Publications by authors named "Andrew Chan"

1,094 Publications

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Plasma concentrations of perfluoroalkyl substances and risk of inflammatory bowel diseases in women: A nested case control analysis in the Nurses' Health Study cohorts.

Environ Res 2021 Oct 16:112222. Epub 2021 Oct 16.

Clinical and Translational Epidemiology Unit, Massachusetts Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Perfluoroalkyl substances (PFASs) are synthetic compounds used in a wide variety of industrial and consumer applications. An association between PFAS exposure and risk of ulcerative colitis (UC) has been reported in a highly exposed population. However, data are limited on risk of inflammatory bowel diseases (IBD) among individuals with background population levels of PFAS exposure.

Objectives: We set out to examine the association between plasma PFAS concentrations and risk of IBD among women in two population-based, prospective cohort studies in which pre-diagnostic blood specimens were available.

Methods: We conducted a nested case-control study in the Nurses' Health Study and Nurses' Health Study II cohorts. We identified 73 participants with incident Crohn's disease (CD) and 80 participants with incident UC who had provided blood samples before diagnosis. Cases were matched 1:2 to IBD-free controls. Plasma concentrations of five major PFASs were measured by liquid chromatography and tandem mass spectrometry. We used conditional logistic models to estimated odds ratios for risk of IBD according to log-transformed PFAS concentrations, adjusting for potential confounders.

Results: In multivariable models, we observed inverse associations between plasma concentrations of three PFASs and risk of CD (all P ≤ 0.012 for a standard deviation increase in logPFAS). The inverse association with CD was strongest for perfluorodecanoate, where, compared to the lowest tertile, the odds ratio (OR) for the highest tertile was 0.39 (95% confidence interval, 0.17-0.92). No associations were observed between PFAS concentrations and UC risk.

Discussion: Our results do not support the hypothesis that elevated PFAS exposure is associated with higher risk of UC. Contrary to expectation, our data suggest that circulating concentrations of some PFASs may be inversely associated with CD development.
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http://dx.doi.org/10.1016/j.envres.2021.112222DOI Listing
October 2021

Unrestrained eating behavior and risk of mortality: A prospective cohort study.

Clin Nutr 2021 Sep 17;40(11):5419-5429. Epub 2021 Sep 17.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Background & Aims: Unrestrained eating behavior has been thought to be a proxy for diet frequency, timing, and caloric intake. We investigated the association of unrestrained eating with mortality risk in the Nurses' Health Study prospectively.

Methods: During follow-up (1994-2016), 21,953 deaths were documented among 63,999 eligible participants in analyses of eating anything at any time, 22,120 deaths were documented among 65,839 participants in analyses of no concern with figure change. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models.

Results: Eating anything at any time was associated with an increased mortality from cancer (overall HR, 95%CI: 1.07, 1.00-1.13; driven by gastrointestinal tract cancer: 1.30, 1.10-1.54) and respiratory disease (1.16, 1.05-1.29), and decreased cardiovascular disease-specific mortality (0.92, 0.86-0.99), compared to those without this behavior; however, no association was observed between this behavior and all-cause mortality (1.02, 0.99-1.05). Women who reported having no concern with figure change experienced higher risk of mortality from all-cause (1.08, 1.05-1.11), cancer (1.08, 1.02-1.14), and respiratory disease (1.18, 1.08-1.30), compared to those not reporting this behavior. Their combined effect was associated with a higher all-cause (1.09, 1.04-1.14), cancer-specific (overall: 1.18, 1.09-1.28; gastrointestinal tract cancer: 1.36, 1.08-1.71; lung cancer: 1.09; 1.04-1.14), and respiratory disease-specific (1.30, 1.13-1.50) mortality, and was inversely associated with cardiovascular disease-specific mortality (0.88, 0.80-0.98), compared to those exhibiting the opposite.

Conclusions: Unrestrained eating was associated with increased risk of all-cause, cancer-specific (particularly for gastrointestinal tract cancer and lung cancer), and respiratory disease-specific mortality, and decreased risk of cardiovascular disease-specific mortality.
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http://dx.doi.org/10.1016/j.clnu.2021.09.014DOI Listing
September 2021

Classifying Patients Operated for Spondylolisthesis: A K-Means Clustering Analysis of Clinical Presentation Phenotypes.

Neurosurgery 2021 Oct 11. Epub 2021 Oct 11.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Background: Trials of lumbar spondylolisthesis are difficult to compare because of the heterogeneity in the populations studied.

Objective: This study aims to define patterns of clinical presentation.

Methods: This is a study of the prospective Quality Outcomes Database spondylolisthesis registry, including patients who underwent single-segment surgery for grade 1 degenerative lumbar spondylolisthesis. Twenty-four-month patient-reported outcomes (PROs) were collected. A k-means clustering analysis-an unsupervised machine learning algorithm-was used to identify clinical presentation phenotypes.

Results: Overall, 608 patients were identified, of which 507 (83.4%) had 24-mo follow-up. Clustering revealed 2 distinct cohorts. Cluster 1 (high disease burden) was younger, had higher body mass index (BMI) and American Society of Anesthesiologist (ASA) grades, and globally worse baseline PROs. Cluster 2 (intermediate disease burden) was older and had lower BMI and ASA grades, and intermediate baseline PROs. Baseline radiographic parameters were similar (P > .05). Both clusters improved clinically (P < .001 all 24-mo PROs). In multivariable adjusted analyses, mean 24-mo Oswestry Disability Index (ODI), Numeric Rating Scale Back Pain (NRS-BP), Numeric Rating Scale Leg Pain, and EuroQol-5D (EQ-5D) were markedly worse for the high-disease-burden cluster (adjusted-P < .001). However, the high-disease-burden cluster demonstrated greater 24-mo improvements for ODI, NRS-BP, and EQ-5D (adjusted-P < .05) and a higher proportion reaching ODI minimal clinically important difference (MCID) (adjusted-P = .001). High-disease-burden cluster had lower satisfaction (adjusted-P = .02).

Conclusion: We define 2 distinct phenotypes-those with high vs intermediate disease burden-operated for lumbar spondylolisthesis. Those with high disease burden were less satisfied, had a lower quality of life, and more disability, more back pain, and more leg pain than those with intermediate disease burden, but had greater magnitudes of improvement in disability, back pain, quality of life, and more often reached ODI MCID.
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http://dx.doi.org/10.1093/neuros/nyab355DOI Listing
October 2021

Gallstone Disease and Risk of Conventional Adenomas and Serrated Polyps: A Prospective Study.

Cancer Epidemiol Biomarkers Prev 2021 Oct 7. Epub 2021 Oct 7.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Gallstone disease has been associated with colorectal cancer and some form of polyps, although the findings are inconclusive. It remains unknown whether gallstone disease influences the initiation of colorectal cancer.

Methods: We prospectively assessed the association of gallstone disease with risk of colorectal cancer precursors, including conventional adenomas and serrated polyps, in the Nurses' Health Study (1992-2012), the Nurses' Health Study II (1991-2011), and the Health Professionals Follow-up Study (1992-2012). Gallstone diseases were assessed using biennial follow-up questionnaires. Self-reported polyp diagnosis was confirmed by review of medical records. Logistic regression models were used to calculate the ORs with adjustment for smoking and other potential confounders.

