Structure-Activity Relationship Studies of Aryl Sulfoxides as Reversible Monoacylglycerol Lipase Inhibitors.

Monoacylglycerol lipase (MAGL) is the key enzyme for the hydrolysis of endocannabinoid 2-arachidonoylglycerol (2-AG). The central role of MAGL in the metabolism of 2-AG makes it an attractive therapeutic target for a variety of disorders, including inflammation-induced tissue injury, pain, multiple sclerosis, and cancer. Previously, we reported LEI-515, an aryl sulfoxide, as a peripherally restricted, covalent reversible MAGL inhibitor that reduced neuropathic pain and inflammation in preclinical models. Here, we describe the structure-activity relationship (SAR) of aryl sulfoxides as MAGL inhibitors that led to the identification of LEI-515. Optimization of the potency of high-throughput screening (HTS) hit 1 yielded compound ±43. However, ±43 was not metabolically stable due to its ester moiety. Replacing the ester group with α-CF2 ketone led to the identification of compound ±73 (LEI-515) as a metabolically stable MAGL inhibitor with subnanomolar potency. LEI-515 is a promising compound to harness the therapeutic potential of MAGL inhibition.

Efficacy and safety of once-weekly subcutaneous semaglutide on weight loss in patients with overweight or obesity without diabetes mellitus-A systematic review and meta-analysis of randomized controlled trials.

Semaglutide is found to be efficient for weight loss in patients with overweight or obesity with diabetes mellitus (DM). With a wide range of adverse events reported, the efficacy and safety of once-weekly subcutaneous semaglutide in individuals without DM, with overweight or obesity, is unclear. We conducted a comprehensive meta-analysis of randomized studies on once-weekly semaglutide in this patient population. We identified nine studies with 11,641 patients in the semaglutide group and 10,479 in the placebo group. We observed that semaglutide resulted in significant benefits, including change in body weight (%): mean difference (MD) of -11.49% (p < 0.0001), change in absolute body weight: MD of -11.74 kg (p < 0.0001), and change in waist circumference: MD of -9.06 cm (p < 0.0001). Gastrointestinal side effects are predominant including nausea: odds ratio (OR) of 4.06 (p < 0.0001), vomiting: OR of 4.43 (p < 0.0001), diarrhea: OR of 2.10 (p < 0.0001), constipation: OR of 2.43 (p < 0.0001), gallbladder disorders: OR of 1.26 (p = 0.010), and cholelithiasis: OR of 2.06 (p = 0.04). Serious adverse events were not statistically significant: OR of 1.06 (p = 0.82). However, the percentage of participants discontinuing due to adverse events and gastrointestinal side effects was statistically significant: ORs of 2.22 (p < 0.0001) and 3.77 (p < 0.0001), respectively. This study shows that in patients with overweight or obesity without DM, once-weekly subcutaneous semaglutide can significantly decrease body weight without risk of serious adverse events when compared with a placebo. However, gastrointestinal side effects are predominant with semaglutide, which can result in medication discontinuation.

Modeling longitudinal oral health status and pneumonia risk: secondary data analyses of an integrated dental-medical cohort.

