Implementing the WHO Indicators for Assessing Palliative Care Development in Three Countries: A Do-It-Yourself Approach.

CONTEXT: Palliative care is an essential health service, with over 56.8 million people needing it yearly, particularly in low- and middle-income countries. The World Health Assembly has recognized palliative care as an ethical responsibility and called for comprehensive primary health care. The World Health Organization has published a technical report titled "Assessing the Development of Palliative Care Worldwide," as a crucial first step in addressing palliative care. The report includes 14 indicators to help decision-makers identify service provision gaps and inform health priorities, piloted by WHO's ATLANTES in Benin, Morocco, and Uruguay as part of a global assessment. OBJECTIVES: To describe, for the three countries, the primary outcomes and lessons learned to enable replication in further countries. METHODS: A step-by-step description of the assessment project, a summary of the main results obtained through evaluations, and a description of how the selected countries effectively implemented the WHO indicators through a six-step process, including a phase of action plan design. We advocated a 'Do-it-yourself' approach. RESULTS: The summary data from three country reports reveals national development at a national level. A SWOT analysis involving consultants and program managers was conducted. A stakeholder guide was developed, providing trigger questions and practical recommendations for assessing development using specific indicators. Full information can be found in the specific published reports. CONCLUSION: The WHO approach has proven effective in identifying health system deficiencies and disseminating information about palliative care evaluation processes. The report provides a 'Do-it-yourself' approach, encouraging self-management without expert guidance.

Predictors of quality of childcare centers in low-income settings: findings from a cross-sectional study in two Nairobi slums.

Background: Rapid urbanization and increased women's involvement in paid work have contributed to the upsurge of informal childcare centers, especially in low-income settings where quality is a major issue. However, there are limited data on the factors associated with the quality of childcare centers in informal settlements in Africa. Methods: We conducted a quantitative observation and questionnaire survey of 66 childcare centers to identify the factors associated with the quality of childcare services in two informal settlements (Korogocho and Viwandani) in Nairobi. The quality of the centers (outcome variable) was assessed using a locally developed tool. Data on center characteristics including type, size, location, length of operation, charges, and number of staff were collected. Center providers' knowledge, attitude, and practices (KAP) in childcare were assessed through a questionnaire, focusing on nurturing care and business management. Data were described using means and standard deviation or frequencies and percentages. Associations between quality center score (outcome variable) and other variables were examined using multivariable linear regression to identify potential predictors of the quality of the center environment. Findings: A total of 129 childcare centers were identified and categorized as home-based (n = 45), center-based (n = 14), school-based (n = 61), and church-based (n = 9). The number of home-based centers was particularly high in Viwandani (n = 40; 52%). Only 9% of home-based centers reported any external support and 20% had any training on early childhood development. Of the 129 centers, 66 had complete detailed assessment of predictors of quality reported here. Unadjusted linear regressions revealed associations between quality of childcare center and center providers' education level, type of center, support received, caregiver-child ratio, number of children in the center, and center providers' KAP score (p < 0.05). However, in the multivariable regression, only higher levels of center provider KAP (ß = 0.51; 95% CI: 0.18, 0.84; p = 0.003) and center type (ß = 8.68; 95% CI: 2.32, 15.04; p = 0.008) were significantly associated with center quality score. Implication: Our results show that center providers' knowledge and practices are a major driver of the quality of childcare centers in informal settlements in Nairobi. Interventions for improving the quality of childcare services in such settings should invest in equipping center providers with the necessary knowledge and skills through training and supportive supervision.

The feasibility, acceptability, cost and benefits of a "communities of practice" model for improving the quality of childcare centres: a mixed-methods study in the informal settlements in Nairobi.

