Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19.

BACKGROUND: We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world's largest international, standardized data sets concerning hospitalized patients. METHODS: The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). RESULTS: Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60 years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. CONCLUSIONS: Age was the strongest determinant of risk of death, with a ∼30-fold difference between the oldest and youngest groups; each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death. The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death.

Clinical utility of a serum biomarker panel in distinguishing prostate cancer from benign prostate hyperplasia.

Prostate-specific antigen (PSA) screening for prostate cancer (PCa) is limited by the lack of specificity but is further complicated in the benign prostatic hyperplasia (BPH) population which also exhibit elevated PSA, representing a clear unmet need to distinguish BPH from PCa. Herein, we evaluated the utility of FLNA IP-MRM, age, and prostate volume to stratify men with BPH from those with PCa. Diagnostic performance of the biomarker panel was better than PSA alone in discriminating patients with negative biopsy from those with PCa, as well as those who have had multiple prior biopsies (AUC 0.75 and 0.87 compared to AUC of PSA alone 0.55 and 0.57 for patients who have had single compared to multiple negative biopsies, respectively). Of interest, in patients with PCa, the panel demonstrated improved performance than PSA alone in those with Gleason scores of 5-7 (AUC 0.76 vs. 0.56) and Gleason scores of 8-10 (AUC 0.74 vs. 0.47). With Gleason scores (8-10), the negative predictive value of the panel is 0.97, indicating potential to limit false negatives in aggressive cancers. Together, these data demonstrate the ability of the biomarker panel to perform better than PSA alone in men with BPH, thus preventing unnecessary biopsies.

Predictors of Bicuspid Aortic Valve-Associated Aortopathy in Childhood: A Report From the MIBAVA Consortium.

BACKGROUND: Bicuspid aortic valve (BAV) is the most prevalent congenital heart defect affecting 1% to 2% of the population. It is associated with ascending aorta dilatation. Valve morphology, aortic stenosis (AS), and aortic insufficiency (AI) have been proposed as potential risk factors; however, evaluating their role is difficult, as these factors are inherently related. The aim of this study was to determine whether BAV morphology and dysfunction are independent determinants for ascending aorta dilatation in pediatric patients. METHODS: A multicenter, retrospective, cross-sectional study of pediatric BAV patients followed since 2004 was performed. Imaging data were assessed for BAV morphology, severity of AS and AI, history of coarctation, and aortic dimensions. Associations were determined using multivariable regression analysis. A subset of patients undergoing aortic interventions (balloon dilation or Ross) were assessed longitudinally. RESULTS: Data were obtained from 2122 patients (68% male; median age 10.2 years). Fifty percent of patients had ascending aorta dilatation. Right and noncoronary cusp fusion, increasing AS and AI, and older age were independently associated with ascending aorta dilatation. A history of coarctation was associated with less ascending aorta dilatation. In patients with neither AS nor AI, 37% had ascending aorta dilatation (4% severe). No complications related to aortic dilatation occurred in this cohort. Aortic Z scores were determined, and a Z-score calculator was created for this population. CONCLUSIONS: In this large pediatric cohort of patients with BAV, valve morphology, AS, and AI are independently associated with ascending aorta dilatation, suggesting that hemodynamic factors influence aortopathy. However, even in BAVs with no AS or AI, there is significant ascending aorta dilatation independent of valve morphology. Interventions that led to changes in degree of AI and AS did not seem to influence change in aortic dimensions. The current BAV cohort can be used as a reference group for expected changes in aortic dimensions during childhood.

Prevalence and predictors of cannabis use among men receiving androgen-deprivation therapy for advanced prostate cancer.

INTRODUCTION: Prostate cancer patients receiving androgen-deprivation therapy (ADT) often experience a combination of disease symptoms and treatment side effects. The therapeutic use of cannabis to alleviate these side effects has not been studied, despite increasing patient interest. With the increasing availability of cannabis, it is important for clinicians to understand the prevalence, predictors, and perceived benefits of cannabis use among patients with prostate cancer. METHODS: A total of 222 men undergoing ADT were assessed in this two-part study. In part one, the cannabis-use questionnaire was administered to 56 men, probing demographics, usage habits, perspectives, and degrees of symptom relief related to cannabis use. In part two, 191 cryopreserved urine samples were retrieved and analyzed for the presence of tetrahydrocannabidiol (THC) metabolite 11-nor-Δ9-THC-COOH. The respondents were then stratified into two groups, users vs. non-users, and statistical analyses were conducted. RESULTS: Questionnaire data revealed that 23.2% of surveyed men had recently used cannabis. In contrast, 5.8% of men had detectable levels of THC metabolite in their urine. Combined questionnaire and urine data revealed that cannabis users were significantly younger (p=0.003) and had lower testosterone levels (p=0.003) than non-users. The majority of men experiencing common ADT side effects reported some degree of relief following cannabis use. CONCLUSIONS: Cannabis use among men with advanced prostate cancer receiving ADT is more prevalent than in the general population and the majority of other oncological cohorts. Lower testosterone levels and reported therapeutic benefit among cannabis users warrants confirmation in appropriate clinical trials.

