Enhancement and Comparison of (Ceftazidime-)Avibactam Plus Aztreonam Susceptibility Tests for Stenotrophomonas maltophilia in Clinical Diagnostics.

Stenotrophomonas maltophilia is naturally resistant to many antimicrobials. We evaluated the in vitro activity and reproducibility of two different super-position methods of aztreonam in combination with ceftazidime-avibactam for S. maltophilia and compared these results with the recently available aztreonam-avibactam gradient strip. We recommend an improved super-position method that avoids the possible risk of handling a contaminated aztreonam strip. In addition, we report that the cefazidime-avibactam and aztreonam super-position method showed increased in vitro activity in comparison with aztreonam-avibactam indicating activity of the ceftazidime component in vitro.

The Effects of ICU Crisis Reorganization on Outcomes in Patients Not Infected With Coronavirus Disease 2019 During the Initial Surge of the Coronavirus Disease 2019 Pandemic.

To determine if ICU reorganization due to the coronavirus disease 2019 pandemic affected outcomes in critically ill patients who were not infected with coronavirus disease 2019. DESIGN: This was a Before-After study, with coronavirus disease 2019-induced ICU reorganization as the intervention. A retrospective chart review of adult patients admitted to a reorganized ICU during the coronavirus disease 2019 surge (from March 23, 2020, to May 06, 2020: intervention group) was compared with patients admitted to the ICU prior to coronavirus disease 2019 surge (from January 10, 2020, to February 23, 2020: before group). SETTING: High-intensity cardiac, medical, and surgical ICUs of a community hospital in metropolitan Missouri. PATIENTS: All patients admitted to the ICU during the before and intervention period were included. Patients younger than 18 years old and those admitted after an elective procedure or surgery were excluded. Patients with coronavirus disease 2019 were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified a total of 524 eligible patients: 342 patients in the before group and 182 in the intervention group. The 28-day mortality was 25.1% (86/342) and 28.6% (52/182), respectively (p = 0.40). The ICU length of stay, ventilator length of stay, and ventilator-free days were similar in both groups. Rates of patient adverse events including falls, inadvertent endotracheal tube removal, reintubation within 48 hours of extubation, and hospital acquired pressure ulcers occurred more frequently in the study group (20 events, 11%) versus control group (12 events, 3.5%) (p = 0.001). CONCLUSIONS: Twenty-eight-day mortality, in patients who required ICU care and were not infected with coronavirus disease 2019, was not significantly affected by ICU reorganization during a pandemic.

Lifestyle, Diet, and Colorectal Cancer Risk According to (Epi)genetic Instability: Current Evidence and Future Directions of Molecular Pathological Epidemiology.

PURPOSE OF REVIEW: In this review, we describe molecular pathological epidemiology (MPE) studies from around the world that have studied diet and/or lifestyle factors in relation to molecular markers of (epi)genetic pathways in colorectal cancer (CRC), and explore future perspectives in this realm of research. The main focus of this review is diet and lifestyle factors for which there is evidence for an association with CRC as identified by the World Cancer Research Fund reports. In addition, we review promising hypotheses, that warrant consideration in future studies. RECENT FINDINGS: Associations between molecular characteristics of CRC have been published in relation to smoking, alcohol consumption; body mass index (BMI); waist:hip ratio; adult attained height; physical activity; early life energy restriction; dietary acrylamide, fiber, fat, methyl donors, omega 3 fatty acids; meat, including total protein, processed meat, and heme iron; and fruit and vegetable intake. SUMMARY: MPE studies help identify where associations between diet, lifestyle, and CRC risk may otherwise be masked and also shed light on how timing of exposure can influence etiology. Sample size is often an issue, but this may be addressed in the future by pooling data.

The CpG island methylator phenotype: what's in a name?