Background: Informal childcare centres have mushroomed in the informal settlements of Nairobi, Kenya to meet the increasing demand. However, centre providers are untrained and the facilities are below standard putting children at risk of poor health and development. We aimed to co-design and test the feasibility, acceptability, cost and potential benefits of a communities of practice (CoP) model where trained community health volunteers (CHVs) provide group training sessions to build skills and improve practices in informal childcare centres. Methods: A CoP model was co-designed with sub-county health teams, centre providers and parents with inputs from Kidogo, government nutritionists and ECD experts and implemented in 68 childcare centres by trained CHVs. Its feasibility and potential benefits were measured quantitatively and qualitatively. Centre provider (n = 68) and CHV (n = 20) knowledge and practice scores before and after the intervention were assessed and compared. Intervention benefits were examined using linear regressions adjusting for potential confounding factors. We conducted in-depth interviews with 10 parents, 10 CHVs, 10 centre providers and 20 local government officials, and two focus groups with CHVs and centre providers. Qualitative data were analysed, focusing on feasibility, acceptability, potential benefits, challenges and ideas for improvement. Cost for delivering and accessing the intervention were examined. Results: The intervention was acceptable and feasible to deliver within existing government community health systems; 16 CHVs successfully facilitated CoP sessions to 58 centre providers grouped into 13 groups each with 5-6 centre providers, each group receiving four sessions representing the four modules. There were significant improvements in provider knowledge and practice (effect size = 0.40; p < 0.05) and quality of centre environment (effect size = 0.56; p < 0.01) following the intervention. CHVs' scores showed no significant changes due to pre-existing high knowledge levels. Qualitative interviews also reported improvements in knowledge and practices and the desire among the different participants for the support to be continued. The total explicit costs were USD 22,598 and the total opportunity costs were USD 3,632 (IQR; USD 3,570, USD 4,049). Conclusion: A simple model delivered by CHVs was feasible and has potential to improve the quality of informal childcare centres. Leveraging these teams and integration of the intervention into the health system is likely to enable scale-up and sustainability in Kenya and similar contexts.

Developing a Real-Time Electroencephalogram-Guided Anesthesia-Management Curriculum for Educating Residents: A Single-Center Randomized Controlled Trial.

BACKGROUND: Different anesthetic drugs and patient factors yield unique electroencephalogram (EEG) patterns. Yet, it is unclear how best to teach trainees to interpret EEG time series data and the corresponding spectral information for intraoperative anesthetic titration, or what effect this might have on outcomes. METHODS: We developed an electronic learning curriculum (ELC) that covered EEG spectrogram interpretation and its use in anesthetic titration. Anesthesiology residents at a single academic center were randomized to receive this ELC and given spectrogram monitors for intraoperative use versus standard residency curriculum alone without intraoperative spectrogram monitors. We hypothesized that this intervention would result in lower inhaled anesthetic administration (measured by age-adjusted total minimal alveolar concentration [MAC] fraction and age-adjusted minimal alveolar concentration [aaMAC]) to patients ≥60 old during the postintervention period (the primary study outcome). To study this effect and to determine whether the 2 groups were administering similar anesthetic doses pre- versus postintervention, we compared aaMAC between control versus intervention group residents both before and after the intervention. To measure efficacy in the postintervention period, we included only those cases in the intervention group when the monitor was actually used. Multivariable linear mixed-effects modeling was performed for aaMAC fraction and hospital length of stay (LOS; a non-prespecified secondary outcome), with a random effect for individual resident. A multivariable linear mixed-effects model was also used in a sensitivity analysis to determine if there was a group (intervention versus control group) by time period (post- versus preintervention) interaction for aaMAC. Resident EEG knowledge difference (a prespecified secondary outcome) was compared with a 2-sided 2-group paired t test. RESULTS: Postintervention, there was no significant aaMAC difference in patients cared for by the ELC group (n = 159 patients) versus control group (N = 325 patients; aaMAC difference = -0.03; 95% confidence interval [CI], -0.09 to 0.03; P =.32). In a multivariable mixed model, the interaction of time period (post- versus preintervention) and group (intervention versus control) led to a nonsignificant reduction of -0.05 aaMAC (95% CI, -0.11 to 0.01; P = .102). ELC group residents (N = 19) showed a greater increase in EEG knowledge test scores than control residents (N = 20) from before to after the ELC intervention (6-point increase; 95% CI, 3.50-8.88; P < .001). Patients cared for by the ELC group versus control group had a reduced hospital LOS (median, 2.48 vs 3.86 days, respectively; P = .024). CONCLUSIONS: Although there was no effect on mean aaMAC, these results demonstrate that this EEG-ELC intervention increased resident knowledge and raise the possibility that it may reduce hospital LOS.

