having "attributional insight". SLE Patients (surveys n = 676, interviews n = 27) estimated higher attributability of neuropsychiatric symptoms to the direct effects of SLE on the nervous system than clinicians (p < 0.001 for all symptoms excluding mania), and 24% reported that their self-assessment of disease activity was never/rarely concordant with their clinicians. Reports of misattributions were common, particularly of non-verifiable diffuse symptoms. Terminology differed between clinicians and influenced attribution estimates. CONCLUSION: NPSLE diagnostic tests and clinician assessments have numerous limitations, particularly in detecting diffuse neuropsychiatric symptoms that can be directly attributable and benefit from immunosuppression. Our findings suggest that incorporating patient attributional insights-although also subject to limitations-may improve attribution decision-making. Consensus regarding terminology and interpretations of "direct attributability" is required.

Window of opportunity treatment in breast cancer.

Window of opportunity therapies, which involve short-term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone-receptor positive breast cancer, a 2-week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision-making regarding treatment options. Changes in short-term biomarker endpoints such as cell proliferation measured by Ki-67 can act as surrogate markers of long-term outcomes. Paired tissues obtained pre- and post-investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.

Comorbidities Rather Than Age Are Associated With the Use of Immunomodulators in Elderly-onset Inflammatory Bowel Disease.

BACKGROUND AND AIM: The use of immunomodulators (IMs) is often avoided in elderly patients with inflammatory bowel disease (IBD) due to concerns about complications. Our aim is to compare the use of IMs in elderly and younger patients with Crohn's disease (CD) or ulcerative colitis (UC) and identify markers that predict their use. METHODS: In this retrospective cohort study, patients diagnosed with IBD from 1970 to 2009 were recruited from the "Sydney IBD Cohort." Patients diagnosed at age 60 years old or older and between 16 and old 40 years were classified as "elderly-onset" and "young-onset" respectively. RESULTS: A total of 255 elderly-onset patients (115 CD, 140 UC) and 1244 young-onset patients (657 CD, 587 UC) were recruited. Most elderly-onset patients had colonic CD (61.4%), whereas young-onset patients had predominantly ileocolonic CD (42.8%, P < 0.0001). Left-sided UC was the most common disease localization for both elderly-onset (52.1%) and young-onset patients (42.2%, P = 0.013). The cumulative probability of IM exposure at 5 years post-diagnosis was significantly less in elderly-onset patients compared with young-onset patients for CD (20.0% vs 33.4%, P = 0.0002) and UC (7.8% vs 13.4%, P = 0.0007). Age at diagnosis was not associated with the time to IMs introduction. Charlson Comorbidity Index was shown to delay IM introduction in CD (hazard ratio [HR] 0.863; 95% CI, 0.787-0.946; P = 0.002) and UC (HR 0.807; 95% CI, 0.711-0.917; P = 0.001). Early IM use was associated with reduced need for abdominal and perianal surgery in CD (HR 0.177; 95% CI, 0.089-0.351; P < 0.0001). CONCLUSIONS: Comorbidity and not age at diagnosis is associated with IM introduction. Early IM is associated with reduced surgery in both young- and elderly-onset CD but not UC.

Early use of thiopurines or methotrexate reduces major abdominal and perianal surgery in Crohn's disease.

BACKGROUND: Earlier introduction of immunomodulators (IM) thiopurine or methotrexate is advocated to improve Crohn's disease (CD) outcomes, but whether abdominal surgery can be prevented remains controversial. METHODS: A specialist-referred cohort of CD was recruited from 1970 to 2009. Early IM use was defined as commencement of azathioprine or methotrexate within 3 years of CD diagnosis and adherence of at least 6 months. Propensity score matching was conducted to correct for confounders influencing early IM introduction. Outcomes of interest were rates of initial and recurrent major abdominal surgery for CD and their predictive factors. RESULTS: A total of 1035 consecutive patients with CD (13,061 patient-years) were recruited. The risk of first and recurrent major abdominal surgery at 1, 5, and 10 years were 17.5%, 28.4%, and 39.5% and 5.9%, 19.0%, and 33.3%, respectively. Early IM use increased over time from 1.3% to 55.3% (P < 0.0001) and was a significant independent predictor of lower rates of initial abdominal surgery (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.35-0.69), recurrent abdominal surgery (HR, 0.44; 95% CI, 0.25-0.79) and perianal surgery (HR, 0.30; 95% CI, 0.16-0.56). Using propensity score matching, early IM significantly reduced surgical rates (HR, 0.54; 95% CI, 0.37-0.79). Number needed to treat to prevent a surgical event at 5 years from diagnosis and after initial surgery was 6.99 (95% CI, 5.34-11.95) and 8.59 (95% CI, 6.26-23.93), respectively. CONCLUSIONS: Early IM use with thiopurines or methotrexate was significantly associated with the reduced need for abdominal and perianal surgery in CD.