Results: Among participants who had undergone a total of 323,832 endoscopies, 16.5% had gallstone disease and 11.3% received cholecystectomy. We documented 1,724, 1,212, and 1,943 cases of conventional adenomas and 1,470, 1,090, and 1,643 serrated polyps in patients with gallstones, cholecystectomy, and either of them, respectively. The OR for adenomas was 1.00 [95% confidence interval (CI): 0.95-1.06] for gallstones, 0.99 (95% CI: 0.93-1.06) for cholecystectomy, and 1.00 (95% CI: 0.95-1.05) for either exposure. The corresponding ORs for serrated polyps were 0.98 (95% CI: 0.92-1.04), 0.99 (95% CI: 0.93-1.06), and 0.97(95% CI: 0.92-1.03), respectively.

Conclusions: Gallstone disease is not associated with colorectal polyps.

Impact: Patients with gallstones appear to have similar risk of colorectal polyps compared with those without and may therefore follow average-risk colorectal cancer screening guidelines.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0515DOI Listing
October 2021

Single versus dual operative spine fractures in ankylosing spondylitis.

Neurosurg Focus 2021 10;51(4):E6

1Department of Neurological Surgery, University of California, San Francisco.

Objective: Ankylosing spondylitis, the most common spondyloarthritis, fuses individual spinal vertebrae into long segments. The unique biomechanics of the ankylosed spine places patients at unusually high risk for unstable fractures secondary to low-impact mechanisms. These injuries are unique within the spine trauma population and necessitate thoughtful management. Therefore, the authors aimed to present a richly annotated data set of operative AS spine fractures with a significant portion of patients with simultaneous dual noncontiguous fractures.

Methods: Patients with ankylosing spondylitis with acute fractures who received operative management between 2012 and 2020 were reviewed. Demographic, admission, surgical, and outcome parameters were retrospectively collected and reviewed.

Results: In total, 29 patients were identified across 30 different admissions. At admission, the mean age was 71.7 ± 11.8 years. The mechanism of injury in 77% of the admissions was a ground-level fall; 30% also presented with polytrauma. Of admissions, 50% were patient transfers from outside hospitals, whereas the other half presented primarily to our emergency departments. Fifty percent of patients sustained a spinal cord injury, and 35 operative fractures were identified and treated in 32 surgeries. The majority of fractures clustered around the cervicothoracic (C4-T1, 48.6%) and thoracolumbar (T8-L3, 37.11%) junctions. Five patients (17.2%) had simultaneous dual noncontiguous operative fractures; these patients were more likely to have presented with a higher-energy mechanism of injury such as a bicycle or motor vehicle accident compared with patients with a single operative fracture (60% vs 8%, p = 0.024). On preoperative MRI, 56.3% of the fractures had epidural hematomas (EDHs); 25% were compressive of the underlying neural elements, which dictated the number of laminectomy levels performed (no EDH, 2.1 ± 2.36; noncompressive EDH, 2.1 ± 1.85; and compressive EDH, 7.4 ± 4 [p = 0.003]). The mean difference in instrumented levels was 8.7 ± 2.6 with a mean estimated blood loss (EBL) of 1183 ± 1779.5 mL. Patients on a regimen of antiplatelet therapy had a significantly higher EBL (2635.7 mL vs 759.4 mL, p = 0.015). Overall, patients had a mean hospital length of stay of 15.2 ± 18.5 days; 5 patients died during the same admission or after transfer to an outside hospital. Nine of 29 patients (31%) had died by the last follow-up (the mean follow-up was 596.3 ± 878.9 days).

Conclusions: Patients with AS who have been found to have unstable spine fractures warrant a thorough diagnostic evaluation to identify secondary fractures as well as compressive EDHs. These patients experienced prolonged inpatient hospitalizations with significant morbidity and mortality.
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http://dx.doi.org/10.3171/2021.7.FOCUS21329DOI Listing
October 2021

Anxiety and depression symptoms after COVID-19 infection: results from the COVID Symptom Study app.

J Neurol Neurosurg Psychiatry 2021 Sep 28. Epub 2021 Sep 28.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK

Background: Mental health issues have been reported after SARS-CoV-2 infection. However, comparison to prevalence in uninfected individuals and contribution from common risk factors (eg, obesity and comorbidities) have not been examined. We identified how COVID-19 relates to mental health in the large community-based COVID Symptom Study.

Methods: We assessed anxiety and depression symptoms using two validated questionnaires in 413148 individuals between February and April 2021; 26998 had tested positive for SARS-CoV-2. We adjusted for physical and mental prepandemic comorbidities, body mass index (BMI), age and sex.

Findings: Overall, 26.4% of participants met screening criteria for general anxiety and depression. Anxiety and depression were slightly more prevalent in previously SARS-CoV-2-positive (30.4%) vs SARS-CoV-2-negative (26.1%) individuals. This association was small compared with the effect of an unhealthy BMI and the presence of other comorbidities, and not evident in younger participants (≤40 years). Findings were robust to multiple sensitivity analyses. Association between SARS-CoV-2 infection and anxiety and depression was stronger in individuals with recent (<30 days) versus more distant (>120 days) infection, suggesting a short-term effect.

Interpretation: A small association was identified between SARS-CoV-2 infection and anxiety and depression symptoms. The proportion meeting criteria for self-reported anxiety and depression disorders is only slightly higher than prepandemic.
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http://dx.doi.org/10.1136/jnnp-2021-327565DOI Listing
September 2021

Does reduction of the Meyerding grade correlate with outcomes in patients undergoing decompression and fusion for grade I degenerative lumbar spondylolisthesis?

J Neurosurg Spine 2021 Sep 17:1-8. Epub 2021 Sep 17.

1Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.

Objective: Reduction of Meyerding grade is often performed during fusion for spondylolisthesis. Although radiographic appearance may improve, correlation with patient-reported outcomes (PROs) is rarely reported. In this study, the authors' aim was to assess the impact of spondylolisthesis reduction on 24-month PRO measures after decompression and fusion surgery for Meyerding grade I degenerative lumbar spondylolisthesis.

Methods: The Quality Outcomes Database (QOD) was queried for patients undergoing posterior lumbar fusion for spondylolisthesis with a minimum 24-month follow-up, and quantitative correlation between Meyerding slippage reduction and PROs was performed. Baseline and 24-month PROs, including the Oswestry Disability Index (ODI), EQ-5D, Numeric Rating Scale (NRS)-back pain (NRS-BP), NRS-leg pain (NRS-LP), and satisfaction (North American Spine Society patient satisfaction questionnaire) scores were noted. Multivariable regression models were fitted for 24-month PROs and complications after adjusting for an array of preoperative and surgical variables. Data were analyzed for magnitude of slippage reduction and correlated with PROs. Patients were divided into two groups: < 3 mm reduction and ≥ 3 mm reduction.

