To characterize the clinical course, therapies, and outcomes of children with fatal and near-fatal asthma admitted to the pediatric intensive care unit (PICU).
Retrospective chart abstraction across the eight tertiary-care PICUs in the Collaborative Pediatric Critical Care Research Network (CPCCRN). Inclusion criteria: children (1–18 years) admitted 2005 to 2009 (inclusive) for asthma receiving ventilation (near-fatal) or died (fatal). Data collected included medications, ventilator strategies, concomitant therapies, demographics and risk variables.
Of 261 eligible children, 33 (13%) had no previous history of asthma, 218 (84%) survived with no known complications, and 32 (12%) had complications. Eleven (4%) died, 10 having had cardiac arrest before admission. Patients intubated outside the PICU had shorter ventilation (median 25 vs. 84 hours, p<0.001). African-Americans were disproportionately represented by numbers intubated and had shorter durations of intubation. Barotrauma occurred in 15 (6%) children before admission. Pharmacological therapies were highly variable with similar outcomes.
Of children ventilated in CPCCRN PICUs, 96% survived to hospital discharge. Most children who died experienced cardiac arrest prior to admission. Intubation outside the PICU was correlated with shorter ventilation duration. The complications of barotrauma and neuromyopathy were uncommon. Practice patterns varied widely between CPCCRN sites.
status asthmaticus; intensive care; death; cause of death; morbidity; intubation; barotraumas; mechanical ventilation; clinical practices; variability; child
To describe pediatric severe asthma care, complications and outcomes to plan for future prospective studies by the Collaborative Pediatric Critical Care Research Network (CPCCRN).
Retrospective cohort study.
Pediatric intensive care units (PICU)s in the United States that submit administrative data to the Pediatric Health Information System (PHIS).
Children 1-18 years treated in a PHIS PICU for asthma during 2004 to 2008.
Measurement and Main Results
13,552 children were studied; 2,812 (21%) treated in a CPCCRN and 10,740 (79%) in a non-CPCCRN PICU. Medication use in individual CPCCRN centers differed widely: ipratropium bromide (41-84%) terbutaline (11-74%), magnesium sulfate (23-64%) and methylxanthines (0-46%). Complications including pneumothorax (0-0.6%), cardiac arrest (0.2-2%) and aspiration (0.2-2%) were rare. Overall use of medical therapies and complications at CPCCRN centers were representative of pediatric asthma care at non-CPCCRN PICUs.
Median length of PICU stay at CPCCRN centers was 1 to 2 days and death was rare (0.1-3%). Ten percent of children treated at CPCCRN centers received invasive mechanical ventilation compared to12 percent at non-CPCCRN centers. Overall 44% of patients who received invasive mechanical ventilation were intubated in the PICU. Children intubated outside the PICU had significantly shorter median ventilation days (1 vs.3), PICU days (2 vs. 4) and hospital days (4 vs. 7) compared to those intubated in the PICU. Among children who received mechanical respiratory support significantly more (41 vs. 25%) were treated with non-invasive ventilation and significantly fewer (41 vs. 58%) were intubated prior to PICU care when treated in a PHIS hospital emergency department.
Marked variations in medication therapies and mechanical support exist. Death and other complications were rare. Over half of patients treated with mechanical ventilation were intubated prior to PICU care. Site of respiratory mechanical support initiation is associated with length of stay.
Asthma; mechanical ventilation; non-invasive ventilation; variation; pediatric; terbutaline; heliox; magnesium sulfate; methylxanthines
The object of this study was to determine if cerebrospinal fluid (CSF) shunt revision(s) are associated with increased risk of CSF shunt infection, after adjusting for baseline factors that contribute to infection risk.
This was a retrospective cohort study of 579 children ages 0 to 18 who underwent initial CSF shunt placement between 1/1/97 and 10/12/06 at a tertiary care children’s hospital. The outcome of interest was CSF shunt infection. Data for all subsequent CSF shunt revisions leading up to and including the initial CSF shunt infection, when applicable, were obtained. The likelihood of infection was determined using a Cox proportional hazard model accounting for patient characteristics and CSF shunt revisions, and is reported using hazard ratios (HR) with 95% confidence intervals (CI).
