Vitamin D treatment induces in vitro and ex vivo transcriptomic changes indicating anti-tumor effects.

Vitamin D deficiency is associated with risk of several common cancers, including colorectal cancer (CRC). Here we have utilized patient derived epithelial organoids (ex vivo) and CRC cell lines (in vitro) to show that calcitriol (1,25OHD) increased the expression of the CRC tumor suppressor gene, CDH1, at both the transcript and protein level. Whole genome expression analysis demonstrated significant differential expression of a further six genes after 1,25OHD treatment, including genes with established links to carcinogenesis GADD45, EFTUD1 and KIAA1199. Furthermore, gene ontologies relevant to carcinogenesis were enriched by 1,25OHD treatment (e.g., 'regulation of Wnt signaling pathway', 'regulation of cell death'), with common enriched processes across in vitro and ex vivo cultures including 'negative regulation of cell proliferation', 'regulation of cell migration' and 'regulation of cell differentiation'. Our results identify genes and pathways that are modifiable by calcitriol that have links to CRC tumorigenesis. Hence the findings provide potential mechanism to the epidemiological and clinical trial data indicating a causal association between vitamin D and CRC. We suggest there is strong rationale for further well-designed trials of vitamin D supplementation as a novel CRC chemopreventive and chemotherapeutic agent.

A sensitive and affordable multiplex RT-qPCR assay for SARS-CoV-2 detection.

With the ongoing COVID-19 (Coronavirus Disease 2019) pandemic, caused by the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), there is a need for sensitive, specific, and affordable diagnostic tests to identify infected individuals, not all of whom are symptomatic. The most sensitive test involves the detection of viral RNA using RT-qPCR (quantitative reverse transcription PCR), with many commercial kits now available for this purpose. However, these are expensive, and supply of such kits in sufficient numbers cannot always be guaranteed. We therefore developed a multiplex assay using well-established SARS-CoV-2 targets alongside a human cellular control (RPP30) and a viral spike-in control (Phocine Herpes Virus 1 [PhHV-1]), which monitor sample quality and nucleic acid extraction efficiency, respectively. Here, we establish that this test performs as well as widely used commercial assays, but at substantially reduced cost. Furthermore, we demonstrate >1,000-fold variability in material routinely collected by combined nose and throat swabbing and establish a statistically significant correlation between the detected level of human and SARS-CoV-2 nucleic acids. The inclusion of the human control probe in our assay therefore provides a quantitative measure of sample quality that could help reduce false-negative rates. We demonstrate the feasibility of establishing a robust RT-qPCR assay at approximately 10% of the cost of equivalent commercial assays, which could benefit low-resource environments and make high-volume testing affordable.

Cerebrospinal fluid shunt malfunctions: A reflective review.

PURPOSE: Pediatric hydrocephalus is a common and challenging condition. To date, the ventriculoperitoneal shunt (VPS) is still the main lifesaving treatment option. Nonetheless, it remains imperfect and is associated with multiple short- and long-term complications. This paper is a reflective review of the current state of the VPS, our knowledge gaps, and the future state of shunts in neurosurgical practice. METHODS AND RESULTS: The authors' reflections are based on a review of shunts and shunt-related literature. CONCLUSION: Overall, there is still an urgent need for the neurosurgical community to actively improve current strategies for shunt failures and shunt-related morbidity. The authors emphasize the role of collaborative efforts amongst like-minded clinicians to establish pragmatic approaches to avoid shunt complications.

How do stroke early supported discharge services achieve intensive and responsive service provision? Findings from a realist evaluation study (WISE).

