Research Paper

Study #1: Association between Blood 25-Hydroxyvitamin D Levels and Survival in Colorectal Cancer Patients: An Updated Systematic Review and Meta-Analysis. Maalmi et al. Nutrients. 2018 Jul 13;10(7)
Abstract
Previous meta-analyses have shown an improved survival with higher blood 25-hydroxyvitamin D (25(OH)D) concentrations in patients with colorectal cancer (CRC). However, a number of much larger studies have been published since then. We provide an updated meta-analysis to synthesize current evidence. PubMed and Web of Science databases were systematically searched for eligible studies. The dose-response relationships and pooled hazard ratios for overall and CRC-specific survival comparing the highest versus the lowest categories of blood 25(OH)D concentrations were assessed. Subgroup analyses based on study geographic location, year of publication, sample size, length of follow-up time and stage were conducted to explore potential sources of heterogeneity. Overall, 11 original studies with a total of 7718 CRC patients were included. The dose-response meta-analysis showed an improvement in survival outcomes with increasing blood 25(OH)D concentrations. Pooled hazard ratios (95% confidence intervals) comparing highest versus lowest categories were 0.68 (0.55–0.85) and 0.67 (0.57–0.78) for overall and CRC-specific survival, respectively. Associations were more prominent among studies conducted in Europe, with larger sample sizes, and including stage I–IV patients. This updated meta-analysis reveals robust evidence of an association between higher blood 25(OH)D concentrations and better survival in CRC patients. The potential for enhancing prognosis of CRC patients by vitamin D supplementation should be explored by randomized trials.
2. Materials and Methods
2.1. Search Strategy
The reporting of meta-analyses of observational studies in epidemiology (MOOSE) guidelines were followed to perform this systematic review and meta-analysis [14] (Table S1). We carried out a systematic literature search in PubMed and Web of Science databases for articles reporting results of cohort studies conducted in CRC patients and assessing the association between blood 25(OH)D concentrations and overall and CRC-specific survival, using a comprehensive list of search terms (Table S2). The current literature search was restricted to articles published from 2013 until September 2017 with no language restrictions, thereby complementing our previous corresponding literature search of articles published up to 2013 [10].
2.2. Selection
We excluded studies (i) with non-longitudinal design; (ii) restricted to non-CRC patients; (iii) without measurement of blood 25(OH)D and (iv) without measurement of the association between exposure and outcome of interest. In addition, we excluded conference abstracts due to the insufficient data obtainable from them.
2.3. Data Extraction
From each included study, data were independently extracted by two investigators (H.M and V.W) using a standardized data extraction form. Briefly, we recorded study characteristics including first author name, year of publication, a country in which study was conducted, study acronym and time period of study conduction (period of recruitment and mean/median duration of follow-up). We also extracted the following information about study populations: sample size, sex, CRC stage, age and number of total and CRC deaths. In addition, we extracted data about the time between 25(OH)D measurement and cancer diagnosis, categories of blood 25(OH)D concentrations and the median/mid-point/interval of 25(OH)D concentrations in each category. Finally, we recorded hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of 25(OH)D with overall and CRC-specific survival as well as confounders adjusted for in the analysis. Disagreements between investigators were discussed and resolved by an additional review. In this report, blood 25(OH)D concentrations were expressed in nmol/L. To convert concentrations reported in ng/mL, an adequate conversion factor (1 ng/mL = 2.5 nmol/L) was used.