Although the CpG island methylator phenotype (CIMP) was first identified and has been most extensively studied in colorectal cancer, the term "CIMP" has been repeatedly used over the past decade to describe CpG island promoter methylation in other tumor types, including bladder, breast, endometrial, gastric, glioblastoma (gliomas), hepatocellular, lung, ovarian, pancreatic, renal cell, and prostate cancers, as well as for leukemia, melanoma, duodenal adenocarninomas, adrenocortical carcinomas, and neuroblastomas. CIMP has been reported to be useful for predicting prognosis and response to treatment in a variety of tumor types, but it remains unclear whether or not CIMP is a universal phenomenon across human neoplasia or if there should be cancer-specific definitions of the phenotype. Recently, it was shown that somatic isocitrate dehydrogenase-1 (IDH1) mutations, frequently observed in gliomas, establish CIMP in primary human astrocytes by remodeling the methylome. Interestingly, somatic IDH1 and IDH2 mutations, and loss-of-function mutations in ten-eleven translocation (TET) methylcytosine dioxygenase-2 (TET2) associated with a hypermethylation phenotype, are also found in multiple enchondromas of patients with Ollier disease and Mafucci syndrome, and leukemia, respectively. These data provide the first clues for the elucidation of a molecular basis for CIMP. Although CIMP appears as a phenomenon that occurs in various cancer types, the definition is poorly defined and differs for each tumor. The current perspective discusses the use of the term CIMP in cancer, its significance in clinical practice, and future directions that may aid in identifying the true cause and definition of CIMP in different forms of human neoplasia.

The mTOR Pathway and the Role of Energy Balance Throughout Life in Colorectal Cancer Etiology and Prognosis: Unravelling Mechanisms Through a Multidimensional Molecular Epidemiologic Approach.

Timing of exposure to lifestyle factors that influence energy balance may differentially affect colorectal cancer (CRC) risk and prognosis. Caloric restriction in youth and short stature, as markers of early-life exposures, have shown to decrease CRC risk, whereas large body size and low physical activity levels in adulthood are established risk factors for CRC. Regarding prognosis, overweight, sarcopenia, and their co-occurrence (sarcopenic obesity) may negatively influence the health and quality of life of CRC survivors. There is mechanistic support for disruption of the mammalian target of rapamycin (mTOR) pathway as an underlying mechanism possibly driving these associations, because mTOR integrates signals from growth factors, nutrients, mutagens, and hormones to induce cell proliferation, resistance to apoptosis, and autophagy. However, epidemiologic evidence connecting mTOR to energy-balance-related CRC throughout the lifespan is scarce. This perspective proposes how multidimensional molecular epidemiologic studies can shed light on the etiology and prognosis of energy-balance-related CRC.

Physical activity, occupational sitting time, and colorectal cancer risk in the Netherlands cohort study.

We investigated occupational energy expenditure and sitting time in the longest held job (in men only), nonoccupational physical activity, and former sports participation in relation to colorectal cancer endpoints. The Netherlands Cohort Study includes 120,852 participants who completed a self-administered questionnaire in 1986 when they were aged 55-69 years. By 2002, 1,819 male and 1,366 female colorectal cancer cases were available for case-cohort analyses. In men, higher occupational energy expenditure levels and fewer occupational sitting hours were associated with decreased hazard ratios for colon cancer, particularly distal colon cancer (occupational energy expenditure of ≥12 vs. <8 kJ/minute, hazard ratio (HR) = 0.71, 95% confidence interval (CI): 0.52, 0.97; P for trend = 0.01; occupational sitting hours of <2 vs. 6-8 hours/day, HR = 0.63, 95% CI: 0.48, 0.83; P for trend = 0.001). The median duration of the longest held job for male subcohort members was 29 years. Nonoccupational physical activity was inconsistently associated with colorectal cancer endpoints in men, and it was inversely associated with colon cancer in women, particularly distal colon cancer (>90 vs. ≤30 minutes/day, HR = 0.69, 95% CI: 0.50, 0.96; P for trend = 0.06), and rectal cancer (>90 vs. ≤30 minutes/day, HR = 0.59, 95% CI: 0.39, 0.90; P for trend = 0.02). In conclusion, regular long-term physical activity and fewer sitting hours may protect against colon cancer, particularly distal colon cancer; results for rectal cancer were mixed.

