Lithium salts as a treatment for COVID-19: Pre-clinical outcomes.

INTRODUCTION: Identifying effective drugs for Coronavirus disease 2019 (COVID-19) is urgently needed. An efficient approach is to evaluate whether existing approved drugs have anti-SARS-CoV-2 effects. The antiviral properties of lithium salts have been studied for many years. Their anti-inflammatory and immune-potentiating effects result from the inhibition of glycogen synthase kinase-3. AIMS: To obtain pre-clinical evidence on the safety and therapeutic effects of lithium salts in the treatment of COVID-19. RESULTS: Six different concentrations of lithium, ranging 2-12 mmol/L, were evaluated. Lithium inhibited the replication of SARS-CoV-2 virus in a dose-dependent manner with an IC50 value of 4 mmol/L. Lithium-treated wells showed a significantly higher percentage of monolayer conservation than viral control, particularly at concentrations higher than 6 mmol/L, verified through microscopic observation, the neutral red assay, and the determination of N protein in the supernatants of treated wells. Hamsters treated with lithium showed less intense disease with fewer signs. No lithium-related mortality or overt signs of toxicity were observed during the experiment. A trend of decreasing viral load in nasopharyngeal swabs and lungs was observed in treated hamsters compared to controls. CONCLUSIONS: These results provide pre-clinical evidence of the antiviral and immunotherapeutic effects of lithium against SARS-CoV-2, which supports an advance to clinical trials on COVID-19's patients.

A prospective evaluation of the American College of Surgeons Surgical Risk Calculator as a predictor of complications for breast surgery.

BACKGROUND: The infection rates for operative management of breast cancer are often unpredictable and higher than average for a clean surgical procedure (0.8% and 28%). We aimed to assess the effectiveness of the American College of Surgeons (ACS) Surgical Risk Calculator (SRC), a preoperative scoring system to calculate the risk of surgical site infection (SSI) and serious complications following breast surgery. METHODS: Prospective risk scoring using the SRC on 213 patients in the preoperative clinic and the incidence of SSI and serious complications within 30 days postoperatively was prospectively collected. RESULTS: The overall SSI rate in our sample was 5% (n=11/210 patients). For a one-unit increase in SRC score, the odds of having SSI increased by a factor of 1.88 (95% CI 1.33 to 2.74). Odds of developing SSI were higher in patients with high Body Mass Index (OR 1.25; 95% 1.13 to 1.40) and American Society of Anesthesiologists score 3 (OR 11.54; 95% CI 2.98 to 43.65). The odds of developing an SSI were ∼19 times higher if a patient had an SRC score >3.0 versus those with an SRC score <3.0. Only 3% (n=4) of patients who had an SRC score of <3.0 experienced SSI, compared with 33% (n=7) for those with a risk score of >3.0. Out of 210 patients, 9 had serious complications (4.2%). CONCLUSIONS: ACS SRC Score of more than 3 was associated with a higher likelihood of SSI. SRC was able to predict the risk of SSI and serious complications and can be used preoperatively for identification and risk minimisation.

A feasibility study using time-driven activity-based costing as a management tool for provider cost estimation: lessons from the national TB control program in Zimbabwe in 2018.

