Publications by authors named "Jane Green"

159 Publications

Social isolation and risk of heart disease and stroke: analysis of two large UK prospective studies.

Lancet Public Health 2021 04 2;6(4):e232-e239. Epub 2021 Mar 2.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address:

Background: Social isolation has been associated with increased risk of coronary heart disease and stroke. However, it is unclear whether the associations differ between fatal and non-fatal events or by the type of isolation (living alone or having few social contacts). We aimed to examine these associations in two large UK prospective cohorts.

Methods: Million Women Study and UK Biobank participants without previous coronary heart disease or stroke who provided data in median year 2010 (IQR 2009-2011) on social contacts were included in this prospective analysis. Participants were followed up to median year 2017 (2017-2017) by electronic linkage to national hospital and death records. Risk ratios (RRs) were calculated using Cox regression for first coronary heart disease and stroke event (overall, and separately for hospital admission as the first event and for death without an associated hospital admission as the first event) by three levels of social isolation (based on living alone, contact with family or friends, and group participation) adjusted for age, sex, study, region, deprivation, smoking, alcohol intake, body-mass index, physical activity, and self-rated health.

Findings: 938 558 participants were included in our analyses (mean age 63 years [SD 9]): 481 946 participants from the Million Women Study (mean age 68 years [5]) and 456 612 participants (mean age 57 years [8]) from UK Biobank. During a mean follow-up period of 7 years (2), 42 402 first coronary heart disease events (of which 1834 were fatal without an associated hospital admission) and 19 999 first stroke events (of which 529 were fatal without an associated hospital admission) occurred. Little, if any, association was found between social isolation and hospital admission for a first coronary heart disease or stroke event (combined RR for both studies 1·01 [95% CI 0·98-1·04] for coronary heart disease and 1·13 [1·08-1·18] for stroke, when comparing the most isolated group with the least isolated group). However, the risk of death without an associated hospital admission was substantially higher in the most isolated group than the least isolated group for coronary heart disease (1·86 [1·63-2·12]) and stroke (1·91 [1·48-2·46]). For coronary heart disease or stroke death as the first event, RRs were substantially higher (test for heterogeneity, p=0·002) for participants living alone versus those not living alone (1·60 [1·46-1·75]) than for those with fewer versus more contact with family, friends, or groups (1·27 [1·16-1·38]). These findings did not differ greatly between studies, or by self-rated health.

Interpretation: Social isolation seems to have little direct effect on the risk of developing a first coronary heart disease or stroke. By contrast, social isolation substantially increases the risk that the first such event is fatal before reaching hospital, particularly among people who live alone, perhaps because of the absence of immediate help in responding to an acute heart attack or stroke.

Funding: UK Medical Research Council, Cancer Research UK.
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http://dx.doi.org/10.1016/S2468-2667(20)30291-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994247PMC
April 2021

Cognitive and social activities and long-term dementia risk: the prospective UK Million Women Study.

Lancet Public Health 2021 02;6(2):e116-e123

Cancer Epidemiology Unit, University of Oxford, Oxford, UK.

Background: Although dementia is associated with non-participation in cognitive and social activities, this association might merely reflect the consequences of dementia, rather than any direct effect of non-participation on the subsequent incidence of dementia. Because of the slowness with which dementia can develop, unbiased assessment of any such direct effects must relate non-participation in such activities to dementia detection rates many years later. Prospective studies with long-term follow-up can help achieve this by analysing separately the first and second decade of follow-up. We report such analyses of a large, 20-year study.

Methods: The UK Million Women Study is a population-based prospective study of 1·3 million women invited for National Health Service (NHS) breast cancer screening in median year 1998 (IQR 1997-1999). In median year 2001 (IQR 2001-2003), women were asked about participation in adult education, groups for art, craft, or music, and voluntary work, and in median year 2006 (IQR 2006-2006), they were asked about reading. All participants were followed up through electronic linkage to NHS records of hospital admission with mention of dementia, the first mention of which was the main outcome. Comparing non-participation with participation in a particular activity, we used Cox regression to assess fully adjusted dementia risk ratios (RRs) during 0-4, 5-9, and 10 or more years, after information on that activity was obtained.

Findings: In 2001, 851 307 women with a mean age of 60 years (SD 5) provided information on participation in adult education, groups for art, craft, or music, and voluntary work. After 10 years, only 9591 (1%) had been lost to follow-up and 789 339 (93%) remained alive with no recorded dementia. Follow-up was for a mean of 16 years (SD 3), during which 31 187 (4%) had at least one hospital admission with mention of dementia, including 25 636 (3%) with a hospital admission with dementia mentioned for the first time 10 years or more after follow-up began. Non-participation in cognitive or social activities was associated with higher relative risks of dementia detection only during the first decade after participation was recorded. During the second decade, there was little association. This was true for non-participation in adult education (RR 1·04, 99% CI 0·98-1·09), in groups for art, craft, or music (RR 1·04, 0·99-1·09), in voluntary work (RR 0·96, 0·92-1·00), or in any of these three (RR 0·99, 0·95-1·03). In 2006, 655 118 women provided information on reading. For non-reading versus any reading, there were similar associations with dementia, again with strong attenuation over time since reading was recorded, but longer follow-up is needed to assess this reliably.

Interpretation: Life has to be lived forwards, but can be understood only backwards. Long before dementia is diagnosed, there is a progressive reduction in various mental and physical activities, but this is chiefly because its gradual onset causes inactivity and not because inactivity causes dementia.

Funding: UK Medical Research Council, Cancer Research UK.
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http://dx.doi.org/10.1016/S2468-2667(20)30284-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848753PMC
February 2021

Low rate of subsequent surgery and serious complications following intra-articular steroid injection for base of thumb osteoarthritis: national cohort analysis.

Rheumatology (Oxford) 2021 Jan 7. Epub 2021 Jan 7.

Oxford NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University of Oxford, Oxford, UK.

Objectives: Intra-articular steroid injection is commonly used to treat base of thumb osteoarthritis (BTOA), despite a lack of large scale data on safety and effectiveness. We estimate the incidence of serious complications and further procedures following BTOA injection, including the risk of post-operative serious surgical site infection for subsequent operative intervention.

Methods: Hospital Episode Statistics data linked to mortality records from 01/04/1998-31/03/2017 were used to identify all BTOA injections undertaken in adults in the National Health Service secondary care in England. Patients were followed up longitudinally until death or 31/03/2017. A multivariable regression with a Fine and Gray model adjusting for the competing risk of mortality in addition to age, sex and socioeconomic deprivation was used to identify factors associated with progression to further procedure. Secondary outcomes included serious complications after injection and subsequent surgical site infection.