Body size and risk for colorectal cancers showing BRAF mutations or microsatellite instability: a pooled analysis.

BACKGROUND: How body size influences risk of molecular subtypes of colorectal cancer (CRC) is unclear. We investigated whether measures of anthropometry differentially influence risk of tumours according to BRAF c.1799T>A p.V600E mutation (BRAF) and microsatellite instability (MSI) status. METHODS: Data from The Netherlands Cohort Study (n = 120,852) and Melbourne Collaborative Cohort Study (n = 40,514) were pooled and included 734 and 717 colorectal cancer cases from each study, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for body mass index (BMI), waist measurement and height were calculated and compared for subtypes defined by BRAF mutation and MSI status, measured from archival tissue. RESULTS: Results were consistent between studies. When pooled, BMI modelled in 5 kg/m(2) increments was positively associated with BRAF wild-type (HR: 1.16, 95% CI: 1.08-1.26) and MS-stable tumours (HR: 1.15, 95% CI: 1.06-1.24). Waist measurement was also associated with BRAF wild-type (highest vs lowest quartile, HR: 1.59, 95% CI: 1.33-1.90) and MS-stable tumours (highest vs lowest quartile HR: 1.68, 95% CI: 1.31-2.15). The HRs for BRAF mutation tumours and MSI tumours were smaller and non-significant, but differences between the HRs by tumour subtypes were not significant. Height, modelled per 5-cm increase, was positively associated with BRAF wild-type and BRAF mutation tumours, but the HR was greater for tumours with a BRAF mutation than BRAF wild-type (HR: 1.23, 95% CI: 1.11-1.37, P(heterogeneity) = 0.03). Similar associations were observed with respect to height and MSI tumours (HR: 1.26, 95% CI: 1.13-1.40, P(heterogeneity) = 0.02). CONCLUSIONS: Generally, overweight increases the risk of CRC. Taller individuals have an increased risk of developing a tumour with a BRAF mutation or MSI.

Longitudinal changes in BMI in older adults are associated with meat consumption differentially, by type of meat consumed.

Hypotheses regarding the role of meat consumption in body weight modulation are contradictory. Prospective studies on an association between meat consumption and BMI change are limited. We assessed the association between meat consumption and change in BMI over time in 3902 men and women aged 55-69 y from the Netherlands Cohort Study. Dietary intake was estimated at baseline using a FFQ. BMI was ascertained through baseline self-reported height (1986) and weight (1986, 1992, and 2000). Analyses were based on sex-specific categories of daily total fresh meat, red meat, beef, pork, minced meat, chicken, processed meat, and fish consumption at baseline. Linear mixed effect modeling adjusted for confounders was used to assess longitudinal associations. Significant cross-sectional differences in BMI between quintiles of total meat intake were observed (P-trend < 0.01; both sexes). No association between total fresh meat consumption and prospective BMI change was observed in men (BMI change highest vs. lowest quintile after 14 y: -0.06 kg/m²; P = 0.75) and women (BMI change: 0.26 kg/m²; P = 0.20). Men with the highest intake of beef experienced a significantly lower increase in BMI after 6 and 14 y than those with the lowest intake (BMI change after 14 y 0.60 kg/m²). After 14 y, a significantly higher increase in BMI was associated with higher intakes of pork in women (BMI change highest vs. lowest quintile: 0.47 kg/m²) and chicken in both sexes (BMI change highest vs. lowest category in both men and women: 0.36 kg/m²). The results remained similar when stratifying on median baseline BMI, and age-stratified analyses yielded mixed results. Differential BMI change effects were observed for several subtypes of meat. However, total meat consumption, or factors directly related to total meat intake, was not strongly associated with weight change during the 14-y prospective follow-up in this elderly population.

Cross-sectional survey of antimicrobial prescribing patterns in UK small animal veterinary practice.