BACKGROUND: Insufficient cost data and limited capacity constrains the understanding of the actual resources required for effective TB control. This study used process maps and time-driven activity-based costing to document TB service delivery processes. The analysis identified the resources required to sustain TB services in Zimbabwe, as well as several opportunities for more effective and efficient use of available resources. METHODS: A multi-disciplinary team applied time-driven activity-based costing (TDABC) to develop process maps and measure the cost of clinical pathways used for Drug Susceptible TB (DS-TB) at urban polyclinics, rural district and provincial hospitals, and community based targeted screening for TB (Tas4TB). The team performed interviews and observations to collect data on the time taken by health care worker-patient pairs at every stage of the treatment pathway. The personnel's practical capacity and capacity cost rates were calculated on five cost domains. An MS Excel model calculated diagnostic and treatment costs. FINDINGS: Twenty-five stages were identified in the TB care pathway across all health facilities except for community targeted screening for TB. Considerable variations were observed among the facilities in how health care professionals performed client registration, taking of vital signs, treatment follow-up, dispensing medicines and processing samples. The average cost per patient for the entire DS-TB care was USD324 with diagnosis costing USD69 and treatment costing USD255. The average cost for diagnosis and treatment was higher in clinics than in hospitals (USD392 versus USD256). Nurses in clinics were 1.6 time more expensive than in hospitals. The main cost components were personnel (USD130) and laboratory (USD119). Diagnostic cost in Tas4TB was twice that of health facility setting (USD153 vs USD69), with major cost drivers being demand creation (USD89) and sputum specimen transportation (USD5 vs USD3). CONCLUSION: TDABC is a feasible and effective costing and management tool in low-resource settings. The TDABC process maps and treatment costs revealed several opportunities for innovative improvements in the NTP under public health programme settings. Re-engineering laboratory testing processes and synchronising TB treatment follow-up with antiretroviral treatments could produce better and more uniform TB treatments at significantly lower cost in Zimbabwe.

Effects of a dietary supplement enriched in palmitoleic acid on fatty acid composition of follicular fluid, granulosa cell metabolism, and oocyte developmental capacity in early lactation dairy cows.

In high-yielding dairy cows, some fertility traits can be influenced by the fatty acid (FA) composition of the follicular fluid during early lactation. The first objective of the current study was to evaluate the potential of dietary supplements enriched in specific FA to influence the FA composition of follicular fluid lipid classes in early lactation dairy cows. The second objective was to determine the influence of the resulting follicular fluid FA composition on the folliculogenesis, lipid and energy metabolism of granulosa cells, as well as oocyte quality and embryo development. Twenty Holstein multiparous cows in late gestation were randomly assigned to 200 g/d of FA supplements enriched in (1) palmitic acid (control treatment; 82% 16:0; PA) in the rumen or (2) palmitoleic acid (sea buckthorn oil; 27% cis-9 16:1, 28% 16:0, 22% cis-9 18:1, and 11% cis-9,cis-12 18:2; SBT) in the abomasum. The treatment period ranged from 20 ± 5 d precalving to 67 ± 2 d postcalving. Cumulus-oocyte complexes, granulosa cells, and follicular fluid were recovered from 2 sequential sessions of ovum pick-up (OPU-1 and OPU-2) at 46 and 67 ± 2 d postcalving (mean ± standard deviation). On the same days, blood samples were collected. Milk performance was recorded, and feed and milk samples were collected from d 8 to 10 ± 3 (onset of lactation), d 35 to 37 ± 2 (before OPU-1), and d 63 to 65 ± 2 (before OPU-2). Treatments did not affect milk yield or fat concentration throughout the experimental trial. Compared with PA, SBT increased the cis-9 16:1 concentration in milk fat, in plasma esterified lipid classes (phospholipids, cholesterol esters, and triacylglycerols), and in follicular fluid phospholipids and cholesterol esters at OPU-1. Abundance of mRNA for stearoyl-CoA desaturase 1 and 5, and perilipin 2 in granulosa cells was not different between treatments, but an increase in the level of stearoyl-CoA desaturase 5 was observed between the 2 OPU periods. Treatments did not affect oocyte quality and developmental capacity or embryo lipid metabolism when cultivated in vitro. These results suggest that limited modifications in the FA composition of the oocyte microenvironment via dietary lipid supplements enriched in specific FA had no major effects on granulosa cell metabolism and oocyte developmental capacity in early lactation cows.

Isolation and Purification of Pyrazines Produced by Reaction of Cellulosic-Derived Sugars with NH4OH and Selected Amino Acids.