Results: 19120 primary injections were performed during the 19-year period in 18356 patients. 76.5% were female; mean age 62 years (SD 10.6).50.48% underwent further procedure; 22.40% underwent surgery. Median time to further intervention was 412 days (IQR 110-1945). Female sex was associated with increased risk of proceeding to surgery. Serious complication rate following injection was 0.04% (0.01-0.08) within 90 days. Of those proceeding to surgery, 0.16% (0.06-0.34) presented with a wound infection within 30 days and 90 days, compared with an overall post-operative wound infection rate of 0.03% (0.02-0.05).

Conclusions: Very low rates of serious complications were identified following BTOA injections performed in secondary care; only one in five patients proceeded to subsequent surgery.

Clinical Trial Registration: clinicaltrials.gov, https://www.clinicaltrials.gov, NCT03573765.
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http://dx.doi.org/10.1093/rheumatology/keaa925DOI Listing
January 2021

Serious postoperative complications and reoperation after carpal tunnel decompression surgery in England: a nationwide cohort analysis.

Lancet Rheumatol 2021 Jan 30;3(1):e49-e57. Epub 2020 Sep 30.

Oxford National Institute for Health Research Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University of Oxford, Oxford, UK.

Background: Carpal tunnel decompression surgery to treat carpal tunnel syndrome is a common procedure, yet data on safety and effectiveness of the operation in the general population remain scarce. We aimed to estimate the incidence of reoperation and serious postoperative complications (requiring admission to hospital or further surgery) following carpal tunnel decompression in routine clinical practice and to identify the patient factors associated with these adverse outcomes.

Methods: We did a nationwide cohort analysis including all carpal tunnel decompression surgeries in patients aged 18 years or older, done in the National Health Service in England between April 1, 1998, and March 31, 2017, using the Hospital Episode Statistics dataset linked to mortality records. Patients were followed-up until death or until the end of the study (March 31, 2017). Primary outcomes were the overall incidence of carpal tunnel decompression reoperation and serious postoperative complications (surgical site infection or dehiscence, or neurovascular or tendon injury, requiring admission to hospital or further surgery) within 30 days and 90 days after surgery. Multivariable Cox regression analysis was used to identify factors influencing complications and reoperation, and the Fine and Gray method was used to adjust for the competing risk of mortality. This study is registered with ClinicalTrials.gov, NCT03573765.

Findings: 855 832 carpal tunnel decompression surgeries were done between April 1, 1998, and March 31, 2017 (incidence rate 1·10 per 1000 person-years [95% CI 1·02-1·17]). 29 288 procedures (3·42%) led to carpal tunnel decompression reoperation (incidence rate 3·18 per 1000 person-years [95% CI 3·12-3·23]). Of the 855 832 initial surgeries, 620 procedures (0·070% [95% CI 0·067-0·078]) led to a serious complication within 30 days after surgery, and 698 procedures (0·082% [0·076-0·088]) within 90 days. Local complications within 90 days after surgery were associated with male sex (adjusted hazard ratio 2·32 [95% CI 1·74-3·09]) and age category 18-29 years (2·25 [1·10-4·62]). Male sex (adjusted subhazard ratio 1·09 [95% CI 1·06-1·13]), old age (>80 years 50-59 years: 1·09 [1·03-1·15]), and greater levels of comorbidity (Charlson score ≥5 0: 1·25 [1·19-1·32]) and socioeconomic deprivation (most deprived 10% least deprived 10%: 1·18 [1·10-1·27]) were associated with increased reoperation risk.

Interpretation: To our knowledge, this is the largest national study on carpal tunnel decompression to date, providing strong evidence on serious postoperative complication and reoperation rates. Carpal tunnel decompression appears to be a safe operation in most patients, with an overall serious complication rate (requiring admission to hospital or further surgery) of less than 0·1%.

Funding: Versus Arthritis; Medical Research Council; Royal College of Surgeons of England and National Joint Registry research fellowship; University of Oxford; National Institute for Health Research; and National Institute for Health Research Biomedical Research Centre, Oxford.
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http://dx.doi.org/10.1016/S2665-9913(20)30238-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762724PMC
January 2021

Chlamydia testing in New Zealand: analysis of the 2014/15 National Health Survey.

Sex Transm Dis 2020 Dec 1. Epub 2020 Dec 1.

Department of Preventive and Social Medicine, University of Otago, Dunedin 9054, New Zealand.

Background: Diagnosis rates of Chlamydia trachomatis are high in New Zealand, 1.3% of men and 3.7% of women aged 15-29 were diagnosed in 2016. As testing rates are also higher in women, we sought to understand chlamydia testing by demographic and behavioral characteristics.

Methods: Chlamydia testing in the past year, sexual behavior and demographic characteristics were reported in the population-based 2014/15 New Zealand Health Survey. Those aged 16-44 who had a sexual partner in the past year were included. Testing prevalence was calculated and associations modelled.

Results: 1,677 men and 2,323 women participated (89% response rate). Of these, 5.6% (95% CI 4.3-7.2%) of men and 16.6% (14.7-18.7%) of women were tested in the past year. Likelihood of testing in men was associated with having multiple partners and any condomless sex (adjusted relative risk 11.93, 95% CI 5.70-24.98) and multiple partners with consistent condom use (3.77, 1.40-10.15), compared with one sexual partner and consistent condom use; and with Māori ethnicity (1.87, 1.05-3.31, compared with European/Other). Among women, testing was associated with multiple partners with and without condomless sex (3.61, 2.69-4.85, and 2.81, 1.95-4.05, respectively), pregnancy (1.61, 1.18-2.18), and Asian ethnicity (0.52, 0.30-0.89).

Conclusion: The study confirms New Zealand men are much less likely to be tested than women; a potential reason for ongoing high chlamydia incidence among both sexes. The high testing rate in women includes many at low risk and this divergence from recommendations is another issue to address.
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http://dx.doi.org/10.1097/OLQ.0000000000001338DOI Listing
December 2020

A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features.

Sci Rep 2020 07 2;10(1):10827. Epub 2020 Jul 2.

Discipline of Genetics, Memorial University of Newfoundland, Faculty of Medicine, St. Johns, NL, A1B 3V6, Canada.

Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients' hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients.
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http://dx.doi.org/10.1038/s41598-020-66978-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331723PMC
July 2020

The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate.

Eur J Hum Genet 2020 07 28;28(7):925-937. Epub 2020 May 28.

Faculty of Medicine, Memorial University, St. John's, NL, A1B 3V6, Canada.