BACKGROUND: Mounting evidence indicates potential associations between poor oral health status (OHS) and increased pneumonia risk. Relative pneumonia risk was assessed in the context of longitudinally documented OHS. METHODS: Electronic medical/dental patient data captured from 2007 through 2019 were retrieved from the integrated health records of Marshfield Clinic Health Systems. Participant eligibility initiated with an assessment of OHS, stratified into the best, moderate, or worst OHS groups, with the additional criterion of 'no pneumonia diagnosis in the past 90 days'. Pneumonia incidence was longitudinally monitored for up to 1 year from each qualifying dental visit. Models were assessed, with and without adjustment for prior pneumonia incidence, adjusted for smoking and subjected to confounding mitigation attributable to known pneumonia risk factors by applying propensity score analysis. Time-to-event analysis and proportional hazard modeling were applied to investigate relative pneumonia risk over time among the OHS groups. RESULTS: Modeling identified associations between any incident pneumonia subtype and 'number of missing teeth' (p < 0.001) and 'clinically assessed periodontal status' (p < 0.01), which remained significant following adjustment for prior pneumonia incidence and smoking. The hazard ratio (HR) for 'any incident pneumonia' in the best OHS group for 'number of missing teeth' was 0.65, 95% confidence interval (CI) [0.54 - 0.79] (unadjusted) and 0.744, 95% CI [0.61 - 0.91] (adjusted). The HR for 'any incident pneumonia' in the best 'clinically assessed periodontal status' group was 0.72, 95% CI [0.58 - 0.90] (unadjusted) and 0.78, 95% CI [0.62 - 0.97] (adjusted). CONCLUSION/CLINICAL RELEVANCE: Poor OHS increased pneumonia risk. Proactive attention of medical providers to patient OHS and health literacy surrounding oral-systemic disease association is vital, especially in high-risk populations.

Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA.

Phenotypic screening is a powerful approach to identify novel antibiotics, but elucidation of the targets responsible for the antimicrobial activity is often challenging in the case of compounds with a polypharmacological mode of action. Here, we show that activity-based protein profiling maps the target interaction landscape of a series of 1,3,4-oxadiazole-3-ones identified in a phenotypic screen to have high antibacterial potency against multidrug-resistant Staphylococcus aureus. In situ competitive and comparative chemical proteomics with a tailor-made activity-based probe, in combination with transposon and resistance studies, revealed several cysteine and serine hydrolases as relevant targets. Our data showcase oxadiazolones as a novel antibacterial chemotype with a polypharmacological mode of action, in which FabH, FphC, and AdhE play a central role.

Hydrochlorothiazide use, sun exposure, and risk of keratinocyte cancer.

BACKGROUND: Keratinocyte cancer (KC) rates are increasing in the U.S., particularly in older age groups. Use of hydrochlorothiazide (HCTZ), due to its photosensitizing properties, and high sun exposure are two known NMSC risk factors, but their synergistic effects are undetermined. The purpose of this study was to examine the development of NMSC between adults who did and did not use HCTZ, as well as those with high and low sun exposure. METHODS: A retrospective case-control sample was assembled from adult patients in north-central Wisconsin (USA). Duration of HCTZ use and occupational sun exposure were extracted from electronic health records, along with a linked survey of lifetime sun exposure. RESULTS: There were 333 cases and 666 controls in the analytical sample. A significant main effect was observed for HCTZ duration in the full sample. Under low sun exposure, the odds of NMSC was 14% greater for each additional year of HCTZ use (aOR = 1.14 [1.11, 1.18], p < 0.001). In a sensitivity analysis of participants age 70 years and over, there was a borderline significant (p = 0.086) HCTZ use by high sun exposure interaction, suggesting modestly increased HCTZ risk in older, high sun exposure adults. CONCLUSIONS: Consistent with prior studies, longer duration of HCTZ use was a predictor of NMSC in north-central Wisconsin adults. NMSC may be accelerated in HCTZ users with outdoor lifestyles, but future studies should attempt to further disaggregate specific effects of sun exposure time, HCTZ duration, and age on NMSC development.

Systematic review of studies examining contribution of oral health variables to risk prediction models for undiagnosed Type 2 diabetes and prediabetes.