Various pyrazines have been synthesized via reaction of selected cellulosic-derived sugars, ammonium hydroxide and amino acids at 110°C for 2 hours. Different methods of sample cleanup such as liquid-liquid extraction (LLE), liquid-solid extraction, column chromatography and distillation were employed to isolate pyrazines from the reaction mixture. Effective LLE of pyrazines from aqueous solution using either hexane, methyl-t-butyl ether (MTBE) or ethyl acetate required multiple extraction steps with fresh solvent each time. When hexane was used as the extraction solvent, no imidazole derivatives were extracted with the pyrazines. However, when MTBE or ethyl acetate was employed, 4-methyl imidazole was co-extracted and further cleanup was required. Passing the organic solvent extracts through a column of silica revealed that the silica retained the undesirable imidazoles, such as 4-methyl imidazole. A mixture of 90/10 hexane/ethyl acetate as eluting solvent provided the desirable pyrazines, but it also provided a desirable separation of pyrazines as a function of total alkyl substituent content. Distillation of the aqueous reaction mixture was also used to isolate the pyrazines, leaving the undesirable imidazoles in the undistilled portion of the reaction. Additional chromatographic methods were used to isolate pyrazines from the aqueous distillate including a column packed with C18-bonded silica.

The Growth Hormone Releasing Hormone Analogue, Tesamorelin, Decreases Muscle Fat and Increases Muscle Area in Adults with HIV.

BACKGROUND: Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue in people living with HIV, however, the effects on skeletal muscle fat and area are unknown. OBJECTIVES: The goals of this exploratory secondary analysis were to determine the effects of tesamorelin on muscle quality (density) and quantity (area). DESIGN: Secondary, exploratory analysis of two previously completed randomized (2:1), clinical trials. SETTING: U.S. and Canadian sites. PARTICIPANTS: People living with HIV and with abdominal obesity. Tesamorelin participants were restricted to responders (visceral adipose tissue decrease ≥8%). INTERVENTION: Tesamorelin or placebo. MEASUREMENTS: Computed tomography scans (at L4-L5) were used to quantify total and lean density (Hounsfield Units, HU) and area (centimeters2) of four trunk muscle groups using a semi-automatic segmentation image analysis program. Differences between muscle area and density before and after 26 weeks of tesamorelin or placebo treatment were compared and linear regression models were adjusted for baseline and treatment arm. RESULTS: Tesamorelin responders (n=193) and placebo (n=148) participants with available images were similar at baseline; most were Caucasian (83%) and male (87%). In models adjusted for baseline differences and treatment arm, tesamorelin was associated with significantly greater increases in density of four truncal muscle groups (coefficient 1.56-4.86 Hounsfield units; all p<0.005), and the lean anterolateral/abdominal and rectus muscles (1.39 and 1.78 Hounsfield units; both p<0.005) compared to placebo. Significant increases were also seen in total area of the rectus and psoas muscles (0.44 and 0.46 centimeters2; p<0.005), and in the lean muscle area of all four truncal muscle groups (0.64-1.08 centimeters2; p<0.005). CONCLUSIONS: Among those with clinically significant decrease in visceral adipose tissue on treatment, tesamorelin was effective in increasing skeletal muscle area and density. Long term effectiveness of tesamorelin among people with and without HIV, and the impact of these changes in daily life should be further studied.

Gene expression changes and toxicity of selected rare earth elements in rainbow trout juveniles.