There were 123 children who developed infection. Baseline factors independently associated with hazard of infection included age 0 to <6 months at CSF shunt placement (HR 2.4, 95% CI: 1.02, 6.7) and myelomeningocele (HR 0.4, 95% CI: 0.2, 0.8). Controlling for baseline factors, the risk of infection after shunt revision was significantly greater than at the time of initial placement (HR 3.0, 95% CI: 1.9, 4.7), and this risk increased as numbers of revisions increased (≥2 revisions HR 6.5, 95% CI: 3.6, 11.4).
While younger age is associated with increased hazard of infection, subsequent CSF shunt revision significantly increases infection risk.
cerebrospinal; shunt; infection; revision; failure; children
Few prospective cohort studies of workplace low back pain (LBP) with quantified job physical exposure have been performed. There are few prospective epidemiological studies for LBP occupational risk factors and reported data generally have few adjustments for many personal and psychosocial factors.
A multi-center prospective cohort study has been incepted to quantify risk factors for LBP and potentially develop improved methods for designing and analyzing jobs. Due to the subjectivity of LBP, six measures of LBP are captured: 1) any LBP, 2) LBP ≥ 5/10 pain rating, 3) LBP with medication use, 4) LBP with healthcare provider visits, 5) LBP necessitating modified work duties and 6) LBP with lost work time. Workers have thus far been enrolled from 30 different employment settings in 4 diverse US states and performed widely varying work. At baseline, workers undergo laptop-administered questionnaires, structured interviews, and two standardized physical examinations to ascertain demographics, medical history, psychosocial factors, hobbies and physical activities, and current musculoskeletal disorders. All workers’ jobs are individually measured for physical factors and are videotaped. Workers are followed monthly for the development of low back pain. Changes in jobs necessitate re-measure and re-videotaping of job physical factors. The lifetime cumulative incidence of low back pain will also include those with a past history of low back pain. Incident cases will exclude prevalent cases at baseline. Statistical methods planned include survival analyses and logistic regression.
Data analysis of a prospective cohort study of low back pain is underway and has successfully enrolled over 800 workers to date.
Epidemiology; Ergonomics; Cohort; Low back pain; NIOSH lifting equation
Clinicians use several measures to estimate adiposity. Body mass index (BMI), although not a measure of adiposity, is commonly used to define weight status. Percent body fat (%BF) measures total body fatness, which is composed of central and peripheral fat, estimated by waist circumference (WC) and skinfold thickness, respectively. Abnormal increases in fat during puberty may reflect an increased risk of developing cardiovascular disease. Therefore, it is important to establish the normal patterns of change in clinically relevant measures of adiposity.
To describe the normal patterns of change in clinical measures of adiposity during puberty.
Multilevel modeling and linear regression analyses of 642 children in Project HeartBeat!, aged 8–18 years (non-black and black), who had assessments of BMI, %BF, WC, sums of 2- and 6-skinfolds, and pubertal stage (PS) triennially between 1991 and 1995.
In males, the normal pattern from PS1 to PS5 is for %BF to decrease, skinfold thickness to remain stable, and WC to increase. However, after adjusting for height, WC does not change. In females, %BFremains stable from PS1 to PS5, whereas skin fold thickness increases. As in males waist-height ratio does not change, indicating that central adiposity does not normally increase during puberty. Although BMI increases in both genders and races from PS1 to PS5, mean values at PS5 were well below 25 kg/m2.
During puberty, increase in %BF is abnormal in females and even more so in males. Likewise, increase in waist-height ratio is also abnormal and may suggest an increased risk for adiposity-associated morbidity.
Adiposity; Adolescent; Body composition; Children; Puberty
Few prospective cohort studies of distal upper extremity musculoskeletal disorders have been performed. Past studies have provided somewhat conflicting evidence for occupational risk factors and have largely reported data without adjustments for many personal and psychosocial factors.