2.4. Statistical Analysis
2.4.1. Meta-Analysis
The pooled hazard ratios (HR) and 95% confidence intervals (CI) for the association of categories of patients with highest vs. lowest 25(OH)D concentrations with overall and CRC-specific survival were estimated using the DerSimonian and Laird (DL) random-effects model to account for heterogeneity of study populations and designs [15]. The heterogeneity among the included studies was investigated using the I2 index and Cochran’s Q test, with significant heterogeneity assumed for I2 > 50% or a Q-test p-value < 0.05 [16]. Subgroup analyses were conducted to explore potential sources of heterogeneity across studies. Publication bias was assessed graphically with funnel plots and statistically with Kendall’s tau [17] and Egger’s test [18]. A p-value < 0.05 in these tests suggests the presence of publication bias. Sensitivity analyses were performed, to test the stability of the pooled HR estimates and 95% CIs, by exclusion/or inclusion of some specific studies. Study quality was assessed based on the adjustment level used in each included study, considering age, sex and season which are among the most important potential confounders. CRC-specific survival was not reported in many studies. Therefore, sensitivity and subgroup analyses were only performed for overall survival. For these analyses, we used the R statistical software, version 3.3.2, and package “metaphor”, version 2.0 (R Foundation for Statistical Computing, Vienna, Austria). Study 1 Questions: 1. Describe how this study type ranks on the hierarchy of evidence. (1 mark) 2. “Pooled hazard ratios (95% confidence intervals) comparing highest versus lowest categories was and 0.67 (0.57–0.78) for CRC-specific survival.” Was having the highest level of vitamin D associated with an increased or decreased risk of dying from colorectal cancer. Was this result statistically significant? What was the % increase or decrease compared to individuals with the lowest levels? (2 marks) 3. Look at the forest plot. How many studies reported a reduction in risk with higher levels of vitamin D? (1 mark) Of these, how many were statistically significant? How can you tell? (2 marks) 4. What are the results of this study? Please describe using language you would use to share this research with a patient. (2 marks) 5. What is a limitation of this study? (1 mark) 6. What are two strengths of this study? (2 marks) 7. What follow up study could be designed to further explore this research question? (1 mark) 8. You are curious if any better-quality meta-analyses exist on this topic. Name one database you would search: (1 mark) Then write out the search string and limits you would use to quickly check this. (2 marks) 9. You find the abstract of an interesting study but don’t have access to the full text through CCNM’s subscriptions. What is 1 way you might try to locate the full text. (1 marks)   Study #2: Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances Julien Cases at al. Med J Nutrition Metab. 2011 Dec; 4(3): 211–218. 1. What is the study methodology? (1 mark) 2. What was the PICO question? (2 marks) 3. Describe how this study type ranks on the hierarchy of evidence. (2 marks) 4. What are the results of this study? Please describe using language you would use to share this research with a patient. (1 mark) 5. What are three limitations of this study? (3 marks) 6. What are three strengths of this study? (3 marks) 7. What information is not reported in this paper which could further help you to interpret the results of this study? (1 mark) 8. What follow up study could be designed to further explore this research question using improved methodology? (2 mark) 9. What are the 3 components of EIP? (1 mark) What other factors might you consider when applying the results of this study to a clinical case, keeping the components of EIP in mind. (2 marks) 10. You would like to research other naturopathic interventions that are helpful for insomnia and have evidence to support their use. Provide 3 search strings that you might enter into PubMed when looking for other interventions. (3 marks)   Study #3: Association of Exposure to Artificial Light at Night While Sleeping With Risk of Obesity in Women Yong-Moon Mark Park at al. JAMA Intern Med. Published online June 10, 2019. Importance Short sleep has been associated with obesity, but to date the association between exposure to artificial light at night (ALAN) while sleeping and obesity is unknown. Objective To determine whether ALAN exposure while sleeping is associated with the prevalence and risk of obesity. Design, Setting, and Participants This baseline and prospective analysis included women aged 35 to 74 years enrolled in the Sister Study in all 50 US states and Puerto Rico from July 2003 through March 2009. Follow-up was completed on August 14, 2015. A total of 43 722 women with no history of cancer or cardiovascular disease who were not shift workers, daytime sleepers, or pregnant at baseline were included in the analysis. Data were analyzed from September 1, 2017, through December 31, 2018. Exposures Artificial light at night while sleeping reported at enrollment, categorized as no light, small nightlight in the room, light outside the room, and light or television in the room. Main Outcomes and Measures Prevalent obesity at baseline was based on measured general obesity (body mass index [BMI] ≥30.0) and central obesity (waist circumference [WC] ≥88 cm, waist-to-hip ratio [WHR] ≥0.85, or waist-to-height ratio [WHtR]≥0.5). To evaluate incident overweight and obesity, self-reported BMI at enrollment