Association between patient ethnicity and prostate cancer diagnosis following a prostate-specific antigen test: a cohort study of 730,000 men in primary care in the UK.

BACKGROUND: Black men have higher prostate-specific antigen (PSA) levels and higher prostate cancer incidence and mortality than White men, while Asian men tend to have lower prostate cancer incidence and mortality than White men. Much of the evidence comes from the USA, and information from UK populations is limited. METHODS: This retrospective cohort study used data on patients registered at general practices in England contributing to the Clinical Practice Research Datalink (CPRD) Aurum dataset. Those eligible were men aged 40 and over with a record of ethnicity and a PSA test result recorded between 2010 and 2017 with no prior cancer diagnosis. The aim was to assess the incidence of prostate cancer following a raised PSA test result in men from different ethnic groups. Additionally, incidence of advanced prostate cancer was investigated. Cancer incidence was estimated from multi-level logistic regression models adjusting for potential confounding factors. RESULTS: 730,515 men with a PSA test were included (88.9% White). Black men and men with mixed ethnicity had higher PSA values, particularly for those aged above 60 years. In the year following a raised PSA result (using age-specific thresholds), Black men had the highest prostate cancer incidence at 24.7% (95% CI 23.3%, 26.2%); Asian men had the lowest at 13.4% (12.2%, 14.7%); incidence for White men was 19.8% (19.4%, 20.2%). The peak incidence of prostate cancer for all groups was in men aged 70-79. Incidence of prostate cancer diagnosed at an advanced stage was similar between Black and White men. CONCLUSIONS: More prostate cancer was diagnosed in Black men with a raised PSA result, but rates of advanced prostate cancer were not higher in this group. In this large primary care-based cohort, the incidence of prostate cancer in men with elevated PSA levels increases with increasing age, even when using age-adjusted thresholds, with Black men significantly more likely to be diagnosed compared to White or Asian men. The incidence of advanced stage prostate cancer at diagnosis was similar for Black and White men with a raised PSA result, but lower for Asian men.

Exploring ethnic differences in the distribution of blood test results in healthy adult populations to inform earlier cancer detection: a systematic review.

BACKGROUND: In primary care, health professionals use blood tests to investigate nonspecific presentations to inform referral decisions. Reference ranges for the commonly used blood tests in western countries were developed in predominately White populations, and so may perform differently when applied to non-White populations. Knowledge of ethnic variation in blood test results in healthy/general populations could help address ethnic inequalities in cancer referral for diagnosis and outcomes. OBJECTIVE: This systematic review explored evidence of ethnic differences in the distribution of selected blood test results among healthy/general populations to inform future research aimed at addressing inequalities in cancer diagnosis. METHODS: We searched PubMed and EMBASE to identify studies reporting measures of haemoglobin, MCV, calcium, albumin, platelet count, and CRP in nondiseased adults from at least 2 different ethnic groups. Two reviewers independently screened studies, completed data extraction and quality assessment using an adapted Newcastle-Ottawa scale. Participants were stratified into White, Black, Asian, Mixed, and Other groups. Data were synthesised narratively and meta-analyses were conducted where possible. RESULTS: A total of 47 papers were included. Black men and women have lower average values of haemoglobin, MCV, and albumin, and higher average values of CRP relative to their White counterparts. Additionally, Black men have lower average haemoglobin than Asian men, whereas Asian women have lower average CRP values when compared with White women. CONCLUSIONS: There is evidence of ethnic differences in average values of haemoglobin, MCV, CRP, and albumin in healthy/general populations. Further research is needed to explore the reasons for these differences. Systematic review registration: CRD42021274580.

Validation of the family health scale among heterosexual couples: a dyadic analysis.

BACKGROUND: The Family Health Scale (FHS) is a recently validated comprehensive measure of family health for use in survey research with the potential to also be used as a clinical measure. However, previous research has only validated the FHS among one member of the family rather than multiple family members. The objective of the study was to examine the psychometric properties of the FHS long- and short-form among married and cohabitating partners (dyads). METHOD: The sample for this study was comprised of 482 married or cohabitating heterosexual couples (dyads) who were parents of a child between the ages of 3-13, heterosexual, and living in the United States. Each member of the dyad completed a survey about his or her perception of family health, personal health, childhood experiences, and demographic characteristics. Confirmatory factor analyses (CFA) were conducted to examine the factor structure. Unidimensional, correlational, and second-order factor structures were examined using responses from both partners. The relationships between family health with individual health and demographic covariates were also examined. RESULTS: Women and men reported their family health similarly. The unidimensional factor structure had the best fit for the FHS short-form while either the unidimensional model or the second-order model would be appropriate for the FHS long-form. Household income, individual member mental health, and childhood experiences were associated with family health in the expected direction. CONCLUSION: The results demonstrate that the FHS is a valid and reliable family measure when examining family health among dyads including married and cohabitating heterosexual couples who have children.

