Nevin Manimala

Nucleic Acids Res. 2021 Dec 6:gkab1167. doi: 10.1093/nar/gkab1167. Online ahead of print.

ABSTRACT

While large-scale studies applying various statistical approaches have identified hundreds of mutated driver genes across various cancer types, the contribution of epigenetic changes to cancer remains more enigmatic. This is partly due to the fact that certain regions of the cancer genome, due to their genomic and epigenomic properties, are more prone to dysregulated DNA methylation than others. Thus, it has been difficult to distinguish which promoter methylation changes are really driving carcinogenesis from those that are mostly just a reflection of their genomic location. By developing a novel method that corrects for epigenetic covariates, we reveal a small, concise set of potential epigenetic driver events. Interestingly, those changes suggest different modes of epigenetic carcinogenesis: first, we observe recurrent inactivation of known cancer genes across tumour types suggesting a higher convergence on common tumour suppressor pathways than previously anticipated. Second, in prostate cancer, a cancer type with few recurrently mutated genes, we demonstrate how the epigenome primes tumours towards higher tolerance of other aberrations.

PMID:34871444 | DOI:10.1093/nar/gkab1167

J Clin Endocrinol Metab. 2021 Dec 6:dgab873. doi: 10.1210/clinem/dgab873. Online ahead of print.

ABSTRACT

BACKGROUND: Familial hypercholesterolemia (FH) confers a greatly increased risk for premature cardiovascular disease (CVD), but remains very under-diagnosed and under-treated in primary care populations. We assessed whether using a hybrid model consisting of two existing FH diagnostic criteria coupled with electronic medical record (EMR) data, would accurately identify patients with FH in a midwest US metropolitan healthcare system.

METHODS AND RESULTS: We conducted a retrospective, records-based, cross-sectional study using datasets from unique EMRs of living patients. Using Structured Query Language (SQL) to identify components of two currently approved FH diagnostic criteria, we created a hybrid model to identify individuals with FH. Of 264 264 records analyzed, between 794 and 1571 patients were identified as having FH based on the hybrid diagnostic model, with a prevalence of 1:300 to 1:160. These patients had a higher prevalence of premature coronary artery disease (CAD) (38%-58%) compared with the general population (1.8%) and compared with those having a high CAD risk, but no FH (10%). Although most patients were receiving lipid-lowering therapies (LLT), only 50% were receiving guideline-recommended high-intensity LLT.

CONCLUSION: Using the hybrid model, we identified FH with a higher clinical and genetic detection rate compared with using standard diagnostic criteria, individually. Statin and other LLT use were suboptimal and below guideline recommendations. Because FH under-diagnosis and under-treatment are due partially to the challenges of implementing existing diagnostic criteria in a primary care setting, this hybrid model potentially can improve FH diagnosis and subsequent early access to appropriate treatment.

PMID:34871430 | DOI:10.1210/clinem/dgab873

J Nutr. 2021 Dec 6:nxab412. doi: 10.1093/jn/nxab412. Online ahead of print.

ABSTRACT

BACKGROUND: The relationship between dietary n-3 PUFAs and the prevention of cardiometabolic diseases, including type 2 diabetes, is unresolved. Examination of the association between n-3 PUFAs and chronic low-grade inflammation in a population where many individuals have had an extremely high intake of marine mammals and fish throughout their lifespan may provide important clues regarding the impact of n-3 PUFAs on health.

OBJECTIVE: The aim of this study was to explore associations between concentrations of n-3 PUFAs resulting from habitual intake of natural food sources high in fish and marine mammals with immune biomarkers of metabolic inflammation and parameters of glucose regulation.

DESIGN: A total of 569 Yup’ik Alaska Native adults (18-87 years) were enrolled in this cross-sectional study between December 2016 and November 2019. The red blood cell (RBC) nitrogen isotope ratio (15N/14N, or NIR) was used as a validated measure of n-3 PUFA intake to select 165 participant samples from the first and fourth quartiles of n-3 PUFA intake. Outcomes included 38 pro- and anti-inflammatory cytokines and eight measures of glucose homeostasis associated with type 2 diabetes risk. These outcomes were evaluated for their association with direct measurements of EPA, DHA and arachidonic acid in RBCs.

ANALYSIS: Linear regression was used to detect significant relationships with cytokines and n-3 PUFAs, adiposity, and glucose related variables.