Stargardt disease (STGD1) is a form of inherited retinal dystrophy attributed to variants affecting function of the large ABCA4 gene and is arguably the most complex monogenic disease. Therapeutic trials in patients depend on identifying causal ABCA4 variants in trans, which is complicated by extreme allelic and clinical heterogeneity. We report the genetic architecture of STGD1 in the young genetically isolated population of Newfoundland, Canada. Population-based clinical recruitment over several decades yielded 29 STGD1 and STGD1-like families (15 multiplex, 14 singleton). Family interviews and public archival records reveal the vast majority of pedigree founders to be of English extraction. Full gene sequencing and haplotype analysis yielded a high solve rate (38/41 cases; 92.7%) for STGD1 and identified 16 causative STGD1 alleles, including a novel deletion (NM_000350.3: ABCA4 c.67-1delG). Several STGD1 alleles of European origin (including NM_000350.3: ABCA4 c.5714 + 5G>A and NM_000350.3: ABCA4 c.5461-10T>C) have drifted to a relatively high population frequency due to founder effect. We report on retinal disease progression in homozygous patients, providing valuable allele-specific insights. The least involved retinal disease is seen in patients homozygous for c.5714 + 5G>A variant, a so-called "mild" variant which is sufficient to precipitate a STGD1 phenotype in the absence of other pathogenic variants in the coding region and intron/exon boundaries of ABCA4. The most severe retinal disease is observed in cases with ABCA4 c.[5461-10T>C;5603A>T] complex allele. We discuss the advantages of determining genetic architecture in genetic isolates in order to begin to meet the grand challenge of human genetics.
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http://dx.doi.org/10.1038/s41431-020-0581-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316815PMC
July 2020

Qualitative Interviews to Better Understand the Patient Experience and Evaluate Patient-Reported Outcomes (PRO) in RLBP1 Retinitis Pigmentosa (RLBP1 RP).

Adv Ther 2020 06 5;37(6):2884-2901. Epub 2020 May 5.

Novartis Pharma AG, Basel, Switzerland.

Introduction: RLBP1 RP is an autosomal recessive form of retinitis pigmentosa (RP), characterized by night blindness, prolonged dark adaptation, constricted visual fields and impaired macular function. This study aimed to better understand the patient experience of RLBP1 RP and evaluate the content validity of existing patient reported outcome (PRO) instruments in this condition.

Methods: Semi-structured concept elicitation and cognitive debriefing interviews were conducted with RLBP1 RP patients in Canada and Sweden. Interviews started with open-ended concept elicitation questioning, and then patients were cognitively debriefed on The National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25), the Low Luminance Questionnaire (LLQ) and four light/dark adaptation items of the Visual Activities Questionnaire (VAQ). Qualitative interviews were also conducted with three expert clinicians. Anonymized, verbatim transcripts were analyzed using thematic analysis.

Results: Twenty-one patients were interviewed (Canada n = 10; Sweden n = 11). Symptoms reported included night blindness (n = 21), difficulty adapting to changes in lighting (n = 21) and difficulties seeing in bright lighting (n = 18). Patients experienced substantial impacts on daily activities (n = 21) and physical functioning (n = 17). Patients had difficulty interpreting and selecting a response for some items in the NEI VFQ-25 and LLQ. Some items were not relevant to patients' disease experience. There were both gaps and overlaps in the conceptual coverage of the instruments.

Conclusions: Visual impairment due to RLBP1 RP has a substantial impact on physical functioning and daily activities. To adequately assess all important symptoms and associated functional impacts in RLBP1 RP, it is recommended to either modify one or more existing instruments or to develop a new non-syndromic RP specific instrument.
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http://dx.doi.org/10.1007/s12325-020-01275-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467452PMC
June 2020

Optimum nutritional strategies for cardiovascular disease prevention and rehabilitation (BACPR).

Heart 2020 05 25;106(10):724-731. Epub 2020 Feb 25.

BACPR Diet Working Group.

Nutrition has a central role in both primary and secondary prevention of cardiovascular disease yet only relatively recently has food been regarded as a treatment, rather than as an adjunct to established medical and pharmacotherapy. As a field of research, nutrition science is constantly evolving making it difficult for patients and practitioners to ascertain best practice. This is compounded further by the inherent difficulties in performing double-blind randomised controlled trials. This paper covers dietary patterns that are associated with improved cardiovascular outcomes, including the Mediterranean Diet but also low-carbohydrate diets and the potential issues encountered with their implementation. We suggest there must be a refocus away from macronutrients and consideration of whole foods when advising individuals. This approach is fundamental to practice, as clinical guidelines have focused on macronutrients without necessarily considering their source, and ultimately people consume foods containing multiple nutrients. The inclusion of food-based recommendations aids the practitioner to help the patient make genuine and meaningful changes in their diet. We advocate that the cardioprotective diet constructed around the traditional Mediterranean eating pattern (based around vegetables and fruits, nuts, legumes, and unrefined cereals, with modest amounts of fish and shellfish, and fermented dairy products) is still important. However, there are other approaches that can be tried, including low-carbohydrate diets. We encourage practitioners to adopt a flexible dietary approach, being mindful of patient preferences and other comorbidities that may necessitate deviations away from established advice, and advocate for more dietitians in this field to guide the multi-professional team.
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http://dx.doi.org/10.1136/heartjnl-2019-315499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229899PMC
May 2020

Body mass index, diet, physical inactivity, and the incidence of dementia in 1 million UK women.

Neurology 2020 01 18;94(2):e123-e132. Epub 2019 Dec 18.

From the Cancer Epidemiology Unit (S.F., R.F.S., A.B., A.B., A.G., G.K.R., J.G., V.B.) and MRC Population Health Research Unit (S.P.), Nuffield Department of Population Health (R.P.), and Department of Psychiatry (J.G.), University of Oxford; Centre for Medical Informatics (C.S.), Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, UK; Royal Prince Alfred Hospital (P.H.), Sydney, Australia; and Department of Epidemiology (A.H.), Harvard T.H. Chan School of Public Health, Boston, MA.

Objective: To help determine whether midlife obesity is a cause of dementia and whether low body mass index (BMI), low caloric intake, and physical inactivity are causes or merely consequences of the gradual onset of dementia by recording these factors early in a large 20-year prospective study and relating them to dementia detection rates separately during follow-up periods of <5, 5 to 9, 10 to 14, and 15+ years.

Methods: A total of 1,136,846 UK women, mean age 56 (SD 5) years, were recruited in 1996 to 2001 and asked about height, weight, caloric intake, and inactivity. They were followed up until 2017 by electronic linkage to National Health Service records, detecting hospital admissions with mention of dementia. Cox regression yielded adjusted rate ratios (RRs) for first dementia detection during particular follow-up periods.