The Clinical Value of Pre-Diagnostic Thrombocytosis for the Detection of Lung Cancer in Primary Care.

Thrombocytosis is a risk marker for lung cancer in primary care. We investigated whether thrombocytosis presents pre-diagnostically for all the histological subtypes of lung cancer and its association with the stage at diagnosis. A matched cohort study used English electronic primary care data linked to the national cancer registry. Patients diagnosed with lung cancer aged ≥40 years with no prior history of malignancy were matched by age, sex, and general practice to five controls without lung cancer. Multivariable logistic regression models quantified the incidence of pre-diagnostic thrombocytosis and advanced-stage diagnoses, adjusting for COPD diagnosis, smoking status, and anti-platelet drug prescriptions. A total of 9504 cases were matched to 45,647 controls, consisting of 3260 (34%) adenocarcinomas (ADC), 2020 (21%) squamous cell carcinomas (SCC), 70 (<1%) large-cell carcinomas (LCC), and 1089 (12%) small-cell lung cancers (SCLC). The patients with lung cancer were 8.9 (95% CI 8.0-9.9) times more likely to exhibit pre-diagnostic thrombocytosis than the controls. The odds ratios were highest for the comparison between SCC and ADC (1.8, 95% CI 1.5-2.1). Thrombocytosis is associated with advanced-stage ADC and SCC but presented equally for early- and advanced-stage SCLC. Pre-diagnostic thrombocytosis may aid in the detection of all the histological subtypes in primary care.

The diagnostic performance of CA-125 for the detection of ovarian cancer in women from different ethnic groups: a cohort study of English primary care data.

BACKGROUND: CA-125 testing is a recommended first line investigation for women presenting with possible symptoms of ovarian cancer in English primary care, to help determine whether further investigation for ovarian cancer is needed. It is currently not known how well the CA-125 test performs in ovarian cancer detection for patients from different ethnic groups. METHODS: A retrospective cohort study utilising English primary care data linked to the national cancer registry was undertaken. Women aged ≥ 40 years with a CA-125 test between 2010 and 2017 were included. Logistic regression predicted one-year ovarian cancer incidence by ethnicity, adjusting for age, deprivation status, and comorbidity score. The estimated incidence of ovarian cancer by CA-125 level was modelled for each ethnic group using restricted cubic splines. RESULTS: The diagnostic performance of CA-125 differed for women from different ethnicities. In an unadjusted analysis, predicted CA-125 levels for Asian and Black women were higher than White women at corresponding probabilities of ovarian cancer. The higher PPVs for White women compared to Asian or Black women were eliminated by inclusion of covariates. CONCLUSION: The introduction of ethnicity-specific thresholds may increase the specificity and PPVs of CA-125 in ovarian cancer detection at the expense of sensitivity, particularly for Asian and Black women. As such, we cannot recommend the use of ethnicity-specific thresholds for CA-125.

Positive adult experiences as turning points for better adult mental health after childhood adversity.

Background: The purpose of this study was to examine whether positive adult experiences (PAEs) were associated with lower odds for anxiety and depression even in the presence of high adverse childhood experiences (ACEs) or low positive childhood experiences (PCEs). Methods: The sample was comprised of 435 adults (48% female), ages 18-56 years and who were living in the United States. Participants completed a survey about their childhood experiences, PAEs, and mental health. A series of multiple logistic regression models were estimated in Stata 17 to examine the aims. Results: Positive childhood experiences were associated with higher PAE scores, but ACEs did not significantly correlate with PAEs. Positive adult experiences were associated with lower odds of moderate-to-severe anxiety and depression, especially among those who had experienced high ACEs or low PCEs. Younger adults were more likely to experience a positive benefit from PAEs compared to adults 35 years and older. Conclusion: Even when ACEs were high or PCEs were low, adults with high PAEs had lower odds for moderate-to-severe anxiety and/depression. Positive adult experiences may be an opportunity to turn the tide for individuals who experienced childhood adversity and/or low levels of support or connection.