Results: Of 608 patients from 12 participating sites, 206 patients with complete data were identified in the QOD and included in this study. Baseline patient demographics, comorbidities, and clinical characteristics were similarly distributed between the cohorts except for depression, listhesis magnitude, and the proportion with dynamic listhesis (which were accounted for in the multivariable analysis). One hundred four (50.5%) patients underwent lumbar decompression and fusion with slippage reduction ≥ 3 mm (mean 5.19, range 3 to 11), and 102 (49.5%) patients underwent lumbar decompression and fusion with slippage reduction < 3 mm (mean 0.41, range 2 to -2). Patients in both groups (slippage reduction ≥ 3 mm, and slippage reduction < 3 mm) reported significant improvement in all primary patient reported outcomes (all p < 0.001). There was no significant difference with regard to the PROs between patients with or without intraoperative reduction of listhesis on univariate and multivariable analyses (ODI, EQ-5D, NRS-BP, NRS-LP, or satisfaction). There was no significant difference in complications between cohorts.

Conclusions: Significant improvement was found in terms of all PROs in patients undergoing decompression and fusion for lumbar spondylolisthesis. There was no correlation with clinical outcomes and magnitude of Meyerding slippage reduction.
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http://dx.doi.org/10.3171/2021.3.SPINE202059DOI Listing
September 2021

Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer.

Cancer Immunol Immunother 2021 Sep 16. Epub 2021 Sep 16.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave., EBRC Room 404A, Boston, MA, 02115, USA.

Background: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 "early onset," 50-54 "intermediate onset,"  ≥ 55 "later onset").

Methods: We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells.

Results: Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14HLA-DR cells (P = 0.015), and CD3CD4FOXP3 cells (P = 0.039).

Conclusions: This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.
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http://dx.doi.org/10.1007/s00262-021-03056-6DOI Listing
September 2021

Is Colorectal Cancer Screening Absolutely Beneficial for Older Adults?

JAMA Oncol 2021 Sep 16. Epub 2021 Sep 16.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston.

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http://dx.doi.org/10.1001/jamaoncol.2021.4155DOI Listing
September 2021

Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigator-initiated, single-centre, open-label study.

Lancet Rheumatol 2021 Sep 7. Epub 2021 Sep 7.

Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: B-cell-depleting therapies increase the risk of morbidity and mortality due to COVID-19. Evidence-based SARS-CoV-2 vaccination strategies for patients on B-cell-depleting therapies are scarce. We aimed to investigate humoral and cell-mediated immune responses to SARS-CoV-2 mRNA-based vaccines in patients receiving CD20-targeted B-cell-depleting agents for autoimmune disease, malignancy, or transplantation.

Methods: The RituxiVac study was an investigator-initiated, single-centre, open-label study done at the Bern University Hospital (Bern, Switzerland). Patients with a treatment history of anti-CD20-depleting agents (rituximab or ocrelizumab) and with no previous history of SARS-CoV-2 infection were enrolled between April 26 and June 30, 2021, for analysis of humoral and cell-mediated immune responses (by interferon-γ [IFNγ] release assay) at least 4 weeks after completing vaccination against SARS-CoV-2. Healthy controls without a history of SARS-CoV-2 infection were also enrolled at least 4 weeks after completing vaccination against SARS-CoV-2. All study participants received two doses of either the Pfizer-BioNTech BNT162b2 vaccine or the Moderna mRNA-1273 vaccine. The primary outcome was the proportion of patients with a history of anti-CD20 treatment who showed a humoral immune response against the SARS-CoV-2 spike protein in comparison with immunocompetent controls. Prespecified secondary endpoints were the effect of anti-CD20 therapy (including time since last treatment and cumulative dose) on humoral or cell-mediated immune responses to SARS-CoV-2 vaccination, and biomarkers of immunocompetence. This study is registered with ClinicalTrials.gov, NCT04877496.

Findings: The final study population comprised 96 patients and 29 immunocompetent controls. The median age of patients was 67 years (IQR 57-72) and of controls was 54 years (45-62), and 51 (53%) of 96 patients and 19 (66%) of 29 controls were female. The median time since last anti-CD20 treatment was 1·07 years (IQR 0·48-2·55) and the median cumulative dose of an anti-CD20 depleting agent was 2·80 g (1·50-5·00). Anti-spike IgG antibodies were detected in 47 (49%) of 96 patients 1·79 months (IQR 1·16-2·48) after the second vaccine dose compared to 29 (100%) of 29 controls 1·81 months (1·17-2·48) after the second vaccine dose (p<0·001). SARS-CoV-2-specific IFNγ release was detected in 13 (20%) of 66 patients and 21 (75%) of 28 of healthy controls (p<0·001). Only nine (14%) of 66 patients were double positive for anti-SARS-CoV-2 spike IgG and cell-mediated responses, compared with 21 (75%) of 28 healthy controls (p<0·001). Time since last anti-CD20 therapy (>7·6 months; positive predictive value 0·78), peripheral CD19 cell count (>27 cells per μL; positive predictive value 0·70), and CD4 lymphocyte count (>653 cells per μL; positive predictive value 0·71) were predictive of humoral vaccine response (area under the curve [AUC] 67% [95% CI 56-78] for time since last anti-CD20 therapy, 67% [55-80] for peripheral CD19 count, and 66% [54-79] for CD4 count).

Interpretation: This study provides further evidence of blunted humoral and cell-mediated immune responses elicited by SARS-CoV-2 mRNA vaccines in patients with a history of CD20 B-cell-depleting treatment. Lymphocyte subpopulation counts were associated with vaccine response in this highly vulnerable population. On validation, these results could help guide both the administration of SARS-CoV-2 vaccines and B-cell-depleting agents in this population.

Funding: Bern University Hospital.
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http://dx.doi.org/10.1016/S2665-9913(21)00251-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423431PMC
September 2021

Diet quality and risk and severity of COVID-19: a prospective cohort study.

Gut 2021 11 6;70(11):2096-2104. Epub 2021 Sep 6.

Clinical and Translational Epidemiological Unit, Massachusetts General Hospital, Boston, MA, USA

Objective: Poor metabolic health and unhealthy lifestyle factors have been associated with risk and severity of COVID-19, but data for diet are lacking. We aimed to investigate the association of diet quality with risk and severity of COVID-19 and its interaction with socioeconomic deprivation.

Design: We used data from 592 571 participants of the smartphone-based COVID-19 Symptom Study. Diet information was collected for the prepandemic period using a short food frequency questionnaire, and diet quality was assessed using a healthful Plant-Based Diet Score, which emphasises healthy plant foods such as fruits or vegetables. Multivariable Cox models were fitted to calculate HRs and 95% CIs for COVID-19 risk and severity defined using a validated symptom-based algorithm or hospitalisation with oxygen support, respectively.

Results: Over 3 886 274 person-months of follow-up, 31 815 COVID-19 cases were documented. Compared with individuals in the lowest quartile of the diet score, high diet quality was associated with lower risk of COVID-19 (HR 0.91; 95% CI 0.88 to 0.94) and severe COVID-19 (HR 0.59; 95% CI 0.47 to 0.74). The joint association of low diet quality and increased deprivation on COVID-19 risk was higher than the sum of the risk associated with each factor alone (P=0.005). The corresponding absolute excess rate per 10 000 person/months for lowest vs highest quartile of diet score was 22.5 (95% CI 18.8 to 26.3) among persons living in areas with low deprivation and 40.8 (95% CI 31.7 to 49.8) among persons living in areas with high deprivation.