The increase in the prevalence of antimicrobial resistance has resulted in both human and veterinary antimicrobial use coming under increased scrutiny. The aim of this study was to characterise antimicrobial prescribing patterns in small-animal veterinary practices in the UK. A cross-sectional survey of UK small animal veterinarians was undertaken. A postal questionnaire to evaluate antimicrobial prescribing habits was sent to 900 clinicians. Data were collected on the clinicians, their practices and their sources of information regarding antimicrobials and their use. Respondents were asked if they would prescribe antimicrobials to animals described in four clinical scenarios, and, if so, to provide details of the prescription(s). Questionnaires were completed by 51% of the veterinarians. Only 3.5% of clinicians reported that their practice had an antimicrobial use policy. Penicillins were most commonly prescribed in three clinical scenarios, and 1st generation cephalosporins were most commonly prescribed in a scenario about canine pyoderma. In one scenario, fluoroquinolones and 3rd generation cephalosporins accounted for 10% and 13% of prescriptions respectively. Five percent of all prescriptions were under the recommended dose and 20% were over the recommended dose. Overall, 2.3% of prescriptions were not licensed for use in dogs or cats in the UK. Associations between the use of various antimicrobial drugs and independent variables were analysed using multivariable logistic regression models. Off-license prescriptions and inaccurate dosing of antimicrobials by small-animal clinicians in the UK appears to occur. Antimicrobial use guidelines are rare in small animal practice. The introduction of such guidelines has been shown to lead to more appropriate use of antimicrobials and is therefore recommended.

The CpG island methylator phenotype in colorectal cancer: progress and problems.

In recent years, attention has focused on the biology and potential clinical importance of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). While it is generally well accepted that etiologically and clinically distinct subgroups exist in this disease, a precise definition of CIMP remains to be established. Here, we summarize existing literature that documents the prevalence of CIMP in CRC, with particular attention to the various methods and definitions used to classify a tumor as CIMP positive. Through a systematic review on both case-series and population based studies, we examined only original research articles reporting on sporadic CRC and/or adenomas in unselected cases. Forty-eight papers published between January 1999 and August 2011 met the inclusion criteria. We describe the use of multiple gene panels, marker threshold values, and laboratory techniques which results in a wide range in the prevalence of CIMP. Because there is no universal standard or consensus on quantifying the phenotype, establishing its true prevalence is a challenge. This bottleneck is becoming increasingly evident as molecular pathological epidemiology continues to offer possibilities for clear answers regarding environmental risk factors and disease trends. For the first time, large, unselected series of cases are available for analysis, but comparing populations and pooling data will remain a challenge unless a universal definition of CIMP and a consensus on analysis can be reached, and the primary cause of CIMP identified.

Body size and colorectal cancer risk after 16.3 years of follow-up: an analysis from the Netherlands Cohort Study.

A large body size may differentially influence risk of colorectal cancer (CRC) by anatomic location. The Netherlands Cohort Study includes 120,852 men and women aged 55-69 years who self-reported weight, height, and trouser/skirt size at baseline (1986), as well as weight at age 20 years. Derived variables included body mass index (BMI; weight (kg)/height (m)(2)), BMI at age 20 years, and BMI change. After 16.3 years of follow-up (1986-2002), 2,316 CRC cases were available for case-cohort analysis. In men, the highest risk estimates were observed for body fat (per 5-unit increase in BMI, hazard ratio (HR) = 1.25, 95% confidence interval (CI): 1.05, 1.46; for highest quintile of trouser size vs. lowest, HR = 1.63, 95% CI: 1.17, 2.29 (P-trend = 0.02)) and appeared more closely associated with distal colon tumors (for BMI (5-unit increase), HR = 1.42, 95% CI: 1.13, 1.79; for highest quintile of trouser size, HR = 2.56, 95% CI: 1.55, 4.24 (P-trend < 0.01)) than with proximal colon or rectal tumors. In women, body fat was not associated with CRC risk unless it was considered simultaneously with physical activity; a large trouser/skirt size and a low level of physical activity increased risk for all subtypes. Height was associated with risk of CRC, especially distal colon tumors (highest quintile vs. lowest: HR = 1.53, 95% CI: 1.03, 2.27; P-trend = 0.05), in women only.