A multi-center prospective cohort study was incepted to quantify risk factors for distal upper extremity musculoskeletal disorders and potentially develop improved methods for analyzing jobs. Disorders to analyze included carpal tunnel syndrome, lateral epicondylalgia, medial epicondylalgia, trigger digit, deQuervain’s stenosing tenosynovitis and other tendinoses. Workers have thus far been enrolled from 17 different employment settings in 3 diverse US states and performed widely varying work. At baseline, workers undergo laptop administered questionnaires, structured interviews, two standardized physical examinations and nerve conduction studies to ascertain demographic, medical history, psychosocial factors and current musculoskeletal disorders. All workers’ jobs are individually measured for physical factors and are videotaped. Workers are followed monthly for the development of musculoskeletal disorders. Repeat nerve conduction studies are performed for those with symptoms of tingling and numbness in the prior six months. Changes in jobs necessitate re-measure and re-videotaping of job physical factors. Case definitions have been established. Point prevalence of carpal tunnel syndrome is a combination of paraesthesias in at least two median nerve-served digits plus an abnormal nerve conduction study at baseline. The lifetime cumulative incidence of carpal tunnel syndrome will also include those with a past history of carpal tunnel syndrome. Incident cases will exclude those with either a past history or prevalent cases at baseline. Statistical methods planned include survival analyses and logistic regression.
A prospective cohort study of distal upper extremity musculoskeletal disorders is underway and has successfully enrolled over 1,000 workers to date.
Epidemiology; Ergonomics; Cohort; Carpal tunnel syndrome; Strain index; TLV for HAL
There is little consensus regarding the indications for surgical CSF diversion (either with implanted temporizing devices [reservoir or subgaleal shunt] or shunt alone) in preterm infants with posthemorrhagic hydrocephalus. The authors determined clinical and neuroimaging factors associated with the use of surgical CSF diversion among neonates with intraventricular hemorrhage (IVH), and describe variations in practice patterns across 4 large pediatric centers.
The use of implanted temporizing devices and conversion to permanent shunts was examined in a consecutive sample of 110 neonates surgically treated for IVH related to prematurity from the 4 clinical centers of the Hydrocephalus Clinical Research Network (HCRN). Clinical, neuroimaging, and so-called processes of care factors were analyzed.
Seventy-three (66%) of the patients underwent temporization procedures, including 50 ventricular reservoir and 23 subgaleal shunt placements. Center (p < 0.001), increasing ventricular size (p = 0.04), and bradycardia (p = 0.07) were associated with the use of an implanted temporizing device, whereas apnea, occipitofrontal circumference (OFC), and fontanel assessments were not. Implanted temporizing devices were converted to permanent shunts in 65 (89%) of the 73 neonates. Only a full fontanel (p < 0.001) and increased ventricular size (p = 0.002) were associated with conversion of the temporizing devices to permanent shunts, whereas center, OFCs, and clot characteristics were not.
Considerable center variability exists in neurosurgical approaches to temporization of IVH in prematurity within the HCRN; however, variation between centers is not seen with permanent shunting. Increasing ventricular size—rather than classic clinical findings such as increasing OFCs—represents the threshold for either temporization or shunting of CSF.
hydrocephalus; preterm infant; temporizing implant; intraventricular hemorrhage; cerebrospinal fluid shunt; Hydrocephalus Clinical Research Network
Nosocomial infection / sepsis occurs in up to 40% of children requiring long stay intensive care. Zinc, selenium, glutamine, metoclopramide (a prolactin secretalogue), and or whey protein supplementation have been effective in reducing infection and sepsis in other populations. We evaluated whether daily nutriceutical supplementation with zinc, selenium, glutamine, and metoclopramide, compared to whey protein would reduce the occurrence of nosocomial infection / sepsis in this at-risk population.
Randomized double blinded comparative effectiveness trial.
Eight pediatric intensive care units in the NICHD Collaborative Pediatric Critical Care Research Network.
Two hundred and ninety three long stay intensive care patients (age 1–17 years) expected to require more than 72 hours of invasive care.
Patients were stratified according to immunocompromised status and center and then randomly assigned to receive daily enteral zinc, selenium, glutamine and IV metoclopramide (n = 149 ZSGM), or daily enteral whey protein (n = 144 WHEY) and IV saline, for up to 28 days of intensive care unit stay. The primary endpoint was time to development of nosocomial sepsis / infection. The analysis was intention to treat.
Measurements and Main Results
There were no differences by assigned treatment in the overall population with respect to time until the first episode of nosocomial infection / sepsis (median WHEY 13.2 days vs ZSGM 12.1 days, p=0.29 by log rank test) or the rate of nosocomial infection / sepsis (4.83/100 days WHEY vs. 4.99/100 days ZSGM, p = 0.81). Only 9% of the 293 subjects were immunocompromised and there was a reduction in rate of nosocomial infection / sepsis with ZSGM in this immunocompromised group (6.09/100 days WHEY vs 1.57/100 days ZSGM, p value = 0.011).