Conclusions: A diet characterised by healthy plant-based foods was associated with lower risk and severity of COVID-19. This association may be particularly evident among individuals living in areas with higher socioeconomic deprivation.
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http://dx.doi.org/10.1136/gutjnl-2021-325353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500931PMC
November 2021

Vedolizumab Is Associated With a Lower Risk of Serious Infections Than Anti-TNF Agents in Older Adults.

Clin Gastroenterol Hepatol 2021 Sep 3. Epub 2021 Sep 3.

Center for Gastrointestinal Disease and Biology, University of North Carolina, Chapel Hill, North Carolina; Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

Background & Aims: Despite the increased numbers of older adults with inflammatory bowel diseases (IBDs), there are few studies regarding the safety and effectiveness of IBD treatments in older adults. The aim of this study was to compare the safety and effectiveness of anti-tumor necrosis factor (TNF)-α agents and vedolizumab in older adults with IBD.

Methods: We conducted a retrospective cohort study using an active comparator, new-user design for adults age 65 years and older with IBD initiating anti-TNF-α agents and vedolizumab in the Medicare claims database from 2014 to 2017. The primary safety outcome was infection-related hospitalization (excluding intra-abdominal and perianal abscesses). Co-primary outcomes to estimate effectiveness were IBD-related hospitalization, IBD-related surgery, and new corticosteroid use 60 days or more after biologic initiation. We performed propensity score weighting to control for confounding and estimated adjusted hazard ratios and 95% CIs using standardized morbidity ratio-weighted variables.

Results: We identified 1152 anti-TNF-α new users and 480 vedolizumab new users. The median age was 71 years in both cohorts and 11% were age 80 years or older. Crohn's disease patients comprised 54% of the anti-TNF-α cohort and 57% of the vedolizumab cohort. There was no significant difference in demographics, health care utilization, or frailty in both cohorts. More than half of both cohorts had a Charlson comorbidity index of 2 or higher. Vedolizumab users had a decreased risk of infection-related hospitalization (adjusted hazard ratio, 0.47; 95% CI, 0.25-0.86). There was no significant difference in the outcomes approximating effectiveness.

Conclusions: Older IBD patients treated with vedolizumab had a lower risk of infection-related hospitalization compared with those initiating anti-TNFs. We observed no difference in effectiveness defined by hospitalizations, surgery, or new corticosteroid use.
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http://dx.doi.org/10.1016/j.cgh.2021.08.047DOI Listing
September 2021

Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study.

Lancet Infect Dis 2021 Sep 1. Epub 2021 Sep 1.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK; Department of Ageing and Health, Guy's and St Thomas' NHS Foundation Trust, London, UK. Electronic address:

Background: COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination. This study aimed to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of post-vaccination illness.

Methods: This prospective, community-based, nested, case-control study used self-reported data (eg, on demographics, geographical location, health risk factors, and COVID-19 test results, symptoms, and vaccinations) from UK-based, adult (≥18 years) users of the COVID Symptom Study mobile phone app. For the risk factor analysis, cases had received a first or second dose of a COVID-19 vaccine between Dec 8, 2020, and July 4, 2021; had either a positive COVID-19 test at least 14 days after their first vaccination (but before their second; cases 1) or a positive test at least 7 days after their second vaccination (cases 2); and had no positive test before vaccination. Two control groups were selected (who also had not tested positive for SARS-CoV-2 before vaccination): users reporting a negative test at least 14 days after their first vaccination but before their second (controls 1) and users reporting a negative test at least 7 days after their second vaccination (controls 2). Controls 1 and controls 2 were matched (1:1) with cases 1 and cases 2, respectively, by the date of the post-vaccination test, health-care worker status, and sex. In the disease profile analysis, we sub-selected participants from cases 1 and cases 2 who had used the app for at least 14 consecutive days after testing positive for SARS-CoV-2 (cases 3 and cases 4, respectively). Controls 3 and controls 4 were unvaccinated participants reporting a positive SARS-CoV-2 test who had used the app for at least 14 consecutive days after the test, and were matched (1:1) with cases 3 and 4, respectively, by the date of the positive test, health-care worker status, sex, body-mass index (BMI), and age. We used univariate logistic regression models (adjusted for age, BMI, and sex) to analyse the associations between risk factors and post-vaccination infection, and the associations of individual symptoms, overall disease duration, and disease severity with vaccination status.

Findings: Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50-2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01-1·23; p=0·039). Individuals without obesity (BMI <30 kg/m) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75-0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older.

Interpretation: To minimise SARS-CoV-2 infection, at-risk populations must be targeted in efforts to boost vaccine effectiveness and infection control measures. Our findings might support caution around relaxing physical distancing and other personal protective measures in the post-vaccination era, particularly around frail older adults and individuals living in more deprived areas, even if these individuals are vaccinated, and might have implications for strategies such as booster vaccinations.

Funding: ZOE, the UK Government Department of Health and Social Care, the Wellcome Trust, the UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging and Artificial Intelligence Centre for Value Based Healthcare, the UK National Institute for Health Research, the UK Medical Research Council, the British Heart Foundation, and the Alzheimer's Society.
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http://dx.doi.org/10.1016/S1473-3099(21)00460-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409907PMC
September 2021

Metabolomics as a Tool for Biomarker Discovery in Gastric Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Sep;30(9):1601-1603

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Globally, early detection and interception of gastric cancer remains limited by the lack of a broad screening paradigm for individuals with the exception of those at established hereditary risk (e.g., hereditary diffuse gastric cancer or germline mutation status). The path forward will likely rely on establishment of biomarkers using multiple -omic approaches to detect molecular profiles associated with gastric cancer risk that can in turn be leveraged to identify individuals who may benefit from more intensive evaluation, such as screening endoscopy. In this issue, Shu and colleagues describe the results of a case-control cohort study of Asian individuals that demonstrates baseline metabolite levels are predictive of future gastric cancer risk above and beyond lifestyle and demographic risk factors. We discuss the promise and limitations of these exemplar circulating biomarkers and emphasize the need for a multifactorial risk assessment to advance precision prevention and early detection of gastric cancer..
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477789PMC
September 2021

Alcohol Consumption is Associated With An Increased Risk of Microscopic Colitis: Results From 2 Prospective US Cohort Studies.

Inflamm Bowel Dis 2021 Sep 2. Epub 2021 Sep 2.

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background: No dietary factors have yet been shown to conclusively impact the incidence of microscopic colitis (MC). Here, we sought to examine the relationship between alcohol intake and the risk of MC.

Methods: We conducted a prospective cohort study of 209,902 participants (age range, 28.5-66.7 years) enrolled in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII). Validated data on alcohol consumption were collected at baseline in 1986 in the NHS and 1991 in the NHSII and updated every 4 years. Diagnoses of MC were confirmed via review of histopathology data. We used Cox proportional hazards modeling to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).