Evidence of spread of the emerging infectious disease, finch trichomonosis, by migrating birds.

Finch trichomonosis emerged in Great Britain in 2005 and led to epidemic mortality and a significant population decline of greenfinches, Carduelis chloris and chaffinches, Fringilla coelebs, in the central and western counties of England and Wales in the autumn of 2006. In this article, we show continued epidemic spread of the disease with a pronounced shift in geographical distribution towards eastern England in 2007. This was followed by international spread to southern Fennoscandia where cases were confirmed at multiple sites in the summer of 2008. Sequence data of the ITS1/5.8S/ITS2 ribosomal region and part of the small subunit (SSU) rRNA gene showed no variation between the British and Fennoscandian parasite strains of Trichomonas gallinae. Epidemiological and historical ring return data support bird migration as a plausible mechanism for the observed pattern of disease spread, and suggest the chaffinch as the most likely primary vector. This finding is novel since, although intuitive, confirmed disease spread by migratory birds is very rare and, when it has been recognised, this has generally been for diseases caused by viral pathogens. We believe this to be the first documented case of the spread of a protozoal emerging infectious disease by migrating birds.

Pulsed-field gel electrophoresis supports the presence of host-adapted Salmonella enterica subsp. enterica serovar Typhimurium strains in the British garden bird population.

Salmonellosis is a frequently diagnosed infectious disease of passerine birds in garden habitats within Great Britain with potential implications for human and domestic animal health. Postmortem examinations were performed on 1,477 garden bird carcasses of circa 50 species from England and Wales, 1999 to 2007 inclusive. Salmonellosis was confirmed in 263 adult birds of 10 passerine species in this 11-year longitudinal study. A subset of 124 fully biotyped Salmonella enterica subsp. enterica serovar Typhimurium isolates was examined using pulsed-field gel electrophoresis to investigate the hypothesis that these strains are host adapted and to determine whether this molecular technique offers greater resolution in understanding the epidemiology of Salmonella Typhimurium infection than phage typing alone. For the two most common phage types, definitive type (DT) 40 and DT56v, which together accounted for 97% (120/124) of isolates, pulsed-field gel electrophoresis groupings closely correlated with phage type with remarkably few exceptions. A high degree of genetic similarity (>90%) was observed within and between the two most common pulsed-field gel electrophoresis groups. No clustering or variation was found in the pulsed-field gel electrophoresis groupings by bird species, year, or geographical region beyond that revealed by phage typing. These findings support the hypothesis that there are currently two host-adapted Salmonella phage types, S. Typhimurium DT40 and DT56v, circulating widely in British garden birds and that the reservoir of infection is maintained within wild bird populations. Large-scale multilocus sequence typing studies are required to further investigate the epidemiology of this infection.

A clonal strain of Trichomonas gallinae is the aetiologic agent of an emerging avian epidemic disease.

Trichomonas gallinae is a protozoan parasite that is well characterised as a cause of trichomonosis in columbid and raptor species world-wide. The parasite emerged as a novel infection of British passerines in 2005, leading to epidemic mortality associated with significant declines of breeding populations of greenfinches (Carduelis chloris) and chaffinches (Fringilla coelebs). We characterised the extent of T. gallinae genotypic heterogeneity within the affected wild British avifauna by analysing individual isolates from 17 of the species affected. To do so, we employed improved platform-based multilocus typing tools as well as the hydrogenosomal Fe-hydrogenase gene as a single marker locus for fine-typing. We found no evidence of heterogeneity amongst the parasites infecting British passerines, indicating that a clonal strain of T. gallinae is the causative agent of this emerging infectious disease.

Body size, physical activity and risk of colorectal cancer with or without the CpG island methylator phenotype (CIMP).