was compared with self-reported BMI at follow-up (mean [SD] follow-up, 5.7 [1.0] years). Generalized log-linear models with robust error variance were used to estimate multivariable-adjusted prevalence ratios (PRs) and relative risks (RRs) with 95% CIs for prevalent and incident obesity. Results Among the population of 43 722 women (mean [SD] age, 55.4 [8.9] years), having any ALAN exposure while sleeping was positively associated with a higher prevalence of obesity at baseline, as measured using BMI (PR, 1.03; 95% CI, 1.02-1.03), WC (PR, 1.12; 95% CI, 1.09-1.16), WHR (PR, 1.04; 95% CI, 1.00-1.08), and WHtR (PR, 1.07; 95% CI, 1.04-1.09), after adjusting for confounding factors, with P < .001 for trend for each measure. Having any ALAN exposure while sleeping was also associated with incident obesity (RR, 1.19; 95% CI, 1.06-1.34). Compared with no ALAN, sleeping with a television or a light on in the room was associated with gaining 5 kg or more (RR, 1.17; 95% CI, 1.08-1.27; P < .001 for trend), a BMI increase of 10% or more (RR, 1.13; 95% CI, 1.02-1.26; P = .04 for trend), incident overweight (RR, 1.22; 95% CI,1.06-1.40; P = .03 for trend), and incident obesity (RR, 1.33; 95% CI, 1.13-1.57; P < .001 for trend). Results were supported by sensitivity analyses and additional multivariable analyses including potential mediators such as sleep duration and quality, diet, and physical activity. Conclusions and Relevance These results suggest that exposure to ALAN while sleeping may be a risk factor for weight gain and development of overweight or obesity. Further prospective and interventional studies could help elucidate this association and clarify whether lowering exposure to ALAN while sleeping can promote obesity prevention. Study 3 Questions: 1. What is the study methodology? (1 mark) 2. What was the PICO question? (2 marks) 3. Describe how this study type ranks on the hierarchy of evidence. (2 marks) 4. “Compared with no ALAN, sleeping with a television or a light on in the room was associated with gaining 5 kg or more (RR, 1.17; 95% CI, 1.08-1.27)” Sleeping with a light increased the risk of gaining 5kg by what percent? Was this statistically significant? (2 marks) 5. What are the results of this study? Please describe using language you would use to share this research with a patient. (1 mark) 6. What are two limitations of this study? (2 marks) 7. What are two strengths of this study or this type of methodology in general? (2 marks) 8. Your patient is interested in weight loss and found this article. They want to know if sleeping in the dark would be a way for them to lose weight. What do you tell them? Justify your response (2 marks). 9. What follow up study could be designed to further explore this research question and improve on this study design? (2 marks)   Study #4: Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study J Psychiatry Neurosci. 2019 Jul; 44(4): 269–276. Abstract Background: Approximately one-third of people with schizophrenia have elevated levels of antigliadin antibodies of the immunoglobulin G type (AGA IgG) — a higher rate than seen in healthy controls. We performed the first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA IgG. Methods: In this pilot feasibility study, 16 participants with schizophrenia or schizoaffective disorder who had elevated AGA IgG (≥ 20 U) but were negative for celiac disease were admitted to an inpatient unit for a 5-week trial. All participants received standardized gluten-free meals and were randomized in a double-blind fashion to receive a shake containing 10 g of gluten flour or 10 g of rice flour each day. Participants were rated for psychiatric, cognitive and gastrointestinal symptoms at baseline and end point. Results: Of the 16 participants, 14 completed the 5-week trial (2 discontinued early for administrative reasons). Compared with participants on the gluten-containing diet, participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale (Cohen d = −0.75) and in negative symptoms (Cohen d = −0.53). We noted no improvement in positive or global cognitive symptoms, but did observe an improvement in attention favouring the gluten-free diet (Cohen d = 0.60). Robust improvements in gastrointestinal adverse effects occurred in the gluten-free group relative to the gluten-containing group. Adverse effects were similar between groups. Limitations: This study was limited by its small sample size; larger studies are needed. Conclusion: This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder. Methods Study procedures: Those who were eligible for screening had a diagnosis of schizophrenia or schizoaffective disorder, were not currently on a gluten-free diet and were between the ages of 18 and 64 years. Screening laboratory tests included AGA IgG, AGA IgA and tTG. If participants tested positive for tTG, they were excluded, and they and their clinical team were notified of their potential for celiac disease. Participants who tested positive for AGA IgG (> 20 U) were eligible for study enrolment, which involved 5 weeks of randomized, double-blind treatment with a gluten-free or gluten-containing diet in an inpatient setting with strict dietary procedures. Participants who opted to enrol in the clinical trial were admitted to the research hospital unit and continued previous antipsychotic treatment. At the end of the 5-week double-blind trial, half of the discharged participants were randomly selected to continue a gluten-free diet in the community; they were called at week 4 for follow-up and returned at 8 weeks postdischarge for assessments and blood work.
