Nevin Manimala

Nucleic Acids Res. 2021 Dec 6:gkab1147. doi: 10.1093/nar/gkab1147. Online ahead of print.

ABSTRACT

Data alignment is one of the first key steps in single cell analysis for integrating multiple datasets and performing joint analysis across studies. Data alignment is challenging in extremely large datasets, however, as the major of the current single cell data alignment methods are not computationally efficient. Here, we present VIPCCA, a computational framework based on non-linear canonical correlation analysis for effective and scalable single cell data alignment. VIPCCA leverages both deep learning for effective single cell data modeling and variational inference for scalable computation, thus enabling powerful data alignment across multiple samples, multiple data platforms, and multiple data types. VIPCCA is accurate for a range of alignment tasks including alignment between single cell RNAseq and ATACseq datasets and can easily accommodate millions of cells, thereby providing researchers unique opportunities to tackle challenges emerging from large-scale single-cell atlas.

PMID:34871454 | DOI:10.1093/nar/gkab1147

J Econ Entomol. 2021 Dec 6;114(6):2524-2533. doi: 10.1093/jee/toab192.

ABSTRACT

Australia is the third largest exporting country of cereals and a leader in other major commodity crops, yet little data exist on pesticide usage patterns in agriculture. This knowledge gap limits the management of off-target chemical impacts, such as the evolution of pesticide resistance. Here, for the first time, we quantify spatial patterns in neonicotinoid applications in Australia by coalescing land use data with sales and market research data contributed by agrichemical and agribusiness companies. An example application to resistance management is explored through the development of recommendations for the cosmopolitan crop pest, Myzus persicae (Sulzer) (Hemiptera: Aphididae), utilizing spatial statistical models. This novel dataset identified Australian neonicotinoid usage patterns, with most neonicotinoid products in Australia applied as cereal, canola, cotton and legume seed treatments and soil applications in sugarcane. Importantly, there were strong regional differences in pesticide applications, which will require regionally specific strategies to manage off-target impacts. Indeed, the estimated spatial grid of neonicotinoid usage demonstrated a statistically significant influence on the distribution of M. persicae neonicotinoid resistance, indicating off-target impacts are unevenly distributed in space. Future research on neonicotinoid usage will be supported by the spatial grids generated and made available through this study. Overall, neonicotinoid pesticides are widely relied upon throughout Australia’s plant production systems but will face increasing pressure from resistance evolution, emerging research on off-target impacts, and stricter regulatory pressures.

PMID:34871446 | DOI:10.1093/jee/toab192

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