Compared with WHEY supplementation, ZSGM conferred no advantage in the immunecompetent population. Further evaluation of ZSGM supplementation is warranted in the immunocompromised long stay PICU patient.
Whey protein; zinc; selenium; glutamine; prolactin; nosocomial infection / sepsis
To update the Pediatric Critical Care Community on the progress of the Collaborative Pediatric Critical Care Research Network (CPCCRN) and plans for the future.
The six sites, seven hospitals of the CPCCRN.
Since its inception in August 2005 the Network has engaged in a number of observational and interventional trials, several of which are ongoing. Several additional studies are in the planning stages. To date these have resulted in the publication of 6 manuscripts and 5 abstracts, with 5 additional manuscripts accepted and in press.
The Network remains committed to its stated goal “to initiate a multi-centered program designed to investigate the safety and efficacy of treatment and management strategies to care for critically ill children, as well as the pathophysiologic basis of critical illness and injury in childhood”.
Collaborative Pediatric Critical Care Research Network; NICHD; bereavement; corticosteroids; sepsis; severity scoring systems; metoclopramide; zinc; selenium; glutamine; pertussis; opioid tolerance; withdrawal; pulmonary hypertension; decision support; weaning; cardiac arrest; hypothermia; asthma
There is a commonly held belief that randomized, placebo-controlled trials in pediatric critical care should incorporate “rescue” therapy (open-label administration of active drug) when a child’s condition is deteriorating. The ethical, conceptual and analytic challenges related to “rescue” therapy in randomized trials can be misrepresented.
The ethical basis of “rescue” therapy, the equipoise concept, and intention-to-treat analysis are examined in the setting of a hypothetical randomized trial comparing corticosteroids versus placebo in pediatric septic shock.
The perceived need for “rescue” therapy may be partly motivated by the moral imperative to save a child’s life. However, allowing “rescue” therapy in a trial is misconceived and inconsistent with equipoise regarding the efficacy of the study drug. If “rescue” therapy is permitted, intention-to-treat analysis can only compare immediate versus delayed use of the study drug. When “rescue” therapy is beneficial, the observed treatment effect is substantially diminished from true effect of the study drug, leading to increased sample size and thereby placing more children at risk (18 “excess” placebo-arm deaths occur in our hypothetical example). Analysis of a trial incorporating “rescue” therapy cannot definitively assess overall efficacy of the agent, or distinguish beneficial or harmful treatment effects related to timing of drug use.
While a “rescue” therapy component in a randomized trial may be perceived as ethically desirable, inconsistency of “rescue” therapy with full equipoise may itself raise significant ethical concerns. Increased sample sizes expose more children to the risks of study participation, including death. Researchers should be aware that clinical trials designed with “rescue” therapy cannot definitively determine the beneficial or harmful effects of a treatment per se, and can only assess the effects of delayed versus immediate provision of the treatment.
clinical trials, randomized; critical care; corticosterone; equipoise; ethics; placebos; shock; septic; rescue therapy
The neurosurgical literature has conflicting findings regarding the association between indications for CSF shunt placement and subsequent shunt surgery. The object of this study was to identify baseline factors at the time of initial CSF shunt placement that are independently associated with subsequent surgery.
This was a retrospective cohort study of children ages 0–18 years who underwent initial CSF shunt placement between January 1, 1997, and October 12, 2006, at a tertiary care children’s hospital. The outcome of interest was CSF shunt surgery (either for revision or infection) within 12 months after initial placement. Associations between subsequent CSF shunt surgery and indication for the initial shunt, adjusting for patient age and surgeon factors at the time of initial placement, were estimated using multivariate logistic regression. Medical and surgical decisions, which varied according to surgeon, were examined separately in a univariate analysis.
Of the 554 children in the study cohort, 233 (42%) underwent subsequent CSF shunt surgery, either for revision (167 patients [30%]) or infection (66 patients [12%]). In multivariate logistic regression modeling, significant risk factors for subsequent CSF shunt surgery included (compared with aqueductal stenosis) intraventricular hemorrhage (IVH) secondary to prematurity (adjusted odds ratio [AOR] 2.2, 95% CI 1.1–4.5) and other unusual indications (AOR 3.7, 95% CI 1.0–13.6). The patient’s age at initial CSF shunt placement was not significantly associated with increased odds of subsequent surgery after adjusting for other associated factors.