Results: Fifteen years after the baseline survey, only 1% were lost to follow-up, and 89% remained alive with no detected dementia, of whom 18,695 had dementia detected later, at a mean age of 77 (SD 4) years. Dementia detection during years 15+ was associated with baseline obesity (BMI 30+ vs 20-24 kg/m: RR 1.21, 95% confidence interval 1.16-1.26, < 0.0001) but not clearly with low BMI, low caloric intake, or inactivity at baseline. The latter 3 factors were associated with increased dementia rates during the first decade, but these associations weakened substantially over time, approaching null after 15 years.

Conclusions: Midlife obesity may well be a cause of dementia. In contrast, behavioral changes due to preclinical disease could largely or wholly account for associations of low BMI, low caloric intake, and inactivity with dementia detection during the first decade of follow-up.
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http://dx.doi.org/10.1212/WNL.0000000000008779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988985PMC
January 2020

Social influences on smoking cessation in mid-life: Prospective cohort of UK women.

PLoS One 2019 6;14(12):e0226019. Epub 2019 Dec 6.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kindom.

Introduction: Decisions to quit smoking are thought to be influenced by social factors such as friends, family and social groups, but there have been few attempts to examine comprehensively the influence of a range of social factors on smoking cessation. In the largest study to date, we examined whether smoking cessation was associated with marital status and the smoking habits of a partner, socio-economic status and social participation.

Methods: In the prospective Million Women Study, 53,650 current smokers in 2001 (mean age 58.3, SD 4.4) reported their smoking status 4 years later; and reported on social factors on both occasions. Logistic regression yielded odds ratios (ORs) and 99% confidence intervals (CIs) for stopping smoking in the next 4 years by marital status, whether their partner smoked, deprivation, education, and participation in social activities.

Results: 31% (16,692) of the current smokers at baseline had stopped after 4 years. Smokers who were partnered at baseline were more likely to quit than those who were not partnered (OR 1.13, 99% CI 1.06-1.19). Compared to having a partner who smoked throughout, those who had a non-smoking partner throughout were more likely to quit (OR 2.01, 99% CI 1.86-2.17), and those who had a partner who smoked at baseline but stopped smoking in the next 4 years were even more likely to quit (OR 6.00, 5.41-6.67). There was no association with cessation for education or deprivation. The association with social participation varied by type of activity but was null overall.

Conclusion: Women who were partnered were most likely to stop smoking if their partner also stopped smoking. There was little evidence of a strong influence of either socio-economic status or social participation on smoking cessation. These results emphasise the importance of a spouse's smoking habits on the likelihood of a smoker successfully quitting smoking.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226019PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897408PMC
March 2020

A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect.

Mol Genet Genomic Med 2020 02 28;8(2):e1070. Epub 2019 Nov 28.

Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.

Background: RAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer.

Methods: Five female HBOC probands sequenced negative for moderate- and high-risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.571 + 4A > G). Participant recruitment was followed by haplotype and case/control analyses, RNA splicing analysis, gene and protein expression assays, and Sanger sequencing of tumors.

Results: The RAD51C c.571 + 4A > G variant segregates with HBOC, with heterozygotes sharing a 5.07 Mbp haplotype. RAD51C c.571 + 4A > G is increased ~52-fold in the Newfoundland population compared with the general Caucasian population and positive population controls share disease-associated alleles, providing evidence of a founder effect. Splicing analysis confirmed in silico predictions that RAD51C c.571 + 4A > G causes exon 3 skipping, creating an immediate premature termination codon. Gene and protein expression were significantly reduced in a RAD51C c.571 + 4G > A heterozygote compared with a wild-type relative. Sanger sequencing of tumors from two probands indicates loss-of-heterozygosity, suggesting loss of function.

Conclusion: The RAD51C c.571 + 4A > G variant affects mRNA splicing and should be re-classified as pathogenic according to American College of Medical Genetics and Genomics guidelines.
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http://dx.doi.org/10.1002/mgg3.1070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005661PMC
February 2020

Alcohol intake and Parkinson's disease risk in the million women study.

Mov Disord 2020 03 26;35(3):443-449. Epub 2019 Nov 26.

Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Background: Alcohol intake may be associated with a lower risk of Parkinson's disease (PD), but findings from previous studies have been inconclusive.

Objective: To determine the association between alcohol intake and PD risk in the Million Women Study, a large, prospective study of women in the UK.

Methods: Between 1996 and 2001, approximately 1.3 million women in the UK, mean age 56 (standard deviation, 5) years, were recruited into the Million Women Study. Information on alcohol intake, lifestyle factors, and medical history was collected at recruitment by questionnaire. Information on incident cases of PD was ascertained by record linkage to national hospital admission records and death registrations. We estimated multivariable-adjusted relative risks and corresponding 95% confidence intervals using Cox proportional hazards models according to categories of alcohol intake.

Results: During an average of 17.9 years of follow-up, 11,009 women had a new record of PD among 1,309,267 women. In drinkers, the multivariable-adjusted relative risk comparing women who drank more than 14 drinks of alcohol per week with women who drank 1 to 2 drinks of alcohol per week was 0.99 (95% confidence interval: 0.90, 1.10). Results did not materially change after excluding the first 10 years of follow-up (relative risk = 1.01; 95% confidence interval: 0.90, 1.13). There were no significant trends in alcohol-related PD risk among never smokers. Additionally, examining this association by type of alcohol intake also yielded null findings.

Conclusion: These results do not support an association between alcohol intake and PD risk in women. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155013PMC
March 2020

The Associations Between Seven Different Types of Physical Activity and the Incidence of Fracture at Seven Sites in Healthy Postmenopausal UK Women.

J Bone Miner Res 2020 02 15;35(2):277-290. Epub 2019 Nov 15.

Cancer Epidemiology Unit, University of Oxford, Oxford, UK.