OBJECTIVE: To conduct systematic review applying "preferred reporting items for systematic reviews and meta-analyses statement" and "prediction model risk of assessment bias tool" to studies examining the performance of predictive models incorporating oral health-related variables as candidate predictors for projecting undiagnosed diabetes mellitus (Type 2)/prediabetes risk. MATERIALS AND METHODS: Literature searches undertaken in PubMed, Web of Science, and Gray literature identified eligible studies published between January 1, 1980 and July 31, 2018. Systematically reviewed studies met inclusion criteria if studies applied multivariable regression modeling or informatics approaches to risk prediction for undiagnosed diabetes/prediabetes, and included dental/oral health-related variables modeled either independently, or in combination with other risk variables. RESULTS: Eligibility for systematic review was determined for seven of the 71 studies screened. Nineteen dental/oral health-related variables were examined across studies. "Periodontal pocket depth" and/or "missing teeth" were oral health variables consistently retained as predictive variables in models across all systematically reviewed studies. Strong performance metrics were reported for derived models by all systematically reviewed studies. The predictive power of independently modeled oral health variables was marginally amplified when modeled with point-of-care biological glycemic measures in dental settings. Meta-analysis was precluded due to high inter-study variability in study design and population diversity. CONCLUSIONS: Predictive modeling consistently supported "periodontal measures" and "missing teeth" as candidate variables for predicting undiagnosed diabetes/prediabetes. Validation of predictive risk modeling for undiagnosed diabetes/prediabetes across diverse populations will test the feasibility of translating such models into clinical practice settings as noninvasive screening tools for identifying at-risk individuals following demonstration of model validity within the defined population.

Management of a common and proper hepatic artery aneurysm.

First-line management of hepatic artery aneurysms is via an endovascular approach. However, unfavorable anatomy may preclude this. We present a patient with an aneurysm involving most of the common hepatic artery and the entire proper hepatic artery including the emergence of the right and left hepatic artery and the gastroduodenal artery. The endovascular approach was not feasible due to unfavorable anatomy. The patient was successfully treated with an open bifurcated Dacron graft.

Beyond Hemoglobin: When and How to Work Up Possible Polycythemia Vera.

BACKGROUND: World Health Organization (WHO) 2017 diagnostic criteria for hemoglobin levels in polycythemia vera (PV) were lowered from 185 g/L to 165 g/L for men and from 165 g/L to 160 g/L for women, but these cutoffs were not designed for screening. OBJECTIVES: The primary aim of this study was to assess the value of laboratory and clinical parameters in deciding whether to further pursue a diagnosis of PV. A secondary aim was to explore the diagnostic utility of bone marrow morphology. METHODS: We evaluated clinical and laboratory parameters that may be useful when considering further diagnostic work-up, emphasizing PV vs. secondary erythrocytosis (SE). We classified 200 patients with JAK2 V617F testing using WHO criteria. RESULTS: Patients with myeloproliferative neoplasms (MPN) were rarely under age 40 and uncommonly obese (BMI ≥ 30 kg/m2). Current smoking history favored SE, and these patients rarely had a platelet count ≥ 450 × 103/uL. Laboratory parameters suggesting greater PV likelihood were: RBC > 6.8 × 106 for men or > 5.9 × 106 for women; low erythropoietin; and low MCV or low ferritin. Bone marrow morphology (available in 111 cases) was generally more cellular in PV vs. SE and assessed disease progression. CONCLUSIONS: Readily accessible clinical and laboratory data can assist in considering a PV workup, and a possible diagnostic algorithm is presented. These preliminary findings warrant larger studies to develop a more formal PV-risk scoring system with optimal cutoffs and weighting.

Orthopaedic injuries from snowmobile accidents: a multi-centre analysis of demographics, injury patterns, and outcomes.

PURPOSE: More than 2 million people in North America use snowmobiles, resulting in an estimated 200 fatalities and 14,000 injuries annually. The purpose of this study is to document the demographics, orthopaedic injury patterns, and short-term outcomes of patients with snowmobile-related injuries. MATERIALS AND METHODS: A retrospective review was performed at two regional trauma centres in a region where snowmobile use is prevalent. Patients who sustained snowmobile-related injuries over a 12-year period were identified from the hospitals' trauma registries using E-codes (E820-E820.9). Patient demographics were recorded, as were injury characteristics including rates of substance use, open fractures, Injury Severity Score (ISS), Abbreviated Injury Score (AIS) for the extremities, and mortality. Rates of inpatient surgery, as well as hospital and ICU length of stay (LOS), were also recorded. RESULTS: We identified 528 patients with snowmobile-related injuries. Average age was 37 years, and 418 patients (79%) were male. Eighty-eight per cent of all patients with snowmobile injuries were admitted to the hospital with an average LOS of 5.7 days. Among those admitted to the hospital, average ISS was 12.3, and 28% of these patients had ISS > 15. A total of 261 patients (56%) suffered extremity injuries (including 163 upper and 173 lower extremity fractures) with an average extremity AIS of 2.4. There were 700 total fractures (1.5 per patient), and 9% of all fractures were open. A total of 208 patients (45%) suffered head injuries, and 132 patients (28%) sustained vertebral column fractures. A total of 201 patients (43%) required inpatient surgery, and eight patients (1.7%) sustained fatal injuries. CONCLUSIONS: We present a detailed multi-centre analysis of orthopaedic injury patterns and outcomes resulting from snowmobile-related injuries. Patients injured while snowmobiling share similar injury patterns with patients injured in motorcycle and other high-energy motor vehicle accidents.