The occurrence of IVH is associated with increased odds of subsequent CSF shunt surgery within 12 months after shunt placement. Families of and care providers for children with IVH should be attuned to their increased risk of shunt failure.
hydrocephalus; cerebrospinal fluid; shunt failure; prematurity; intraventricular hemorrhage; children
To create a functional status outcome measure for large outcome studies that is well defined, quantitative, sufficiently rapid, reliable, minimally dependent on subjective assessments, and applicable to hospitalized pediatric patients across a wide spectrum of ages and inpatient environments.
Patients and Methods
The Functional Status Scale (FSS) was developed by a multidisciplinary consensus process. Domains of functioning included mental status, sensory, communication, motor, feeding, and respiratory categorized from normal (1) to very severe dysfunction (5). The Adaptive Behavior Assessment System (ABAS) II established construct validity and calibration within domains.
Seven institutions provided pediatric intensive care unit (PICU) patients within 24 hours of PICU discharge, high-risk non-PICU patients within 24 hours of admission, and technology-dependent children. Primary care nurses completed the ABAS II based on patient’s functioning when the FSS was completed. Patients from 10% of the study days were used to evaluate inter-rater reliability. Data were randomly split into estimation and validation sets. Statistical analyses included Pearson correlations, construct validity, linear regression analysis, receiver operating characteristic (ROC) curve analysis for discriminant validity, and the intraclass correlation for inter-rater reliability.
A total of 836 children with a mean FSS of 10.3 (standard deviation 4.4) were studied. Eighteen percent had the minimum possible FSS = 6, 44% had FSS ≥ 10, 14% had a FSS ≥ 15, and 6% had FSS scores ≥ 20. Each FSS domain was associated with mean ABAS II (p<.0001). Cells in each domain were collapsed and reweighted, which improved correlations with ABAS II from −0.58 to −0.62 in the estimation sample, and −0.60 to −0.63 in the validation sample (p<0.001 for improvements). Discrimination was very good for moderate and severe dysfunction (ABAS II categories) and improved with FSS weighting (area under the ROC curve > 0.8). Intraclass correlations of original and weighted total FSS were 0.95 and 0.94 respectively.
The FSS met our objectives and is well suited for large outcome studies.
Pediatrics; functional status; outcome assessment (health care); activities of daily living; adaptive behavior; health status indicators; health utilities index; treatment outcome; child
Quality improvement techniques are being implemented in many areas of medicine. In an effort to reduce the ventriculoperitoneal shunt infection rate, a standardized protocol was developed and implemented at 4 centers of the Hydrocephalus Clinical Research Network (HCRN).
The protocol was developed sequentially by HCRN members using the current literature and prior institutional experience until consensus was obtained. The protocol was prospectively applied at each HCRN center to all children undergoing a shunt insertion or revision procedure. Infections were defined on the basis of CSF, wound, or pseudocyst cultures; wound breakdown; abdominal pseudocyst; or positive blood cultures in the presence of a ventriculoatrial shunt. Procedures and infections were measured before and after protocol implementation.
Twenty-one surgeons at 4 centers performed 1571 procedures between June 1, 2007, and February 28, 2009. The minimum follow-up was 6 months. The Network infection rate decreased from 8.8% prior to the protocol to 5.7% while using the protocol (p = 0.0028, absolute risk reduction 3.15%, relative risk reduction 36%). Three of 4 centers lowered their infection rate. Shunt surgery after external ventricular drainage (with or without prior infection) had the highest infection rate. Overall protocol compliance was 74.5% and improved over the course of the observation period. Based on logistic regression analysis, the use of BioGlide catheters (odds ratio [OR] 1.91, 95% CI 1.19–3.05; p = 0.007) and the use of antiseptic cream by any members of the surgical team (instead of a formal surgical scrub by all members of the surgical team; OR 4.53, 95% CI 1.43–14.41; p = 0.01) were associated with an increased risk of infection.
