Risk assessment of venous thromboembolism in inflammatory bowel disease by inherited risk in a population-based incident cohort

Inflammatory bowel disease(IBD),including Crohn’s disease(CD)and ulcerative colitis(UC),is a chronic inflammatory disease of the digestive tract with increasing prevalence globally.Although venous thromboembolism(VTE)is a major complication in IBD patients,it is often underappreciated with limited tools for risk stratification.AIM To estimate the proportion of VTE among IBD patients and assess genetic risk factors(monogenic and polygenic)for VTE.METHODS Incident VTE was followed for 8465 IBD patients in the UK Biobank(UKB).The associations of VTE with F5 factor V leiden(FVL)mutation,F2 G20210A prothrombin gene mutation(PGM),and polygenic score(PGS003332)were tested using Cox hazards regression analysis,adjusting for age at IBD diagnosis,gender,and genetic background(top 10 principal components).The performance of genetic risk factors for discriminating VTE diagnosis was estimated using the area under the receiver operating characteristic curve(AUC).RESULTS The overall proportion of incident VTE was 4.70%in IBD patients and was similar for CD(4.46%),UC(4.49%),and unclassified(6.42%),and comparable to that of cancer patients(4.66%)who are well-known at increased risk for VTE.Mutation carriers of F5/F2 had a significantly increased risk for VTE compared to non-mutation carriers,hazard ratio(HR)was 1.94,95%confidence interval(CI):1.42-2.65.In contrast,patients with the top PGS decile had a considerably higher risk for VTE compared to those with intermediate scores(middle 8 deciles),HR was 2.06(95%CI:1.57-2.71).The AUC for differentiating VTE diagnosis was 0.64(95%CI:0.61-0.67),0.68(95%CI:0.66-0.71),and 0.69(95%CI:0.66-0.71),respectively,for F5/F2 mutation carriers,PGS,and combined.CONCLUSION Similar to cancer patients,VTE complications are common in IBD patients.PGS provides more informative risk information than F5/F2 mutations(FVL and PGM)for personalized thromboprophylaxis.

The role of the androgen receptor in prostate development and benign prostatic hyperplasia:A review

Benign prostatic hyperplasia(BPH)is a benign enlargement of the prostate in which incidence increases linearly with age,beginning at about 50 years old.BPH is a significant source of morbidity in aging men by causing lower urinary tract symptoms and acute urinary retention.Unfortunately,the etiology of BPH incidence and progression is not clear.This review highlights the role of the androgen receptor(AR)in prostate development and the evidence for its involvement in BPH.The AR is essential for normal prostate development,and individuals with defective AR signaling,such as after castration,do not experience prostate enlargement with age.Furthermore,decreasing dihydrotestosterone availability through therapeutic targeting with 5a-reductase inhibitors diminishes AR activity and results in reduced prostate size and symptoms in some BPH patients.While there is some evidence that AR expression is elevated in certain cellular compartments,how exactly AR is involved in BPH progression has yet to be elucidated.It is possible that AR signaling within stromal cells alters intercellular signaling and a“reawakening”of the embryonic mesenchyme,loss of epithelial AR leads to changes in paracrine signaling interactions,and/or chronic inflammation aids in stromal or epithelial proliferation evident in BPH.Unfortunately,a subset of patients fails to respond to current medical approaches,forcing surgical treatment even though age or associated co-morbidities make surgery less attractive.Fundamentally,new therapeutic approaches to treat BPH are not currently forthcoming,so a more complete molecular understanding of BPH etiology is necessary to identify new treatment options.

Lubiprostone induced ischemic colitis

Ischemic colitis accounts for 6%-18% of the causes of acute lower gastrointestinal bleeding.It is often multifactorial and more commonly encountered in the elderly.Several medications have been implicated in the development of colonic ischemia.We report a case of a 54-year old woman who presented with a two-hour history of nausea,vomiting,abdominal pain,and bloody stool.The patient had recently used lubiprostone with close temporal relationship between the increase in the dose and her symptoms of rectal bleeding.The radiologic,colonoscopic and histopathologic findings were all consistent with ischemic colitis.Her condition improved without any serious complications after the cessation of lubiprostone.This is the first reported case of ischemic colitis with a clear relationship with lubiprostone(Naranjo score of 10).Clinical vigilance for ischemic colitis is recommended for patients receiving lubiprostone who are presenting with abdominal pain and rectal bleeding.