LXR/RXR pathway signaling associated with triple-negative breast cancer in African American women.

BACKGROUND: Triple-negative breast cancer (TNBC) is more prevalent in African and African American (AA) women compared to European American (EA) women. African and AA women diagnosed with TNBC experience high frequencies of metastases and less favorable outcomes. Emerging evidence indicates that this disparity may in fact be the result of the uniquely aggressive biology of African and AA disease. PURPOSE: To understand the reasons for TNBC in AA aggressive biology, we designed the present study to examine the proteomic profiles of TNBC and luminal A (LA) breast cancer within and across patients' racial demographic groups in order to identify proteins or molecular pathways altered in TNBC that offer some explanation for its aggressiveness and potential targets for treatment. MATERIALS AND METHODS: Proteomic profiles of TNBC, LA tumors, and their adjacent normal tissues from AA and EA women were obtained using 2-dimensional gel electrophoresis and bioinformatics, and differentially expressed proteins were validated by Western blot and immunohistochemistry. Our data showed that a number of proteins have significantly altered in expression in LA tumors compared to TNBC, both within and across patients' racial demographic groups. The differentially overexpressed proteins in TNBC (compared to LA) of AA samples were distinct from those in TNBC (compared to LA) of EA women samples. Among the signaling pathways altered in AA TNBC compared to EA TNBC are innate immune signaling, calpain protease, and pyrimidine de novo synthesis pathways. Furthermore, liver LXR/RXR signaling pathway was altered between LA and TNBC in AA women and may be due to the deficiency of the CYP7B1 enzyme responsible for cholesterol degradation. CONCLUSION: These findings suggest that TNBC in AA women enriched in signaling pathways that are different from TNBC in EA women. Our study draws a link between LXR/RXR expression, cholesterol, obesity, and the TNBC in AA women.

A chemical genetic screen reveals that iminosugar inhibitors of plant glucosylceramide synthase inhibit root growth in Arabidopsis and cereals.

Iminosugars are carbohydrate mimics that are useful as molecular probes to dissect metabolism in plants. To analyse the effects of iminosugar derivatives on germination and seedling growth, we screened a library of 390 N-substituted iminosugar analogues against Arabidopsis and the small cereal Eragrostis tef (Tef). The most potent compound identified in both systems, N-5-(adamantane-1-yl-ethoxy)pentyl- L-ido-deoxynojirimycin (L-ido-AEP-DNJ), inhibited root growth in agar plate assays by 92% and 96% in Arabidopsis and Tef respectively, at 10 µM concentration. Phenocopying the effect of L-ido-AEP-DNJ with the commercial inhibitor (PDMP) implicated glucosylceramide synthase as the target responsible for root growth inhibition. L-ido-AEP-DNJ was twenty-fold more potent than PDMP. Liquid chromatography-mass spectrometry (LC-MS) analysis of ceramide:glucosylceramide ratios in inhibitor-treated Arabidopsis seedlings showed a decrease in the relative quantity of the latter, confirming that glucosylceramide synthesis is perturbed in inhibitor-treated plants. Bioinformatic analysis of glucosylceramide synthase indicates gene conservation across higher plants. Previous T-DNA insertional inactivation of glucosylceramide synthase in Arabidopsis caused seedling lethality, indicating a role in growth and development. The compounds identified herein represent chemical alternatives that can overcome issues caused by genetic intervention. These inhibitors offer the potential to dissect the roles of glucosylceramides in polyploid crop species.