There is a paucity of information on associations between specific types of physical activity and fracture risk at different sites in otherwise healthy postmenopausal women. Therefore, we examined risk of fracture at seven different sites associated with seven different types of physical activity in the population-based prospective UK Million Women Study. A total of 371,279 postmenopausal women (mean age 59.8 years), rating their health as good or excellent and reporting participation in walking, cycling, gardening, doing housework, yoga, dance, and sports club activities, were followed for site-specific incident fracture through record linkage to national databases on day-case and overnight hospital admissions. Cox regression yielded adjusted relative risks (RRs) and, because of the large number of statistical tests done, 99% confidence intervals (CIs) for fracture at seven different sites in relation to seven different physical activities. During an average follow-up of 12 years, numbers with a first site-specific fracture were as follows: humerus (2341), forearm (1238), wrist (7358), hip (4354), femur (not neck) (617), lower leg (1184), and ankle (3629). For upper limb fractures there was significant heterogeneity across the seven activity types (test for heterogeneity p = 0.004), with gardening more than 1 hour/week associated with a lower risk (RR = 0.91; 99% CI, 0.86 to 0.96; p < 0.0001), whereas cycling more than 1 hour/week was associated with an increased risk (RR = 1.11; 99% CI, 1.00 to 1.23; p = 0.008). For fractures of the lower limb (including hip) there was no significant heterogeneity by type of activity, with significant approximately 5% to 15% reductions in risk associated with most activities, except cycling. For hip fractures, there was no significant heterogeneity by type of activity, but with significant 15% to 20% reductions in risk associated with walking for 1 hour/day and participating in yoga and sporting activities. Physical activity is a modifiable risk factor for fracture, but the effects differ between different types of activities and different fracture sites. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027536PMC
February 2020

The long-term survival characteristics of a cohort of colorectal cancer patients and baseline variables associated with survival outcomes with or without time-varying effects.

BMC Med 2019 07 29;17(1):150. Epub 2019 Jul 29.

Discipline of Genetics, Faculty of Medicine, Memorial University, 300 Prince Philip Drive, New Medical Education Building, St. John's, NL, A1B 3V6, Canada.

Background: Colorectal cancer is the third most common cancer in the world. In this study, we assessed the long-term survival characteristics and prognostic associations and potential time-varying effects of clinico-demographic variables and two molecular markers (microsatellite instability (MSI) and BRAF Val600Glu mutation) in a population-based patient cohort followed up to ~ 19 years.

Methods: The patient cohort included 738 incident cases diagnosed between 1999 and 2003. Cox models were used to analyze the association between the variables and a set of survival outcome measures (overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), metastasis-free survival (MFS), recurrence/metastasis-free survival (RMFS), and event-free survival (EFS)). Cox proportional hazard (PH) assumption was tested for all variables, and Cox models with time-varying effects were used if any departure from the PH assumption was detected.

Results: During the follow-up, ~ 61% patients died from any cause, ~ 26% died from colorectal cancer, and ~ 10% and ~ 20% experienced recurrences and distant metastases, respectively. Stage IV disease and post-diagnostic recurrence or metastasis were strongly linked to risk of death from colorectal cancer. If a patient had survived the first 6 years without any disease-related event (i.e., recurrence, metastasis, or death from colorectal cancer), their risks became very minimal after this time period. Distinct sets of markers were associated with different outcome measures. In some cases, the effects by variables were constant throughout the follow-up. For example, MSI-high tumor phenotype and older age at diagnosis predicted longer MFS times consistently over the follow-up. However, in some other cases, the effects of the variables varied with time. For example, adjuvant radiotherapy treatment was associated with increased risk of metastasis in patients who received this treatment after 5.5 years post-diagnosis, but not before that.

Conclusions: This study describes the long-term survival characteristics of a prospective cohort of colorectal cancer patients, relationships between baseline variables and a detailed set of patient outcomes over a long time, and time-varying effects of a group of variables. The results presented advance our understanding of the long-term prognostic characteristics in colorectal cancer and are expected to inspire future studies and clinical care strategies.
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http://dx.doi.org/10.1186/s12916-019-1379-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661748PMC
July 2019

Adult cancer risk in women who were breastfed as infants: large UK prospective study.

Eur J Epidemiol 2019 Sep 11;34(9):863-870. Epub 2019 Jun 11.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Oxford, OX3 7LF, UK.

There are known short-term benefits in breastfed infants versus bottle-fed infants in terms of lower risks of infection and obesity in infancy and childhood, but the long-term effect on the risk of adult cancers is unclear. In a cohort of 1 in 4 UK women born in 1935-1950 we report the incidence of adult cancers in relation to having been breastfed in infancy. In median year 2001 (interquartile range 2000-2003) 548,741 women without prior cancer reported whether they had been breastfed. There was 81% agreement between women's report of having been breastfed and information on breastfeeding recorded when they were 2 years old. Participants were followed by record-linkage to national cancer registration, hospital admission and death databases. Cox regression yielded adjusted relative risks (RRs) and 95% confidence intervals (CI) by having been breastfed or not for eight cancer sites with > 2000 incident cases and for related conditions, where appropriate. Of the eight cancers examined here one association was highly statistically significant: an increase in colorectal cancer incidence among women who had been breastfed versus not (RR 1.18, 95% CI 1.12-1.24, n = 8651). To investigate further the findings for colorectal cancer, we studied eight other gastro-intestinal conditions, and found increased risks in women who had been breastfed versus not for benign colorectal polyps (RR 1.09, 95% CI 1.05-1.13, n = 17,677) and for appendicitis (RR 1.19, 95% CI 1.07-1.31, n = 2108). The greater risks of adult colorectal cancer, colorectal polyps and appendicitis associated with having been breastfed in infancy suggest possible long-term effects of infant feeding practices on the gastrointestinal tract. Further studies are required to clarify this novel association.
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http://dx.doi.org/10.1007/s10654-019-00528-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759744PMC
September 2019

Novel Usher syndrome pathogenic variants identified in cases with hearing and vision loss.

BMC Med Genet 2019 05 2;20(1):68. Epub 2019 May 2.

Craig L. Dobbin Research Centre, Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, Newfoundland & Labrador, AIB 3V6, Canada.

Background: Usher syndrome, the most common form of inherited deaf-blindness, is unlike many other forms of syndromic hereditary hearing loss in that the extra aural clinical manifestations are also detrimental to communication. Usher syndrome patients with early onset deafness also experience vision loss due to progressive retinitis pigmentosa that can lead to legal blindness in their third or fourth decade.

Methods: Using a multi-omic approach, we identified three novel pathogenic variants in two Usher syndrome genes (USH2A and ADGRV1) in cases initially referred for isolated vision or hearing loss.

Results: In a multiplex hearing loss family, two affected sisters, the product of a second cousin union, are homozygous for a novel nonsense pathogenic variant in ADGRV1 (c.17062C > T, p.Arg5688*), predicted to create a premature stop codon near the N-terminus of ADGRV1. Ophthalmological examination of the sisters confirmed typical retinitis pigmentosa and prompted a corrected Usher syndrome diagnosis. In an unrelated clinical case, a child with hearing loss tested positive for two novel USH2A splicing variants (c.5777-1G > A, p. Glu1926_Ala1952del and c.10388-2A > G, p.Asp3463Alafs*6) and RNA studies confirmed that both pathogenic variants cause splicing errors. Interestingly, these same USH2A variants are also identified in another family with vision loss where subsequent clinical follow-up confirmed pre-existing hearing loss since early childhood, eventually resulting in a reassigned diagnosis of Usher syndrome.