RESULTS: DHA concentration in RBC membranes was inversely associated with IL-6 (β = -0.0066, P < 0.001); EPA was inversely associated with TNFα (β = -0.4925, P < 0.001); and the NIR was inversely associated with MCP-1 (β = -0.8345, P < 0.001) and IL-10 (β = -1.2868, P < 0.001).

CONCLUSIONS: Habitual intake of marine mammals and fish rich in n-3 PUFAs in this study population of Yup’ik Alaska Native adults is associated with reduced systemic inflammation, which may contribute to the low prevalence of diseases in which inflammation plays an important role.

PMID:34871429 | DOI:10.1093/jn/nxab412

J Nutr. 2021 Dec 6:nxab410. doi: 10.1093/jn/nxab410. Online ahead of print.

ABSTRACT

BACKGROUND: Sorghum is the fifth most consumed cereal grain but limiting in the indispensable amino acid lysine. Complementing sorghum with lentils can improve the quality of sorghum-based diets. However, knowledge of lysine bioavailability in sorghum is lacking.

OBJECTIVE: The study objectives were to determine the bioavailability of lysine in sorghum and to assess the effect of complementation of sorghum and lentils in a mixed meal format.

METHOD: We studied five healthy young men (≤30 y; BMI < 25 kg/m2) in a repeated-measure design using the indicator amino acid oxidation (IAAO) method, with L-[1-13C] phenylalanine as the indicator. Each subject participated in 8 determinations in random order. On the reference diet, subjects received 4 amounts of L-lysine (5, 8, 12, 15 mg. kg-1. d-1) from a crystalline amino acid mixture patterned after egg protein. On the test diet they received 3 levels of lysine (8.2, 12.5 and 15.7 mg. kg-1. d-1) from sorghum and on the complementation diet they received 1 level of lysine from a mixed meal of sorghum and lentils. The bioavailability of lysine in sorghum was estimated by comparing the IAAO responses to the test diet with the IAAO response to the reference diet using the slope-ratio method. Effectiveness of complementation was assessed by comparing the IAAO response to the mixed meal to the IAAO response to the test protein.

RESULTS: The bioavailability of lysine from sorghum was 94%. Upon complementation with lentils, there was a decline in the oxidation of L-[1-13C] phenylalanine by 19% (P < 0.0495), reflecting an improvement in available lysine in the mixed meal due to increased lysine intake.

CONCLUSION: Although the bioavailability of lysine in sorghum is high its lysine content is limiting. Complementation with lentils in a 1:1 ratio is recommended to achieve the lysine requirements for adult males consuming a sorghum-based diet. Clinical Trials Number: Clinical Trials: NCT03411005.

PMID:34871427 | DOI:10.1093/jn/nxab410

Fam Pract. 2021 Dec 6:cmab145. doi: 10.1093/fampra/cmab145. Online ahead of print.

ABSTRACT

BACKGROUND: Primary care manages a significant proportion of healthcare in the United Kingdom and should be a key part of the SARS-CoV-2 pandemic response.

AIM: To assess preparedness for the SARS-CoV-2 pandemic by understanding GPs’ perception of their ability to manage current and future service demand, set-up of triage processes, and training in Covid-19 infection prevention and control procedures.

DESIGN AND SETTING: Cross-sectional survey of practicing GPs in the United Kingdom, with 2 rounds of data collection early in the pandemic.

METHODS: Online survey, scripted and hosted by medeConnect Healthcare, comprising 6 closed prompts on 7-point Likert scales, and an optional free-text component. Quantitative data were analysed using descriptive statistics. Free-text data were analysed thematically.

RESULTS: One thousand two GPs completed each round; 51 GPs completed free-text responses in March, and 64 in April. Quantitative data showed greatest confidence in triage of Covid-19 patients, and GPs were more confident managing current than future Covid-19 demand. GPs’ responses were more optimistic and aligned in April than March. Free-text data highlighted that GPs were concerned about lack of appropriate personal protective equipment and personal risk of Covid-19 infection in March, and unmet needs of non-Covid-19 patients in April. In both rounds, GPs expressed feeling overlooked by government and public health bodies.

CONCLUSION: Guidance to support general practice clinicians to manage future waves of Covid-19 or other health emergencies must be tailored to general practice from the outset, to support clinicians to manage competing health demands, and mitigate impacts on primary care providers’ wellbeing.

PMID:34871397 | DOI:10.1093/fampra/cmab145

Eur J Public Health. 2021 Dec 6:ckab185. doi: 10.1093/eurpub/ckab185. Online ahead of print.

