Search

Escalating prevalence of both diabetes and periodontal disease, two diseases associated with bi-directional exacerbation, has been reported. Periodontal disease represents a modifiable risk factor that may reduce diabetes onset or progression, and integrated models of cross-disciplinary care are needed to establish and manage glycemic control in affected patients. An ad-hoc environmental scan of current literature and media sought to characterize factors impacting status of integrated care models based on review of the existing evidence base in literature and media surrounding: (1) current cross-disciplinary practice patterns, (2) epidemiological updates, (3) status on risk assessment and screening for dysglycemia in the dental setting, (4) status on implementation of quality metrics for oral health, (5) care model pilots, and (6) public health perspectives. The survey revealed: escalating prevalence of diabetes and periodontitis globally; greater emphasis on oral health assessment for diabetic patients in recent medical clinical practice guidelines; high knowledgeability surrounding oral-systemic impacts on diabetes and growing receptivity to medical-dental integration among medical and dental providers; increasing numbers of programs/studies reporting on positive impact of emerging integrated dental-medical care models on diabetic patient healthcare access and health outcomes; a growing evidence base for clinically significant rates of undiagnosed dysglycemia among dental patients reported by point-of-care pilot studies; no current recommendation for population-based screening for dysglycemia in dental settings pending a stronger evidence base; improved definition of true periodontitis prevalence in (pre)/diabetics; emerging recognition of the need for oral health quality indicators and tracking; evidence of persistence in dental access disparity; updated status on barriers to integration. The potential benefit of creating clinically-applicable integrated care models to support holistic management of an escalating diabetic population by targeting modifiable risk factors including periodontitis is being recognized by the health industry. Cross-disciplinary efforts supported by high quality research are needed to mitigate previously- and newly-defined barriers of care integration and expedite development and implementation of integrated care models in various practice settings. Implementation of quality monitoring in the dental setting will support definition of the impact and efficacy of interventional clinical care models on patient outcomes., Competing Interests: Financial Disclosure: AA receives funding from Delta Dental, which provided funding for the study, including the cost of publication., (© 2017 Marshfield Clinic.)

Background: Diagnosis and duration of type 2 diabetes mellitus (DM) appear to be associated with decreased prostate cancer risk. Limitations of previous studies include methods of subject selection and accurate definition of DM diagnosis. We examined the temporal relationship between DM and prostate cancer risk exploring the period of greatest risk starting from the prediabetic to the post-diabetic period using clinical and administrative data to accurately define the date of DM diagnosis., Methods: We identified 5,813 men who developed DM between January 1, 1995 and December 31, 2009 (reference date, date of DM onset or matched date for non-diabetic cohort) and 28,019 non-diabetic men matched by age, smoking history, residence, and reference date. Prostate cancer incidence before and after the reference date was assessed using Cox regression modeling adjusted for matching variables, body mass index, insurance status, and comorbidities. Primary outcomes included hazard ratio (HR) and number needed to be exposed to DM for one additional person to be harmed (NNEH) or benefit (NNEB) with respect to prostate cancer risk., Results: After full adjustment, the HR for prostate cancer before DM diagnosis was 0.96 (95% CI 0.85-1.08; P=0.4752), and the NNEB was 974 at DM diagnosis. After the reference date, the fully-adjusted HR for prostate cancer in diabetic men was 0.84 (95% CI 0.72-0.97, P=0.0167), and the NNEB 3 years after DM onset was 425. The NNEB continued to decrease over time, reaching 63 at 15 years after DM onset, suggesting an increasing protective effect of DM on prostate cancer risk over time. No significant difference between the diabetic and non-diabetic cohort was found prior to reference date., Conclusion: Prostate cancer risk is not reduced in pre-diabetic men but decreases after DM diagnosis and the protective effect of DM onset on prostate cancer risk increases with DM duration.