Ethnic differences in prostate-specific antigen levels in men without prostate cancer: a systematic review.

INTRODUCTION: Black men are twice as likely to be diagnosed with prostate cancer than White men. Raised prostate-specific antigen (PSA) levels can indicate an increased risk of prostate cancer, however it is not known whether PSA levels differ for men of different ethnic groups. METHODS: PubMed and Embase were searched to identify studies that reported levels of PSA for men of at least two ethnic groups without a prostate cancer diagnosis or symptoms suggestive of prostate cancer. An adaptation of the Newcastle-Ottawa scale was used to assess risk of bias and study quality. Findings were stratified into the following broad ethnic groups: White, Black, Asian, Hispanic, and Other. Data were analysed in a narrative synthesis due to the heterogeneity of reported PSA measures and methods in the included studies. RESULTS: A total of 654 197 males from 13 studies were included. By ethnicity, this included 536 201 White (82%), 38 287 Black (6%), 38 232 Asian (6%), 18 029 Pacific Island (3%), 13 614 Maori (2%), 8 885 Hispanic (1%), and 949 Other (<1%) men aged ≥40 years old. Black men had higher PSA levels than White men, and Hispanic men had similar levels to White men and lower levels than Black men. CONCLUSIONS: Black men without prostate cancer have higher PSA levels than White or Hispanic men, which reflects the higher rates of prostate cancer diagnosis in Black men. Despite that, the diagnostic accuracy of PSA for prostate cancer for men of different ethnic groups is unknown, and current guidance for PSA test interpretation does not account for ethnicity. Future research needs to determine whether Black men are diagnosed with similar rates of clinically significant prostate cancer to White men, or whether raised PSA levels are contributing to overdiagnosis of prostate cancer in Black men.

Intergenerational Transmission of Trauma: The Mediating Effects of Family Health.

Family health is important to the well-being of individual family members and the collective family unit, and as such, may serve as a mediator for the intergenerational transmission of trauma (ITT). This study aimed to understand the intergenerational impact of parent's adverse and positive childhood experiences (ACEs and PCEs) on their children's adverse family experiences (AFEs) and how family health mediated those relationships. The sample consisted of 482 heterosexual married or cohabiting couples (dyads) in the United States who had a child between the ages of 3 and 13 years old. Each member of the dyad completed a survey, and data were analyzed using structural equation modeling. Parental ACEs were associated with more AFEs. The fathers', but not the mothers', ACEs were associated with worse family health. Parental PCEs were associated with better family health, and family health was associated with lower AFE scores. Indirect effects indicated that parental PCEs decreased AFEs through their impact on family health. Family health also mediated the relationship between the father's ACEs and the child's AFEs. Interventions designed to support family health may help decrease child AFEs.

RhoA signaling increases mitophagy and protects cardiomyocytes against ischemia by stabilizing PINK1 protein and recruiting Parkin to mitochondria.

Mitophagy, a mitochondria-specific form of autophagy, removes dysfunctional mitochondria and is hence an essential process contributing to mitochondrial quality control. PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin are critical molecules involved in stress-induced mitophagy, but the intracellular signaling mechanisms by which this pathway is regulated are unclear. We tested the hypothesis that signaling through RhoA, a small GTPase, induces mitophagy via modulation of the PINK1/Parkin pathway as a protective mechanism against ischemic stress. We demonstrate that expression of constitutively active RhoA as well as sphingosine-1-phosphate induced activation of endogenous RhoA in cardiomyocytes result in an accumulation of PINK1 at mitochondria. This is accompanied by translocation of Parkin to mitochondria and ubiquitination of mitochondrial proteins leading to recognition of mitochondria by autophagosomes and their lysosomal degradation. Expression of RhoA in cardiomyocytes confers protection against ischemia, and this cardioprotection is attenuated by siRNA-mediated PINK1 knockdown. In vivo myocardial infarction elicits increases in mitochondrial PINK1, Parkin, and ubiquitinated mitochondrial proteins. AAV9-mediated RhoA expression potentiates these responses and a concurrent decrease in infarct size is observed. Interestingly, induction of mitochondrial PINK1 accumulation in response to RhoA signaling is neither mediated through its transcriptional upregulation nor dependent on depolarization of the mitochondrial membrane, the canonical mechanism for PINK1 accumulation. Instead, our results reveal that RhoA signaling inhibits PINK1 cleavage, thereby stabilizing PINK1 protein at mitochondria. We further show that active RhoA localizes at mitochondria and interacts with PINK1, and that the mitochondrial localization of RhoA is regulated by its downstream effector protein kinase D. These findings demonstrate that RhoA activation engages a unique mechanism to regulate PINK1 accumulation, induce mitophagy and protect against ischemic stress, and implicates regulation of RhoA signaling as a potential strategy to enhance mitophagy and confer protection under stress conditions.