BACKGROUND: Stroke Early Supported Discharge (ESD) involves provision of responsive and intensive rehabilitation to stroke survivors at home and it is recommended as part of the stroke care pathway. Core components have been identified to guide the delivery of evidence-based ESD, however, service provision in England is of variable quality. The study sought to understand how and in what conditions the adoption of these components drives the delivery of responsive and intensive ESD services in real world settings. METHODS: This qualitative study was part of a wider multimethod realist evaluation project (WISE) conducted to inform large-scale ESD implementation. Overarching programme theories and related context-mechanism-outcome configurations were used as a framework to guide data collection and analysis. Six case study sites were purposively selected; interviews and focus groups with ESD staff members were conducted and analysed iteratively. RESULTS: We interviewed 117 ESD staff members including clinicians and service managers. Staff highlighted the role of certain core components including eligibility criteria, capacity, team composition and multidisciplinary team (MDT) coordination in achieving responsive and intensive ESD. Regardless of the geographical setting, adhering to evidence-based selection criteria, promoting an interdisciplinary skillset and supporting the role of rehabilitation assistants, allowed teams to manage capacity issues and maximise therapy time. Gaps in the stroke care pathway, however, meant that teams had to problem solve beyond their remit to cater for the complex needs of patients with severe disabilities. Adjusting MDT structures and processes was seen as key in addressing challenges posed by travel times and rural geography. CONCLUSIONS: Despite variations in the wider service model of operation and geographical location, the adoption of core components of ESD helped teams manage the pressures and deliver services that met evidence-based standards. Findings point to a well-recognised gap in service provision in England for stroke survivors who do not meet the ESD criteria and emphasise the need for a more integrated and comprehensive stroke service provision. Transferable lessons could be drawn to inform improvement interventions aimed at promoting evidence-based service delivery in different settings. TRIAL REGISTRATION: ISRCTN: 15,568,163, registration date: 26 October 2018.

Development of the stroke patient concerns inventory: A modified Delphi study.

OBJECTIVES: Stroke survivors often have unmet physical, psychological and/or social concerns. Patient Concerns Inventories (PCIs) have been developed for other health conditions to address concerns. Our objective was to develop a PCI for stroke care. METHODS: This was a development study, including Modified Delphi study design, with academic and healthcare professionals with stroke care expertise. In Stage 1, a draft Stroke PCI (Version 1a) was created through identifying patient-reported concerns post-stroke from three previous studies and through expert panel discussions using Nominal Group Technique. In Stage 2, Version 1a was sent to 92 academic and healthcare professionals with stroke care expertise. Participants ranked their top 20 Stroke PCI items in order of importance and provided feedback. Rankings were converted into scores, and, with the feedback, used to amend the Stroke PCI. Two further rounds of feedback followed until consensus was reached between participants. A final draft of the Stroke PCI was created. RESULTS: In stage 1, 64 potential Stroke PCI items were generated. In Stage 2, 38 participants (41.3%) responded to the request to rank Stroke PCI items. The three highest ranked items were 'Risk of another stroke', 'Walking', 'Recovery'. After three rounds of feedback and amendments, the final draft of the Stroke PCI consisted of 53 items. CONCLUSIONS: A Stroke PCI has been developed using patient-reported concerns in previous studies and input from academic and healthcare professionals. Future work will involve gathering further feedback on the tool and exploring its acceptability and usability in a pilot study.

[How To Teach Uncertainty Management]. / Pédagogie de l'incertitude en médecine.

In this article, we propose a model to teach uncertainty management. Our primary goal is to define the concept of uncertainty and its stakes. We then discuss the effect that uncertainty may have on physicians and patients. We finally present reliable strategies to address medical complexity and how to teach or assess complexity management.

L'objectif de cet article est d'apporter des pistes pédagogiques permettant d'enseigner la gestion de l'incertitude en médecine. En premier lieu, il s'agit de formuler une définition du concept d'incertitude afin d'en comprendre les enjeux. Nous discuterons également des conséquences d'une mauvaise tolérance de l'incertitude pour le médecin et pour le patient. Enfin, nous verrons différentes stratégies qui permettent de mieux appréhender la complexité des situations médicales et quels pourraient être les moyens d'enseigner ou d'évaluer l'incertitude.

Genetically predicted physical activity levels are associated with lower colorectal cancer risk: a Mendelian randomisation study.

BACKGROUND: We conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated through changes in body fat. METHODS: Common genetic variants associated with self-reported moderate-to-vigorous PA (MVPA), acceleration vector magnitude PA (AMPA) and sedentary time were used as instrumental variables. To control for confounding effects of obesity, we included instrumental variables for body mass index (BMI), body fat percentage, waist circumference and arm, trunk and leg fat ratios. We analysed the effect of these instrumental variables in a colorectal cancer genome-wide association study comprising 31,197 cases and 61,770 controls of European ancestry by applying two-sample and multivariable MR study designs. RESULTS: We found decreased colorectal cancer risk for genetically represented measures of MVPA and AMPA that were additional to effects mediated through genetic measures of obesity. Odds ratio and 95% confidence interval (CI) per standard deviation increase in MVPA and AMPA was 0.56 (0.31, 1.01) and 0.60 (0.41, 0.88), respectively. No association has been found between sedentary time and colorectal cancer risk. The proportion of effect mediated through BMI was 2% (95% CI: 0, 14) and 32% (95% CI: 12, 46) for MVPA and AMPA, respectively. CONCLUSION: These findings provide strong evidence to reinforce public health measures on preventing colorectal cancer that promote PA at a population level regardless of body fatness.