Association of Hypertension and <i>β</i>-Blocker Use with Depression during Pregnancy

Objective: To evaluate the association between hypertension and β-blocker (BB) use and antepartum depression risk. Patients and Methods: We conducted a retrospective cohort study of women who delivered within our integrated health system between 2009 and 2015, and completed an Edinburgh Postnatal Depression Scale (EPDS) during pregnancy. Increased depression risk was defined as EPDS score ≥ 10, or an affirmative answer to question ten, endorsing self-harm. Antepartum hypertension was determined by blood pressure measurements and provider ICD-9 codes. Regression analyses examined the independent associations of BB use and hypertension on antepartum depression risk. Results: Of 9192 deliveries during the study time frame, 5% were hypertensive. Within the hypertensive group, 103 (22%) used a single agent BB (BB Group), 325 (68%) required no antihypertensive medication (No-Med Group), and 48 (10%) used a non-BB single agent or multi-agent therapy (All-Other Group). After adjusting for covariates, compared to normotensive pregnancies, antepartum hypertension was significantly associated with both EPDS score ≥ 10 (adjusted odds ratio [aOR] 1.61, 95% confidence interval [CI] 1.17 - 2.21) and endorsement of self-harm (aOR 1.76, 95% CI 1.05 - 2.95). In further analyses of depression risk in hypertensive pregnancies, there was no difference between the BB Group and No-Med Group (EPDS score ≥ 10, aOR 1.22, 95% CI 0.56 - 2.63;self-harm, aOR 0.84, 95% CI 0.32 - 2.21), or between the All-Other Group and No-Med Group (EPDS ≥ 10, aOR 1.42, 95% CI 0.57 - 3.54;self-harm, aOR 1.04, 95% CI 0.29 - 3.74). Conclusion: Women with antepartum hypertension have increased risk for depression and thoughts of self-harm. β-Blocker use is not associated with further increased risk.

The Future of Transcatheter Therapy for Mitral Valve Disease

The develop percutaneous treatments for mitral regurgitation(MR)have been based on established surgical procedures.Most are based in some way on mitral annuloplasty.Indirect angioplasty utilizing coronary sinus and leafl et repair with the MitraClip device have the most development and clinical application.More recently,after the success of transcatheter aortic valve replacement,transcatheter mitral valve replacement has emerged.A critical unanswered question is what the relative roles of valve repair and valve replacement will be.The largest experience in practice is with MitraClip leaflet repair.The evidence base for the development of these novel therapies includes some data in surgical candidates,and registry studies that have been done predominantly in high risk populations.

Assessment of Susceptibility, Pharmacodynamics, and Therapeutic Response for Interpretation of Piperacillin-Tazobactam <i>in Vitro</i>Activity in the Treatment of <i>Pseudomonas aeruginosa</i>Infection

Pseudomonas aeruginosa remains an important pathogen. Our purpose was to determine the minimum inhibitory con-centration (MIC) and pharmacodynamic (PD) parameters predicting a positive response to therapy with piperacil-lin-tazobactam. Medical records were retrospectively reviewed at 3 centers. Data were recorded to assess age, type of disease, renal function, weight (body mass), MIC, antimicrobial treatment, and clinical outcome. Success was response to piperacillin-tazobactam alone, or in combination with another active agent;failure was lack of response. Of 78 eva-luable patients, 63 responded (7 UTI;56 non-UTI) and 15 did not;26 responding received combination therapy and 37 monotherapy. Piperacillin-tazobactam treatment was successful in 53 of 63 of non-UTI disease with a MIC of ≤64/4 μg/mL, but in only 3 of 7 with a MIC of >64/4 μg/mL (P = 0.023);overall 9 of 10 infections by strains with MICs = 32 - 64 μg/mL had a successful outcome. Piperacillin estimated time above MIC at 20% separated those responding from those that did not (P = 0.019).