Rare earth elements (REEs) are increasingly used in electronics industry and other areas of our economy and questions were raised about their impacts to the environment. The purpose of this study was to examine the lethal and sublethal toxicity of REEs in juvenile rainbow (Oncorhynchus mykiss) trout. The fish were exposed to increasing concentrations (0.064, 0.32, 1.6, 8 and 40 mg/L) of the following 7 REEs for 96 h at 15 °C: cerium (CeCl3), erbium (ErCl3), gadolinium (GdCl3), lanthanum (LaCl3), neodymium (NdCl3), samarium (SmCl3) and yttrium (YCl3). The mortality were determined and in the surviving fish, 10 target gene transcripts were measured in the liver to track changes in oxidative stress, DNA repair, tissue growth/proliferation, protein chaperoning, xenobiotic biotransformation and ammonia metabolism. The data revealed that Y, Sm, Er and Gd formed a distinct group based on toxicity (mortality) and gene expression changes. Electronegativity was significantly correlated (r = -0.8, p < 0.01) with the lethal concentration (LC50). Gene expression changes occurred at concentration circa 120 times lower than the LC50 and the following transcripts in protein chaperoning (heat shock proteins), DNA repair (growth arrest DNA Damage) and CYP1A1 gene expression involved in the metabolism of coplanar aromatic hydrocarbons were involved. In conclusion, the study revealed that the more electronegative REEs were the most toxic to trout juveniles and produced sublethal effects at concentrations 2 orders of magnitude lower than the lethal concentrations. The toxicity of REEs depends on the elements were toxicity involves specific pathways at the gene expression level.

Impact of indoor air quality on respiratory health: results of a local survey on housing environment.

OBJECTIVES: The 'Mon habitat: plus qu'un simple toit' (MHPQST) survey was designed to identify public health risks and priorities for local decision makers in relation to housing. The aims of the present study were to describe the exposure of households to indoor air contaminants and to verify the relationship between these contaminants and respiratory symptoms/diseases. STUDY DESIGN: This is a cross-sectional study. METHODS: MHPQST was conducted in Baie-Saint-Paul, a French Canadian municipality (7000 inhabitants) using a protocol adapted from the 'Large Analysis and Review of European Housing and Health Status' study performed in Europe in 2002-2003. Households were selected from two sectors (less favorable and more favorable). Data collection was achieved using three tools (two questionnaires and one inspection grid). Indoor air variables were analyzed in relation to respiratory symptoms/diseases using logistic regression models adjusted for age, gender, income, smoking status, and proximity. RESULTS: A total of 161 dwellings (294 inhabitants) participated in the survey. Presence of mold on walls, ceilings, or floors was detected by the investigators in 21% of the dwellings. Nearly half of the households were in contact with a pet at home and 12% with environmental tobacco smoke. Exposure to these three determinants was significantly associated with certain respiratory symptoms/diseases. CONCLUSION: Molds, pets at home, and environmental tobacco smoke are environmental determinants that were associated with respiratory health in the present survey. These results enabled sensitizing local stakeholders regarding the importance of indoor air quality for the respiratory health of their population.

CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction.

Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic sub-study of patients randomized to sildenafil (n=85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P-value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.

A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials.

We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.

Methylomic changes during conversion to psychosis.

The onset of psychosis is the consequence of complex interactions between genetic vulnerability to psychosis and response to environmental and/or maturational changes. Epigenetics is hypothesized to mediate the interplay between genes and environment leading to the onset of psychosis. We believe we performed the first longitudinal prospective study of genomic DNA methylation during psychotic transition in help-seeking young individuals referred to a specialized outpatient unit for early detection of psychosis and enrolled in a 1-year follow-up. We used Infinium HumanMethylation450 BeadChip array after bisulfite conversion and analyzed longitudinal variations in methylation at 411 947 cytosine-phosphate-guanine (CpG) sites. Conversion to psychosis was associated with specific methylation changes. Changes in DNA methylation were significantly different between converters and non-converters in two regions: one located in 1q21.1 and a cluster of six CpG located in GSTM5 gene promoter. Methylation data were confirmed by pyrosequencing in the same population. The 100 top CpGs associated with conversion to psychosis were subjected to exploratory analyses regarding the related gene networks and their capacity to distinguish between converters and non-converters. Cluster analysis showed that the top CpG sites correctly distinguished between converters and non-converters. In this first study of methylation during conversion to psychosis, we found that alterations preferentially occurred in gene promoters and pathways relevant for psychosis, including oxidative stress regulation, axon guidance and inflammatory pathways. Although independent replications are warranted to reach definitive conclusions, these results already support that longitudinal variations in DNA methylation may reflect the biological mechanisms that precipitate some prodromal individuals into full-blown psychosis, under the influence of environmental factors and maturational processes at adolescence.