Two-step activity-based protein profiling of diacylglycerol lipase.

Diacylglycerol lipases (DAGL) produce the endocannabinoid 2-arachidonoylglycerol, a key modulator of neurotransmitter release. Chemical tools that visualize endogenous DAGL activity are desired. Here, we report the design, synthesis and application of a triazole urea probe for DAGL equipped with a norbornene as a biorthogonal handle. The activity and selectivity of the probe was assessed with activity-based protein profiling. This probe was potent against endogenous DAGLα (IC50 = 5 nM) and it was successfully applied as a two-step activity-based probe for labeling of DAGLα using an inverse electron-demand Diels-Alder ligation in living cells.

Development of a Cannabinoid-Based Photoaffinity Probe to Determine the Δ8/9-Tetrahydrocannabinol Protein Interaction Landscape in Neuroblastoma Cells.

Introduction: Δ9-Tetrahydrocannabinol (THC), the principle psychoactive ingredient in Cannabis, is widely used for its therapeutic effects in a large variety of diseases, but it also has numerous neurological side effects. The cannabinoid receptors (CBRs) are responsible to a large extent for these, but not all biological responses are mediated via the CBRs. Objectives: The identification of additional target proteins of THC to enable a better understanding of the (adverse) physiological effects of THC. Methods: In this study, a chemical proteomics approach using a two-step photoaffinity probe is applied to identify potential proteins that may interact with THC. Results: Photoaffinity probe 1, containing a diazirine as a photocrosslinker, and a terminal alkyne as a ligation handle, was synthesized in 14 steps. It demonstrated high affinity for both CBRs. Subsequently, two-step photoaffinity labeling in neuroblastoma cells led to identification of four potential novel protein targets of THC. The identification of these putative protein hits is a first step towards a better understanding of the protein interaction profile of THC, which could ultimately lead to the development of novel therapeutics based on THC.

Quantifying predictive capability of electronic health records for the most harmful breast cancer.

Improved prediction of the "most harmful" breast cancers that cause the most substantive morbidity and mortality would enable physicians to target more intense screening and preventive measures at those women who have the highest risk; however, such prediction models for the "most harmful" breast cancers have rarely been developed. Electronic health records (EHRs) represent an underused data source that has great research and clinical potential. Our goal was to quantify the value of EHR variables in the "most harmful" breast cancer risk prediction. We identified 794 subjects who had breast cancer with primary non-benign tumors with their earliest diagnosis on or after 1/1/2004 from an existing personalized medicine data repository, including 395 "most harmful" breast cancer cases and 399 "least harmful" breast cancer cases. For these subjects, we collected EHR data comprised of 6 components: demographics, diagnoses, symptoms, procedures, medications, and laboratory results. We developed two regularized prediction models, Ridge Logistic Regression (Ridge-LR) and Lasso Logistic Regression (Lasso-LR), to predict the "most harmful" breast cancer one year in advance. The area under the ROC curve (AUC) was used to assess model performance. We observed that the AUCs of Ridge-LR and Lasso-LR models were 0.818 and 0.839 respectively. For both the Ridge-LR and Lasso-LR models, the predictive performance of the whole EHR variables was significantly higher than that of each individual component (p<0.001). In conclusion, EHR variables can be used to predict the "most harmful" breast cancer, providing the possibility to personalize care for those women at the highest risk in clinical practice.

Screening for dysglycaemia in dental primary care practice settings: systematic review of the evidence.