Genomic predictors for treatment of late stage prostate cancer

In spite of the development of new treatments for late stage prostate cancer, significant challenges persist to match individuals with effective targeted therapies. Genomic classification using high-throughput sequencing technologies has the potential to achieve this goal and make precision medicine a reality in the management of men with castrate-resistant prostate cancer. This chapter reviews some of the most recent studies that have resulted in significant progress in determining the landscape of somatic genomic alterations in this cohort and, more importantly, have provided clinically actionable information that could guide treatment decisions. This chapter reviews the current understanding of common alterations such as alterations of the androgen receptor and PTEN pathway, as well as ETS gene fusions and the growing importance of PARP inhibition. It also reviews recent studies that characterize the evolution to neuroendocrine tumors, which is becoming an increasingly important clinical problem. Finally, this chapter reviews recent innovative studies that characterize the compelling evolutionary history of lethal prostate cancer evidenced by polyclonal seeding and interclonal cooperation between metastasis and the importance of tumor clone dynamics measured serially in response to treatment. The genomic landscape of late stage prostate cancer is becoming better defined, and the prospect for assigning clinically actionable data to inform rationale treatment for individuals with this disease is becoming a reality.

Performance of the Prostate Health Index in predicting prostate biopsy outcomes among men with a negative digital rectal examination and transrectal ultrasonography

The [-2]proPSA （p2PSA） and its derivatives, the p2PSA-to-free PSA ratio （%p2PSA）, and the Prostate Health Index （PHI） have greatly improved discrimination between men with and without prostate cancer （PCa） in prostate biopsies. However, little is known about their performance in cases where a digital rectal examination （DRE） and transrectal ultrasonography （TRUS） are negative. A prospective cohort of 261 consecutive patients in China with negative DRE and TRUS were recruited and underwent prostate biopsies. A serum sample had collected before the biopsy was used to measure various PSA derivatives, including total prostate-specific antigen （tPSA）, free PSA, and p2PSA. For each patient, the free-to-total PSA ratio （%fPSA）, PSA density （PSAD）, p2PSA-to-free PSA ratio （%p2PSA）, and PHI were calculated. Discriminative performance was assessed using the area under the receiver operating characteristic curve （AUC） and the biopsy rate at 91% sensitivity. The AUC scores within the entire cohort with respect to age, tPSA, %fPSA, PSAD, p2PSA, %p2PSA, and PHI were 0.598, 0.751, 0.646, 0.789, 0.814, 0.808, and 0.853, respectively. PHI was the best predictor of prostate biopsy results, especially in patients with a tPSA of 10.1-20 ng ml-1. Compared with other markers, at a sensitivity of 91%, PHI was the most useful for determining which men did not need to undergo biopsy, thereby avoiding unnecessary procedures. The use of PHI could improve the accuracy of PCa detection by predicting prostate biopsy outcomes among men with a negative DRE and TRUS in China.

Phi-based risk calculators performed better in the prediction of prostate cancer in the Chinese population

Risk prediction models including the Prostate Health Index(phi)for prostate cancer have been well established and evaluated in the Western population.The aim of this study is to build phi-based risk calculators in a prostate biopsy population and evaluate their performanee in predicting prostate cancer(PCa)and high-grade PCa(Gleason score 27)in the Chinese population.We developed risk calculators based on 635 men who underwent initial prostate biopsy.Then,we validated the performance of prostate-specific antigen(PSA),phi,and the risk calculators in an additional observational cohort of 1045 men.We observed that the phi-based risk calculators(risk calculators 2 and 4)outperformed the PSA-based risk calculator for predicting PCa and high-grade PCa in the training cohort.In the validation study,the area under the receiver operating characteristic curve(AUC)for risk calculators 2 and 4 reached 0.91 and 0.92,respectively,for predicting PCa and high-grade PCa,respectively;the AUC values were better than those for risk calculator 1(PSA-based model with an AUC of 0.81 and 0.82,respectively)(all P<0.001).Such superiority was also observed in the stratified population with PSA ranging from 2.0 ng ml^-1 to 10.0 ng ml^-1.Decision curves confirmed that a considerable proportion of unnecessary biopsies could be avoided while applying phi-based risk calculators.In this study,we showed that,compared to risk calculators without phi,phi-based risk calculators exhibited superior discrimination and calibration for PCa in the Chinese biopsy population.Applying these risk calculators also considerably reduced the number of unnecessary biopsies for PCa.