Relationships between Child Development at School Entry and Adolescent Health-A Participatory Systematic Review.

The relationship between child development and adolescent health, and how this may be modified by socio-economic conditions, is poorly understood. This limits cross-sector interventions to address adolescent health inequality. This review summarises evidence on the associations between child development at school starting age and subsequent health in adolescence and identifies factors affecting associations. We undertook a participatory systematic review, searching electronic databases (MEDLINE, PsycINFO, ASSIA and ERIC) for articles published between November 1990 and November 2020. Observational, intervention and review studies reporting a measure of child development and subsequent health outcomes, specifically weight and mental health, were included. Studies were individually and collectively assessed for quality using a comparative rating system of stronger, weaker, inconsistent or limited evidence. Associations between child development and adolescent health outcomes were assessed and reported by four domains of child development (socio-emotional, cognitive, language and communication, and physical development). A conceptual diagram, produced with stakeholders at the outset of the study, acted as a framework for narrative synthesis of factors that modify or mediate associations. Thirty-four studies were included. Analysis indicated stronger evidence of associations between measures of socio-emotional development and subsequent mental health and weight outcomes; in particular, positive associations between early externalising behaviours and later internalising and externalising, and negative associations between emotional wellbeing and later internalising and unhealthy weight. For all other domains of child development, although associations with subsequent health were positive, the evidence was either weaker, inconsistent or limited. There was limited evidence on factors that altered associations. Positive socio-emotional development at school starting age appears particularly important for subsequent mental health and weight in adolescence. More collaborative research across health and education is needed on other domains of development and on the mechanisms that link development and later health, and on how any relationship is modified by socio-economic context.

The experiences of socially vulnerable groups in England during the COVID-19 pandemic: A rapid health needs assessment.

OBJECTIVES: This rapid health needs assessment was undertaken to urgently identify the needs of socially vulnerable groups arising during the first wave of cases of the COVID-19 pandemic in England. The objective was to develop recommendations for policy makers and stakeholders to mitigate adverse impacts on socially vulnerable groups throughout the COVID-19 response and recovery period. STUDY DESIGN: Rapid health needs assessment. METHODS: The needs assessment employed qualitative methods to systematically collect data about the knowledge and views of key informants through semi-structured interviews and focus groups. Participants were either topic experts providing services to socially vulnerable groups who routinely face barriers to healthcare access or experts by experience. Participants included people experiencing homelessness, sex workers, people from Gypsy, Roma and Traveller communities and people facing challenges due to their immigration status. Data was collected over a week period in April/May 2020 and followed by thematic analysis to examine interview transcripts. RESULTS: Forty-two participants were included in the study, half of whom were experts by experience. Challenges with accessing and following COVID-19 information and government guidance were described as affecting all groups, due to exclusion from digital technology, translated resources, tailored support and adequate housing. Altered delivery of healthcare services, such as the closure of outreach and drop-in services, remote consultations, and online patient registration, were noted by interviewees as worsening existing barriers to accessing healthcare. Being charged for NHS care remained a key fear for migrants. All groups' access to income, education and social support were reported as being impacted by service closures and job losses, putting them at higher risk of destitution. Isolation, loneliness and deteriorating mental health were frequently reported. CONCLUSIONS: This assessment has highlighted the disproportionate impact of the COVID-19 pandemic on socially vulnerable groups and demonstrated a plethora of unmet needs. As the effects of COVID-19 continue, it is imperative that the needs of these groups are urgently and explicitly addressed and prioritised. This is essential to promote engagement with test and trace services, enable isolation adherence, and achieve high vaccine uptake in socially vulnerable populations.