Results: Through 2016 in the NHS and 2017 in the NHSII, we confirmed 352 incident cases of MC over 4,994,324 person-years. Higher alcohol consumption was associated with an increased risk of MC (Ptrend < .001). Compared to non-users, the aHRs of MC were 1.20 (95% CI, 0.86-1.67) for consumers of 0.1-4.9 g/day of alcohol, 1.90 (95% CI, 1.34-2.71) for consumers of 5-14.9 g/day, and 2.31 (95% CI, 1.54-3.46) for consumers of ≥15 g/day. The associations were consistent across the histologic subtypes of collagenous and lymphocytic colitis (Pheterogeneity = .523). When stratified by alcohol type, the risk according to every 2 servings/week appeared to be strongest with consumption of wine (aHR, 1.08; 95% CI, 1.04-1.12) as compared to beer (aHR, 1.01; 95% CI, 0.91-1.12) or liquor (aHR, 1.00; 95% CI, 0.92-1.09).

Conclusions: Alcohol consumption was associated with an increased risk of MC. Further studies are needed to determine the mechanism underlying these associations, as well as the impact of reducing alcohol intake in patients with MC.
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http://dx.doi.org/10.1093/ibd/izab220DOI Listing
September 2021

Cardiovascular disease related circulating biomarkers and cancer incidence and mortality: is there an association?

Cardiovasc Res 2021 Sep 1. Epub 2021 Sep 1.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA.

Aims: Recent studies suggest an association between cardiovascular disease (CVD) and cancer incidence/mortality, but the pathophysiological mechanisms underlying these associations are unclear. We aimed to examine biomarkers previously associated with CVD and study their association with incident cancer and cancer-related death in a prospective cohort study.

Methods And Results: We used a proteomic platform to measure 71 cardiovascular biomarkers among 5,032 participants in the Framingham Heart Study who were free of cancer at baseline. We used multivariable-adjusted Cox models to examine the association of circulating protein biomarkers with risk of cancer incidence and mortality. To account for multiple testing, we set a 2-sided false discovery rate (FDR Q-value) <0.05.Growth differentiation factor-15 (GDF15; also known as macrophage inhibitory cytokine-1 [MIC1])) was associated with increased risk of incident cancer (hazards ratio [HR] per 1 standard deviation increment 1.31, 95% CI 1.17-1.47), incident gastrointestinal cancer (HR 1.85, 95% CI 1.37-2.50), incident colorectal cancer (HR 1.94, 95% CI 1.29-2.91) and cancer-related death (HR 2.15, 95% CI 1.72-2.70). Stromal cell-derived factor-1 (SFD1) showed an inverse association with cancer-related death (HR 0.75, 95% CI 0.65-0.86). Fibroblast growth factor-23 (FGF23) showed an association with colorectal cancer (HR 1.55, 95% CI 1.20-2.00), and granulin (GRN) was associated with hematologic cancer (HR 1.61, 95% CI 1.30-1.99). Other circulating biomarkers of inflammation, immune activation, metabolism, and fibrosis showed suggestive associations with future cancer diagnosis.

Conclusion: We observed several significant associations between circulating CVD biomarkers and cancer, supporting the idea that shared biological pathways underlie both diseases. Further investigations of specific mechanisms that lead to both CVD and cancer are warranted.

Translational Perspective: In our prospective cohort study, baseline levels of biomarkers previously associated with CVD were found to be associated with future development of cancer. In particular, GDF15 was associated with increased risk of cancer incidence and mortality, including gastrointestinal and colorectal cancers; SDF1 was inversely associated with cancer-related death, and FGF23 and GRN were associated with increased risk of colorectal and hematologic cancers, respectively. Other biomarkers of inflammation, immune activation, metabolism, and fibrosis showed suggestive associations. These results suggest potential shared biological pathways that underlie both development of cancer and CVD.
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http://dx.doi.org/10.1093/cvr/cvab282DOI Listing
September 2021

Ultra-processed Foods and Risk of Crohn's Disease and Ulcerative Colitis: A Prospective Cohort Study.

Clin Gastroenterol Hepatol 2021 Aug 28. Epub 2021 Aug 28.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background & Aims: The rising incidence of inflammatory bowel disease in regions undergoing Westernization has coincided with the increase in ultra-processed food (UPF) consumption over the past few decades. We aimed to examine the association between consumption of UPFs and the risk of Crohn's disease (CD) and ulcerative colitis (UC).

Methods: We performed a prospective cohort study of 3 nationwide cohorts of health professionals in the United States-the Nurses' Health Study (1986-2014), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2012). We employed Cox proportional hazards models with adjustment for confounders to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CD and UC according to self-reported consumption of UPFs.

Results: The study included 245,112 participants. Over 5,468,444 person-years of follow-up, we documented 369 incident cases of CD and 488 incident cases of UC. The median age at diagnosis was 56 years (range, 29-85 years). Compared with participants in the lowest quartile of simple updated UPF consumption, those in the highest quartile had a significantly increased risk of CD (HR, 1.70; 95% CI, 1.23-2.35; P = .0008). Among different UPF subgroups, ultra-processed breads and breakfast foods; frozen or shelf-stable ready-to-eat/heat meals; and sauces, cheeses, spreads, and gravies showed the strongest positive associations with CD risk (HR per 1 standard deviation increase in intake, 1.18 [95% CI, 1.07-1.29], 1.11 [95% CI, 1.01-1.22], and 1.14 [95% CI, 1.02-1.27], respectively). There was no consistent association between UPF intake and UC risk.

Conclusions: Higher UPF intake was associated with an increased risk of incident CD. Further studies are needed to identify specific contributory dietary components.
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http://dx.doi.org/10.1016/j.cgh.2021.08.031DOI Listing
August 2021

Preliminary experience using S1-alar iliac fixation with navigation: technical note.

J Neurosurg Spine 2021 Aug 27:1-6. Epub 2021 Aug 27.

1Department of Neurosurgery, University of California, San Francisco, California; and.

Traditional iliac screws and S2-alar iliac (S2-AI) screws are common methods used for pelvic fixation, and many surgeons advocate pelvic fixation for long-segment fixation to the sacrum. However, in patients without severe deformities and only degenerative conditions, many surgeons may choose S1 screws only. Moreover, even with S2-AI screws, there is more muscular dissection than with using S1 screws, and the rod connection can be cumbersome in both S2-AI fixation and placing iliac screws. Using a surgical video, artist's illustration, and intraoperative photographs, the authors describe the S1-AI screw fixation technique that allows for single-screw sacral and iliac fixation, requires less distal dissection of the sacrum, allows for easier rod connection, and may be an option in degenerative conditions needing pelvic fixation. However, this is a preliminary feasibility study, and in long fusion constructs, this type of fixation has only been used in conjunction with L5-S1 anterior lumbar interbody fusion (ALIF), and there are no long-term data on the use of this screw fixation technique without ALIF. In short-segment revision fusions, this technique may be considered for salvage in cases of large halos in the sacrum from loosened S1 screw fixation.
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http://dx.doi.org/10.3171/2021.1.SPINE201744DOI Listing
August 2021

Multiple Sclerosis Therapy Consensus Group (MSTCG): position statement on disease-modifying therapies for multiple sclerosis (white paper).