Objectives: Calumenin, a molecular chaperone, exerts a regulatory effect on the vitamin K-dependent γ-carboxylation redox cycle that inhibits transfer of the reduced vitamin K from VKORC1, the pharmacological target of warfarin, to the γ-carboxylase. Because of its polymorphic structure and central role in the warfarin metabolic pathway, a contributory role for calumenin to warfarin dose variability has been posited. The current study sought to validate modulation of therapeutic dosing requirements by a single nucleotide polymorphisms (SNP) occurring in the calumenin gene (CALU) reported in previous studies. The CALU SNP was further modeled to detect interaction with SNPs occurring in VKORC1, CYP2C9, and CYP4F2 genes and characterize any additional contribution to variability in therapeutic warfarin dose requirement., Setting: The study was undertaken in an established, well-characterized cohort of subjects treated with warfarin in the Anticoagulation Clinic of Marshfield Clinic in Marshfield, Wisconsin., Methods: Subjects (N=491) previously genotyped for SNPS known to contribute variability to therapeutic warfarin dose requirement were genotyped for CALU SNP rs1043550, using TaqMan assays. Contribution of CALU SNP rs1043550 was modeled relative to other genotypic and phenotypic characteristics including gender, diagnosis, age, body surface area, underlying indication for warfarin, comorbidities, and pharmacological exposures. Interaction between SNPs impacting on warfarin dose requirements and calumenin SNPs was also modeled., Results: Small differences in warfarin dosing requirements detected among individuals encoding the mutant G allele in the calumenin SNP were not statistically or clinically significant relative to therapeutic warfarin dose requirement and did not independently contribute significantly to the warfarin dosing model. Interaction between calumenin and VKORC1 SNPs contributed only minor additional variability to that ascribed to the wild type VKORC1 genotype., Conclusions: The impact of the CALU SNP on warfarin dose variability was minor and did not contribute significantly to therapeutic warfarin dose requirement in our study cohort. While no contribution was noted for the SNP examined in the present study, further examination of interaction between genetic elements contributing major impact on therapeutic warfarin dose requirements and genes exhibiting a lesser contribution is warranted.

Objective: A pilot study to examine accrual rates, efficiency of data capture approaches, study design and genotyping capacity for a future genetic validation study was undertaken., Design: The process pilot evaluated feasibility of applying a matched case-control design to validate association of two candidate estrogen receptor (ER) single nucleotide polymorphisms (SNPs) with incidence of venothromboembolic events (VTE) in breast cancer patients treated with tamoxifen where criteria included frequency matching by age, number of years diagnosed with breast cancer within 4-year intervals, and geographic residency., Setting: The study was conducted at Marshfield Clinic, in central Wisconsin., Participants: Study-eligible cases with a breast cancer diagnosis between 1994 and 2006 who experienced a VTE within 5 years of last tamoxifen exposure were matched at a ratio of 1:4 to controls with a breast cancer diagnosed between 1994 and 2006 with no VTE history following tamoxifen exposure for ≥2 years., Methods: Feasibility of enrolling, phenotyping, and genotyping 20% of the total number of validated eligible cases and controls was tested in order to project enrollment rates and assess probability of enrolling the projected sample size for the prospective validation study and adequacy of planned data capture. Conditional logistic regression analysis was conducted for the matched case-control study design., Results: Enrollment accruals included 19 of 24 targeted cases (79%), and 74 of 96 (77%) targeted controls. Electronic data capture for most variables was nearly 100%. No unexpected statistically significant differences were observed between cases and controls. Capacity to conduct in-house screening for rs2234689 (ER1 PvuII), rs9340799 (ER1 XbaI), rs13146272 (CYP4V2), rs2227589 (SERPINC 1) and rs1613662 (GP6) was successfully established. Association of GP6 with VTE was further validated (P=0.0403; OR, 0.19)., Conclusion: Accrual rates to the larger prospective study will require a multi-center design to ensure enrollment of adequate numbers of cases and controls for achieving the projected sample size required to validate association of the ER SNPs. To prevent study failure due to poor accrual, the importance of conducting feasibility studies before launching large scale validation studies of genetic association and adverse drug events, is discussed.