[The diagnosis and management of idiopathic intracranial hypertension]. / Hypertension intracrânienne idiopathique : quel bilan et quelle prise en charge en médecine interne ?

Idiopathic intracranial hypertension (IIH) is defined by the presence of headache with or without associated visual impairment, elevated cerebrospinal fluid pressure, and exclusion of a secondary etiology. The increased risk of severe visual impairment prompts rapid recognition and initial management by general practitioners, even though the incidence of this condition is low. Based on a case report, the aim of this review is to describe the typical clinical presentation of IIH, to discuss the underlying pathophysiology as well as work-up and management.

L'hypertension intracrânienne idiopathique (HTII) se caractérise par la présence de céphalées, avec ou sans atteintes visuelles, associées à une augmentation de la pression du liquide céphalo-rachidien (LCR), en l'absence d'étiologie secondaire. Bien que son incidence soit faible, le risque d'atteinte visuelle grave en fait une pathologie qui doit être reconnue par les médecins internistes généralistes. En se basant sur un cas pratique, cet article a pour objectif de retracer la présentation clinique typique de cette pathologie, d'aborder les mécanismes physiopathologiques sous-jacents et de présenter le bilan étiologique ainsi que la prise en charge.

Biopsychosocial intervention for stroke carers (BISC): results of a feasibility randomised controlled trial and nested qualitative interview study.

OBJECTIVE: To determine the feasibility of recruiting to and delivering a biopsychosocial intervention for carers of stroke survivors. DESIGN: Feasibility randomised controlled study with nested qualitative interview study. SETTING: The intervention was delivered in the community in either a group or one-to-one format. SUBJECTS: Carers and stroke survivors within one year of stroke onset. INTERVENTIONS: A carer targeted intervention delivered by a research psychologist in six structured two-hour sessions or usual care control. The intervention combined education about the biological, psychological and social effects of stroke with strategies and techniques focussing on adjustment to stroke and caregiving. Stroke survivors in both groups received baseline and follow-up assessment but no intervention. MAIN OUTCOME: Recruitment rate, study attrition, fidelity of intervention delivery, acceptability and sensitivity of outcome measures used (health related quality of life, anxiety and depression and carer burden six months after randomisation). RESULTS: Of the 257 carers approached, 41 consented. Six withdrew before randomisation. Eighteen participants were randomised to receive the intervention and 17 to usual care. Attendance at sessions was greater when treated one-to-one. Feedback interviews suggested that participants found the intervention acceptable and peer support particularly helpful in normalising their feelings. Thirty participants were assessed at follow-up with improvements from baseline on all health measures for both groups. CONCLUSIONS: Our results suggest that a biopsychosocial intervention was acceptable to carers and can be delivered in group and one-to-one formats. Timing of approach and mode of intervention delivery is critical and requires tailoring to the carers individual needs.

[Autoimmune hemolytic anemia in emergency department]. / Anémie hémolytique autoimmune: quelle prise en charge en urgence ?

Autoimmune hemolytic anemia is an uncommon disease that can be challenging to manage both for the emergency department physician and the general practitioner. The diagnosis is based on specific biological changes and on a positive direct Coombs test. Depending on the severity of the anemia and its clinical impact, an urgent blood transfusion can be required. However, ABO blood group typing and antibody screening may be impaired by autoantibodies. In case of vital need, a transfusion of ABO, Rh D and, if possible, C, c, E, e and Kell antigen matched red cells can be performed, before the complete achievement of the pre-transfusion testing. Further management includes the introduction of immunosuppression and the treatment of a possible underlying disease. Early contact with the hematologist, is strongly recommended.