Conclusion: These findings provide empirical evidence to increase Usher syndrome surveillance of at-risk children. Given that novel antisense oligonucleotide therapies have been shown to rescue retinal degeneration caused by USH2A splicing pathogenic variants, these solved USH2A patients may now be eligible to be enrolled in therapeutic trials.
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http://dx.doi.org/10.1186/s12881-019-0777-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498547PMC
May 2019

Use of oral bisphosphonates and risk of hospital admission with osteonecrosis of the jaw: Large prospective cohort study in UK women.

Bone 2019 07 5;124:69-74. Epub 2019 Apr 5.

Cancer Epidemiology Unit, University of Oxford, Richard Doll Building, Old Road Campus, Oxford OX3 7LF, UK.

About 1 in 10 postmenopausal UK women are currently prescribed oral bisphosphonates, but there are concerns about their adverse effects. Osteonecrosis of the jaw is a recognised uncommon but important side effect of intravenous bisphosphonates, but epidemiological evidence on risk of osteonecrosis of the jaw associated with oral bisphosphonate use is less conclusive. The incidence of hospital admission with osteonecrosis of the jaw was examined among 521,695 Million Women Study participants, aged 64.7 years at baseline. Cox proportional hazards regression was used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs) associated with use of oral bisphosphonates in postmenopausal women followed-up by record-linkage to National Health Service hospital admission databases. During mean follow-up of 8.2 years per woman, 100 women were admitted to hospital with first recorded osteonecrosis of the jaw, at mean age 72.4 years. Almost a third (29/100) of the cases had ever-used oral bisphosphonates. Ever-users had a six-fold increased risk of hospital admission for osteonecrosis of the jaw, when compared with never-users (adjusted RR = 6.09, 95% CI 3.83-9.66; p < 0.0001). The relative risk for osteonecrosis of the jaw in never-users of oral bisphosphonates was increased in women with prior cancer (RR = 3.40, 2.22-5.22, p < 0.0001). The estimated absolute risk of hospital admission for osteonecrosis of the jaw over a 5-year period from age 70 to 74 in women without prior cancer was 0.09 per 1000 in never-users and 0.69 per 1000 in ever-users of oral bisphosphonates. In this UK population of postmenopausal women, use of oral bisphosphonates was associated with a 6-fold increased risk of hospital admission with osteonecrosis of the jaw, accounting for around one-third of cases, with an excess risk of about 0.6/1000 users over 5 years.
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http://dx.doi.org/10.1016/j.bone.2019.04.003DOI Listing
July 2019

Screen-detected and interval colorectal cancers in England: Associations with lifestyle and other factors in women in a large UK prospective cohort.

Int J Cancer 2019 08 15;145(3):728-734. Epub 2019 Feb 15.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Headington, Oxford, United Kingdom.

Faecal occult blood (FOB) - based screening programmes for colorectal cancer detect about half of all cancers. Little is known about individual health behavioural characteristics which may be associated with screen-detected and interval cancers. Electronic linkage between the UK National Health Service Bowel Cancer Screening Programme (BCSP) in England, cancer registration and other national health records, and a large on-going UK cohort, the Million Women Study, provided data on 628,976 women screened using a guaiac-FOB test (gFOBt) between 2006 and 2012. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated by logistic and Cox regression for associations between individual lifestyle factors and risk of colorectal tumours. Among screened women, 766 were diagnosed with screen-detected colorectal cancer registered within 2 years after a positive gFOBt result, and 749 with interval colorectal cancers registered within 2 years after a negative gFOBt result. Current smoking was significantly associated with risk of interval cancer (RR 1.64, 95%CI 1.35-1.99) but not with risk of screen-detected cancer (RR 1.03, 0.84-1.28), and was the only factor of eight examined to show a significant difference in risk between interval and screen-detected cancers (p for difference, 0.003). Compared to screen-detected cancers, interval cancers tended to be sited in the proximal colon or rectum, to be of non-adenocarcinoma morphology, and to be of higher stage.
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http://dx.doi.org/10.1002/ijc.32168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563087PMC
August 2019

Diet and risk of glioma: combined analysis of 3 large prospective studies in the UK and USA.

Neuro Oncol 2019 07;21(7):944-952

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Available evidence on diet and glioma risk comes mainly from studies with retrospective collection of dietary data. To minimize possible differential dietary recall between those with and without glioma, we present findings from 3 large prospective studies.

Methods: Participants included 692 176 from the UK Million Women Study, 470 780 from the US National Institutes of Health-AARP study, and 99 148 from the US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox regression yielded study-specific adjusted relative risks for glioma in relation to 15 food groups, 14 nutrients, and 3 dietary patterns, which were combined, weighted by inverse variances of the relative risks. Separate analyses by <5 and ≥5 years follow-up assessed potential biases related to changes of diet before glioma diagnosis.

Results: The 1 262 104 participants (mean age, 60.6 y [SD 5.5] at baseline) were followed for 15.4 million person-years (mean 12.2 y/participant), during which 2313 incident gliomas occurred, at mean age 68.2 (SD 6.4). Overall, there was weak evidence for increased glioma risks associated with increasing intakes of total fruit, citrus fruit, and fiber and healthy dietary patterns, but these associations were generally null after excluding the first 5 years of follow-up. There was little evidence for heterogeneity of results by study or by sex.

Conclusions: The largest prospective evidence to date suggests little, if any, association between major food groups, nutrients, or common healthy dietary patterns and glioma incidence. With the statistical power of this study and the comprehensive nature of the investigation here, it seems unlikely we have overlooked major effects of diet on risk of glioma that would be of public health concern.
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http://dx.doi.org/10.1093/neuonc/noz013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620629PMC
July 2019

Association of ten gastrointestinal and other medical conditions with positivity to faecal occult blood testing in routine screening: a large prospective study of women in England.

Int J Epidemiol 2019 04;48(2):549-558

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: In 2006, the Bowel Cancer Screening Programme (BCSP) in England began offering biennial faecal occult blood testing (FOBt) at ages 60-69 years. Although FOBt is aimed at detecting colorectal neoplasms, other conditions can affect the result. In a large UK prospective study, we examined associations, both before and after screening, between FOBt positivity and 10 conditions that are often associated with gastrointestinal bleeding.

