cAMP Response Element-Binding Protein Deficiency Allows for Increased Neurogenesis and a Rapid Onset of Antidepressant Response

cAMP response element-binding protein (CREB) has been implicated in the molecular and cellular mechanisms of chronic antidepressant (AD) treatment, although its role in the behavioral response is unclear. CREB-deficient (CREBαΔ mutant) mice demonstrate an antidepressant phenotype in the tail suspension test (TST) and forced-swim test. Here, we show that, at baseline, CREBαΔ mutant mice exhibited increased hippocampal cell proliferation and neurogenesis compared with wild-type (WT) controls, effects similar to those observed in WT mice after chronic desipramine (DMI) administration. Neurogenesis was not further augmented by chronic DMI treatment in CREBαΔ mutant mice. Serotonin depletion decreased neurogenesis in CREBαΔ mutant mice toWTlevels, which correlated with a reversal of the antidepressant phenotype in the TST. This effect was specific for the reversal of the antidepressant phenotype in these mice, because serotonin depletion did not alter a baseline anxiety-like behavior in CREB mutant mice. The response to chronic AD treatment in the novelty-induced hypophagia (NIH) test may rely on neurogenesis. Therefore, we used this paradigm to evaluate chronic AD treatment in CREB mutant mice to determine whether the increased neurogenesis in these mice alters their response in the NIH paradigm. Whereas both WT and CREBαΔ mutant mice responded to chronic AD treatment in the NIH paradigm, only CREBαΔ mutant mice responded to acute AD treatment. However, in the elevated zero maze, DMI did not reverse anxiety behavior in mutant mice. Together, these data show that increased hippocampal neurogenesis allows for an antidepressant phenotype as well as a rapid onset of behavioral responses to AD treatment

Age and gender differences in disabling foot pain using different definitions of the manchester foot pain and disability index

Extent: 9p.Background: The Manchester Foot Pain and Disability Index (MFPDI) has been used to determine the prevalence of disabling foot pain in several studies, however there is some debate as to which case definition is most appropriate. The objective of this study was to explore age and gender differences in the proportion of people with disabling foot pain using three different case definitions of the MFPDI and for each individual MFPDI item. Methods: A random sample of 223 participants aged 27 to 90 years (88 males and 135 females) from the North West Adelaide Health Study, who reported having pain, aching or stiffness in either of their feet on most days in the last month, completed the MFPDI by telephone interview. The proportion of people with disabling foot pain was determined using three definitions: (i) Definition A-at least one of the 17 items documented on at least some days in the last month; (ii) Definition B-at least one of the 17 items documented on most/every day(s) in the last month, and; (iii) Definition C-at least one of the ten functional limitation items documented on most/every day(s) in the last month. Cross-tabulations and chi-squared statistics were used to explore differences in responses to the MFPDI items according to age and gender. Results: The proportion of people with disabling foot pain according to each definition was as follows: Definition A (100%), Definition B (95.1%) and Definition C (77.6%). Definition C was most sensitive to age and gender differences. Exploration of individual MFPDI items indicated that age significantly affected both the pain intensity and functional limitation items, with younger people more likely to report their foot pain being worse in the morning, and older people more likely to report functional limitations. Although gender did not influence responses to the personal appearance items, women were more likely report functional limitations than men. Conclusions: Definition C of the MFPDI is more sensitive to age and gender differences in the proportion of people with disabling foot pain, and would therefore seem to be the most appropriate case definition to use in epidemiological studies involving a broad age range of participants.Hylton B Menz, Tiffany K Gill, Anne W Taylor and Catherine L Hil

Factor structure and validity of the shoulder pain and disability index in a population-based study of people with shoulder symptoms