Human papillomavirus type 16 E1 E4-induced G2 arrest is associated with cytoplasmic retention of active Cdk1/cyclin B1 complexes.

Human papillomavirus type 16 (HPV16) can cause cervical cancer. Expression of the viral E1 E4 protein is lost during malignant progression, but in premalignant lesions, E1 E4 is abundant in cells supporting viral DNA amplification. Expression of 16E1 E4 in cell culture causes G2 cell cycle arrest. Here we show that unlike many other G2 arrest mechanisms, 16E1 E4 does not inhibit the kinase activity of the Cdk1/cyclin B1 complex. Instead, 16E1 E4 uses a novel mechanism in which it sequesters Cdk1/cyclin B1 onto the cytokeratin network. This prevents the accumulation of active Cdk1/cyclin B1 complexes in the nucleus and hence prevents mitosis. A mutant 16E1 E4 (T22A, T23A) which does not bind cyclin B1 or alter its intracellular location fails to induce G2 arrest. The significance of these results is highlighted by the observation that in lesions induced by HPV16, there is evidence for Cdk1/cyclin B1 activity on the keratins of 16E1 E4-expressing cells. We hypothesize that E1 E4-induced G2 arrest may play a role in creating an environment optimal for viral DNA replication and that loss of E1 E4 expression may contribute to malignant progression.

Overseas-based online pharmacies: a source of supply for illicit drug users?

Overseas-based online pharmacies dispense prescription medications without a prescription, thus creating an alternative source of pharmaceuticals for people using illicit drugs. Health professionals need to be aware of this new drug source, which may change the rates and patterns of illicit drug use in Australia. Because of the nature of the Internet, this issue needs to be dealt with at both an international and a national level.

Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers.

The productive cycle of human papillomaviruses (HPVs) can be divided into discrete phases. Cell proliferation and episomal maintenance in the lower epithelial layers are followed by genome amplification and the expression of capsid proteins. These events, which occur in all productive infections, can be distinguished by using antibodies to viral gene products or to surrogate markers of their expression. Here we have compared precancerous lesions caused by HPV type 16 (HPV16) with lesions caused by HPV types that are not generally associated with human cancer. These include HPV2 and HPV11, which are related to HPV16 (supergroup A), as well as HPV1 and HPV65, which are evolutionarily divergent (supergroups E and B). HPV16-induced low-grade squamous intraepithelial lesions (CIN1) are productive infections which resemble those caused by other HPV types. During progression to cancer, however, the activation of late events is delayed, and the thickness of the proliferative compartment is progressively increased. In many HPV16-induced high-grade squamous intraepithelial lesions (CIN3), late events are restricted to small areas close to the epithelial surface. Such heterogeneity in the organization of the productive cycle was seen only in lesions caused by HPV16 and was not apparent when lesions caused by other HPV types were compared. By contrast, the order in which events in the productive cycle were initiated was invariant and did not depend on the infecting HPV type or the severity of disease. The distribution of viral gene products in the infected cervix depends on the extent to which the virus can complete its productive cycle, which in turn reflects the severity of cervical neoplasia. It appears from our work that the presence of such proteins in cells at the epithelial surface allows the severity of the underlying disease to be predicted and that markers of viral gene expression may improve cervical screening.

Life cycle heterogeneity in animal models of human papillomavirus-associated disease.

Animal papillomaviruses are widely used as models to study papillomavirus infection in humans despite differences in genome organization and tissue tropism. Here, we have investigated the extent to which animal models of papillomavirus infection resemble human disease by comparing the life cycles of 10 different papillomavirus types. Three phases in the life cycles of all viruses were apparent using antibodies that distinguish between early events, the onset of viral genome amplification, and the expression of capsid proteins. The initiation of these phases follows a highly ordered pattern that appears important for the production of virus particles. The viruses examined included canine oral papillomavirus, rabbit oral papillomavirus (ROPV), cottontail rabbit papillomavirus (CRPV), bovine papillomavirus type 1, and human papillomavirus types 1, 2, 11, and 16. Each papillomavirus type showed a distinctive gene expression pattern that could be explained in part by differences in tissue tropism, transmission route, and persistence. As the timing of life cycle events affects the accessibility of viral antigens to the immune system, the ideal model system should resemble human mucosal infection if vaccine design is to be effective. Of the model systems examined here, only ROPV had a tissue tropism and a life cycle organization that resembled those of the human mucosal types. ROPV appears most appropriate for studies of the life cycles of mucosal papillomavirus types and for the development of prophylactic vaccines. The persistence of abortive infections caused by CRPV offers advantages for the development of therapeutic vaccines.