Ther Adv Neurol Disord 2021 18;14:17562864211039648. Epub 2021 Aug 18.

Neurologie in Meerbusch, MS-Zentrum, Meerbusch, Germany.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland).
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http://dx.doi.org/10.1177/17562864211039648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377320PMC
August 2021

Lymphocele after anterior lumbar interbody fusion: a review of 1322 patients.

J Neurosurg Spine 2021 Aug 20:1-7. Epub 2021 Aug 20.

Departments of1Neurological Surgery and.

Objective: Anterior lumbar interbody fusion (ALIF) is an effective surgical modality for many lumbar degenerative pathologies, but a rare and infrequently reported complication is postoperative lymphocele. The goals of the present study were to review a large consecutive series of patients who underwent ALIF at a high-volume institution, estimate the rate of lymphocele occurrence after ALIF, and investigate the outcomes of patients who developed lymphocele after ALIF.

Methods: A retrospective review of the electronic medical record was completed, identifying all patients (≥ 18 years old) who underwent at a minimum a single-level ALIF from 2012 through 2019. Postoperative spinal and abdominal images, as well as radiologist reports, were reviewed for mention of lymphocele. Clinical data were collected and reported.

Results: A total of 1322 patients underwent a minimum 1-level ALIF. Of these patients, 937 (70.9%) had either postoperative abdominal or lumbar spine images, and the resulting lymphocele incidence was 2.1% (20/937 patients). The mean ± SD age was 67 ± 10.9 years, and the male/female ratio was 1:1. Patients with lymphocele were significantly older than those without lymphocele (66.9 vs 58.9 years, p = 0.006). In addition, patients with lymphocele had a greater number of mean levels fused (2.5 vs 1.8, p < 0.001) and were more likely to have undergone ALIF at L2-4 (95.0% vs 66.4%, p = 0.007) than patients without lymphocele. On subsequent multivariate analysis, age (OR 1.07, 95% CI 1.01-1.12, p = 0.013), BMI (OR 1.10, 95% CI 1.01-1.18, p = 0.021), and number of levels fused (OR 1.82, 95% CI 1.05-3.14, p = 0.032) were independent prognosticators of postoperative lymphocele development. Patients with symptomatic lymphocele were successfully treated with either interventional radiology (IR) drainage and/or sclerosis therapy and achieved radiographic resolution. The mean ± SD length of hospital stay was 9.1 ± 5.2 days. Ten patients (50%) were postoperatively discharged to a rehabilitation center: 8 patients (40%) were discharged to home, 1 (5%) to a skilled nursing facility, and 1 (5%) to a long-term acute care facility.

Conclusions: After ALIF, 2.1% of patients were diagnosed with radiographically identified postoperative lymphocele and had risk factors such as increased age, BMI, and number of levels fused. Most patients presented within 1 month postoperatively, and their clinical presentations included abdominal pain, abdominal distension, and/or wound complications. Of note, 25% of identified lymphoceles were discovered incidentally. Patients with symptomatic lymphocele were successfully treated with either IR drainage and/or sclerosis therapy and achieved radiographic resolution.
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http://dx.doi.org/10.3171/2021.2.SPINE201667DOI Listing
August 2021

Genetic Obesity Variants and Risk of Conventional Adenomas and Serrated Polyps.

Dig Dis Sci 2021 Aug 17. Epub 2021 Aug 17.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Higher body mass index (BMI) is associated with increased risk of colorectal cancer. How genetically predicted BMI may be associated with colorectal cancer precursors is unknown.

Aims: Our objective was to quantify the association of genetically predicted and measured BMI with risk of colorectal cancer precursors.

Methods: We evaluated the association of genetically predicted and measured BMI with risk of conventional adenomas, serrated polyps, and synchronous polyps among 27,426 participants who had undergone at least one lower gastrointestinal endoscopy in the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study. Genetic risk score was derived from 97 BMI-related single nucleotide polymorphisms. Multivariable logistic regression evaluated each polyp subtype compared to non-polyps.

Results: For conventional adenomas, the OR per 2-kg/m increase was 1.03 (95% CI, 1.01-1.04) for measured BMI and 0.98 (95% CI, 0.88-1.10) for genetically predicted BMI; for serrated polyps, the OR was 1.06 (95% CI, 1.04-1.08) and 1.04 (95% CI, 0.90-1.20), respectively; for synchronous polyps, the OR was 1.10 (95% CI, 1.07-1.13) and 1.09 (95% CI, 0.89-1.34), respectively. Genetically predicted BMI was associated with synchronous polyps in women (OR = 1.37, 95% CI: 1.05-1.79).

Conclusion: Genetically predicted BMI was not associated with colorectal cancer precursor lesions. The confidence intervals were wide and encompassed those for measured BMI, indicating that null findings may be due to insufficient power.
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http://dx.doi.org/10.1007/s10620-021-07193-xDOI Listing
August 2021

Transcriptome-wide Effects of Aspirin on Patient-derived Normal Colon Organoids.

Cancer Prev Res (Phila) 2021 Aug 13. Epub 2021 Aug 13.

Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.

Mechanisms underlying aspirin chemoprevention of colorectal cancer remain unclear. Prior studies have been limited because of the inability of preclinical models to recapitulate human normal colon epithelium or cellular heterogeneity present in mucosal biopsies. To overcome some of these obstacles, we performed aspirin treatment of colon organoids derived from normal mucosal biopsies to reveal transcriptional networks relevant to aspirin chemoprevention. Colon organoids derived from 38 healthy individuals undergoing endoscopy were treated with 50 μmol/L aspirin or vehicle control for 72 hours and subjected to bulk RNA sequencing. Paired regression analysis using DESeq2 identified differentially expressed genes (DEG) associated with aspirin treatment. Cellular composition was determined using CIBERSORTx. Aspirin treatment was associated with 1,154 significant ( < 0.10) DEGs prior to deconvolution. We provide replication of these findings in an independent population-based RNA-sequencing dataset of mucosal biopsies (BarcUVa-Seq), where a significant enrichment for overlap of DEGs was observed ( < 2.2E). Single-cell deconvolution revealed changes in cell composition, including a decrease in transit-amplifying cells following aspirin treatment ( = 0.01). Following deconvolution, DEGs included novel putative targets for aspirin such as ( = 0.055), a negative regulator of Wnt signaling. Weighted gene co-expression network analysis identified 12 significant modules, including two that contained hubs for and , the latter being previously implicated in aspirin chemoprevention. In summary, aspirin treatment of patient-derived colon organoids using physiologically relevant doses resulted in transcriptome-wide changes that reveal altered cell composition and improved understanding of transcriptional pathways, providing novel insight into its chemopreventive properties. PREVENTION RELEVANCE: Numerous studies have highlighted a role for aspirin in colorectal cancer chemoprevention, though the mechanisms driving this association remain unclear. We addressed this by showing that aspirin treatment of normal colon organoids diminished the transit-amplifying cell population, inhibited prostaglandin synthesis, and dysregulated expression of novel genes implicated in colon tumorigenesis.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0041DOI Listing
August 2021

Association Between Smoking and Molecular Subtypes of Colorectal Cancer.