Methods: By electronically linking BCSP and Million Women Study records, we identified 604 495 women without previous colorectal cancer who participated in their first routine FOBt screening between 2006 and 2012. Regression models, using linked national hospital admission records, yielded adjusted relative risks (RRs) in FOBt-positive versus FOBt-negative women for colorectal cancer, adenoma, diverticular disease, inflammatory bowel disease, haemorrhoids, upper gastrointestinal cancer, oesophagitis, peptic ulcer, anaemia and other haematological disorders.

Results: RRs in FOBt-positive versus FOBt-negative women were 201.3 (95% CI 173.8-233.2) for colorectal cancer and 197.9 (95% CI 180.6-216.8) for adenoma within 12 months after screening and 3.49 (95% CI 2.31-5.26) and 4.88 (95% CI 3.80-6.26), respectively, 12-24 months after screening; P < 0.001 for all RRs. In the 12 months after screening, the RR for inflammatory bowel disease was 26.3 (95% CI 19.9-34.7), and ranged between 2 and 5 for the upper gastrointestinal or haematological disorders. The RRs of being diagnosed with any of the eight conditions other than colorectal neoplasms before screening, and in the 12-24 months after screening, were 1.81 (95% CI 1.81-2.01) and 1.92 (95% CI 1.66-2.13), respectively.

Conclusions: Whereas FOBt positivity is associated with a substantially increased risk of colorectal neoplasms after screening, eight other gastrointestinal and haematological conditions are also associated with FOBt positivity, both before and after screening.
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http://dx.doi.org/10.1093/ije/dyy271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469304PMC
April 2019

Body mass index and use and costs of primary care services among women aged 55-79 years in England: a cohort and linked data study.

Int J Obes (Lond) 2019 09 19;43(9):1839-1848. Epub 2018 Dec 19.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Oxford, OX3 7LF, USA.

Background: Excess weight is associated with poor health and increased healthcare costs. There are no reliable data describing the association between BMI and the use and costs of primary care services in the United Kingdom.

Methods: Among 69,440 participants in the Million Women Study with primary care records in the Clinical Practice Research Datalink between April 2006 (mean age 64 years) and March 2014, the annual rates and costs of their primary care consultations, prescription medications, and diagnostic and monitoring tests were estimated in relation to their self-reported body mass index (BMI) at recruitment in 1996-2001 (mean age 56 years). Associations of BMI with annual costs were projected to all women in England aged 55-79 years in 2013.

Results: Over an average follow-up of 6.0 years, annual rates and mean costs were lowest for women with a BMI of 20 to <22.5 kg/m for consultations (7.0 consultations, 99% CI 6.8-7.1; £288, £280-£295) and prescription medications (27.0 prescribed items, 26.0-27.9; £227, £216-£237). Above 20 kg/m, a 2 kg/m higher BMI (a 5 kg change in weight for a woman of average height) was associated with 5.2% (4.8-5.6) and 9.9% (9.2-10.6) higher mean annual consultation and prescription medication costs, respectively. Annual rates and mean costs of diagnostic and monitoring tests were similar for women with different BMIs. Among all women aged 55-79 years in England, excess weight accounted for an estimated 11% (£229 million/£2.2 billion) of all consultation costs and 20% (£384 million/£1.9 billion) of all prescription medication costs, of which 27% were for diabetes drugs, 19% for circulatory system drugs, and 13% for analgesics.

Conclusions: Excess body weight is associated with higher use and costs of primary care services among women in England. Reducing the prevalence of excess weight could improve the health of women and reduce pressures on primary care.
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http://dx.doi.org/10.1038/s41366-018-0288-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451629PMC
September 2019

Alcohol drinking patterns and liver cirrhosis risk: analysis of the prospective UK Million Women Study.

Lancet Public Health 2019 01 22;4(1):e41-e48. Epub 2018 Nov 22.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, UK.

Background: Alcohol is a known cause of cirrhosis, but it is unclear if the associated risk varies by whether alcohol is drunk with meals, or by the frequency or type of alcohol consumed. Here we aim to investigate the associations between alcohol consumption with meals, daily frequency of consumption, and liver cirrhosis.

Methods: The Million Women Study is a prospective study that includes one in every four UK women born between 1935 and 1950, recruited between 1996 and 2001. In 2001 (IQR 2000-03), the participants reported their alcohol intake, whether consumption was usually with meals, and number of days per week it was consumed. Cox regression analysis yielded adjusted relative risks (RRs) for incident cirrhosis, identified by follow-up through electronic linkage to routinely collected national hospital admission, and death databases.

Findings: During a mean of 15 years (SD 3) of follow-up of 401 806 women with a mean age of 60 years (SD 5), without previous cirrhosis or hepatitis, and who reported drinking at least one alcoholic drink per week, 1560 had a hospital admission with cirrhosis (n=1518) or died from the disease (n=42). Cirrhosis incidence increased with amount of alcohol consumed (≥15 drinks [mean 220 g of alcohol] vs one to two drinks [mean 30 g of alcohol] per week; RR 3·43, 95% CI 2·87-4·10; p<0·0001). About half of the participants (203 564 of 401 806) reported usually drinking with meals and, after adjusting for amount consumed, cirrhosis incidence was lower for usually drinking with meals than not (RR 0·69, 0·62-0·77; p<0·0001; wine-only drinkers RR 0·69, 0·56-0·85; all other drinkers RR 0·72, 0·63-0·82). Among 175 618 women who consumed seven or more drinks per week, cirrhosis incidence was greater for daily consumption than non-daily consumption (adjusted RR 1·61, 1·40-1·85; p<0·0001). Daily consumption, together with not drinking with meals, was associated with more than a doubling of cirrhosis incidence (adjusted RR 2·47, 1·96-3·11; p<0·0001).

Interpretation: In middle-aged women, cirrhosis incidence increases with total alcohol intake, even at moderate levels of consumption. For a given weekly intake of alcohol, this excess incidence of cirrhosis is higher if consumption is usually without meals, or with daily drinking.

Funding: UK Medical Research Council and Cancer Research UK.
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http://dx.doi.org/10.1016/S2468-2667(18)30230-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323353PMC
January 2019

Coffee and pancreatic cancer risk among never-smokers in the UK prospective Million Women Study.

Int J Cancer 2019 09 28;145(6):1484-1492. Epub 2018 Dec 28.

Cancer Epidemiology Unit, Nuffield Department of Population Health, Oxford, OX3 7LF, United Kingdom.