Anti-cancer effects of aloe-emodin: a systematic review.

BACKGROUND: Anthraquinones are a possible treatment option for oncological patients due to their anti-cancer properties. Cancer patients often exhaust a plethora of resources that ultimately fail to provide fully curative measures. Alternative treatments are subsequently sought in the hope of finding a therapeutic remedy. Po¬tential regimens include aloe-emodin and its related derivatives. This review therefore summarizes the effects of aloe-emodin and other aloe components in light of their anti-proliferative and anti-carcinogenic properties. METHODS: A systematic search was performed in PubMed for aloe-emodin and cancer in humans. Sixty abstracts of in vitrostudies were selected and reviewed with subsequent screening of the full text. Thirty-eight articles were summarized. RESULTS: Aloe-emodin possesses multiple anti-proliferative and anti-carcinogenic properties in a host of human cancer cell lines, with often multiple vital pathways affected by the same molecule. The most notable effects include inhibition of cell proliferation, migration, and invasion; cycle arrest; induction of cell death; mitochondrial membrane and redox perturbations; and modulation of immune signaling. The effects of aloe-emodin are not ubiquitous across all cell lines but depend on cell type. CONCLUSIONS: On the basis of this systematic review, the multiple consistent effects of aloe-emodin in hu¬man-derived cancer cell lines suggest that aloe-emodin is a potential anti-cancer agent that acts on cancer cells in a pleiotropic manner. RELEVANCE FOR PATIENTS: Cancer patients often utilize alternative therapies as a result of suboptimal efficacy of conventional treatments. Aloe-emodin might become a therapeutic option for cancer patients if the basic research is confirmed in clinical trials.

Double-blind, randomized crossover study of intravenous infusion of magnesium sulfate versus 5% dextrose on depressive symptoms in adults with treatment-resistant depression.

AIM: Treatment-resistant depression patients are more likely to suffer from comorbid physical and mental disorders, experience marked and protracted functional impairment, and incur higher health-care costs than non-affected individuals. Magnesium sulfate is a treatment option that may offer great potential for patients with treatment-resistant depression based on prior work in animals and humans. METHODS: Twelve subjects with mild or moderate treatment-resistant depression were randomized into a double-blind crossover trial to receive an infusion of 4 g of magnesium sulfate in 5% dextrose or placebo infusion of 5% dextrose with a 5-day washout in between the 8-day intervention period. Subjects were assessed before and after the intervention for serum and urine magnesium, lipid panel, the Hamilton Rating Scale for Depression, and the Patient Health Questionnaire-9. RESULTS: We found a difference in serum magnesium from day 2 to 8 (pre-infusion) (P < 0.002) and from baseline to day 8 (P < 0.02). No changes were noted on the Hamilton Rating Scale for Depression or the Patient Health Questionnaire-9 24 h post-treatment, but as serum magnesium increased from baseline to day 7, the Patient Health Questionnaire-9 decreased from baseline to day 7 (P = 0.02). CONCLUSION: Magnesium sulfate did not significantly affect depression 24 h post-infusion, but other results were consistent with the literature. The association between changes in serum magnesium and the Patient Health Questionnaire-9 supports the idea that magnesium sulfate may be used to address treatment-resistant depression, an ongoing medical challenge.

Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21.

Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.

The effect of exercise training on disease progression, fitness, quality of life, and mental health in people living with HIV on antiretroviral therapy: a systematic review.

