Proteome analysis using machine learning approaches and its applications to diseases.

With the tremendous developments in the fields of biological and medical technologies, huge amounts of data are generated in the form of genomic data, images in medical databases or as data on protein sequences, and so on. Analyzing this data through different tools sheds light on the particulars of the disease and our body's reactions to it, thus, aiding our understanding of the human health. Most useful of these tools is artificial intelligence and deep learning (DL). The artificially created neural networks in DL algorithms help extract viable data from the datasets, and further, to recognize patters in these complex datasets. Therefore, as a part of machine learning, DL helps us face all the various challenges that come forth during protein prediction, protein identification and their quantification. Proteomics is the study of such proteins, their structures, features, properties and so on. As a form of data science, Proteomics has helped us progress excellently in the field of genomics technologies. One of the major techniques used in proteomics studies is mass spectrometry (MS). However, MS is efficient with analysis of large datasets only with the added help of informatics approaches for data analysis and interpretation; these mainly include machine learning and deep learning algorithms. In this chapter, we will discuss in detail the applications of deep learning and various algorithms of machine learning in proteomics.

Type-specific seroprevalence of bluetongue in India during 2018 and 2019.

BACKGROUND AND AIM: Bluetongue (BT) is a major disease of sheep and goats and is endemic to India. It is known to cause significant economic losses to the sheep industry. The current study aimed to determine the type-specific seroprevalence of BT in sheep population of India during 2018-2019. MATERIALS AND METHODS: Blood samples (n=405) were collected from 6 months to 1 year old sheep from six districts (Nalgonda, Karimnagar, Khammam, Mahabubnagar, Warangal, and Ranga Reddy) of Telangana state, India. Group- and type-specific seroprevalence (against BT virus [BTV] serotypes BTV-1, 2, 4, 5, 9, 10, 12, 16, 21, 23, and 24) was studied by competitive enzyme-linked immunosorbent assay and serum neutralization test, respectively. RESULTS: Results showed an overall seroprevalence of 14.81% (n=60) with the highest seroprevalence of 50% in Khammam district. Seroprevalence of BTV-1, 2, 4, 5, 9, 10, 12, 16, 21, 23, and 24 was noted as 16.66%, 11.66%, 31.66%, 11.66%, 05%, 6.66%, 16.66%, 8.33%, 13.33%, 6.66%, and 16.66%, respectively. The majority of the sera neutralized more than 1 serotype, indicating superinfection or circulation of multiple serotypes in the sampled flocks. This mixed seroprevalence was observed in 43.33% of the sera with number of BTV serotype-specific antibodies ranging from two to eight in individual animals. CONCLUSION: Regular monitoring of circulating serotypes, especially in young herds, elucidates pattern of dominating serotypes in a particular area during a season. This knowledge can be applied to design appropriate vaccination strategies by including particular serotypes of virus as part of a multivalent vaccine for a particular period, in a particular area.

Audio-Visual Hallucinations in a Patient Poststem Cell Transplant.

Tramadol is the most common weak opioid used today. It has unique pharmacology and is notorious for numerous side effects as well as drug interactions. Patients undergoing stem cell transplant are susceptible to polypharmacy as a result of the generous use of antibiotics and symptom management drugs. Here, we describe a case where concurrent use of tramadol and fluconazole can cause hallucinations as a result of drug interaction.

Determination of sexual dimorphism in humans by measurements of mandible on digital panoramic radiograph.

BACKGROUND: Identification of sex is the first step in forensic science obtained from skeletal remains. Mandible, being a strong bone that is difficult to damage and disintegrate, is an important tool in sex determination. The present study is aimed to assess, compare, and evaluate the mandibular measurements as seen on digital panoramic radiographs to analyze their use in sexual dimorphism assessment. MATERIALS AND METHODS: This retrospective study was conducted using digital panoramic images of 100 each in both genders. Mandibular measurements were carried out utilizing RadiAnt DICOM Viewer 2.2.9 (32 bit) software (Medixant Company, Poland) and subjected to statistical analysis. RESULTS: Descriptive statistics for all the parameters on the right and left sides of mandible in both males and females were analyzed. Inferential statistics were performed using t-test to compare males and females with different variables. A statistical significance of P < 0.001 has been demonstrated for all the variables (except linear measurement of mandibular foramen). All variables showed increased measurements in males than in females. The accuracy of sex determination in mandibular ramus measurements is 79.5% on right side and 77% on left side, where as, in linear mandibular measurements it is 76% on right side and 79.5% on left side. CONCLUSION: Mandibular measurements on digital radiograph are useful in sex determination, and this study can be compared with other similar studies.