Objective: Warfarin is an FDA-approved oral anticoagulant for long-term prevention of thromboembolism. Substantial inter-individual variation in dosing requirements and the narrow therapeutic index of this widely-prescribed drug make safe initiation and dose stabilization challenging. Single nucleotide polymorphisms (SNPs) occurring in CYP2C9, VKORC1, and CYP4F2 genes are known to impact dose, and VKORC1 and CYP4F2 polymorphisms are associated with higher therapeutic dose requirements in our cohort. However, the most advanced regression models using personal, clinical, and genetic factors to predict individual stable dose account for only 50% to 60% of the observed variability in stable therapeutic dose in Caucasians., Design and Methods: In this study, we used DNA sequence analysis to determine whether additional variants in CYP4F2 and VKORC1 gene coding regions contribute to variable dosing requirements among individuals for whom the actual dose was the highest relative to regression model- predicted dose., Results and Conclusions: No novel DNA variants in the coding regions of these genes were identified among subjects requiring high warfarin doses, suggesting that other factors yet to be defined contribute to variability in warfarin dose requirements in this subset of our cohort.

Purpose: Altered glycosylation has been associated with oncogenic potential. Relationships of blood types (where expression is due to glycosylation pattern) and HER2/neu (where expression arises due to altered glycosylation) and breast cancer-associated markers like estrogen receptor/progesterone receptor (ER/PR) were examined and related to outcomes in patients with breast cancer., Methods: A population-based retrospective study of 426 surgical breast cancer patients examined relationships between (1) patient characteristics, (2) breast tumor characteristics, and (3) outcomes of women diagnosed at the same medical center over a 10-year period relative to specific molecules defined by glycosylation patterns (eg. blood group, HER2/neu) and (4) ER/PR status., Results: Following stratification by blood group, subjects exhibited significant differences in tumor size with persons in blood groups A and B having greater numbers of tumors ≤ 2 cm and those with blood types AB and O having tumors >2 cm. After adjusting for age, disease stage, and treatment with trastuzumab, tamoxifen, or aromatase inhibitors, no significant differences were observed in 5-year overall and disease-free survival based on blood type grouping. Blood group B was over-represented among the breast cancer cohort compared to the reference population, while blood group AB was under-represented., Conclusion: No significant differences were observed in overall and disease-free survival based on blood group. No correlation was noted between HER2/neu, ER or PR status, and blood group type. Among this cohort, HER2/neu positivity was less than 20% and correlated with a 5-year disease-free survival rate ≥ 75% and overall survival of >80% across all blood groups.

Background: Although some genes associated with increased risk of Alzheimer Disease (AD) have been identified, few data exist related to gene/gene and gene/environment risk of AD. The purpose of this pilot study was to explore gene/gene and gene/environment associations in AD and to obtain data for sample size estimates for larger, more definitive studies of AD., Methods: The effect of gene/gene and gene/environment interaction related to late onset Alzheimer Disease (LOAD) was investigated in 153 subjects with LOAD and 302 gender matched controls enrolled in the Personalized Medicine Research Project, a population-based bio-repository. Genetic risk factors examined included APOE, ACE, OLR1,and CYP46 genes, and environmental factors included smoking, total cholesterol, LDL, HDL, triglycerides, C-reactive protein, blood pressure, statin use, and body mass index., Results: The mean age of the cases was 78.2 years and the mean age of the controls was 87.2 years. APOE4 was significantly associated with LOAD (OR=3.55, 95%CL=1.70, 7.45). Cases were significantly more likely to have ever smoked cigarettes during their life (49.3% versus 38.4%, p=0.03). The highest recorded blood pressure and pulse pressure measurements were significantly higher in the controls than the cases (all P<0.005). Although not statistically significant in this pilot study, the relationship of the following factors was associated in opposite directions with LOAD based on the presence of an APOE4 allele: obesity at the age of 50, ACE, OLR1, and CYP46., Conclusions: These pilot data suggest that gene/gene and gene/environment interactions may be important in LOAD, with APOE, a known risk factor for LOAD, affecting the relationship of ACE and OLR1 to LOAD. Replication with a larger sample size and in other racial/ethnic groups is warranted and the allele and risk factor frequencies will assist in choosing an appropriate sample size for a definitive study.

