Comparative Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With Blood-Based Biomarkers (Liquid Biopsy) vs Fecal Tests or Colonoscopy.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening is highly effective but underused. Blood-based biomarkers (liquid biopsy) could improve screening participation. METHODS: Using our established Markov model, screening every 3 years with a blood-based test that meets minimum Centers for Medicare & Medicaid Services' thresholds (CMSmin) (CRC sensitivity 74%, specificity 90%) was compared with established alternatives. Test attributes were varied in sensitivity analyses. RESULTS: CMSmin reduced CRC incidence by 40% and CRC mortality by 52% vs no screening. These reductions were less profound than the 68%-79% and 73%-81%, respectively, achieved with multi-target stool DNA (Cologuard; Exact Sciences) every 3 years, annual fecal immunochemical testing (FIT), or colonoscopy every 10 years. Assuming the same cost as multi-target stool DNA, CMSmin cost $28,500/quality-adjusted life-year gained vs no screening, but FIT, colonoscopy, and multi-target stool DNA were less costly and more effective. CMSmin would match FIT's clinical outcomes if it achieved 1.4- to 1.8-fold FIT's participation rate. Advanced precancerous lesion (APL) sensitivity was a key determinant of a test's effectiveness. A paradigm-changing blood-based test (sensitivity >90% for CRC and 80% for APL; 90% specificity; cost ≤$120-$140) would be cost-effective vs FIT at comparable participation. CONCLUSIONS: CMSmin could contribute to CRC control by achieving screening in those who will not use established methods. Substituting blood-based testing for established effective CRC screening methods will require higher CRC and APL sensitivities that deliver programmatic benefits matching those of FIT. High APL sensitivity, which can result in CRC prevention, should be a top priority for screening test developers. APL detection should not be penalized by a definition of test specificity that focuses on CRC only.

Management of postinfectious inflammatory arthritis.

PURPOSE OF REVIEW: Postinfectious inflammatory arthritis can result from various pathogens, including bacteria, viruses, fungi, and parasites. Prompt identification and treatment of acute infection is vital, but some cases progress to chronic arthritis despite successful treatment of infection. Postinfectious inflammatory arthritis varies from mild, self-limited arthralgia to severe, refractory arthritis, necessitating ongoing disease-modifying treatment. This review explores the spectrum of postinfectious inflammatory arthritis to provide insights into effective management. RECENT FINDINGS: Research continues regarding the benefit of antimicrobial therapy, beyond treatment of the acute infection, to diminish the severity of postinfectious inflammatory arthritis. Following treatment of acute infection, most cases are self-limited so treatment is symptomatic. However, a difficult-to-predict fraction of cases develop chronic postinfectious inflammatory arthritis that can be challenging to manage. Recently, as more biologic, and targeted synthetic DMARDs have become available, treatment options have expanded. SUMMARY: In this article, we use the term 'postinfectious inflammatory arthritis' rather than 'reactive arthritis' because it describes a broader spectrum of diseases and emphasizes the common pathogenesis of a postinfectious inflammatory process. We summarize the conventional therapies and recent management developments for the most frequently encountered postinfectious inflammatory arthritides.

An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis.

AIMS/HYPOTHESIS: Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk. METHODS: We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10-8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence. RESULTS: In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10-3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints. CONCLUSIONS/INTERPRETATION: Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis. DATA AVAILABILITY: Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer ( https://bcac.ccge.medschl.cam.ac.uk/bcacdata/ ); and overall prostate cancer ( http://practical.icr.ac.uk/blog/ ). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

Clinical and Genomic Characterization of Interval Colorectal Cancer in 3 Prospective Cohorts.

BACKGROUND & AIMS: Interval colorectal cancers (CRCs), cancers diagnosed after a screening/surveillance examination in which no cancer is detected, and before the date of next recommended examination, reflect an unprecedented challenge in CRC detection and prevention. To better understand this poorly characterized CRC variant, we examined the clinical and mutational characteristics of interval CRCs in comparison with screen detected CRCs. METHODS: We included 1175 CRCs documented in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and 3661 CRCs in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Multivariable Cox models were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of death risk. Whole exome sequencing was conducted in 147 PLCO cases and 796 NHS/HPFS cases. RESULTS: A total of 619 deaths (312 CRC-specific) and 2404 deaths (1904 CRC-specific) were confirmed during follow-up of PLCO and NHS/HPFS, respectively. Compared with screen detected CRCs, interval CRCs had a multivariate-adjusted HR (95% CI) of 1.47 (1.21-1.78) for CRC-specific mortality and 1.27 (1.09-1.47) for overall mortality (meta-analysis combining all 3 cohorts). However, we did not observe significant differences in mutational features between interval and screen detected CRCs (false discovery rate adjusted P > .05). CONCLUSION: Interval CRCs had a significantly increased risk of death compared with screen detected CRCs that were not explained by established clinical prognostic factors, including stage at diagnosis. The survival disadvantage of interval CRCs did not appear to be explained by differences in the genomic landscape of tumors characterized by whole exome sequencing.