Participants
Inclusion criteria: Women and men (ages 18–64 years) who met DSM-IV-TR46 criteria for schizophrenia or schizoaffective disorder were eligible for the study. All participants must have had positive results (> 20 U) on their AGA IgG screening. Participants must have been taking the same antipsychotic for at least 4 weeks prior to the study. As noted earlier, all participants were required to score at least a 10 out of 12 on the Evaluation to Sign Consent,45 which documented their capacity to provide informed consent.
Exclusion criteria: All those who participated in screening and tested positive for tTG were excluded so that their presumed celiac disease could be treated appropriately. Those who tested positive for AGA IgA but negative for AGA IgG were excluded. Also excluded were participants who were already on a gluten-free diet, were pregnant or lactating, had an organic brain disorder or intellectual disability, had a medical condition whose pathology or treatment could alter the presentation or treatment of schizophrenia or significantly increase the risk associated with the proposed treatment protocol, and who met DSM-IV criteria for alcohol or substance abuse (other than nicotine) within the last month. Participants were excluded if they had gluten ataxia, determined by a physician with the aid of the Brief Ataxia Rating Scale.47 To increase the possibility of detecting positive change, participants who had a Brief Psychiatric Rating Scale (BPRS)48 total score of 29 or lower (lower quartile) were excluded.
Screening assessments: Screening involved 1–2 visits and a variety of assessments to determine study eligibility. Participants were educated about the study and possible adverse effects or consequences of participation. Psychiatric diagnosis was confirmed by the Structured Clinical Interview for Diagnosis of DSM-IV (SCID).49 A medically accountable physician reviewed participants’ medical history and conducted a physical examination to confirm study eligibility. A standard blood chemistry panel, complete blood count, urinalysis and electrocardiography were also conducted. We also evaluated existing gastrointestinal disorders and dermatologic disorders, because gluten sensitivity may be related to both.41 For outpatients admitted to the unit and subsequently discharged following study participation, we worked closely with their community providers and supports to ensure full continuity of care.
Study assessments
Psychiatric symptoms: We measured psychiatric symptoms using the BPRS,48 the Scale for the Assessment of Negative Symptoms (SANS),49 the Calgary Depression Scale (CDS)50 and the Clinical Global Impression scale (CGI).51 We measured positive symptoms using the sum of the following BPRS items: conceptual disorganization, suspiciousness, hallucinatory behaviour and unusual thought content. We assessed negative symptoms using the total score of the SANS52 but subtracted the global items inappropriate affect, poverty of content of speech and attention to be consistent with other studies that measured negative symptoms in schizophrenia.53,54 All of these assessments are widely used in schizophrenia research and have good validity and reliability for use in this population. We administered the assessments each week during the 5 weeks of the study. All raters were trained and reliable, with an intraclass correlation coefficient of > 0.7.