BACKGROUND: We investigated how body size and physical activity influence the risk of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). METHODS: In the Netherlands Cohort Study (n = 120,852), risk factors were self-reported at baseline in 1986. After 7.3 years of follow-up, 603 cases and 4,631 sub-cohort members were available. CIMP status according to the Weisenberger markers was determined using methylation specific PCR on DNA from paraffin embedded tumor tissue. Hazard rate ratios (HR) and 95% confidence intervals for CIMP (27.7%) and non-CIMP (72.3%) tumors were calculated according to BMI, BMI at age 20, BMI change, trouser/skirt size, height, and physical activity. RESULTS: BMI modeled per 5 kg/m(2) increase was associated with both CIMP and non-CIMP tumors, however, HRs were attenuated when additionally adjusted for trouser/skirt size. Trouser/skirt size, per 2 size increase, was associated with both tumor subtypes, even after adjustment for BMI (CIMP HR: 1.20, 95%CI: 1.01-1.43; non-CIMP HR: 1.14, 95%CI: 1.04-1.28). Height per 5 cm was associated with both tumor sub-types, but HRs were attenuated when adjusted for body weight. BMI at age 20 was positively associated with increased risk of CIMP tumors and the association was significantly less pronounced for non-CIMP tumors (P-heterogeneity = 0.01). Physical activity was inversely associated with both subtypes, but a dose-response association was observed only for non-CIMP tumors (P-trend = 0.02). CONCLUSIONS: Body size, especially central adiposity, may increase the risk of both CIMP and non-CIMP tumors. Body fat at young age may differentially influence risk. Physical activity appears to decrease the risk of CRC regardless of these molecular subtypes.

Acute necrotising pneumonitis associated with Suttonella ornithocola infection in tits (Paridae).

Suttonella ornithocola, first isolated from the lungs of British tit species in 1996, was found to be a novel bacterium belonging to the family Cardiobacteriaceae. Comprehensive surveillance of garden bird mortality across Great Britain between April 2005 and April 2009 involved post mortem and microbiological examination of 82 tits (Paridae; multiple species) and six long-tailed tits (Aegithalidae; Aegithalos caudatus). S. ornithocola was isolated from six birds submitted from six incidents of morbidity and mortality involving Paridae and Aegithalidae species with a wide geographical distribution. The mortality incidents occurred sporadically at low incidence throughout the study period, which suggested that the infection is endemic in native bird populations, with a seasonal peak during early spring. Histopathological examination showed multiple foci of acute pulmonary necrosis associated with gram-negative cocco-bacillary bacteria. These findings supported the hypothesis that S. ornithocola is a primary pathogen of tits in Great Britain.

Emerging infectious disease leads to rapid population declines of common British birds.

Emerging infectious diseases are increasingly cited as threats to wildlife, livestock and humans alike. They can threaten geographically isolated or critically endangered wildlife populations; however, relatively few studies have clearly demonstrated the extent to which emerging diseases can impact populations of common wildlife species. Here, we report the impact of an emerging protozoal disease on British populations of greenfinch Carduelis chloris and chaffinch Fringilla coelebs, two of the most common birds in Britain. Morphological and molecular analyses showed this to be due to Trichomonas gallinae. Trichomonosis emerged as a novel fatal disease of finches in Britain in 2005 and rapidly became epidemic within greenfinch, and to a lesser extent chaffinch, populations in 2006. By 2007, breeding populations of greenfinches and chaffinches in the geographic region of highest disease incidence had decreased by 35% and 21% respectively, representing mortality in excess of half a million birds. In contrast, declines were less pronounced or absent in these species in regions where the disease was found in intermediate or low incidence. Also, populations of dunnock Prunella modularis, which similarly feeds in gardens, but in which T. gallinae was rarely recorded, did not decline. This is the first trichomonosis epidemic reported in the scientific literature to negatively impact populations of free-ranging non-columbiform species, and such levels of mortality and decline due to an emerging infectious disease are unprecedented in British wild bird populations. This disease emergence event demonstrates the potential for a protozoan parasite to jump avian host taxonomic groups with dramatic effect over a short time period.