Reported associations between coffee consumption and an increased risk of pancreatic cancer could be due to residual confounding by smoking and/or biased recall of coffee consumption in retrospective studies. Studying associations prospectively in never smokers should minimize these problems, but thus far such studies have included relatively small numbers of cases. In our study, 309,797 never-smoking women self-reported typical daily coffee consumption at a mean age of 59.5 years (SD 5.0 years) and were followed up for a median of 13.7 years (IQR: 12.2-14.9) through record linkage to national health cancer and death registries. During this period, 962 incident cases of pancreatic cancers were registered. Cox regression was used to calculate adjusted relative risks [RRs] of incident pancreatic cancer with 95% confidence intervals [CIs] in relation to coffee consumption at baseline. After adjustment for potential confounding factors, including body mass index and alcohol consumption, RRs of pancreatic cancer in never-smokers who reported usually consuming 1-2, 3-4, and ≥ 5 cups of coffee daily, compared to nondrinkers of coffee, were 1.02 (CI 0.83-1.26), 0.96 (0.76-1.22), and 0.87 (0.64-1.18), respectively (trend p = 0.2). A meta-analysis of results from this cohort and 3 smaller prospective studies found little or no statistically significant association between coffee consumption and pancreatic cancer risk in never smokers (summary RR = 1.00, CI 0.86-1.17 for ≥2 vs. zero cups of coffee per day).
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http://dx.doi.org/10.1002/ijc.31994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767387PMC
September 2019

Foods, macronutrients and breast cancer risk in postmenopausal women: a large UK cohort.

Int J Epidemiol 2019 04;48(2):489-500

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: The role of diet in breast cancer aetiology is unclear; recent studies have suggested associations may differ by estrogen receptor status.

Methods: Baseline diet was assessed in 2000-04 using a validated questionnaire in 691 571 postmenopausal UK women without previous cancer, who had not changed their diet recently. They were followed by record linkage to national cancer and death databases. Cox regression yielded adjusted relative risks for breast cancer for 10 food items and eight macronutrients, subdivided mostly into five categories of baseline intake. Trends in risk across the baseline categories were calculated, assigning re-measured intakes to allow for measurement error and changes in intake over time; P-values allowed for multiple testing.

Results: Women aged 59.9 (standard deviation (SD 4.9)) years at baseline were followed for 12 (SD 3) years; 29 005 were diagnosed with invasive breast cancer. Alcohol intake had the strongest association with breast cancer incidence: relative risk (RR) 1.08 [99% confidence interval (CI) 1.05-1.11] per 10 g/day higher intake, P = 5.8 × 10-14. There were inverse associations with fruit: RR 0.94 (99% CI 0.92-0.97) per 100 g/day higher intake, P = 1.1 × 10-6, and dietary fibre: RR 0.91 (99% CI 0.87-0.96) per 5 g/day increase, P = 1.1 × 10-4. Fruit and fibre intakes were correlated (ρ = 0.62) and were greater among women who were not overweight, so residual confounding cannot be excluded. There was no heterogeneity for any association by estrogen receptor status.

Conclusions: By far the strongest association was between alcohol intake and an increased risk of breast cancer. Of the other 17 intakes examined, higher intakes of fruit and fibre were associated with lower risks of breast cancer, but it is unclear whether or not these associations are causal.
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http://dx.doi.org/10.1093/ije/dyy238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469308PMC
April 2019

Impact of colonoscopic screening in Familial Colorectal Cancer Type X.

Mol Genet Genomic Med 2018 11 9;6(6):1021-1030. Epub 2018 Oct 9.

Clinical Epidemiology Unit, Memorial University, St. John's, Newfoundland, Canada.

Background: Hereditary Non-Polyposis Colorectal cancer is caused by Lynch Syndrome (LS; an autosomal dominant condition) or by Familial Colorectal Cancer Type-X (FCCTX; a condition of high family risk that fulfills Amsterdam criteria). The lifetime risk of developing colorectal cancer (CRC) in FCCTX family members is high and CRC occurs later than in LS.

Methods: To determine the impact of primary prevention colonoscopic screening in asymptomatic first-degree relatives of incident CRC cases in 20 families with FCCTX, we compared cancer incidence and survival in 79 males and 83 females, assumed to be at 50% risk of inheriting a genetic CRC susceptibility factor, who entered screening to an unscreened control group from the families, matched for age at entry into screening and for sex.

Results: In males, median age at entry into screening was 44.8 years, median follow-up 12.4 years, 12% developed CRC, and 46% died after 30 years of follow-up. Compared to the unscreened group, relative risk of CRC was 0.27 (95% confidence intervals (CI) 0.10-0.71). In screened females, comparable results were 44.5 years at entry, 11.2 years of follow-up, 7.1% developed CRC, and 7.2% died after 30 years of follow-up. The relative risk of CRC compared to the unscreened group was 0.19 (95% CI 0.07-0.48).

Conclusion: Primary prevention screening colonoscopy in asymptomatic family members significantly decreased the risk of CRC in FCCTX.
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http://dx.doi.org/10.1002/mgg3.478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305669PMC
November 2018

Heterogeneous relationships of squamous and basal cell carcinomas of the skin with smoking: the UK Million Women Study and meta-analysis of prospective studies.

Br J Cancer 2018 07 14;119(1):114-120. Epub 2018 Jun 14.

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Introduction: Published findings on the associations between smoking and the incidence of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are inconsistent. We aimed to generate prospective evidence on these relationships overall and by anatomical site.

Methods: We followed 1,223,626 women without prior cancer by electronic linkage to national cancer registration data. Questionnaire information about smoking and other factors was recorded at recruitment (1996-2001) and every 3-5 years subsequently. Cox regression yielded adjusted relative risks (RRs) comparing smokers versus never-smokers.

Results: After 14 (SD4) years follow-up per woman, 6699 had a first registered cutaneous SCC and 48,666 a first BCC. In current versus never-smokers, SCC incidence was increased (RR = 1.22, 95% CI 1.15-1.31) but BCC incidence was decreased (RR = 0.80, 0.78-0.82). RRs varied substantially by anatomical site; for the limbs, current smoking was associated with an increased incidence of SCC (1.55, 1.41-1.71) and a decreased incidence of BCC (0.72, 0.66-0.79), but for facial lesions there was little association of current smoking with either SCC (0.93, 0.82-1.06) or BCC (0.92, 0.88-0.96). Findings in meta-analyses of results from this and seven other prospective studies were largely dominated by the findings in this study.

Conclusions: Smoking-associated risks for cutaneous SCC and BCC are in the opposite direction to each other and appear to vary by anatomical site.
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http://dx.doi.org/10.1038/s41416-018-0105-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035218PMC
July 2018

Cohort Profile: the Million Women Study.

Int J Epidemiol 2019 02;48(1):28-29e

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1093/ije/dyy065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380310PMC
February 2019