JNCI Cancer Spectr 2021 Aug 14;5(4):pkab056. Epub 2021 Jun 14.

Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking.

Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including mutation, mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction.

Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers ( < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and . Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; = 2.1 x 10). The association was also stronger in tumors that were positive, MSI high, or wild type when combined ( < .001).

Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.
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http://dx.doi.org/10.1093/jncics/pkab056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346704PMC
August 2021

Association of mutation and PTEN loss with expression of CD274 (PD-L1) in colorectal carcinoma.

Oncoimmunology 2021 2;10(1):1956173. Epub 2021 Aug 2.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Immunotherapy targeting the CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint axis has emerged as a promising treatment strategy for various cancers. Experimental evidence suggests that phosphatidylinositol-4,5-bisphosphonate 3-kinase (PI3K) signaling may upregulate CD274 expression. Thus, we hypothesized that mutation, PTEN loss, or their combined status might be associated with CD274 overexpression in colorectal carcinoma. We assessed tumor CD274 and PTEN expression by immunohistochemistry and assessed mutation by pyrosequencing in 753 patients among 4,465 incident rectal and colon cancer cases that had occurred in two U.S.-wide prospective cohort studies. To adjust for potential confounders and selection bias due to tissue availability, inverse probability weighted multivariable ordinal logistic regression analyses used the 4,465 cases and tumoral data including microsatellite instability, CpG island methylator phenotype, and mutations. mutation and loss of PTEN expression were detected in 111 of 753 cases (15%) and 342 of 585 cases (58%), respectively. Tumor CD274 expression was negative in 306 (41%), low in 195 (26%), and high in 252 (33%) of 753 cases. PTEN loss was associated with CD274 overexpression [multivariable odds ratio (OR) 1.83; 95% confidence interval (CI), 1.22-2.75; = .004]. mutation was statistically-insignificantly ( = .036 with the stringent alpha level of 0.005) associated with CD274 overexpression (multivariable OR, 1.54; 95% CI, 1.03-2.31). -mutated PTEN-lost tumors (n = 33) showed higher prevalence of CD274-positivity (82%) than -wild-type PTEN-lost tumors (n = 204; 70% CD274-positivity) and PTEN-expressed tumors (n = 147; 50% CD274-positivity) ( = .003). Our findings support the role of PI3K signaling in the CD274/PDCD1 pathway.
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http://dx.doi.org/10.1080/2162402X.2021.1956173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331006PMC
October 2021

Predicting conversion to multiple sclerosis in patients with radiologically isolated syndrome: a retrospective study.

Ther Adv Neurol Disord 2021 16;14:17562864211030664. Epub 2021 Jul 16.

Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.

Aims: To retrospectively analyse the Bernese radiologically isolated syndrome (RIS) cohort with the goal of developing a prediction score for conversion to multiple sclerosis (MS).

Methods: A total of 31 patients with RIS were identified by screening medical records of neurological patients seen at the University Hospital of Bern between 2004 and 2017 for the diagnoses 'radiologically isolated syndrome' and 'RIS' adhering to 2009 Okuda recommendations. We analysed clinical, paraclinical and magnetic resonance imaging data during a maximum follow-up period of 3 years and identified significant predictors of conversion to MS.

Results: Data were available for 31 patients meeting 2009 Okuda RIS criteria. During the 3 years of follow up, 5/31 RIS patients converted to relapsing-remitting (RR) MS. In our univariate analysis, gadolinium (Gd) enhancement, brainstem and cerebellar hemisphere lesions, immune cell count and albumin concentration in cerebrospinal fluid (CSF), and anti-nuclear antibody (ANA) positivity in serum were identified as significant predictors of conversion to MS. Integrating these factors into our 'RIS-MS prediction score' enabled us to calculate a cut-off for prediction of conversion to MS within 3 years with high specificity [1.0, 95% confidence interval (CI) 0.84-1.00) and acceptable sensitivity (0.6, 95% CI 0.17-0.93)].

Conclusion: Our RIS-MS prediction score, if validated in an independent cohort, integrating radiological (Gd enhancement, brainstem and cerebellar hemisphere lesions) and paraclinical factors (ANA in serum, cell count and albumin in CSF) could be a useful prognostic tool for early recognition of RIS patients with a high risk of clinical progression to MS.
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http://dx.doi.org/10.1177/17562864211030664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287642PMC
July 2021

Inhibition of Isoleucyl-tRNA Synthetase by the Hybrid Antibiotic Thiomarinol.

J Am Chem Soc 2021 Aug 3;143(31):12003-12013. Epub 2021 Aug 3.

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Hybrid antibiotics are an emerging antimicrobial strategy to overcome antibiotic resistance. The natural product thiomarinol A is a hybrid of two antibiotics: holothin, a dithiolopyrrolone (DTP), and marinolic acid, a close analogue of the drug mupirocin that is used to treat methicillin-resistant (MRSA). DTPs disrupt metal homeostasis by chelating metal ions in cells, whereas mupirocin targets the essential enzyme isoleucyl-tRNA synthetase (IleRS). Thiomarinol A is over 100-fold more potent than mupirocin against mupirocin-sensitive MRSA; however, its mode of action has been unknown. We show that thiomarinol A targets IleRS. A knockdown of the IleRS-encoding gene, , exhibited sensitivity to a synthetic analogue of thiomarinol A in a chemical genomics screen. Thiomarinol A inhibits MRSA IleRS with a picomolar and binds to IleRS with low femtomolar affinity, 1600 times more tightly than mupirocin. We find that thiomarinol A remains effective against high-level mupirocin-resistant MRSA and provide evidence to support a dual mode of action for thiomarinol A that may include both IleRS inhibition and metal chelation. We demonstrate that MRSA develops resistance to thiomarinol A to a substantially lesser degree than mupirocin and the potent activity of thiomarinol A requires hybridity between DTP and mupirocin. Our findings identify a mode of action of a natural hybrid antibiotic and demonstrate the potential of hybrid antibiotics to combat antibiotic resistance.
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http://dx.doi.org/10.1021/jacs.1c02622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479755PMC
August 2021

Potential disease trigger as a therapeutic option: infliximab for paradoxical reaction in tuberculosis of the central nervous system.

BMJ Case Rep 2021 Aug 2;14(8). Epub 2021 Aug 2.

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.

A 36-year-old man of central Asian origin was diagnosed with subacute disseminated tuberculosis. Initially, central nervous system involvement was suggested by an encephalopathic condition and MRI showing extensive basal and spinal meningitis. After initiation of anti-tuberculosis drugs and corticosteroid therapy, clinical and radiological deterioration of spinal damage was noted. We interpreted this in the context of a paradoxical reaction, which is suggested to be an overshooting inflammatory response after reconstitution of the immune system. Despite increased dosage of corticosteroids, a gradual worsening of gait ataxia over several weeks was noted. After administration of infliximab, the patient's condition progressively improved.
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http://dx.doi.org/10.1136/bcr-2020-235511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330559PMC
August 2021

Early detection of COVID-19 in the UK using self-reported symptoms: a large-scale, prospective, epidemiological surveillance study.