Sexual function in multiple sclerosis and associations with demographic, disease and lifestyle characteristics: an international cross-sectional study.

BACKGROUND: Sexual dysfunction (SD) is very common in people with multiple sclerosis (PwMS) and contributes a significant burden of disease, particularly for young people. SD has direct neurological contributions from depression and fatigue, which occur commonly in PwMS. Modifiable factors may represent potential targets for treatment and prevention of SD. We aimed to assess the prevalence of SD and explore associations between SD and demographic and modifiable risk factors, as well as depression and fatigue in a large cohort of PwMS. METHODS: We analysed self-reported data from a large, international sample of PwMS recruited via Web 2.0 platforms, including demographic, lifestyle and disease characteristics. Specific sexual function questions included 4 items from the sexual function scale and 1 item regarding satisfaction with sexual function, part of the MS Quality of Life-54 instrument. RESULTS: 2062 PwMS from 54 countries completed questions on sexual function. 81.1 % were women, mean age was 45 years, most (62.8 %) reported having relapsing-remitting MS. The majority (54.5 %) reported one or more problems with sexual function and were classified as having SD. Lack of sexual interest (41.8 % of women), and difficulty with erection (40.7 % of men) were most common. The median total sexual function score was 75.0 out of 100, and 43.7 % were satisfied with their sexual function. Regression modeling revealed independent associations between sexual function and satisfaction and a range of demographic factors, including age, as well as depression risk, antidepressant use, and fatigue in PwMS. CONCLUSION: This cross-sectional study shows that SD and lack of satisfaction with sexual function are associated with depression risk and fatigue, as well as modifiable lifestyle factors diet and physical activity (after adjusting for depression and fatigue). Planned longitudinal follow-up of this sample may help clarify these associations and the underlying mechanisms. There is potential to prevent and treat SD in PwMS by addressing depression and fatigue and their determinants. Clinicians and PwMS should be aware of SD and associated factors as part of a comprehensive preventive approach to managing MS.

Traumatic right proximal subclavian artery pseudoaneurysm treated with a hybrid procedure: A case report.

Blunt trauma to the right proximal subclavian artery is uncommon and tends to be associated with pseudoaneurysm formation. We report a patient with right proximal subclavian artery pseudoaneurysm after blunt chest trauma following a motor vehicle accident. The condition was successfully treated with a combined insertion of a covered stent and carotid-carotid bypass as a hybrid procedure. Duplex scans at 6 month and 1 year follow-up documented good stent-graft positioning and no pseudoaneurysm recurrence.

Potential Underprediction of Warfarin Drug Interaction From Conventional Interaction Studies and Risk Mitigation: A Case Study With Epacadostat, an IDO1 Inhibitor.

Drug-drug interaction (DDI) studies involving warfarin are typically conducted with subtherapeutic doses of warfarin to ensure the safety of volunteers. However, this approach may potentially have a systemic bias of underestimating pharmacodynamic (PD) DDI effect on warfarin at therapeutic levels of anticoagulation. We demonstrate here the utility of model-based DDI prediction for a clinically relevant warfarin regimen, using the example of epacadostat (INCB024360), the first-in-class indoleamine 2,3-dioxygenase 1 inhibitor in clinical development as a novel orally active immuno-oncological therapy. Observed data from a dedicated clinical DDI study using subtherapeutic warfarin suggested warfarin pharmacokinetics (PK), but not PD (anticoagulation), was significantly affected by concomitant epacadostat. However, subsequent PK/PD modeling and simulations indicated a clinically important DDI effect on warfarin PD at a higher baseline of the international normalization ratio (INR) and enabled recommendation of warfarin dose adjustment that is dependent on epacadostat dosing regimen and target INR.

Clinically significant fatigue: prevalence and associated factors in an international sample of adults with multiple sclerosis recruited via the internet.