ABSTRACT

BACKGROUND: Little is known about factors that may explain the association between depressive symptoms and poor labour market participation (LMP). The aim of this study is to examine the mediation and interaction effects of social support on the association between depressive symptoms and LMP.

METHODS: Data were used from 985 participants (91% of the initial cohort) of the Northern Swedish Cohort, a longitudinal study of Swedish participants followed from adolescence throughout adulthood. Depressive symptoms were measured at age 16, social support at age 21 and LMP from age 30 to 43. Poor LMP was defined as being unemployed for a total of 6 months or more between the ages of 30 and 43. A four-way decomposition approach was applied to identify direct, mediation and interaction effects, together and separately.

RESULTS: Both depressive symptoms during adolescence and social support at young adulthood were associated with poor LMP [odds ratio (OR) = 1.70, 95% confidence interval (CI) 1.17-2.47 and OR = 2.56, 95% CI 1.78-3.68 respectively]. The association between depressive symptoms and poor LMP was partially mediated by a lack of social support. No interaction effect of a lack of social support was found.

CONCLUSION: The results suggest that depressive symptoms influence not only later LMP but also the intermediary level of social support, and in turn influencing later LMP. Recommendations for public health are to detect and treat depressive symptoms at an early stage and to focus on the development of social skills, facilitating the increased availability of social support, thereby improving future LMP.

PMID:34871391 | DOI:10.1093/eurpub/ckab185

Fam Pract. 2021 Dec 6:cmab155. doi: 10.1093/fampra/cmab155. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: New Zealand (NZ) has high rates of colorectal cancer (CRC) but low rates of early detection. The majority of CRC is diagnosed through general practice, where lengthy diagnostic intervals are common. We investigated factors contributing to diagnostic delay in a cohort of patients newly diagnosed with CRC.

METHODS: Patients were recruited from the Midland region and interviewed about their diagnostic experience using a questionnaire based on a modified Model of Pathways to Treatment framework and SYMPTOM questionnaire. Descriptive statistics were used to describe the population characteristics. Chi-square analysis and logistic regression were used to analyse factors influencing diagnostic intervals.

RESULTS: Data from 176 patients were analysed, of which 65 (36.9%) experienced a general practitioner (GP) diagnostic interval of >120 days and 96 (54.5%) experienced a total diagnostic interval (TDI) > 120 days. Patients reporting rectal bleeding were less likely to experience a long TDI (odds ratio [OR] 0.34, 95% confidence interval [CI]: 0.14-0.78) and appraisal/help-seeking interval (OR, 0.19, 95% CI: 0.06-0.59). Patients <60 were more likely to report a longer appraisal/help-seeking interval (OR, 3.32, 95% CI: 1.17-9.46). Female (OR, 2.19, 95% CI: 1.08-4.44) and Māori patients (OR, 3.18, 95% CI: 1.04-9.78) were more likely to experience a long GP diagnostic interval.

CONCLUSION: NZ patients with CRC can experience long diagnostic intervals, attributed to patient and health system factors. Young patients, Māori, females, and patients experiencing change of bowel habit may be at particular risk. We need to increase symptom awareness of CRC for patients and GPs. Concentrated efforts are needed to ensure equity for Māori in access to screening, diagnostics, and treatment.

PMID:34871389 | DOI:10.1093/fampra/cmab155

Interact Cardiovasc Thorac Surg. 2021 Dec 6:ivab330. doi: 10.1093/icvts/ivab330. Online ahead of print.

ABSTRACT

OBJECTIVES: Surgical treatment of destructive infective endocarditis consists of extensive debridement followed by root repair or replacement. However, it remains unknown whether 1 is superior to the other. We aimed to analyse whether long-term results were better after root repair or replacement in patients with root endocarditis.

METHODS: A total of 148 consecutive patients with root endocarditis treated with surgery from 1997 to 2020 at our department were included. Patients were divided into 2 groups: aortic root repair (n = 85) or root replacement using xenografts or homografts (n = 63).

RESULTS: Patients receiving aortic root repair showed significantly better long-term survival compared to patients receiving aortic root replacement (log-rank: P = 0.037). There was no difference in terms of freedom from valvular reoperations among both treatment groups (log-rank: P = 0.58). Patients with aortic root repair showed higher freedom from recurrent endocarditis compared to patients with aortic root replacement (log-rank: P = 0.022). Patients with aortic root repair exhibited higher event-free survival (defined as a combination end point of freedom from death, valvular reoperation or recurrent endocarditis) compared to patients receiving aortic root replacement (log-rank: P = 0.022). Age increased the risk of mortality with 1.7% per year. Multi-variable adjusted statistical analysis revealed improved long-term event-free survival after aortic root repair (hazards ratio: 0.57, 95% confidence interval: 0.39-0.95; P = 0.031).