Lancet Digit Health 2021 09 29;3(9):e587-e598. Epub 2021 Jul 29.

School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK.

Background: Self-reported symptoms during the COVID-19 pandemic have been used to train artificial intelligence models to identify possible infection foci. To date, these models have only considered the culmination or peak of symptoms, which is not suitable for the early detection of infection. We aimed to estimate the probability of an individual being infected with SARS-CoV-2 on the basis of early self-reported symptoms to enable timely self-isolation and urgent testing.

Methods: In this large-scale, prospective, epidemiological surveillance study, we used prospective, observational, longitudinal, self-reported data from participants in the UK on 19 symptoms over 3 days after symptoms onset and COVID-19 PCR test results extracted from the COVID-19 Symptom Study mobile phone app. We divided the study population into a training set (those who reported symptoms between April 29, 2020, and Oct 15, 2020) and a test set (those who reported symptoms between Oct 16, 2020, and Nov 30, 2020), and used three models to analyse the self-reported symptoms: the UK's National Health Service (NHS) algorithm, logistic regression, and the hierarchical Gaussian process model we designed to account for several important variables (eg, specific COVID-19 symptoms, comorbidities, and clinical information). Model performance to predict COVID-19 positivity was compared in terms of sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) in the test set. For the hierarchical Gaussian process model, we also evaluated the relevance of symptoms in the early detection of COVID-19 in population subgroups stratified according to occupation, sex, age, and body-mass index.

Findings: The training set comprised 182 991 participants and the test set comprised 15 049 participants. When trained on 3 days of self-reported symptoms, the hierarchical Gaussian process model had a higher prediction AUC (0·80 [95% CI 0·80-0·81]) than did the logistic regression model (0·74 [0·74-0·75]) and the NHS algorithm (0·67 [0·67-0·67]). AUCs for all models increased with the number of days of self-reported symptoms, but were still high for the hierarchical Gaussian process model at day 1 (0·73 [95% CI 0·73-0·74]) and day 2 (0·79 [0·78-0·79]). At day 3, the hierarchical Gaussian process model also had a significantly higher sensitivity, but a non-statistically lower specificity, than did the two other models. The hierarchical Gaussian process model also identified different sets of relevant features to detect COVID-19 between younger and older subgroups, and between health-care workers and non-health-care workers. When used during different pandemic periods, the model was robust to changes in populations.

Interpretation: Early detection of SARS-CoV-2 infection is feasible with our model. Such early detection is crucial to contain the spread of COVID-19 and efficiently allocate medical resources.

Funding: ZOE, the UK Government Department of Health and Social Care, the Wellcome Trust, the UK Engineering and Physical Sciences Research Council, the UK National Institute for Health Research, the UK Medical Research Council, the British Heart Foundation, the Alzheimer's Society, the Chronic Disease Research Foundation, and the Massachusetts Consortium on Pathogen Readiness.
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http://dx.doi.org/10.1016/S2589-7500(21)00131-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321433PMC
September 2021

The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men.

Clin Transl Gastroenterol 2021 Aug 1;12(8):e00338. Epub 2021 Aug 1.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Introduction: We recently described the sulfur microbial diet, a pattern of intake associated with increased gut sulfur-metabolizing bacteria and incidence of distal colorectal cancer (CRC). We assessed whether this risk differed by CRC molecular subtypes or presence of intratumoral microbes involved in CRC pathogenesis (Fusobacterium nucleatum and Bifidobacterium spp.).

Methods: We performed Cox proportional hazards modeling to examine the association between the sulfur microbial diet and incidence of overall and distal CRC by molecular and microbial subtype in the Health Professionals Follow-Up Study (1986-2012).

Results: We documented 1,264 incident CRC cases among 48,246 men, approximately 40% of whom had available tissue data. After accounting for multiple hypothesis testing, the relationship between the sulfur microbial diet and CRC incidence did not differ by subtype. However, there was a suggestion of an association by prostaglandin synthase 2 (PTGS2) status with a multivariable adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.31 (95% confidence interval: 0.99-1.74, Ptrend = 0.07, Pheterogeneity = 0.04) for PTGS2-high CRC. The association of the sulfur microbial diet with distal CRC seemed to differ by the presence of intratumoral Bifidobacterium spp. with an adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.65 (95% confidence interval: 1.14-2.39, Ptrend = 0.01, Pheterogeneity = 0.03) for Bifidobacterium-negative distal CRC. We observed no apparent heterogeneity by other tested molecular markers.

Discussion: Greater long-term adherence to the sulfur microbial diet could be associated with PTGS2-high and Bifidobacterium-negative distal CRC in men. Additional studies are needed to further characterize the role of gut microbial sulfur metabolism and CRC.
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http://dx.doi.org/10.14309/ctg.0000000000000338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323793PMC
August 2021

Race, ethnicity, community-level socioeconomic factors, and risk of COVID-19 in the United States and the United Kingdom.

EClinicalMedicine 2021 Aug 17;38:101029. Epub 2021 Jul 17.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, 100 Cambridge Street, 15th Floor, Boston, MA 02114, USA.

Background: There is limited prior investigation of the combined influence of personal and community-level socioeconomic factors on racial/ethnic disparities in individual risk of coronavirus disease 2019 (COVID-19).

Methods: We performed a cross-sectional analysis nested within a prospective cohort of 2,102,364 participants from March 29, 2020 in the United States (US) and March 24, 2020 in the United Kingdom (UK) through December 02, 2020 via the COVID Symptom Study smartphone application. We examined the contribution of community-level deprivation using the Neighborhood Deprivation Index (NDI) and the Index of Multiple Deprivation (IMD) to observe racial/ethnic disparities in COVID-19 incidence. ClinicalTrials.gov registration: NCT04331509.

Findings: Compared with non-Hispanic White participants, the risk for a positive COVID-19 test was increased in the US for non-Hispanic Black (multivariable-adjusted odds ratio [OR], 1.32; 95% confidence interval [CI], 1.18-1.47) and Hispanic participants (OR, 1.42; 95% CI, 1.33-1.52) and in the UK for Black (OR, 1.17; 95% CI, 1.02-1.34), South Asian (OR, 1.39; 95% CI, 1.30-1.49), and Middle Eastern participants (OR, 1.38; 95% CI, 1.18-1.61). This elevated risk was associated with living in more deprived communities according to the NDI/IMD. After accounting for downstream mediators of COVID-19 risk, community-level deprivation still mediated 16.6% and 7.7% of the excess risk in Black compared to White participants in the US and the UK, respectively.

Interpretation: Our results illustrate the critical role of social determinants of health in the disproportionate COVID-19 risk experienced by racial and ethnic minorities.
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http://dx.doi.org/10.1016/j.eclinm.2021.101029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285255PMC
August 2021
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