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.

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.

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.

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.

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.

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.

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.

Dietary flavonol, flavone and catechin intake and risk of colorectal cancer in the Netherlands Cohort Study.

Dietary flavonoids are hypothesized to be protective against colorectal cancer, yet findings have been inconsistent. We examined the association of dietary flavonol, flavone and catechin intake with colorectal cancer endpoints within the Netherlands Cohort Study (NLCS). In addition, we explored whether body mass index (BMI) may be an effect modifier of this association. The NLCS includes 120,852 men and women who were 55-69 years and completed a self-administered questionnaire at baseline in 1986. A case-cohort approach was used for data processing and analysis. After 13.3 years, 1,444 male and 1,041 female colorectal cancer cases were available for estimation of hazard ratios and 95% confidence intervals for quintiles of flavonoid intake. After adjustment for potential confounders, no association of total flavonol and flavone intake and total catechin intake with colorectal cancer endpoints was observed. Analyses stratified for BMI showed significant inverse trends in the association of total catechin intake, (+)-catechin intake and (-)-epicatechin intake with rectal cancer in men with a BMI>or=25 kg/m2 and in the association of total catechin intake and intake of kaempferol, myricetin and all individual catechins with colorectal cancer, in particular colon cancer, in women with a BMI<25 kg/m2. In conclusion, our findings generally do not support an association of dietary flavonol, flavone and catechin intake with colorectal cancer endpoints. Dietary catechin intake may be associated with a decreased rectal cancer risk in overweight men. Dietary flavonol and catechin intake may be associated with a decreased colorectal cancer risk in normal weight women.

Self-reported clothing size as a proxy measure for body size.

BACKGROUND: Few studies have considered the potential utility of clothing size as a predictor of diseases associated with body weight. METHODS: We used data on weight-stable men and women from a subcohort of the Netherlands Cohort Study to assess the correlation of clothing size with other anthropometric variables. Cox regression using the case-cohort approach was performed to establish whether clothing size can predict cancer risk after 13.3 years of follow-up, and if additionally considering body mass index (BMI) in the model improves the prediction. RESULTS: Trouser and skirt size correlated well with circumference measurements. Skirt size predicted endometrial cancer risk, and this effect was slightly attenuated when BMI was added to the model. Trouser size predicted risk of renal cell carcinoma, regardless of whether BMI was in the model. CONCLUSIONS: Clothing size appears to predict cancer risk independently of BMI, suggesting that clothing size is a useful measure to consider in epidemiologic studies when waist circumference is not available.

Pharmacoepigenomics in colorectal cancer: a step forward in predicting prognosis and treatment response.

Despite therapeutic innovations and increasing education on lifestyle to prevent colorectal cancer, it is still one of the most common cancer types, and for men the second cause of cancer-related death. Lately, much attention has been given to identify molecular markers involved in colorectal cancer prognosis and treatment with the aim to develop a more accurate classification system based on (epi)genetic alterations and, in addition, find markers that could potentially enhance management of colorectal cancer by predicting treatment response in advance. Although many genetic markers have been claimed to have prognostic or predictive influence, results are often inconclusive and, with some exception, they are not used in standard practice. Epigenetic alterations have received less attention although they are probably even more interesting as they can potentially be reversed through drug treatment. This review describes the current knowledge on the prognostic and predictive value of epigenetic markers in colorectal cancer.

Higher dietary flavone, flavonol, and catechin intakes are associated with less of an increase in BMI over time in women: a longitudinal analysis from the Netherlands Cohort Study.

BACKGROUND: Dietary flavonoids are suggested to have antiobesity effects. Prospective evidence of an association between flavonoids and body mass index (BMI) is lacking in general populations. OBJECTIVE: We assessed this association between 3 flavonoid subgroups and BMI over a 14-y period in 4280 men and women aged 55-69 y at baseline from the Netherlands Cohort Study. DESIGN: Dietary intake was estimated at baseline (1986) by a validated food-frequency questionnaire. BMI was ascertained through self-reported height (in 1986) and weight (in 1986, 1992, and 2000). Analyses were based on sex-specific quintiles for the total intake of 6 catechins and of 3 flavonols/flavones. Linear mixed effect modeling was used to assess longitudinal associations in 3 adjusted models: age only, lifestyle (age, energy intake, physical activity, smoking status, alcohol intake, type 2 diabetes, and coffee consumption), and lifestyle and diet (vegetables, fruit, fiber, grains, sugar, dessert, and dieting habits). RESULTS: After adjustment for age and confounders, the BMI (kg/m(2)) of women with the lowest intake of total flavonols/flavones and total catechins increased by 0.95 and 0.77, respectively, after 14 y. Women with the highest intake of total flavonols/flavones and total catechins experienced a significantly lower increase in BMI of 0.40 and 0.31, respectively (between group difference: P < 0.05). This difference remained after additional adjustment for dietary determinants and after stratification of median baseline BMI. In men, no significant differences in BMI change were observed over the quintiles of flavonoid intake after 14 y. CONCLUSION: Our results suggest that flavonoid intake may contribute to maintaining body weight in the general female population.

Characterisation of Salmonella enterica serotype Typhimurium isolates from wild birds in northern England from 2005 - 2006.

BACKGROUND: Several studies have shown that a number of serovars of Salmonella enterica may be isolated from wild birds, and it has been suggested that wild birds may play a role in the epidemiology of human and livestock salmonellosis. However, little is known about the relationship between wild bird S. enterica strains and human- and livestock- associated strains in the United Kingdom. Given the zoonotic potential of salmonellosis, the main aim of this study was to investigate the molecular epidemiology of S. enterica infections in wild birds in the north of England and, in particular, to determine if wild bird isolates were similar to those associated with disease in livestock or humans. RESULTS: Thirty two Salmonella enterica isolates were collected from wild birds in northern England between February 2005 and October 2006, of which 29 were S. enterica serovar Typhimurium (S. Typhimurium); one S. Newport, one S. Senftenberg, and one isolate could not be classified by serotyping. Further analysis through phage typing and macro-restriction pulsed-field gel electrophoresis indicated that wild passerine deaths associated with salmonellosis were caused by closely-related S. Typhimurium isolates, some of which were clonal. These isolates were susceptible to all antimicrobials tested, capable of invading and persisting within avian macrophage-like HD11 cells in vitro, and contained a range of virulence factors associated with both systemic and enteric infections of birds and mammals. However, all the isolates lacked the sopE gene associated with some human and livestock disease outbreaks caused by S. Typhimurium. CONCLUSION: The wild bird isolates of S. enterica characterised in this investigation may not represent a large zoonotic risk. Molecular characterisation of isolates suggested that S. Typhimurium infection in wild passerines is maintained within wild bird populations and the causative strains may be host-adapted.