L'anémie hémolytique autoimmune (AHAI) est une pathologie peu fréquente, dont la prise en charge peut représenter un défi pour l'urgentiste et le généraliste. Le diagnostic est posé sur la base des modifications spécifiques du bilan biologique et sur la positivité du test de Coombs direct. Selon la sévérité de l'anémie, une transfusion sanguine en urgence peut s'avérer nécessaire. Les tests prétransfusionnels peuvent être perturbés par la présence des autoanticorps. En cas d'urgence vitale, on transfusera en compatibilité ABO, Rh D et en essayant de respecter les antigènes C, c, E, e et Kell, sans attendre les tests prétransfusionnels complets. La suite de la prise en charge s'articulera autour de l'introduction de l'immunosuppression ainsi que sur la recherche d'une maladie sous-jacente. L'appel précoce à l'hématologue est de rigueur.

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study.

BACKGROUND: Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. METHODS: We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. RESULTS: The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10- 11), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P = 0.48). CONCLUSIONS: Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.

Bathing adaptations in the homes of older adults (BATH-OUT): results of a feasibility randomised controlled trial (RCT).

BACKGROUND: Housing adaptations have been identified as an important environmental and prevention intervention for older adults, which may improve health and quality of life. The onset of disability in bathing can act as a warning for further disability in other activities and may therefore be a judicious time-point for intervention. The aim of this study was to determine the feasibility of conducting a Randomised Controlled Trial (RCT) of bathing adaptations, to evaluate whether they improve older adults' perceived health status and quality of life, prevent further functional deterioration, and reduce the use of other health and social care resources. This study was conducted in preparation for a powered RCT. METHOD: Eligibility criteria were aged > 65 and referred to local authority housing adaptations service for an accessible flush-floor shower. Participants were randomised to either usual adaptations (3-4 month wait) or immediate adaptations (no wait). Outcomes were assessed at 3, 6 and 9 months and included perceived physical and mental health status, health and social care related quality of life, independence in activities of daily living (ADL) and bathing, and falls. Data on costs and the use of health and social care resources were collected during follow-up in order to inform a definitive health economic evaluation. RESULTS: Sixty participants were recruited and randomised, 31 to immediate adaptations and 29 to waiting list control. Mean age was 77(SD8), 58% women and 58% living alone. Follow-ups were completed with 90, 85 and 72% at 3, 6 and 9 months respectively. Adaptations were delivered to 65% of participants within the requisite timescales as there were delays with some privately owned properties. There were improvements from baseline in both groups on all outcome measures following the completion of the adaptations. CONCLUSIONS: This is the first RCT of housing adaptations in the UK. We demonstrated the feasibility of using a waiting list control, subject to minor alterations to the timescales for privately owned properties. A powered trial would evaluate the impact on older adults' quality of life and investigate the impact of waiting times on functional outcomes and health and care resource use. TRIAL REGISTRATION: ISRCTN14876332 Registered 12 July 2016.

Is Stroke Early Supported Discharge still effective in practice? A prospective comparative study.

OBJECTIVE: Randomised controlled trials have shown the benefits of Early Supported Discharge (ESD) of stroke survivors. Our aim was to evaluate whether ESD is still beneficial when operating in the complex context of frontline healthcare provision. DESIGN: We conducted a cohort study with quasi experimental design. A total of 293 stroke survivors (transfer independently or with assistance of one, identified rehabilitation goals) within two naturally formed groups were recruited from two acute stroke units: 'ESD' n=135 and 'Non ESD' n=158 and 84 caregivers. The 'ESD' group accessed either of two ESD services operating in Nottinghamshire, UK. The 'Non ESD' group experienced standard practices for discharge and onward referral. Outcome measures (primary: Barthel Index) were administered at baseline, 6 weeks, 6 months and 12 months. RESULTS: The ESD group had a significantly shorter length of hospital stay (P=0.029) and reported significantly higher levels of satisfaction with services received (P<0.001). Following adjustment for age differences at baseline, participants in the ESD group (n=71) had significantly higher odds (compared to the Non ESD group, n=85) of being in the ⩾90 Barthel Index category at 6 weeks (OR = 1.557, 95% CI 2.579 to 8.733), 6 months (OR = 1.541, 95% CI 2.617 to 8.340) and 12 months (OR 0.837, 95% CI 1.306 to 4.087) respectively in relation to baseline. Carers of patients accessing ESD services showed significant improvement in mental health scores (P<0.01). CONCLUSION: The health benefits of ESD are still evident when evidence based models of these services are implemented in practice.

Interventions to reduce dependency in personal activities of daily living in community dwelling adults who use homecare services: a systematic review.