Prospective and Mendelian randomization analyses on the association of circulating fatty acid binding protein 4 (FABP-4) and risk of colorectal cancer.

BACKGROUND: Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach. METHODS: The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. RESULTS: In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37). CONCLUSIONS: Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further.

15-Year Benefits of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality : A Pooled Analysis of Randomized Trials.

BACKGROUND: The effectiveness of screening for colorectal cancer (CRC) by sex and age in randomized trials is uncertain. OBJECTIVE: To evaluate the 15-year effect of sigmoidoscopy screening on CRC incidence and mortality. DESIGN: Pooled analysis of 4 large-scale randomized trials of sigmoidoscopy screening. SETTING: Norway, the United States, the United Kingdom, and Italy. PARTICIPANTS: Women and men aged 55 to 64 years at enrollment. INTERVENTION: Sigmoidoscopy screening. MEASUREMENTS: Primary end points were cumulative incidence rate ratio (IRR) and mortality rate ratio (MRR) and rate differences after 15 years of follow-up comparing screening versus usual care in intention-to-treat analyses. Stratified analyses were done by sex, cancer site, and age at screening. RESULTS: Analyses comprised 274 952 persons (50.7% women), 137 493 in the screening and 137 459 in the usual care group. Screening attendance was 58% to 84%. After 15 years, the rate difference for CRC incidence was 0.51 cases (95% CI, 0.40 to 0.63 cases) per 100 persons and the IRR was 0.79 (CI, 0.75 to 0.83). The rate difference for CRC mortality was 0.13 deaths (CI, 0.07 to 0.19 deaths) per 100 persons, and the MRR was 0.80 (CI, 0.72 to 0.88). Women had less benefit from screening than men for CRC incidence (IRR for women, 0.84 [CI, 0.77 to 0.91]; IRR for men, 0.75 [CI, 0.70 to 0.81]; P = 0.032 for difference) and mortality (MRR for women, 0.91 [CI, 0.77 to 1.17]; MRR for men, 0.73 [CI, 0.64 to 0.83]; P = 0.025 for difference). There was no statistically significant difference in screening effect between persons aged 55 to 59 years and those aged 60 to 64 years. LIMITATION: Data from the U.K. trial were less granular because of privacy regulations. CONCLUSION: This pooled analysis of all large randomized trials of sigmoidoscopy screening demonstrates a significant and sustained effect of sigmoidoscopy on CRC incidence and mortality for 15 years. PRIMARY FUNDING SOURCE: Health Fund of South-East Norway.

Assessing aneuploidy with repetitive element sequencing.

We report a sensitive PCR-based assay called Repetitive Element AneupLoidy Sequencing System (RealSeqS) that can detect aneuploidy in samples containing as little as 3 pg of DNA. Using a single primer pair, we amplified ∼350,000 amplicons distributed throughout the genome. Aneuploidy was detected in 49% of liquid biopsies from a total of 883 nonmetastatic, clinically detected cancers of the colorectum, esophagus, liver, lung, ovary, pancreas, breast, or stomach. Combining aneuploidy with somatic mutation detection and eight standard protein biomarkers yielded a median sensitivity of 80% in these eight cancer types, while only 1% of 812 healthy controls scored positive.

Composite dietary antioxidant index and the risk of colorectal cancer: Findings from the Singapore Chinese Health Study.