Background: The causes of elevated B-Type natriuretic peptide (BNP) levels are multifactorial. Renal dysfunction has been shown to affect BNP levels in some studies and the diagnostic value of BNP levels in the presence of chronic kidney disease has been questioned. Prior studies have involved small patient populations with variable outcomes noted. This study evaluated the association of BNP levels with an estimated glomerular filtration rate (eGFR) and presence or absence of congestive heart failure (CHF)., Methods: A retrospective, cross-sectional study in which medical records were electronically screened, identified patients with a BNP level and serum creatinine measurement on the same day between December 2002 and March 2006., Results: Of 1739 eligible patients, 537 were positive for CHF and 1202 were negative for CHF by our criteria. There was a clear trend for BNP to be higher with the advancement of CHF, as determined by New York Heart Association (NYHA) classification (P<0.001). Median BNP levels increased from 65 pg/mL in patients without CHF to 496 pg/mL in patients with NYHA class IV CHF (P <0.001), and there was a strong inverse association with eGFR (P <0.001)., Conclusion: BNP levels show a strong inverse association with eGFR in both CHF and non-CHF patients. Currently best practice at most institutions involves use of BNP cutoff diagnostic levels not adjusted for eGFR. The data presented underlines that eGFR is a significant confounder of BNP measurement especially when renal status is compromised and interpretation of clinical significance in the presence of elevated BNP measures should take renal status into consideration.

Objective: The quality of documentation of signs and symptoms and validation of the diagnosis of irritable bowel syndrome (IBS) according to case definition criteria of Manning, Rome I and Rome II in an office setting has not been previously described. We sought to identify and validate cases of IBS based on the Manning, Rome I and Rome II diagnostic criteria in a rural practice setting., Setting: Marshfield Epidemiologic Study Area (MESA) Central consisting of 14 ZIP codes in central Wisconsin, USA., Methods: A retrospective cohort study involved 890 patients with the diagnostic codes 564.1 for irritable bowel syndrome and 306.4 spastic colon-psychogenic who had presented to the practice from 1993-2003. Duration, frequency, concordance and intensity of symptoms based on case definitions of IBS were abstracted from the medical records., Results: During the study period, 890 incident cases of IBS were identified. Only 404 met one or more of the three diagnostic criteria, 340 (84%) met only the Manning criteria, 35 (10%) met only Manning and Rome I criteria, 4 (1%) met both Manning and Rome II criteria, and 25 (6%) met Manning and Rome I and Rome II criteria. Age adjusted incidence rates per 100,000 person-years for validated IBS cases during the observational period were 87 to 170 by Manning (lower confidence interval [CI]: 57-127, upper CI: 116-213), 8 to 34 (lower CI: 0-14, upper CI: 16-53) for Rome I and 3 to 16 (lower CI: 0-3, upper CI: 8-28) for Rome II. Comparison of Rome I and Rome II showed moderate concordance (kappa statistic = 0.51; 95% CI: 0.39-0.64)., Conclusions: Only a small percentage of IBS cases with assigned diagnostic codes met case definition criteria for IBS. There were low concordance rates among the three diagnostic criteria applied.

Objectives: Warfarin is a commonly prescribed anticoagulant drug used to prevent thromboses that may arise as a consequence of orthopedic and vascular surgery or underlying cardiovascular disease. Warfarin is associated with a notoriously narrow therapeutic window where small variations in dosing may result in hemorrhagic or thrombotic complications. To ultimately improve dosing of warfarin, we evaluated models for stable maintenance dose that incorporated both clinical and genetic factors., Method: A model was constructed by evaluating the contribution to dosing variability of the following clinical factors: age, gender, body surface area, and presence or absence of prosthetic heart valves or diabetes. The model was then sequentially expanded by incorporating polymorphisms of cytochrome P450 (CYP) 2C9; vitamin K 2,3 epoxide reductase complex, subunit 1 (VKORC1); gamma carboxylase; factor VII; and apolipoprotein (Apo) E genes., Results: Of genetic factors evaluated in the model, CYP2C9 and VKORC1 each contributed substantially to dose variability, and together with clinical factors explained 56% of the individual variability in stable warfarin dose. In contrast, gamma carboxylase, factor VII and Apo E polymorphisms contributed little to dose variability., Conclusion: The importance of CYP2C9 and VKORC1 to patient-specific dose of warfarin has been confirmed, while polymorphisms of gamma carboxylase, factor VII and Apo E genes did not substantially contribute to predictive models for stable warfarin dose.