Faecal occult blood testing screening for colorectal cancer and 'missed' interval cancers: are we ignoring the elephant in the room? Results of a multicentre study.

AIM: Biennial faecal occult blood testing (FOBT) is used to screen for colorectal cancer throughout the UK. Interval cancers are tumours that develop in patients between screening rounds who have had a negative FOBT. Through a multicentre study, we compared the demographics of patients with interval cancers, FOBT screen detected cancers and cancers that developed in patients who chose not to participate in the screening programme. METHOD: Five hundred and sixteen colorectal cancers were detected in the screening age group (60-74 years) population in three UK National Health Service hospitals over 2 years. One hundred and twenty seven (25%) were interval cancers, 161 (31%) were screen detected and 228 (44%) were cancers that developed in patients who had declined FOBT. The interval cancer group had a higher incidence of right-sided cancers (38% vs 29% and 24%), a higher proportion of high tumour stages (Dukes C and D) (70% vs 53% and 33%) and a shorter time from diagnosis to death (10 months vs 13 months and 24 months) compared to patients who had declined the FOBT and the FOBT screen detected cancers. Of all the patients studied, those with right-sided interval cancers had the worst outcome. CONCLUSION: A quarter of the colorectal cancers diagnosed in our study were interval cancers. Patients with right-sided interval cancers had the highest proportion of Dukes C and D tumours coupled with the shortest survival time after diagnosis compared with the other groups.

Isoniazid therapy for Mycobacterium tuberculosis infection in HIV clinics, Los Angeles, California.

SETTING: Publicly funded human immunodeficiency virus (HIV) clinics in Los Angeles County, California, USA. BACKGROUND: HIV-infected persons are a high priority group for targeted testing and treatment for Mycobacterium tuberculosis infection in the United States. OBJECTIVE: To describe rates of isoniazid (INH) initiation and completion among HIV-1 and M. tuberculosis co-infected persons in Los Angeles County. DESIGN: We conducted a cross-sectional study using routinely collected surveillance data from publicly funded HIV clinics. We examined differences in INH treatment initiation and completion between four clinic categories: the three largest clinics (Clinics A, B, and C) and 'Other' clinics (pooled data for the remaining 10 clinics). RESULTS: During 2010-2013, 802 (5.3%) of 15 029 HIV-1-infected persons tested positive for M. tuberculosis infection. INH was initiated in 581 (72.4%) persons, of whom 457 (78.7%) completed treatment. We found significant differences between clinics in terms of treatment initiation (range 59.1-93.4%) and completion (range 58.8-82.3%). Overall, 57% (457/802) of HIV and M. tuberculosis co-infected persons completed the recommended treatment (range across clinics 34.8-76.3%). CONCLUSION: We identified significant gaps in the treatment for M. tuberculosis infection among HIV-infected persons in Los Angeles County. Interventions are needed to improve initiation and completion of treatment for M. tuberculosis infection in this population.

Delay in diagnosis and lessons learnt from a case of abdominal wall abscess caused by fishbone perforation.

Complications following foreign body (FB) ingestion are an uncommon clinical problem. A 59-year-old man presented with a 4-week history of left iliac fossa pain and 1 episode of dark red blood mixed with stools. Inflammatory markers were elevated, and computed tomography (CT) of the abdomen and pelvis showed an ill defined abdominal wall inflammatory collection in close contact with the small bowel loops. He was treated with antibiotics, and follow-up CT, colonoscopy and small bowel enema were mostly unremarkable. The patient presented again ten months later with left iliac fossa cellulitis and fever. Multiplanar CT (the patient's fourth scan) demonstrated a 10cm abdominal wall collection with a linear hyperdense structure in the collection. The radiologists suspected a FB and on close scrutiny of the previous scans, they noted it to have been present on all of them. A targeted incision led to the removal of a 3cm fishbone from the collection. This case highlights the need to consider the possibility of a FB being the underlying cause in any unexplained intra-abdominal or abdominal wall inflammatory process so that the diagnosis is made in a timely manner.