Colorectal cancer (CRC) is a major contributor to cancer death globally. Several studies showed some protections by certain individual dietary antioxidants against CRC development. Epidemiologic data on the composite dietary antioxidant index (CDAI) in relation to CRC risk are sparse. Using the Singapore Chinese Health Study, an ongoing prospective cohort consisting of 61 321 cancer-free participants aged 45 to 74 years at baseline, a food-based CDAI was calculated according to a previously established and validated method that included six food-sourced antioxidants including vitamins A, C and E, manganese, selenium and zinc. Cox proportional hazard regression method was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for CRC associated with various levels of CDAI with adjustment for multiple potential confounders. After an average of 17.5 years of follow-up, 2140 participants developed CRC. HRs (95% CIs) of CRC for quartiles 2, 3 and 4 of CDAI were 0.94 (0.83-1.07), 0.86 (0.75-1.00) and 0.80 (0.66-0.98), respectively, compared to the lowest quartile (Ptrend  = .02). This inverse association between CDAI and CRC risk was more apparent in women or those without a history of diabetes, without family history of CRC, never smokers or overweight/obese individuals. However, none of the heterogeneity tests for the CDAI-CRC risk association reached statistical significance. Our findings suggest that food-based antioxidants may be beneficial for reducing the risk of CRC in the general population.

Genetic variants associated with circulating C-reactive protein levels and colorectal cancer survival: Sex-specific and lifestyle factors specific associations.

Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected Pinteraction  = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.

Relating Period and Cohort Fertility.

From a population perspective, the trajectories of both the total fertility at successive time periods and the total fertility of successive birth cohorts are derived from the same array of age-specific fertility rates. This analysis uses the assumption of constant age-specific fertility proportions to derive new explicit relationships between period and cohort fertility. In short, period total fertility is approximately equal to the total fertility of the cohort born a generation earlier, with a modest additive adjustment. A simple relationship also links both period and cohort total fertility to ACF, the average fertility of the childbearing cohorts in a given year. Assuming that fertility levels follow a cubic curve, cohort values from the derived relationships are then compared to observed cohort fertility values for the United States in 1917-2019. Despite substantial violations of the constant proportional fertility assumption, the calculated values deviate from the observed values by an average of only 7-8%. Short-term projections suggest that U.S. cohort fertility will continue to decline.

Fighting Prejudice and Absorbing Refugees From Nazism: The National Committee for the Resettlement of Foreign Physicians, 1939-1945.

In the 1930s and 1940s, the medical profession reacted with hostility and erected formidable barriers to refugee physicians from Nazi-dominated Europe who sought to practice medicine in the United States. Yet, refugee physicians ultimately succeeded, with 77% of them working as doctors by 1945 and 98.6% by 1947. Although physician skills are readily transferable, and the United States had a genuine need for doctors after World War II drew 55 000 physicians into the military, refugee physicians' success can be attributed to the courageous physician leaders who lobbied on their behalf and the creation of the National Committee for the Resettlement of Foreign Physicians-an organization that helped immigrant physicians pass licensing examinations, identify locations for employment, and overcome barriers to integration into American society.

A Mixed-Effects Model for Powerful Association Tests in Integrative Functional Genomics.

Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants for many complex diseases; however, these variants explain only a small fraction of the heritability. Recently, genetic association studies that leverage external transcriptome data have received much attention and shown promise for discovering novel variants. One such approach, PrediXcan, is to use predicted gene expression through genetic regulation. However, there are limitations in this approach. The predicted gene expression may be biased, resulting from regularized regression applied to moderately sample-sized reference studies. Further, some variants can individually influence disease risk through alternative functional mechanisms besides expression. Thus, testing only the association of predicted gene expression as proposed in PrediXcan will potentially lose power. To tackle these challenges, we consider a unified mixed effects model that formulates the association of intermediate phenotypes such as imputed gene expression through fixed effects, while allowing residual effects of individual variants to be random. We consider a set-based score testing framework, MiST (mixed effects score test), and propose two data-driven combination approaches to jointly test for the fixed and random effects. We establish the asymptotic distributions, which enable rapid calculation of p values for genome-wide analyses, and provide p values for fixed and random effects separately to enhance interpretability over GWASs. Extensive simulations demonstrate that our approaches are more powerful than existing ones. We apply our approach to a large-scale GWAS of colorectal cancer and identify two genes, POU5F1B and ATF1, which would have otherwise been missed by PrediXcan, after adjusting for all known loci.

Strategies for Colorectal Cancer Screening.

The incidence of colorectal cancer (CRC) is increasing worldwide. CRC has high mortality when detected at advanced stages, yet it is also highly preventable. Given the difficulties in implementing major lifestyle changes or widespread primary prevention strategies to decrease CRC risk, screening is the most powerful public health tool to reduce mortality. Screening methods are effective but have limitations. Furthermore, many screen-eligible people remain unscreened. We discuss established and emerging screening methods, and potential strategies to address current limitations in CRC screening. A quantum step in CRC prevention might come with the development of new screening strategies, but great gains can be made by deploying the available CRC screening modalities in ways that optimize outcomes while making judicious use of resources.