INTRODUCTION: Increasing prevalence of diabetes and periodontal disease is prompting identification of additional clinical settings to identify patients at risk for dysglycaemia. A systematic review of studies that have examined feasibility of screening for at-risk patients in general dentistry settings at point-of-care (POC) was undertaken. MATERIALS AND METHODS: Systematic review of pragmatic clinical field trials piloting POC screening for dysglycaemia risk in dental settings was undertaken in studies whose primary objective was to explore rates of dysglycaemia among undiagnosed patient populations. RESULTS: Among 17 dental clinical field trials identified, 10 were systematically reviewed. High rates of undiagnosed dysglycaemia were detected among dental patients by biological screening in all trials. Notably, substantive differences in study design and population characteristics were identified, precluding meta-analysis. CONCLUSION: Screening for dysglycaemia in dental offices effectively identified high-risk patients requiring triage for glycaemic management. Considerations for future clinical trial design were advanced to establish an evidence base amenable to meta-analysis of the relative translational value of glycaemic screening in dental settings.

Metabolic profiles of triple-negative and luminal A breast cancer subtypes in African-American identify key metabolic differences.

Breast cancer, a heterogeneous disease with variable pathophysiology and biology, is classified into four major subtypes. While hormonal- and antibody-targeted therapies are effective in the patients with luminal and HER-2 subtypes, the patients with triple-negative breast cancer (TNBC) subtype do not benefit from these therapies. The incidence rates of TNBC subtype are higher in African-American women, and the evidence indicates that these women have worse prognosis compared to women of European descent. The reasons for this disparity remain unclear but are often attributed to TNBC biology. In this study, we performed metabolic analysis of breast tissues to identify how TNBC differs from luminal A breast cancer (LABC) subtypes within the African-American and Caucasian breast cancer patients, respectively. We used High-Resolution Magic Angle Spinning (HR-MAS) 1H Nuclear magnetic resonance (NMR) to perform the metabolomic analysis of breast cancer and adjacent normal tissues (total n=82 samples). TNBC and LABC subtypes in African American women exhibited different metabolic profiles. Metabolic profiles of these subtypes were also distinct from those revealed in Caucasian women. TNBC in African-American women expressed higher levels of glutathione, choline, and glutamine as well as profound metabolic alterations characterized by decreased mitochondrial respiration and increased glycolysis concomitant with decreased levels of ATP. TNBC in Caucasian women was associated with increased pyrimidine synthesis. These metabolic alterations could potentially be exploited as novel treatment targets for TNBC.

Health and Well-Being Among Young People From Canadian Farms: Associations With a Culture of Risk-Taking.

PURPOSE: To determine whether patterns of adolescent risk behavior in rural populations, and especially farm populations, are associated with negative indicators of adolescent health and well-being, beyond an established association between risk-taking and injury. METHODS: The study base was Cycle 7 (2014) of the Canadian Health Behaviour in School-Aged Children study. Children aged 11-16 years (n = 2,565; 2,533 weighted) who reported living or working on farms were matched within schools in a 1:1 ratio with other rural children. We related a scale describing engagement in multiple risk behavior to a series of indicators of adolescent health and well-being. FINDINGS: Farm children, particularly male farm children, showed the highest levels of risk behavior. Multiple risk behavior was strongly and consistently associated with negative indicators of general health, mental health (life satisfaction, psychosomatic symptoms), and academic performance in all subpopulations. CONCLUSIONS: Adolescent risk behavior in rural populations, and especially farm populations, is common and associated with a variety of negative indicators of adolescent health and well-being. We speculate that the origins of this risk-taking lifestyle surround cultural definitions of self and identity, which have both protective and negative effects.

Thromboembolic complications following a first isolated episode of superficial vein thrombosis: a cross-sectional retrospective study.