The association between thrombocytosis and subtype of lung cancer: a systematic review and meta-analysis.

BACKGROUND: Thrombocytosis is associated with poor lung cancer prognosis and has recently been identified as having a high positive predictive value in lung cancer detection. Lung cancer has multiple histological and genetic subtypes and it is not known whether platelet levels differ across these subtypes, or whether thrombocytosis is predictive of a particular subtype. METHODS: PubMed and Embase were systematically searched for studies that reported pre-treatment platelet count, as either averages or proportion of patients with thrombocytosis, by subtype of lung cancer using a pre-specified search strategy. The Newcastle-Ottowa scale was used to assess study quality and risk of bias. Suitable studies were synthesised in meta-analyses and subgroup analyses examined for differences across subtypes. RESULTS: The prevalence of pre-treatment thrombocytosis across all lung cancer patients was 27% (95% CI: 17% to 37%). By subtype, this was 22% (95% CI: 7% to 41%) for adenocarcinoma, 28% (95% CI: 15% to 43%) for squamous cell carcinoma (SCC), 36% (95% CI: 13% to 62%) for large cell carcinoma (LCC), and 30% (95% CI: 8% to 58%) for small cell lung cancer (SCLC). The pooled mean platelet count for lung cancer patients was 289×109/L (95% CI: 268 to 311). By subtype, this was 282×109/L (95% CI: 259 to 306) for adenocarcinoma, 297×109/L (95% CI: 238 to 356) for SCC, 290×109/L (95% CI: 176 to 404) for LCC, and 293×109/L (95% CI: 244 to 342) for SCLC. There was no difference in thrombocytosis prevalence (P=0.76) or mean platelet count (P=0.96) across the subtypes. CONCLUSIONS: These findings suggest thrombocytosis is no more indicative of one lung cancer subtype over another. We therefore conclude a high platelet count is likely to be generic across all lung cancer subtypes.

Physiological activation of Akt by PHLPP1 deletion protects against pathological hypertrophy.

AIMS: To examine the role of physiological Akt signalling in pathological hypertrophy through analysis of PHLPP1 (PH domain leucine-rich repeat protein phosphatase) knock-out (KO) mice. METHODS AND RESULTS: To investigate the in vivo requirement for 'physiological' control of Akt activation in cardiac growth, we examined the effect of deleting the Akt phosphatase, PHLPP, on the induction of cardiac hypertrophy. Basal Akt phosphorylation increased nearly two-fold in the cardiomyocytes from PHLPP1 KO mice and physiological hypertrophy induced by swimming exercise was accentuated as assessed by increased heart size and myocyte cell area. In contrast, the development of pathophysiological hypertrophy induced by pressure overload and assessed by increases in heart size, myocyte cell area, and hypertrophic gene expression was attenuated. This attenuation coincided with decreased fibrosis and cell death in the KO mice. Cast moulding revealed increased capillary density basally in the KO hearts, which was further elevated relative to wild-type mouse hearts in response to pressure overload. In vitro studies with isolated myocytes in co-culture also demonstrated that PHLPP1 deletion in cardiomyocytes can enhance endothelial tube formation. Expression of the pro-angiogenic factor VEGF was also elevated basally and accentuated in response to transverse aortic constriction in hearts from KO mice. CONCLUSION: Our data suggest that enhancing Akt activity by inhibiting its PHLPP1-mediated dephosphorylation promotes processes associated with physiological hypertrophy that may be beneficial in attenuating the development of pathological hypertrophy.