Population-Based Analysis Of The Use Of Radium-223 For Bone-Metastatic Castration-Resistant Prostate Cancer In Ontario, And Of Factors Associated With Treatment Completion And Outcome.

INTRODUCTION: Radium-223 (Ra223) prolongs the survival and improves the quality of life of men with metastatic, castration-resistant prostate cancer (mCRPC) to bones. However, compared to other mCRPC therapies, using Ra223 comes with its unique challenges. Hence, we aimed to identify Ra223 utilization patterns under real-world conditions, as well as factors predicting treatment completion and outcome. METHODS: In this retrospective chart analysis, 198 mCRPC patients were identified that had received Ra223 outside of clinical trials or access programs from January 2015 to October 2016 at four cancer centres in Ontario. The main outcomes studied were Ra223 completion rate, reasons for early treatment discontinuation, overall survival, and survival differences in patients completing Ra223 therapy versus patients receiving <6 cycles of Ra223. In addition, patient and disease characteristics were analysed to identify predictors of treatment completion and survival. RESULTS: In this cohort of patients mostly pretreated with abiraterone and/or enzalutamide (92.4%), almost half of which had also received docetaxel (48.5%), the Ra223 completion rate was 46.5%, and the actuarial median survival was 13.3 months. The main reason for early Ra223 discontinuation was disease progression, and Ra223 non-completion was associated with poorer outcome (median survival 8.1 months [6.0-12.2] versus 18.7 months [15.3-22.3] in men completing Ra223, p<0.0001). Lymph node metastases and a high baseline prostate-specific antigen (PSA) were independent predictors of early treatment discontinuation. Multivariable Cox proportional hazards models revealed early Ra223 discontinuation, baseline anemia, high PSA, prior skeletal-related events, visceral metastases, and being referred to another centre for Ra223 therapy as predictors of worse outcome. CONCLUSION: Despite a lower completion rate than observed under clinical trial conditions, the real-world results achieved with Ra223 are encouraging. If prospectively validated, predictive patient and disease characteristics identified in our cohort might become instrumental to identify mCRPC patients likely to complete and to most benefit from Ra223 therapy.

Crying, oral contraceptive use and the menstrual cycle.

BACKGROUND: Crying, a complex neurobiological behavior with psychosocial and communication features, has been little studied in relationship to the menstrual cycle. METHODS: In the Mood and Daily Life study (MiDL), a community sample of Canadian women aged 18-43 years, n=76, recorded crying proneness and crying frequency daily for six months along with menstrual cycle phase information. RESULTS: Crying proneness was most likely during the premenstruum, a little less likely during menses and least likely during the mid-cycle phase, with statistically significant differences although the magnitude of these differences were small. By contrast, actual crying did not differ between the three menstrual cycle phases. Oral contraceptive use did not alter the relationship between menstrual cycle phase and either crying variable. A wide range of menstrual cycle phase - crying proneness patterns were seen with visual inspection of the individual women's line graphs. LIMITATIONS: timing of ovulation was not ascertained. Using a three phase menstrual cycle division precluded separate late follicular and early luteal data analysis. The sample size was inadequate for a robust statistical test of actual crying. CONCLUSIONS: reproductive aged women as a group report feeling more like crying premenstrually but may not actually cry more during this menstrual cycle phase. Individual patterns vary substantially. Oral contraceptive use did not affect these relationships. Suggestions for future research are included.

Sleep quality and the menstrual cycle.

OBJECTIVE: This study aimed to assess the temporal relationship of subjective sleep quality to menstrual cycle phase in a community (non help-seeking) sample of adult women over six months. Previous work has produced contradictory results and often used student samples. PATIENTS/METHODS: This was a cohort study, using daily electronic data collection in the Greater Toronto Area, Ontario, Canada; 76 women aged 18-42 years recruited by random digit telephone dialing, recorded mood, sleep quality, and other health variables on a daily basis for 24 weeks. RESULTS: Using linear mixed models, we assessed the relationship between subjective sleep quality and three menstrual cycle phases (menses, premenstrual and midcycle) over 395 cycles. Premenstrual sleep quality was poorer than during the rest of the cycle, with a mean difference of 1.32 between premenstrual and midcycle reference phase, on a 1-100 quality scale (higher score denotes poorer quality). This difference held when the independent variables of daily exercise and physical health were added to the model; it became non-significant when perceived stress and later, social support were also added to the model. CONCLUSIONS: Sleep quality in adult non-help seeking women is statistically poorer in the premenstruum but the size of the difference is of little clinical significance and was no longer statistically significant with inclusion of the potentially confounding variables, perceived stress and social support.

Mood and the menstrual cycle.