Superficial vein thrombosis (SVT) may be associated with complications such as venous thromboembolism (VTE) and recurrent SVT. The purpose of this study was to explore risk factors among patients with a first isolated episode of SVT (index SVT) involving upper and lower extremities and to estimate the prevalence of VTE complications within 1 year of index SVT. Retrospective chart review of electronic records at Marshfield Clinic in Wisconsin identified 381 subjects with a first isolated SVT diagnosis (male/female: 170/211; median age 59.4 years). Patients were stratified based on whether they did (n = 44; 11.5 %) or did not (n = 337; 88.5 %) experience VTE complications and whether they did (n = 25; 6.6 %) or did not (n = 356; 93.4 %) experience pulmonary embolism (PE) and/or deep vein thrombosis (DVT) within 1 year of index SVT. There were 49 complications among 44 patients; these included DVT (n = 18, 36.7 %), propagation of SVT (n = 18, 36.7 %), PE (n = 9, 18.4 %), new SVT at different location (n = 3, 6.1 %), and recurrent SVT (n = 1, 2.0 %). Univariate analysis of all VTE complications identified seven potential risk factors and similar analysis of PE/DVT complications identified eight potential risk factors, with six common risk factors identified in both analyses. Multivariate analysis identified indwelling venous catheter 30 days prior to SVT (p = 0.044), cancer history with treatment in the previous year (p = 0.001), and non-surgical trauma 7 days prior to SVT (p < 0.001) as independent risk factors for PE/DVT complications. Independent risk factors identified in the current study may convey greater risk for VTE complications, especially PE/DVT, following an initial isolated SVT episode.

Periprosthetic joint infection.

Periprosthetic joint infections are a devastating complication after arthroplasty and are associated with substantial patient morbidity. More than 25% of revisions are attributed to these infections, which are expected to increase. The increased prevalence of obesity, diabetes, and other comorbidities are some of the reasons for this increase. Recognition of the challenge of surgical site infections in general, and periprosthetic joint infections particularly, has prompted implementation of enhanced prevention measures preoperatively (glycaemic control, skin decontamination, decolonisation, etc), intraoperatively (ultraclean operative environment, blood conservation, etc), and postoperatively (refined anticoagulation, improved wound dressings, etc). Additionally, indications for surgical management have been refined. In this Review, we assess risk factors, preventive measures, diagnoses, clinical features, and treatment options for prosthetic joint infection. An international consensus meeting about such infections identified the best practices and further research needs. Orthopaedics could benefit from enhanced preventive, diagnostic, and treatment methods.

Next-generation analysis of cataracts: determining knowledge driven gene-gene interactions using biofilter, and gene-environment interactions using the Phenx Toolkit*.

Investigating the association between biobank derived genomic data and the information of linked electronic health records (EHRs) is an emerging area of research for dissecting the architecture of complex human traits, where cases and controls for study are defined through the use of electronic phenotyping algorithms deployed in large EHR systems. For our study, cataract cases and controls were identified within the Marshfield Personalized Medicine Research Project (PMRP) biobank and linked EHR, which is a member of the NHGRI-funded electronic Medical Records and Genomics (eMERGE) Network. Our goal was to explore potential gene-gene and gene-environment interactions within these data for 527,953 and 527,936 single nucleotide polymorphisms (SNPs) for gene-gene and gene-environment analyses, respectively, with minor allele frequency > 1%, in order to explore higher level associations with cataract risk beyond investigations of single SNP-phenotype associations. To build our SNP-SNP interaction models we utilized a prior-knowledge driven filtering method called Biofilter to minimize the multiple testing burden of exploring the vast array of interaction models possible from our extensive number of SNPs. Using Biofilter, we developed 57,376 prior-knowledge directed SNP-SNP models to test for association with cataract status. We selected models that required 6 sources of external domain knowledge. We identified 13 statistically significant SNP-SNP models with an interaction with p-value < 1 × 10(-4), as well as an overall model with p-value < 0.01 associated with cataract status. We also conducted gene-environment interaction analyses for all GWAS SNPs and a set of environmental factors from the PhenX Toolkit: smoking, UV exposure, and alcohol use;these environmental factors have been previously associated with the formation of cataracts. We found a total of 782 gene-environment models that exhibit an interaction with a p-value < 1 × 10(-4) associatedwith cataract status. Our results show these approaches enable advanced searches for epistasis and gene-environment interactions beyond GWAS, and that the EHR based approach provides an additional source of data for seeking these advanced explanatory models of the etiology of complex disease/outcome such as cataracts.