The standardized protocol for shunt surgery significantly reduced shunt infection across the HCRN. Overall protocol compliance was good. The protocol has established a common baseline within the Network, which will facilitate assessment of new treatments. Identification of factors associated with infection will allow further protocol refinement in the future.
hydrocephalus; quality improvement; shunt; infection; standardized protocol
Despite implementation of CDC recommendations and bundled interventions for preventing catheter-associated blood stream infection, ventilator-associated pneumonia, or urinary catheter–associated infections, nosocomial infections and sepsis remain a significant cause of morbidity and mortality in critically ill children. Recent studies suggest that acquired critical illness stress-induced immune suppression (CRISIS) plays a role in the development of nosocomial infection and sepsis. This condition can be related to inadequate zinc, selenium, and glutamine levels, as well as hypoprolactinemia, leading to stress-induced lymphopenia, a predominant TH2 monocyte/macrophage state, and subsequent immune suppression. Prolonged immune dysfunction increases the likelihood of nosocomial infections associated with invasive devices. Although strategies to prevent common complications of critical illness are routinely employed (eg, prophylaxis for gastrointestinal bleeding, thrombophlebitis), no prophylactic strategy is used to prevent stress-induced immune suppression. This is the authors’ rationale for the pediatric CRISIS prevention trial (NCT00395161), designed as a randomized, double-blind, controlled clinical investigation to determine if daily enteral supplementation with zinc, selenium, and glutamine as well as parenteral metoclopramide (a dopamine 2 receptor antagonist that reverses hypoprolactinemia) prolongs the time until onset of nosocomial infection or sepsis in critically ill children compared to enteral supplementation with whey protein. If effective, this combined nutritional and pharmacologic approach may lessen the excess morbidity and mortality as well as resource utilization associated with nosocomial infections and sepsis in this population. The authors present the design and analytic plan for the CRISIS prevention trial.
critical care; nosocomial infection; prolactin; zinc; selenium; lymphocyte function
The objective of these two studies was to assess the efficacy of FL-41 tinted lenses in the treatment of benign essential blepharospasm (BEB).
A randomized crossover study and a randomized crossover case-control study.
The first study included 30 subjects with BEB. The second study included 26 subjects with BEB and 26 controls.
For the first study, subjects were randomized to wear either FL-41 or gray tinted lenses for 2 weeks. After a two-week washout period, the other lens was worn for 2 weeks. Questionnaires were completed at baseline, after the first lens, and after the second lens. In the second study, surface electromyography (EMG) was used to measure blink frequency, duration, and force while subjects read and wore FL-41, rose, or gray tinted lenses.
Main Outcome Measures
Questionnaires were used to assess perceptions of light sensitivity and the effect of light sensitivity on activities of daily living. EMG was used to measure blink frequency, duration, and force.
Most participants observed improvement while wearing both FL-41 and gray tinted lenses. FL-41 tinted lenses provided superior improvement in the areas of reading, fluorescent light sensitivity, overall light sensitivity, blepharospasm frequency, and blepharospasm severity. FL-41 lenses reduced mean blink rate compared to both rose and gray tinted lenses, and reduced eyelid contraction force compared to rose tinted lenses.
FL-41 lenses provided both subjective and objective benefit to subjects with BEB. Physicians should consider recommending this noninvasive and inexpensive lens tint to patients with BEB.
Little is known about the contribution of polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and the folate metabolism pathway in rectal cancer alone. Data were from participants in a case-control study conducted in Northern California and Utah (751 cases and 979 controls). We examined independent associations and interactions of folate, B vitamins, methionine, alcohol, and MTHFR polymorphisms (MTHFR C677T and A1298C) with rectal cancer. Dietary folate intake was associated with a reduction in rectal cancer OR 0.66, 95% CI 0.48-0.92 (>475 mcg day compared to < = 322 mcg) as was a combination of nutrient intakes contributing to higher methyl donor status (OR 0.79, 95% CI 0.66-0.95). Risk was reduced among women with the 677 TT genotype (OR 0.54, 95% CI 0.30-0.9), but not men (OR 1.11, 95% CI 0.70-1.76) and with the 1298 CC genotype in combined gender analysis (OR 0.67, 95% CI 0.46-0.98). These data are consistent with a protective effect of increasing dietary folate against rectal cancer and suggest a protective role of the MTHFR 677 TT genotype in women and 1298 CC in men and women. Folate intake, low methyl donor status, and MTHFR polymorphisms may play independent roles in the etiology of rectal cancer.
Diet; Pteroylpolyglutamic Acids; Rectal Neoplasms; Polymorphism; Genetic