BACKGROUND: Exercise has been associated with improvements in adverse physiological and psychological effects of long-term antiretroviral therapy (ART) in people living with HIV (PLWH). AIM: To summarizes the findings on the effects of aerobic or resistance training alone or combined aerobic and resistance exercise training (CARET) on disease progression, fitness, physical functioning, mental health, and quality of life (QOL) in PLWH receiving ART. A systematic search of articles was performed in several databases, and 20 articles that met inclusion criteria were summarized. RELEVANCE FOR PATIENTS: Aerobic exercise was associated with improvements in aerobic capacity, QOL, and depressive symptoms, while resistance training improved strength. CARET was related to improved aerobic fitness, strength, physical functioning, QOL, and self-efficacy. At least one of the exercise interventions resulted in improvements in CD4+ cell count and HIV RNA viral load. Moreover, another study showed that HIV-specific biomarkers remained unchanged in the exercise intervention group, while they significantly worsened in the non-exercise group. In general, in spite of their well-known benefits, exercise programs have not been extensively utilized or widely recognized as viable therapeutic treatment options for this patient population. Knowing the possible health benefits of increasing physical activity level is important to better recommend exercise programs. However, the prescription must be done carefully and on an individual basis. Additional studies investigating the efficiency and effectiveness of different exercise training regimens for PLWH are needed.

Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease.

Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p ≤ 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.

Germline mutations in HOXB13 and prostate-cancer risk.

BACKGROUND: Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. METHODS: We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. RESULTS: Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P=8.5x10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P=2.0x10(-6)). CONCLUSIONS: The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.).

Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG).

Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case-control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case-control GWAS are also associated with disease risk in HPC families.

Early onset prostate cancer has a significant genetic component.

BACKGROUND: Prostate cancer (PCa) affects more than 190,000 men each year with ∼10% of men diagnosed at ≤55 years, that is, early onset (EO) PCa. Based on historical findings for other cancers, EO PCa likely reflects a stronger underlying genetic etiology. METHODS: We evaluated the association between EO PCa and previously identified single nucleotide polymorphisms (SNPs) in 754 Caucasian cases from the Michigan Prostate Cancer Genetics Project (mean 49.8 years at diagnosis), 2,713 Caucasian controls from Illumina's iControlDB database and 1,163 PCa cases diagnosed at >55 years from the Cancer Genetic Markers of Susceptibility Study (CGEMS). RESULTS: Significant associations existed for 13 of 14 SNPs (rs9364554 on 6q25, rs10486567 on 7p15, rs6465657 on 7q21, rs6983267 on 8q24, rs1447295 on 8q24, rs1571801 on 9q33, rs10993994 on 10q11, rs4962416 on 10q26, rs7931342 on 11q13, rs4430796 on 17q12, rs1859962 on 17q24.3, rs2735839 on 19q13, and rs5945619 on Xp11.22, but not rs2660753 on 3p12). EO PCa cases had a significantly greater cumulative number of risk alleles (mean 12.4) than iControlDB controls (mean 11.2; P = 2.1 × 10(-33)) or CGEMS cases (mean 11.9; P = 1.7 × 10(-5)). Notably, EO PCa cases had a higher frequency of the risk allele than CGEMS cases at 11 of 13 associated SNPs, with significant differences for five SNPs. EO PCa cases diagnosed at <50 (mean 12.8) also had significantly more risk alleles than those diagnosed at 50-55 years (mean 12.1; P = 0.0003). CONCLUSIONS: These results demonstrate the potential for identifying PCa-associated genetic variants by focusing on the subgroup of men diagnosed with EO disease.

Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21.

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10(-13)). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.

Hereditary prostate cancer as a feature of Lynch syndrome.