DNA alterations in the tumor genome and their associations with clinical outcome in prostate cancer

Although most prostate cancer （PCa） cases are not life-threatening, approximately 293 000 men worldwide die annually due to PCa. These lethal cases are thought to be caused by coordinated genomic alterations that accumulate over time. Recent genome-wide analyses of DNA from subjects with PCa have revealed most, if not all, genetic changes in both germline and PCa tumor genomes. In this article, I first review the major, somatically acquired genomic characteristics of various subtypes of PCa. I then recap key findings on the relationships between genomic alterations and clinical parameters, such as biochemical recurrence or clinical relapse, metastasis and cancer-specific mortality. Finally, I outline the need for, and challenges with, validation of recent findings in prospective studies for clinical utility. It is clearer now than ever before that the landscape of somatically acquired aberrations in PCa is highlighted by DNA copy number alterations （CNAs） and TMPRSS2-ERG fusion derived from complex rearrangements, numerous single nucleotide variations or mutations, tremendous heterogeneity, and continuously punctuated evolution. Genome-wide CNAs, PTEN loss, MYC gain in primary tumors, and TP53 loss/mutation and AR amplification/mutation in advanced metastatic PCa have consistently been associated with worse cancer prognosis. With this recently gained knowledge, it is now an opportune time to develop DNA-based tests that provide more accurate patient stratification for prediction of clinical outcome, which will ultimately lead to more personalized cancer care than is possible at present.

Eyes and stroke:the visual aspects of cerebrovascular disease

A large portion of the central nervous system is dedicated to vision and therefore strokes have a high likelihood of involving vision in some way.Vision loss can be the most disabling residual effect after a cerebral infarction.Transient vision problems can likewise be a harbinger of stroke and prompt evaluation after recognition of visual symptoms can prevent future vascular injury.In this review,we discuss the visual aspects of stroke.First,anatomy and the vascular supply of the visual system are considered.Then,the different stroke syndromes which involve vision are discussed.Finally,topics involving the assessment,prognosis,treatment and therapeutic intervention of vision-specific stroke topics are reviewed.

Population-standardized genetic risk score： the SNP-based method of choice for inherited risk assessment of prostate cancer

Several different approaches are available to clinicians for determining prostate cancer （PCa） risk. The clinical validity of various PCa risk assessment methods utilizing single nucleotide polymorphisms （SNPs） has been established; however, these SNP-based methods have not been compared. The objective of this study was to compare the three most commonly used SNP-based methods for PCa risk assessment. Participants were men （n = 1654） enrolled in a prospective study of PCa development. Genotypes of 59 PCa risk-associated SNPs were available in this cohort. Three methods of calculating SNP-based genetic risk scores （GRSs） were used for the evaluation of individual disease risk such as risk allele count （GRS-RAC）, weighted risk allele count （GRS-wRAC）, and population-standardized genetic risk score （GRS-PS）. Mean GRSs were calculated, and performances were compared using area under the receiver operating characteristic curve （AUC） and positive predictive value （PPV）. All SNP-based methods were found to be independently associated with PCa （all P 〈 0.05; hence their clinical validity）. The mean GRSs in men with or without PCa using GRS-RAC were 55.15 and 53.46, respectively, using GRS-wRAC were 7.42 and 6.97, respectively, and using GRS-PS were 1.12 and 0.84, respectively （all P 〈 0.05 for differences between patients with or without PCa）. All three SNP-based methods performed similarly in discriminating PCa from non-PCa based on AUC and in predicting PCa risk based on PPV （all P 〉 0.05 for comparisons between the three methods）, and all three SNP-based methods had a significantly higher AUC than family history （all P 〈 0.05）. Results from this study suggest that while the three most commonly used SNP-based methods performed similarly in discriminating PCa from non-PCa at the population level, GRS-PS is the method of choice for risk assessment at the individual level because its value （where 1.0 represents average population risk） can be easily interpreted regardless of the number of risk-associated SNPs used in the calculation.