We used the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) to assess cognitive function.55 This battery was developed specifically to be the gold standard for assessing cognition in schizophrenia.55 We also administered the Brief Assessment of Cognition in Schizophrenia Tower of London Test to assure adequate coverage of executive function. 56 In recent multicentre clinical trials that our research team has participated in, individual tests of the MCCB have had intraclass correlation coefficients between 0.6 and 0.8, and the overall MCCB composite score has had an intraclass correlation coefficient of 0.9.
Adverse effect measures: We measured gastrointestinal effects using the Gastrointestinal Symptom Rating Scale (GSRS) at baseline and end point.57 This 15-item scale has 5 domains (reflux, constipation, diarrhea, pain and indigestion), and has been used in people with psychiatric symptoms.58
To assess medication adverse effects, we administered the Simpson–Angus Extrapyramidal Symptom Rating Scale,59 the Barnes Akathisia Rating Scale60 and a 25-item adverse effect checklist each week.59,60
Laboratory assessments: At screening and each week throughout the trial, we assessed weight and vital signs (heart rate, pulse, blood pressure). We drew a chemistry panel, including liver enzymes, lipids and fasting blood glucose, along with complete blood counts at baseline and end point, all analyzed by LabCorp. We also measured AGA IgG at baseline and end point in the Čiháková Laboratory at Johns Hopkins University using the Inova Diagnostics kit 708655. Units were determined by the manufacturer based on standard curve calculations. For this study, AGA IgG negative status was defined as < 20 U, and positive status as ≥ 20 U. Randomization procedures and medications: Participants, researchers and clinical team members were blinded to intervention assignment. Participants received 10 g of either rice flour (treatment) or gluten flour (control; Bob’s Red Mill) mixed in a protein shake each afternoon. A hospital nurse mixed the blinded powder in a high-power blender with water, ice, protein powder and optional syrup of the participants’ choice to make a protein shake (Sunwarrior Plant-Based Protein). The research staff ensured that the entire shake was ingested. Each participant had a separate colour-coded container that was never shared to avoid cross-contamination. Treatments were assigned at random, using computer-generated permuted block randomization sequences with randomly varied block sizes to limit imbalance in the number of patients assigned to each group, while making it difficult for staff to predict what treatment patients were receiving. All participants received a gluten-free meal plan during the 5 weeks of the study. The hospital kitchen had fully functioning operating procedures for the creation of gluten-free meals, including 21 days of meals in a rotating schedule. During the study, participants attended weekly group sessions about gluten-free nutrition and diet counselling, and they had the opportunity to taste, shop for and prepare new gluten-free foods in this setting. We maintained a strict regimen and oversight for maintaining a gluten-free diet. All staff in the inpatient setting were required to ensure that all participants remained gluten-free. During the day, the staff:participant ratio was 1:1, and all nursing staff and aides were required to report if any deviation occurred. Each participant had an individual snack bucket with gluten-free snacks if needed, and no other free food was given out on the inpatient unit. All packaged food consumed was certified gluten-free. All participants received a gluten-free cookbook. After the end of their trial participation, study participants were discharged if they were considered stable according to the treating psychiatrist, and all were encouraged to follow a gluten-free diet. The study intervention was added to participants’ ongoing antipsychotic regimen. Study physicians were instructed to avoid changing doses of other somatic and psychotropic medications during the study. Anticholinergic medications for extrapyramidal side effects (e.g., benztropine and diphenhydramine), propranolol for akathisia and benzodiazepines for anxiety or agitation (e.g., lorazepam) could be prescribed as needed. Study 4 Questions: 1. What is one limitations of this study? (1 mark) 2. Randomization and blinding are strengths of this study. How do randomization and blinding decrease the risk of bias? (2 marks) 3. Besides randomization and blinding, what are three strengths of this study? (3 marks) 4. What two tools could you use to further assess the study quality? (2 marks) 5. Would this study influence your clinical decision making? Justify your answer. (1 mark) 6. The study had 2 patients drop out. What are the 2 ways to account for drop outs and which can over-estimate a treatment effect? (2 marks)