Lynch Syndrome is an autosomal dominant condition characterized by early onset colorectal cancer (CRC) and is associated with cancers of the gastrointestinal and reproductive tracts. Germline mutations in DNA mismatch repair (MMR) genes have been causally associated with cancers of Lynch Syndrome. We investigated the occurrence of prostate cancer (PCa) in families with a history of colorectal cancer to assess prostate cancer as a feature of the Lynch Syndrome spectrum. Family pedigrees containing at least one CRC case as well as those meeting guidelines for Lynch Syndrome were identified and tumors were requested from participants who underwent radical prostatectomy (RP). Selected families were analyzed for association with type of PCa and clinical characteristics of aggressive disease. Microsatellite Instability (MSI) analysis was preformed on available tumors and correlated to loss of expression in MMR genes by immunohistochemical (IHC) staining. 95 individuals were identified as members of potential Lynch Syndrome families who underwent RP and 35 tumors from 31 families were received for MSI analysis. Two tumors from two unrelated families with known MMR mutations were MSI-high and one additional case from a third family was MSI-low. The remainder of the prostate cancer cases demonstrated no evidence of MSI. PCa incidence in families enriched for hereditary PCa with a history of Lynch Syndrome cancers is not strongly suggestive of the presence of an MMR mutation. However prostate tumors in known MMR mutation carriers did display MSI and loss of gene expression suggesting that PCa may arise in Lynch Syndrome due to defective DNA mismatch repair.

Evidence for an association between prostate cancer and chromosome 8q24 and 10q11 genetic variants in African American men: the Flint Men's Health Study.

BACKGROUND: Prostate cancer is the most commonly diagnosed non-skin cancer in men in the United States and the second leading cause of cancer-related mortality. African American men have substantially increased risk of both being diagnosed and dying from the disease. Recent genome-wide genetic association studies have identified a number of common single nucleotide genetic polymorphisms (SNPs) that are associated with prostate cancer in men of European descent. Only a small number of studies have evaluated the association between these genetic variants and prostate cancer in African Americans. METHODS: We used logistic regression models to assess the association between prostate cancer in African American men and 24 SNPs from regions previously reported to be associated with prostate cancer in men of European descent. RESULTS: We found nominal evidence (P < 0.05) for association between prostate cancer and three chromosome 8q24 (rs6983561, rs16901979, and rs7000448) and two 10q11 (rs7904463 and rs10740051) SNPs. CONCLUSIONS: We confirm recent reports that 8q24 variants identified to be associated with prostate cancer in men of European descent are also associated with prostate cancer in African Americans. Our report is the first to find evidence of association between SNPs near MSMB and prostate cancer in African Americans. Of note, rs7000448 is in strong linkage disequilibrium with rs10761581 in NCOA4, a SNP that has been implicated to be independently associated, with respect to the widely reported SNP rs10993994 in the nearby gene MSMB, with prostate cancer in men of European descent.

Sequence variation in the mitochondrial gene cytochrome c oxidase subunit I and prostate cancer in African American men.

BACKGROUND: Previous studies have found associations between mitochondrial DNA (mtDNA) mutations and several cancer types. Recently, we found that mutations in the mtDNA gene cytochrome c oxidase subunit 1 (COI) were both linked to and associated with prostate cancer (PCa) in Caucasian men. Here we examine the association between COI mutations and PCa in African American men. METHODS: The entire COI gene was directly sequenced in 132 PCa cases and 135 controls from the Flint Men's Health Study, a community-based sample of African American men with and without PCa. Associations between all variants and PCa were evaluated. RESULTS: We identified 102 COI single nucleotide polymorphisms (SNPs), including 15 missense variants. Overall, the presence of one or more COI missense variants was not significantly associated with PCa. Individually, two SNPs (T6221C and T7389C) were significantly associated with prostate cancer (P < 0.05) and in strong linkage disequilibrium with each other (r(2) > 0.6). CONCLUSIONS: Of the two significantly associated SNPs, one is a synonymous substitution and the other is part of the African-specific mitochondrial haplogroup (L). Additional research will be needed to determine the clinical relevance of these associations in African populations.

Pioneering health care. Interview by Carol Davis.

A major overhaul of services means patients in Lancashire can have their heart conditions diagnosed at a single clinic visit.