Background: The Shoulder Pain and Disability Index (SPADI) is a self-administered questionnaire that aims to measure pain and disability associated with shoulder disease. The aim of the present study was to investigate the construct validity and factor structure of the SPADI in a population-based study of patients with self-reported chronic shoulder symptoms. Methods: The North West Adelaide Health Study is a representative longitudinal cohort study of people aged 18 years and over. The original sample was randomly selected and recruited by telephone interview. Overall, 3 206 participants returned to the clinic during the second stage (2004-2006) and were asked to report whether they had pain, aching or stiffness on most days in either of their shoulders. Data was also collected on body mass index and shoulder range of motion (ROM) and demographic factors. The SPADI (numeric rating scale) was administered to participants with shoulder symptoms. Principal components factor analysis, with varimax rotation of factor loadings, was used to assess subscale structure of SPADI. Correlations between the SPADI, shoulder ROM and SF-36 were performed. Results: Overall, 22.3% of participants indicated that they had pain, aching or stiffness in either of their shoulders. SPADI results were available for 588 of participants with current shoulder symptoms. The internal consistency of the SPADI subscales were high (Cronbach's alpha > 0.92). Two factors, explaining 61.4% of the total variance were extracted by factor analysis. These were interpreted as disability and pain respectively. There was a strong negative correlation between SPADI disability subscale scores and shoulder range of motion. SPADI disability, but not pain, subscale scores were correlated with age. Conclusions: The SPADI is a valid measure to assess pain and disability in people with shoulder pain in a population-based study. In this setting, the SPADI had a bidimensional structure with both pain and disability subscales.Catherine L Hill, Susan Lester, Anne W Taylor, Michael E Shanahan, Tiffany K Gil

Prevalence and correlates of foot pain in a population-based study: the North West Adelaide health study

Background: Few population-based studies have examined the prevalence of foot pain in thegeneral community. The aims of this study were therefore to determine the prevalence, correlatesand impact of foot pain in a population-based sample of people aged 18 years and over living in the northwest region of Adelaide, South Australia.Methods: The North West Adelaide Health Study is a representative longitudinal cohort study ofn = 4,060 people randomly selected and recruited by telephone interview. The second stage of datacollection on this cohort was undertaken between mid 2004 and early 2006. In this phase,information regarding the prevalence of musculoskeletal conditions was included. Overall, n = 3,206 participants returned to the clinic during the second visit, and as part of the assessment were asked to report whether they had pain, aching or stiffness on most days in either of their feet. Data were also collected on body mass index (BMI); major medical conditions; other joint symptoms and health-related quality of life (the Medical Outcomes Study Short Form 36 [SF-36]).Results: Overall, 17.4% (95% confidence interval 16.2 – 18.8) of participants indicated that theyhad foot pain, aching or stiffness in either of their feet. Females, those aged 50 years and over,classified as obese and who reported knee, hip and back pain were all significantly more likely to report foot pain. Respondents with foot pain scored lower on all domains of the SF-36 afteradjustment for age, sex and BMI.Conclusion: Foot pain affects nearly one in five of people in the community, is associated withincreased age, female sex, obesity and pain in other body regions, and has a significant detrimental impact on health-related quality of life.Catherine L Hill, Tiffany K Gill, Hylton B Menz and Anne W Taylo

Increased Incidence of Vestibular Disorders in Patients With SARS-CoV-2

OBJECTIVE: Determine the incidence of vestibular disorders in patients with SARS-CoV-2 compared to the control population. STUDY DESIGN: Retrospective. SETTING: Clinical data in the National COVID Cohort Collaborative database (N3C). METHODS: Deidentified patient data from the National COVID Cohort Collaborative database (N3C) were queried based on variant peak prevalence (untyped, alpha, delta, omicron 21K, and omicron 23A) from covariants.org to retrospectively analyze the incidence of vestibular disorders in patients with SARS-CoV-2 compared to control population, consisting of patients without documented evidence of COVID infection during the same period. RESULTS: Patients testing positive for COVID-19 were significantly more likely to have a vestibular disorder compared to the control population. Compared to control patients, the odds ratio of vestibular disorders was significantly elevated in patients with untyped (odds ratio [OR], 2.39; confidence intervals [CI], 2.29-2.50; CONCLUSIONS: The incidence of vestibular disorders differed between COVID-19 variants and was significantly elevated in COVID-19-positive patients compared to the control population. These findings have implications for patient counseling and further research is needed to discern the long-term effects of these findings

Federated learning enables big data for rare cancer boundary detection.

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing

Author Correction: Federated learning enables big data for rare cancer boundary detection.

10.1038/s41467-023-36188-7NATURE COMMUNICATIONS14

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common