Personalized prostate cancer care： from screening totreatment

Unprecedented progress has been made in genomic personalized medicine in the last several years, allowing for more individualized healthcare assessments and recommendations than ever before. However, most of this progress in prostate cancer （PCa） care has focused on developing and selecting therapies for late-stage disease. To address this issue of limited focus, we propose a model for incorporating genomic-based personalized medicine into all levels of PCa care, from prevention and screening to diagnosis, and ultimately to the treatment of both early-stage and late-stage cancers. We have termed this strategy the ＂Pyramid Model＂ of personalized cancer care. In this perspective paper, our objective is to demonstrate the potential application of the Pyramid Model to PCa care. This proactive and comprehensive personalized cancer care approach has the potential to achieve three important medical goals： reducing mortality, improving quality of life and decreasing both individual and societal healthcare costs.

Clinically available RNA profiling tests of prostate tumors： utility and comparison

In the postscreening era, physicians are in need of methods to discriminate aggressive from nonaggressive prostate cancer （PCa） to reduce overdiagnosis and overtreatment. However, studies have shown that prognoses （e.g., progression and mortality） differ even among individuals with similar clinical and pathological characteristics. Existing risk classifiers （TMN grading system, Gleason score, etc.） are not accurately enough to represent the biological features of PCa. Using new genomic technologies, novel biomarkers and classifiers have been developed and shown to add value to clinical or pathological risk factors for predicting aggressive disease. Among them, RNA testing （gene expression analysis） is useful because it can not only reflect genetic variations but also reflect epigenetic regulations. Commercially available RNA profiling tests （Oncotype Dx, Prolaris, and Decipher） have demonstrated strong abilities to discriminate PCa with poor prognosis from less aggressive diseases. For instance, these RNA profiling tests can predict disease progression in active surveillance patients or early recurrence after radical treatments. These tests may offer more dependable methods for PCa prognosis prediction to make more accurate and personal medical decisions.

Clinical validity and utility of genetic risk scores in prostate cancer

Current issues related to prostate cancer （PCa） clinical care （e.g., over-screening, over-diagnosis, and over-treatment of nonaggressive PCa） call for risk assessment tools that can be combined with family history （FH） to stratify disease risk among men in the general population. Since 2007, genome-wide association studies （GWASs） have identified more than 100 SNPs associated with PCa susceptibility. In this review, we discuss （1） the validity of these PCa risk-associated SNPs, individually and collectively; （2） the various methods used for measuring the cumulative effect of multiple SNPs, including genetic risk score （GRS）; （3） the adequate number of SNPs needed for risk assessment; （4） reclassification of risk based on evolving numbers of SNPs used to calculate genetic risk, （5） risk assessment for men from various racial groups, and （6） the clinical utility of genetic risk assessment. In conclusion, data available to date support the clinical validity of PCa risk-associated SNPs and GRS in risk assessment among men with or without FH. PCa risk-associated SNPs are not intended for diagnostic use; rather, they should be used the same way as FH. Combining GRS and FH can significantly improve the performance of risk assessment. Improved risk assessment may have important clinical utility in targeted PCa testing. However, clinical trials are urgently needed to evaluate this clinical utility as well as the acceptance of GRS by patients and physicians.