CONCLUSIONS: Aortic root repair and replacement are feasible options for the surgical treatment of root endocarditis and are complementary methods, depending on the extent of infection. Patients with less advanced infection have a more favourable prognosis.

CLINICAL TRIAL REGISTRATION: UN4232 382/3.1 (retrospective study).

PMID:34871383 | DOI:10.1093/icvts/ivab330

Eur J Prev Cardiol. 2021 Dec 6:zwab208. doi: 10.1093/eurjpc/zwab208. Online ahead of print.

ABSTRACT

AIMS: As the potential impact of statins on cognitive decline and dementia is still debated, we conducted a meta-analysis of observational studies to examine the effect of statin use on the risk of Alzheimer’s disease (AD) and dementia.

METHODS AND RESULTS: PubMed, Cochrane, and EMBASE were searched since inception to January 2021. Inclusion criteria were: (i) cohort or case-control studies; (ii) statin users compared to non-users; and (iii) AD and/or dementia risk as outcome. Estimates from original studies were pooled using restricted maximum-likelihood random-effect model. Measure of effects were reported as odds ratio (OR) and 95% confidence intervals (CIs). In the pooled analyses, statins were associated with a decreased risk of dementia [36 studies, OR 0.80 (CI 0.75-0.86)] and of AD [21 studies, OR 0.68 (CI 0.56-0.81)]. In the stratified analysis by sex, no difference was observed in the risk reduction of dementia between men [OR 0.86 (CI 0.81-0.92)] and women [OR 0.86 (CI 0.81-0.92)]. Similar risks were observed for lipophilic and hydrophilic statins for both dementia and AD, while high-potency statins showed a 20% reduction of dementia risk compared with a 16% risk reduction associated with low-potency statins, suggesting a greater efficacy of the former, although a borderline statistical significance (P = 0.05) for the heterogeneity between estimates.

CONCLUSION: These results confirm the absence of a neurocognitive risk associated with statin treatment and suggest a potential favourable role of statins. Randomized clinical trials with an ad hoc design are needed to explore this potential neuroprotective effect.

PMID:34871380 | DOI:10.1093/eurjpc/zwab208

Arch Pathol Lab Med. 2021 Dec 6. doi: 10.5858/arpa.2021-0175-OA. Online ahead of print.

ABSTRACT

CONTEXT.—: Despite continued surveillance and intravesical therapy, a significant subset of patients with lamina propria-invasive bladder cancer (T1) will progress to muscle-invasive disease or metastases.

OBJECTIVE.—: To analyze the value of pathologic subcategorization of T1 disease in predicting progression.

DESIGN.—: Six substaging methods were applied to a retrospective cohort of 73 patients, with pT1 urothelial carcinoma diagnosed on biopsy/transurethral resection. Additionally, the immunohistochemistry for GATA3 and cytokeratin 5/6 (CK5/6) was performed to study the prognostic value of stratifying T1 cancers into luminal or basal phenotypes.

RESULTS.—: On follow-up (mean, 46 months), 21 (29%) experienced at least 1 recurrence without progression, and 16 (22%) had progression to muscle-invasive disease and/or distant metastasis. No differences were noted between progressors and nonprogressors with regard to sex, age, treatment status, medical history, tumor grade, and presence of carcinoma in situ. Substaging using depth of invasion (cutoff ≥1.4 mm), largest invasive focus (≥3.6 mm), aggregate linear length of invasion (≥8.9 mm), and number of invasive foci (≥3 foci) correlated significantly with progression and reduced progression-free survival, whereas invasion into muscularis mucosa or vascular plexus, or focal versus extensive invasion (focal when ≤2 foci, each <1 mm) failed. Patients with luminal tumors had higher incidence of progression than those with nonluminal tumors (27% versus 11%), although the difference was statistically insignificant (P = .14).

CONCLUSIONS.—: Substaging of T1 bladder cancers should be attempted in pathology reports. Quantifying the number of invasive foci (≥3) and/or measuring the largest contiguous focus of invasive carcinoma (≥3.6 mm) are practical tools for prognostic substaging of T1 cancers.

PMID:34871364 | DOI:10.5858/arpa.2021-0175-OA