Surgical resection of a liver metastasis from breast cancer.

We report a case of a solitary liver metastasis from breast cancer in a 65-year-old woman. The patient underwent a mastectomy and axillary lymph node clearance for right breast cancer in 1990. A solitary metastasis was found in the left lobe of the liver by ultrasonography, 20 years after the initial mastectomy. A left lateral segmentectomy was performed in January 2011 and adjuvant hormonal therapy was also initiated. At present, she remains disease free. This case demonstrates the implementation of liver resection to provide an effective treatment for metachronous metastatic breast cancer. We encourage surgeons to offer suitable patients this surgical treatment option, which is shown to provide a survival benefit.

Genetic markers of cisplatin-induced hearing loss in children.

This journal recently published a Commentary by Ratain and colleagues at the University of Chicago that criticizes our work on cisplatin-induced hearing loss in children. It is unfortunate that neither the authors nor the editors of Clinical Pharmacology & Therapeutics corresponded with us to provide an earlier opportunity to address these questions. Here we correct the authors' inaccuracies and provide additional analyses that further strengthen our published findings.

Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive brain disorder that causes gradual and irreversible loss of higher brain functions and is the most common cause of dementia in the elderly, as assessed by autopsy and clinical series. Furthermore, it has an annual incidence of approximately 3% in the 65-74-year-old age group. This incidence rate doubles with every increment of 5 years above the age of 65. In Morocco, AD affects almost 30,000 individuals and this number will possibly increase to 75,000 by 2020 (projections of the World Health Organization (WHO)). Genetically, AD is caused by a mutation in one of at least 3 genes: presenilin 1 (PS1), presenilin 2 (PS2) and the amyloid precursor protein (APP). Most cases are late onset and apparently sporadic, most likely as a result of a combination of environmental and non-dominant genetic factors. In Morocco, the genes predisposing individuals to AD and predicting disease incidence remain elusive. The purpose of the present study was to evaluate the genetic contribution of mutations in PS1 and PS2 genes to familial early-onset AD cases and sporadic late-onset AD cases. Seventeen sporadic late-onset AD cases and eight familial early-onset AD cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging and laboratory tests. Direct sequencing of each exon in PS1 and PS2 genes was performed on genomic DNA of AD patients. Further, we identified 1 novel frameshift mutation in the PS1 gene and 2 novel frameshift mutations in the PS2 gene. Our mutational analysis reports a correlation between clinical symptoms and genetic factors in our cases of Early-Onset Alzheimer's Disease (EOAD). These putative mutations cosegregate with affected family members suggesting a direct mutagenic effect.

Cuckoo search epistasis: a new method for exploring significant genetic interactions.

The advent of high-throughput sequencing technology has resulted in the ability to measure millions of single-nucleotide polymorphisms (SNPs) from thousands of individuals. Although these high-dimensional data have paved the way for better understanding of the genetic architecture of common diseases, they have also given rise to challenges in developing computational methods for learning epistatic relationships among genetic markers. We propose a new method, named cuckoo search epistasis (CSE) for identifying significant epistatic interactions in population-based association studies with a case-control design. This method combines a computationally efficient Bayesian scoring function with an evolutionary-based heuristic search algorithm, and can be efficiently applied to high-dimensional genome-wide SNP data. The experimental results from synthetic data sets show that CSE outperforms existing methods including multifactorial dimensionality reduction and Bayesian epistasis association mapping. In addition, on a real genome-wide data set related to Alzheimer's disease, CSE identified SNPs that are consistent with previously reported results, and show the utility of CSE for application to genome-wide data.