Childhood and adolescent energy restriction and subsequent colorectal cancer risk: results from the Netherlands Cohort Study.

BACKGROUND: Energy restriction during childhood and adolescence is suggested to lower colorectal cancer (CRC) risk. We investigated this in the Netherlands Cohort Study. METHODS: Information on diet and other risk factors was collected by a baseline questionnaire in 1986 when cohort members were 55-69 years of age (n = 120 852). Three indicators of early life exposure to energy restriction were assessed: father's employment status during the Economic Depression (1932-40), place of residence during Second World War years (1940-44) and the 'Hunger Winter' (1944-45), a severe famine. Using the case-cohort approach, incidence rate ratios (RRs) and 95% confidence intervals (CIs) were calculated for total colorectal, proximal colon, distal colon, rectosigmoid and rectal cancers, according to the three time periods of energy restriction. After 16.3 years of follow-up, 2573 cases were available for multivariate analyses. RESULTS: Men who lived in a western city during the Hunger Winter and therefore exposed to the highest degree of energy restriction, had a lower risk of developing CRC (RR: 0.81, 95% CI: 0.68-0.98), and tumours of the proximal colon (RR: 0.72, 95% CI: 0.54-0.96) and rectum (RR: 0.71, 95% CI: 0.53-0.96). In women, non-statistically significant inverse associations were observed for tumours of the distal colon, rectosigmoid and rectum. Inverse associations were also observed between the other two exposure times and studied endpoints, though not statistically significant. CONCLUSIONS: This unique observational evidence suggests that severe energy restriction during childhood and adolescence may lower CRC risk, especially in men, thus providing insight regarding the role of energy intake during early life in CRC development.

Early life exposure to famine and colorectal cancer risk: a role for epigenetic mechanisms.

BACKGROUND: Exposure to energy restriction during childhood and adolescence is associated with a lower risk of developing colorectal cancer (CRC). Epigenetic dysregulation during this critical period of growth and development may be a mechanism to explain such observations. Within the Netherlands Cohort Study on diet and cancer, we investigated the association between early life energy restriction and risk of subsequent CRC characterized by the (promoter) CpG island methylation phenotype (CIMP). METHODOLOGY/PRINCIPAL FINDINGS: Information on diet and risk factors was collected by baseline questionnaire (n = 120,856). Three indicators of exposure were assessed: place of residence during the Hunger Winter (1944-45) and World War II years (1940-44), and father's employment status during the Economic Depression (1932-40). Methylation specific PCR (MSP) on DNA from paraffin embedded tumor tissue was performed to determine CIMP status according to the Weisenberger markers. After 7.3 years of follow-up, 603 cases and 4631 sub-cohort members were available for analysis. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals for CIMP+ (27.7%) and CIMP- (72.3%) tumors according to the three time periods of energy restriction, adjusted for age and gender. Individuals exposed to severe famine during the Hunger Winter had a decreased risk of developing a tumor characterized by CIMP compared to those not exposed (HR 0.65, 95%CI: 0.45-0.92). Further categorizing individuals by an index of '0-1' '2-3' or '4-7' genes methylated in the promoter region suggested that exposure to the Hunger Winter was associated with the degree of promoter hypermethylation ('0-1 genes methylated' HR = 1.01, 95%CI:0.74-1.37; '2-3 genes methylated' HR = 0.83, 95% CI:0.61-1.15; '4-7 genes methylated' HR = 0.72, 95% CI:0.49-1.04). No associations were observed with respect to the Economic Depression and WWII years. CONCLUSIONS: This is the first study indicating that exposure to a severe, transient environmental condition during adolescence and young adulthood may result in persistent epigenetic changes that later influence CRC development.

Genetically diverse coronaviruses in wild bird populations of northern England.

Infectious bronchitis virus (IBV) causes a costly respiratory viral disease of chickens. The role of wild birds in the epidemiology of IBV is poorly understood. We detected diverse coronaviruses by PCR in wildfowl and wading birds in England. Sequence analysis showed some viruses to be related to IBV.