BACKGROUND: Premenstrual mood symptoms are considered common in women, but such prevailing attitudes are shaped by social expectations about gender, emotionality and hormonal influences. There are few prospective, community studies of women reporting mood data from all phases of the menstrual cycle (MC). We aimed (i) to analyze daily mood data over 6 months for MC phase cyclicity and (ii) to compare MC phase influences on a woman's daily mood with that attributable to key alternate explanatory variables (physical health, perceived stress and social support). METHOD: A random sample of Canadian women aged 18-40 years collected mood and health data daily over 6 months, using telemetry, producing 395 complete MCs for analysis. RESULTS: Only half the individual mood items showed any MC phase association; these links were either with the menses phase alone or the menses plus the premenstrual phase. With one exception, the association was not solely premenstrual. The menses-follicular-luteal MC division gave similar results. Less than 0.5% of the women's individual periodogram records for each mood item showed MC entrainment. Physical health, perceived stress and social support were much stronger predictors of mood (p < 0.0001 in each case) than MC phase. CONCLUSIONS: The results of this study do not support the widespread idea of specific premenstrual dysphoria in women. Daily physical health status, perceived stress and social support explain daily mood better than MC phase.

Mood and the menstrual cycle: a review of prospective data studies.

BACKGROUND: The human menstrual cycle (MC) has historically been the focus of myth and misinformation, leading to ideas that constrain women's activities. OBJECTIVES: We wished to examine one pervasive idea, that the MC is a cause of negative mood, by studying the scientific literature as a whole. We briefly reviewed the history of the idea of premenstrual syndrome and undertook a systematic review of quality studies. METHODS: We searched PubMed, PsycINFO, and article bibliographies for published studies using non-help-seeking samples with daily mood data collected prospectively for a minimum of 1 complete MC. We critiqued their methodologies and tabulated the key findings. RESULTS: Of 47 English language studies identified, 18 (38.3%) found no association of mood with any MC phase; 18 found an association of negative mood in the premenstrual phase combined with another MC phase; and only 7 (14.9%) found an association of negative mood and the premenstrual phase. Finally, the remaining 4 studies (8.5%) showed an association between negative mood and a non-premenstrual phase. Considering the only 41 adequately powered studies, the same phase links were reported by 36.6%, 41.5%, and 13.5% of studies, respectively. Their diversity of methods (sampling, instruments, and cycle phase definitions) precluded a meta-analysis. CONCLUSIONS: Taken together, these studies failed to provide clear evidence in support of the existence of a specific premenstrual negative mood syndrome in the general population. This puzzlingly widespread belief needs challenging, as it perpetuates negative concepts linking female reproduction with negative emotionality.

Women's perceptions of influences on their mood.

AIMS: Knowledge of prevailing community ideas about mood determination can guide research about variability in mood. A random sample of urban Canadian women, aged 18-40 years (n = 507), was asked to compare the relative importance of three specified domains (physical health, social support, stress) as influences on their mood and then to list additional life experiences they considered important. They also rated the frequency and recurrence patterns (cyclicity) of their daily positive and negative moods. RESULTS: More women reported a positive overall mood than negative mood. Of three domains studied, social support was listed as the greatest influence on positive mood and stress on negative mood in the bivariate tests. More frequent moods (both positive and negative) were more likely to be viewed as recurrent or cyclical. Patterns of influence for positive mood differed from those for negative mood. Multivariate modeling found that women reporting frequent positive mood were more often North American and employed full-time and likely to consider stress or lack of stress was unimportant as an influence on positive mood. The only factors in the model associated with frequent negative mood were the perception of physical health and stress as important influences on negative mood. Less than 5% cited menstrual cycle phase as an influence. CONCLUSIONS: These subjective data suggest that women perceived a wide range of external, usually interpersonal, influences as relevant to their mood, however menstrual cycle was rarely mentioned. Perceptions of influences on mood are statistically related to frequency of moods. In addition, ethnicity and paid employment are independently associated with positive mood.

Genetic reduction of chronic muscle pain in mice lacking calcium/calmodulin-stimulated adenylyl cyclases.

BACKGROUND: The Ca2+/calmodulin-stimulated adenylyl cyclase (AC) isoforms AC1 and AC8, couple NMDA receptor activation to cAMP signaling pathways in neurons and are important for development, learning and memory, drug addiction and persistent pain. AC1 and AC8 in the anterior cingulate cortex (ACC) and the spinal cord were previously shown to be important in subcutaneous inflammatory pain. Muscle pain is different from cutaneous pain in its characteristics as well as conducting fibers. Therefore, we conducted the present work to test the role of AC1 and AC8 in both acute persistent and chronic muscle pain. RESULTS: Using an acute persistent inflammatory muscle pain model, we found that the behavioral nociceptive responses of both the late phase of acute muscle pain and the chronic muscle inflammatory pain were significantly reduced in AC1 knockout (KO) and AC1&8 double knockout (DKO) mice. Activation of other adenylyl cyclases in these KO mice by microinjection of forskolin into the ACC or spinal cord, but not into the peripheral tissue, rescued the behavioral nociceptive responses. Additionally, intra-peritoneal injection of an AC1 inhibitor significantly reduced behavioral responses in both acute persistent and chronic muscle pain. CONCLUSION: The results of the present study demonstrate that neuronal Ca2+/calmodulin-stimulated adenylyl cyclases in the ACC and spinal cord are important for both late acute persistent and chronic inflammatory muscle pain.