Background: The benefits and efficacy of the influenza vaccine have been controversial and have had mixed reviews in the recent literature. Immunosuppressed patients and those receiving chemotherapy are particularly at risk for infectious complications and are therefore given high priority to receiving prophylactic vaccines., Method: We administered the influenza vaccine to 29 patients with malignant lymphoma who were receiving chemotherapy or had recently completed therapy during the flu season of 2003-2004. An aged-matched control group received the same vaccine during the same period. The ability of both groups to mount a protective titer of antibodies to the antigens in the vaccine was measured., Results: Three of 29 patients (10%) in the lymphoma group were able to mount a 4-fold titer to at least one of the influenza A antigens. One patient developed a protective titer to both influenza A and B antigens and 3 of 29 responded to the influenza B antigen. In the control group 13 of 29 (45%) responded to an influenza A antigen and 14 of 29 (48%) had a 4-fold response to the B antigen. Seven of 29 controls (24%) had a 4-fold increase in their titers to both the A and B antigens., Conclusions: This study confirmed the low incidence of response or efficacy to the influenza vaccine reported in previous studies. Only a small percentage (10%) of immunosuppressed patients with malignant lymphoma responded with a 4-fold increase in their antibody titer to the major antigens of the 2003 influenza vaccine. Most interestingly, less than 50% of the aged-matched control population studied responded with a 4-fold increase in their antibody titer. Additional studies are needed to determine methods for improving the efficacy of the vaccine and the effectiveness of the influenza vaccination program in preventing influenza infections in the United States.

Background: Rapid genetic screening for cytochrome P450 (CYP) 2C9 variants may play a role in improving the efficacy and safety of warfarin in individuals with CYP2C9 variants. The feasibility of prospective CYP2C9 model-based warfarin dosing has not yet been assessed., Objectives: To evaluate the feasibility of applying a CYP2C9 gene-based warfarin dosing model in clinical practice., Design: Prospective, randomized, single-blinded clinical pilot trial., Setting: Large multispecialty group practice., Patients: Candidates were recruited from a list of clinic patients eligible for warfarin initiation. This included patients with newly diagnosed thromboembolic disease or atrial arrhythmia, as well as patients anticipating elective valvuloplasty or arthroplasty. Patients who previously received warfarin were excluded., Interventions: Subjects were randomized to receive either 1) a standard initiation dose of 5 mg warfarin/day, or 2) rapid CYP2C9 genotyping and an initiation dose determined using parameters estimated from a previously published multivariate model [including age, body size, co-morbidity (e.g., diabetes), clinical indication (e.g., valvuloplasty) and CYP2C9 genotype]., Measurements: Primary outcome measurements were patient willingness to participate, physician willingness to refer, sample processing time, ability to administer calculated dosage and adequacy of follow-up., Limitations: This pilot trial was designed to assess the feasibility of model-based warfarin dosing. Power was insufficient for statistical comparison of adverse event rates., Results: Forty-three of 117 patients had no prior warfarin treatment and were eligible. Five declined to participate. Twenty patients were randomized to a standard initiation dose of 5 mg daily. Eighteen patients were randomized to model-based dosing. All but one participant received the assigned initiation dose. Blood draw to dosage calculation time (including genotyping) required approximately 4 hours. Six adverse events occurred within the standard dosing group, and two adverse events occurred within the model-based dosing group., Conclusions: Prospective application of a multivariate CYP2C9 gene-based warfarin dosing model is feasible.