Colorectal cancer prevention: Immune modulation taking the stage.

Prevention or early detection is one of the most promising strategies against colorectal cancer (CRC), the second leading cause of cancer death in the US. Recent studies indicate that antitumor immunity plays a key role in CRC prevention. Accumulating evidence suggests that immunosurveillance represents a critical barrier that emerging tumor cells have to overcome in order to sustain the course of tumor development. Virtually all of the agents with cancer preventive activity have been shown to have an immune modulating effect. A number of immunoprevention studies aimed at triggering antitumor immune response against early lesions have been performed, some of which have shown promising results. Furthermore, the recent success of immune checkpoint blockade therapy reinforces the notion that cancers including CRC can be effectively intervened via immune modulation including immune normalization, and has stimulated various immune-based combination prevention studies. This review summarizes recent advances to help better harness the immune system in CRC prevention.

DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility.

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

Meta-analysis of 16 studies of the association of alcohol with colorectal cancer.

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

Lyme disease: diagnosis and treatment.

PURPOSE OF REVIEW: Lyme disease is an important, vector-borne infection found throughout the temperate Northern hemisphere. The disease causes rash, acute systemic illness, and in some untreated patients, inflammatory arthritis. This review examines the emergence, clinical features and management of early Lyme disease and Lyme arthritis. RECENT FINDINGS: There has been continuing progress in characterizing the clinical manifestations, diagnostic testing and treatment of Lyme disease. Almost all patients with early Lyme disease can be cured with antibiotic treatment. In most cases, Lyme arthritis also responds to antibiotics, but some patients require additional treatment approaches. SUMMARY: The diagnosis of Lyme disease is based on clinical manifestations and adjunctive laboratory testing. For the rheumatologist, Lyme arthritis should be recognized by a pattern of attacks of asymmetric, oligo-arthritis, recognizable by clinical manifestations in the same way that other rheumatic diseases, such as gout or rheumatoid arthritis, are diagnosed.

Contribution of Surveillance Colonoscopy to Colorectal Cancer Prevention.

BACKGROUND & AIMS: The contribution of surveillance colonoscopy, as opposed to that of initial colonoscopy examination, to prevention of colorectal cancer (CRC) is uncertain. We estimated the preventive effect of surveillance colonoscopy by applying the recently developed metric of adenoma dwell time avoided needed to prevent 1 CRC case (DTA). METHODS: We followed subjects in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial who underwent colonoscopies following positive findings from sigmoidoscopies (colonoscopy cohort, n = 15,935) for CRC incidence for 10 years. The number and timing of adenomas removed during surveillance were measured in a subset (n = 3492) of patients and extrapolated to the entire cohort to estimate the total avoided adenoma dwell time. A previously determined DTA value of 612 dwell years was applied to estimate the number of CRC cases prevented by surveillance. Proportional reduction in CRC was computed as CP/(CO+CP), where CO and CP are observed and estimated prevented cases, respectively. RESULTS: In the colonoscopy cohort of the PLCO, 2882 subjects had advanced adenomas (AAs), 572 had 3 or more non-advanced adenomas (NAA3+), 4496 had 1-2 non-advanced adenomas (NAA1-2), and 7985 had no adenoma (NA). The mean number of subsequent colonoscopy examinations over 10 years were 1.80 for subjects with AAs, 1.63 for subjects with NAA3+, and 1.46 for subjects with NAA1-2. Average years of avoided adenoma dwell time per subject were 4.0 for subjects with AAs, 5.5 for subjects with NAA3+, and 2.4 for subjects with NAA1-2. There were 56 cases of CRC in subjects with AAs, 4 cases of CRC in subjects with NAA3+, and 33 cases of CRC in subjects with NAA1-2. Estimated proportional reductions in CRC incidence were 25.0% in subjects with AAs (95% CI, 16%-34%), 34.4% in subjects with NAA1-2 (95% CI, 25%-40%), and 30.4% overall (in subjects with AAs, NAA3+, or NAA1-2; 95% CI, 25%-40%). Absolute CRC incidence reductions were 7.1 per 10,000 PY in subjects with AAs and 4.1 per 10,000 PY in subjects with NAA1-2. CONCLUSIONS: Using the recently developed metric of DTA, we estimated that surveillance colonoscopy in the PLCO colonoscopy cohort during 10 years of follow up prevented 30% of CRC cases. Because the methodology for estimation is indirect, the true effect is uncertain.