A comparison of genetic risk score with family history for estimating prostate cancer risk

Prostate cancer （PCa） testing is recommended by most authoritative groups for high-risk men including those with a family history of the disease. However, family history information is often limited by patient knowledge and clinician intake, and thus, many men are incorrectly assigned to different risk groups. Alternate methods to assess PCa risk are required. In this review, we discuss how genetic variants, referred to as PCa-risk single-nucleotide polymorphisms, can be used to calculate a genetic risk score （GRS）. GRS assigns a relatively unique value to all men based on the number of PCa-risk SNPs that an individual carries. This GRS value can provide a more precise estimate of a man＇s PCa risk. This is particularly relevant in situations when an individual is unaware of his family history. In addition, GRS has utility and can provide a more precise estimate of risk even among men with a positive family history. It can even distinguish risk among relatives with the same degree of family relationships. Taken together, this review serves to provide support for the clinical utility of GRS as an independent test to provide supplemental information to family history. As such, GRS can serve as a platform to help guide-shared decision-making processes regarding the timing and frequency of PCa testing and biopsies.

Race-specific genetic risk score is more accurate than nonrace-specific genetic risk score for predicting prostate cancer and high-grade diseases

Genetic risk score （GRS） based on disease risk-associated single nucleotide polymorphisms （SNPs） is an informative tool that can be used to provide inherited information for specific diseases in addition to family history, However, it is still unknown whether only SNPs that are implicated in a specific racial group should be used when calculating GRSs. The objective of this study is to compare the performance of race-specific GRS and nonrace-specitic GRS for predicting prostate cancer （PCa） among 1338 patients underwent prostate biopsy in Shanghai, China. A race-specific GRS was calculated with seven PCa risk-associated SNPs implicated in East Asians （GRS7）, and a nonrace-specific GRS was calculated based on 76 PCa risk-associated SNPs implicated in at least one racial group （GRS76）. The means of GRS7 and GRS76 were 1.19 and 1.85, respectively, in the study population. Higher GRS7 and GRS76 were independent predictors for PCa and high-grade PCa in univariate and multivariate analyses. GRS7 had a better area under the receiver-operating curve （AUC） than GRS76 for discriminating PCa （0.602 vs 0.573） and high-grade PCa （0.603 vs 0.575） but did not reach statistical significance. GRS7 had a better （up to 13% at different cutoffs） positive predictive value （PPV） than GRS76. In conclusion, a race-specific GRS is more robust and has a better performance when predicting PCa in East Asian men than a GRS calculated using SNPs that are not shown to be associated with East Asians.

Posterior contraction rate of sparse latent feature models with application to proteomics

The Indian buffet process(IBP)and phylogenetic Indian buffet process(pIBP)can be used as prior models to infer latent features in a data set.The theoretical properties of these models are under-explored,however,especially in high dimensional settings.In this paper,we show that under mild sparsity condition,the posterior distribution of the latent feature matrix,generated via IBP or pIBP priors,converges to the true latent feature matrix asymptotically.We derive the posterior convergence rate,referred to as the contraction rate.We show that the convergence results remain valid even when the dimensionality of the latent feature matrix increases with the sample size,therefore making the posterior inference valid in high dimensional settings.We demonstrate the theoretical results using computer simulation,in which the parallel-tempering Markov chain Monte Carlo method is applied to overcome computational hurdles.The practical utility of the derived properties is demonstrated by inferring the latent features in a reverse phase protein arrays(RPPA)dataset under the IBP prior model.

Translation of genomics and epigenomics in prostate cancer： progress and promising directions

During the last several years, exciting discoveries have been madein prostate cancer （PCa） as a result of significant advances in genomic technology and information. For example, using genome-wide association studies, more than 100 inherited genetic variants associated with PCa risk have been identified. Similarly, with the use of next-generation sequencing, various types of recurrent somatic DNA alterations in prostate tumors have been revealed. Some of these discoveries have potential clinical application to supplement existing tools for better decision-making regarding the need for screening, biopsy, and treatment of PCa. However, because of the complexity of these genomic findings and incomplete understanding of the genetics of this multifactorial disease, this potential has not yet been fully realized.