OBJECTIVES: To identify interventions that aim to reduce dependency in activities of daily living (ADL) in homecare service users. To determine: content; effectiveness in improving ability to perform ADL; and whether delivery by qualified occupational therapists influences effectiveness. DATA SOURCES: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, OTseeker, PEDro, Web of Science, CIRRIE, and ASSIA. REVIEW METHODS: We included: randomised controlled trials, non-randomised controlled trials and controlled before and after studies. Two reviewers independently screened studies for inclusion, assessed risk of bias and extracted data. A narrative synthesis of the findings was conducted. RESULTS: Thirteen studies were included, totalling 4975 participants. Ten (77%) were judged to have risk of bias. Interventions were categorised as those termed 're-ablement' or 'restorative homecare' (n=5/13); and those involving separate components which were not described using this terminology (n=8/13). Content of the intervention and level of health professional input varied within and between studies. Effectiveness on ADL: eight studies included an ADL outcome, five favoured the intervention group, only two with statistical significance, both these were controlled before and after studies judged at high risk of bias. ADL outcome was reported using seven different measures. Occupational therapy: there was insufficient evidence to determine whether involvement of qualified occupational therapists influenced effectiveness. CONCLUSION: There is limited evidence that interventions targeted at personal ADL can reduce homecare service users' dependency with activities, the content of evaluated interventions varies greatly.

Care provision for poststroke visual impairment.

BACKGROUND: We sought to explore the care provision for poststroke visual impairment and variations in this in the United Kingdom. METHODS: Survey questions were developed and piloted with clinicians, academics, and users. Questions addressed types of visual problems; how these were identified, treated, and followed up; care pathways in use; links with other professions; and referral options. The survey was accessed via a Weblink, which was circulated through UK professional organizations to multiprofessional members of ophthalmic and stroke teams. RESULTS: A total of 548 completed electronic surveys were obtained. In all, 49.5% of respondents represented stroke teams, 42.5% eye teams, and 8% from other teams, for example, emergency care. Many respondents (41%) saw patients within 1 week of stroke. Nineteen percent did not personally test vision: 11% had a visiting clinician to test vision, and 22% used screening tools. Validated tests were used for the assessment of visual acuity (39.5%), visual field (57.5%), eye movement (48.5%), and visual function (58.5%). Visual problems suspected by family or professionals were high (88.5%). Typical overall follow-up period of vision care was less than 3 months. In all, 46% of respondents used designated care pathways for stroke survivors with visual problems; 33.5% of respondents did not provide visual information leaflets. CONCLUSIONS: Significant inequality exists in care for stroke survivors who experience visual problems. There is great variability in how vision screening is undertaken, which vision tests are used, methods of referral to eye care services, how visual problems are managed, and what vision information is provided to stroke survivors/carers. Further work is required to ensure equality and effective care.

Implementing evidence-based stroke Early Supported Discharge services: a qualitative study of challenges, facilitators and impact.

OBJECTIVES: To explore the perspectives of healthcare professionals and commissioners working with a stroke Early Supported Discharge service in relation to: (1) the factors that facilitate or impede the implementation of the service, and (2) the impact of the service. DESIGN: Cross-sectional qualitative study using semi-structured interviews. Data were analysed by two researchers using a thematic analysis approach. SETTING: Two Early Supported Discharge services in Nottinghamshire. PARTICIPANTS: Purposive sampling identified 35 key informants including practitioners, managers and commissioners. RESULTS: The identified facilitators to the implementation of evidence-based services were: (1) the adaptability of the intervention to the healthcare context, (2) the role of rehabilitation assistants and (3) cross-service working arrangements. Perceived challenges included: (1) lack of clarity regarding the referral decision making process, (2) delays in securing social care input and (3) lack of appropriate follow-on services in the region. Most respondents perceived the impact of the services to be: (1) reducing in-hospital stay, (2) aiding the seamless transfer of care from hospital to the community and (3) providing intensive stroke specific therapy. Commissioners called for greater evidence of service impact and clarity regarding where it fits into the stroke pathway. CONCLUSIONS: Early Supported Discharge services were perceived as successful in providing home-based, stroke specific rehabilitation. Teams would benefit from capitalising on identified facilitators and developing strategies to address the challenges. The remit and impact of the services should be clear and demonstrable, with teams strengthening links with other health and social care providers.

Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer.

Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.