Item response theory analysis of cognitive tests in people with dementia:a systematic review

BACKGROUND: Performance on psychometric tests is key to diagnosis and monitoring treatment of dementia. Results are often reported as a total score, but there is additional information in individual items of tests which vary in their difficulty and discriminatory value. Item difficulty refers to an ability level at which the probability of responding correctly is 50%. Discrimination is an index of how well an item can differentiate between patients of varying levels of severity. Item response theory (IRT) analysis can use this information to examine and refine measures of cognitive functioning. This systematic review aimed to identify all published literature which had applied IRT to instruments assessing global cognitive function in people with dementia. METHODS: A systematic review was carried out across Medline, Embase, PsychInfo and CINHAL articles. Search terms relating to IRT and dementia were combined to find all IRT analyses of global functioning scales of dementia. RESULTS: Of 384 articles identified four studies met inclusion criteria including a total of 2,920 people with dementia from six centers in two countries. These studies used three cognitive tests (MMSE, ADAS-Cog, BIMCT) and three IRT methods (Item Characteristic Curve analysis, Samejima’s graded response model, the 2-Parameter Model). Memory items were most difficult. Naming the date in the MMSE and memory items, specifically word recall, of the ADAS-cog were most discriminatory. CONCLUSIONS: Four published studies were identified which used IRT on global cognitive tests in people with dementia. This technique increased the interpretative power of the cognitive scales, and could be used to provide clinicians with key items from a larger test battery which would have high predictive value. There is need for further studies using IRT in a wider range of tests involving people with dementia of different etiology and severity

GNASR201C Induces Pancreatic Cystic Neoplasms in Mice That Express Activated KRAS by Inhibiting YAP1 Signaling

Background & aimsMutations at hotspots in GNAS, which encodes stimulatory G-protein, α subunits, are detected in approximately 60% of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. We generated mice with KRAS-induced IPMNs that also express a constitutively active form of GNAS in pancreas and studied tumor development.MethodsWe generated p48-Cre; LSL-KrasG12D; Rosa26R-LSL-rtTA-TetO-GnasR201C mice (Kras;Gnas mice); pancreatic tissues of these mice express activated KRAS and also express a mutant form of GNAS (GNASR201C) upon doxycycline administration. Mice that were not given doxycycline were used as controls, and survival times were compared by Kaplan-Meier analysis. Pancreata were collected at different time points after doxycycline administration and analyzed by histology. Pancreatic ductal adenocarcinomas (PDACs) were isolated from mice and used to generate cell lines, which were analyzed by reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and colony formation and invasion assays. Full-length and mutant forms of yes-associated protein (YAP) were expressed in PDAC cells. IPMN specimens were obtained from 13 patients with IPMN undergoing surgery and analyzed by immunohistochemistry.ResultsAll Kras;Gnas mice developed pancreatic cystic lesions that resemble human IPMNs; the grade of epithelial dysplasia increased with time. None of the control mice developed cystic lesions. Approximately one third of Kras;Gnas mice developed PDACs at a median of 30 weeks after doxycycline administration, whereas 33% of control mice developed PDACs. Expression of GNASR201C did not accelerate the development of PDACs compared with control mice. However, the neoplasms observed in Kras;Gnas mice were more differentiated, and expressed more genes associated with ductal phenotypes, than in control mice. PDACs isolated from Kras;Gnas mice had activation of the Hippo pathway; in cells from these tumors, phosphorylated YAP1 was sequestered in the cytoplasm, and this was also observed in human IPMNs with GNAS mutations. Sequestration of YAP1 was not observed in PDAC cells from control mice.ConclusionsIn mice that express activated KRAS in the pancreas, we found expression of GNASR201C to cause development of more differentiated tumors, with gene expression pattern associated with the ductal phenotype. Expression of mutant GNAS caused phosphorylated YAP1 to be sequestered in the cytoplasm, altering tumor progression

Supplementary information files for "Association between endometriosis and type and age of menopause: a pooled analysis of 279 948 women from five cohort studies"

Supplementary files for article "Association between endometriosis and type and age of menopause: a pooled analysis of 279 948 women from five cohort studies"STUDY QUESTION - What is the association between endometriosis and the type and age of menopause?SUMMARY ANSWER - Women with endometriosis had a 7-fold increased risk of undergoing surgical menopause rather than natural menopause and were more likely to experience premature or early menopause, both surgically and naturally.WHAT IS KNOWN ALREADY - Endometriosis is associated with reduced ovarian reserve, but evidence on its relationship with the type of menopause (surgical vs natural) and timing (especially premature and early menopause) is limited. Women with endometriosis are more likely to undergo hysterectomy and/or oophorectomy (either unilateral or bilateral), but the average age of these surgeries remains unclear.STUDY DESIGN, SIZE, DURATION - The study analysed individual-level data from 279 948 women in five cohort studies conducted in the UK, Australia, Sweden, and Japan between 1996 and 2022.PARTICIPANTS/MATERIALS, SETTING, METHODS - Women whose menopause type and age could not be determined due to premenopausal hysterectomy with ovarian preservation or use of menopausal hormone therapy were excluded. Endometriosis was identified through self-reports and administrative data. Surgical menopause was defined as premenopausal bilateral oophorectomy. Fine–Gray subdistribution hazard models estimated hazard ratios (HRs) for surgical and natural menopause. Age at menopause was determined by the ages at the final menstrual period or bilateral oophorectomy. Linear regression assessed mean differences in menopause age, while multinomial logistic regression estimated odds ratios (ORs) for categorical menopause age: MAIN RESULTS AND THE ROLE OF CHANCE - Endometriosis was identified in 3.7% of women. By the end of follow-up, 7.9% had surgical menopause and 58.2% experienced natural menopause. Using a competing risk model, women with endometriosis had a 7-fold increased risk of surgical menopause (HR: 7.54, 95% CI 6.84, 8.32) and were less likely to experience natural menopause (HR: 0.40, 95% CI 0.33, 0.49). On average, surgical menopause occurred 1.6 years (19 months) earlier (β: −1.59, 95% CI −1.77, −1.42) in women with endometriosis. Among women who experienced natural menopause, it was 0.4 years (5 months) earlier (β: −0.37, 95% CI −0.46, −0.28) for those with endometriosis. Women with endometriosis were twice as likely to experience premature surgical menopause (LIMITATIONS, REASONS FOR CAUTION - This study could not differentiate between subtypes and stages of endometriosis or assess treatments for ovarian endometrioma, which may impact ovarian reserve. Self-reported menopause type and age could introduce recall bias.WIDER IMPLICATIONS OF THE FINDINGS - Given the consistent findings across individual studies, our results are likely to be generalizable to different populations, highlighting the need for tailored management of endometriosis to prevent medically induced or premature menopause. Long-term monitoring of women with endometriosis is recommended, given their elevated risk of surgical menopause and premature or early menopause, which are associated with adverse health outcomes in later life.STUDY FUNDING/COMPETING INTEREST(S) - The InterLACE Consortium is funded by the Australian National Health and Medical Research Council project grant (APP1027196) and Centres of Research Excellence (APP1153420). G.D.M. is funded by the Australian National Health and Medical Research Council Leadership Fellowship (APP2009577). This research is funded in part by the Japan Society for the Promotion of Science (JSPS KAKENHI: 19KK0235, 23KK0167). The authors have no conflict of interest. Where authors are identified as personnel of the International Agency for Research on Cancer or WHO, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer or WHO.TRIAL REGISTRATION NUMBER - N/A.© The Author(s), CC BY 4.0</p