BACKGROUND: Fatigue contributes a significant burden of disease for people with multiple sclerosis (PwMS). Modifiable lifestyle factors have been recognized as having a role in a range of morbidity outcomes in PwMS. There is significant potential to prevent and treat fatigue in PwMS by addressing modifiable risk factors. OBJECTIVES: To explore the associations between clinically significant fatigue and demographic factors, clinical factors (health-related quality of life, disability and relapse rate) and modifiable lifestyle, disease-modifying drugs (DMD) and supplement use in a large international sample of PwMS. METHODS: PwMS were recruited to the study via Web 2.0 platforms and completed a comprehensive survey measuring demographic, lifestyle and clinical characteristics, including health-related quality of life, disability, and relapse rate. RESULTS: Of 2469 participants with confirmed MS, 2138 (86.6%) completed a validated measure of clinically significant fatigue, the Fatigue Severity Scale. Participants were predominantly female from English speaking countries, with relatively high levels of education, and due to recruitment methods may have been highly pro-active about engaging in lifestyle management and self-help. Approximately two thirds of our sample (1402/2138; 65.6% (95% CI 63.7-67.7)) screened positive for clinically significant fatigue. Bivariate associations were present between clinically significant fatigue and several demographic, clinical, lifestyle, and medication variables. After controlling for level of disability and a range of stable socio-demographic variables, we found increased odds of fatigue associated with obesity, DMD use, poor diet, and reduced odds of fatigue with exercise, fish consumption, moderate alcohol use, and supplementation with vitamin D and flaxseed oil. CONCLUSION: This study supports strong and significant associations between clinically significant fatigue and modifiable lifestyle factors. Longitudinal follow-up of this sample may help clarify the contribution of reverse causation to our findings. Further research is required to explore these associations including randomized controlled trials of lifestyle interventions that may alleviate fatigue.

Engagement in a program promoting lifestyle modification is associated with better patient-reported outcomes for people with MS.

There is increasing interest in patient-centered approaches to chronic disease management and prevention. For people with multiple sclerosis (PwMS), patient empowerment plays a role in improving a range of health-related outcomes. This study aimed to compare health-related quality of life (HRQOL), fatigue, and depression risk between people who have and have not attended a week-long physician-led residential educational retreat or accessed other self-help resources (a book and online content) that foster patient empowerment including the adoption of healthy lifestyle behaviors. PwMS were recruited to the study using online platforms and asked to complete a comprehensive online survey. Data from 2,233 respondents were analysed. Bivariate results indicated that PwMS who had attended a retreat (n = 247), read the associated book (n = 1,167) or regularly visited online sites promoting lifestyle modification (n = 795), had better HRQOL and lower rates of depression and fatigue than those who had not. The depression risk among retreat attendees (8.6 %) was around half that of the whole sample. Regression analysis showed that, controlling for age and gender, compared to the highest level of engagement, no engagement with the resources was associated with nearly threefold higher odds of clinically significant fatigue, tenfold higher odds of depression risk, and physical and mental HRQOL scores 19.5 and 15.6 points lower, respectively. These results are congruent with previously reported post-retreat improvements in HRQOL, and strongly support a role for patient engagement in resources promoting lifestyle modification. Physicians should encourage more active involvement of PwMS in their own health care.

The association of diet with quality of life, disability, and relapse rate in an international sample of people with multiple sclerosis.

OBJECTIVES: To explore the association between dietary factors including fat, fruit and vegetable intake, dairy and meat consumption, and health-related quality of life (HRQOL), disability and relapse rate in a large international sample of people with multiple sclerosis (MS). METHODS: Participants with MS were recruited to the study via Web 2.0 platforms and completed a comprehensive survey measuring demographic and clinical characteristics, HRQOL, disability, relapse rate, and the Diet Habits Questionnaire (DHQ). RESULTS: Of 2469 participants with confirmed MS, 2087 (84.5%) provided complete data on their dietary habits (DHQ total score). Multivariate regression models demonstrated that every 10-point increase on the DHQ total score was associated with nearly a six-point and five-point increase in physical and mental HRQOL, respectively, and 30.0% reduced likelihood of a higher level of disability. After controlling for age and gender, and the other dietary covariates, 'healthy' consumption of fruit and vegetables and dietary fat predicted better quality of life and less likelihood of higher disability when compared to respondents with a 'poor' diet. For those with relapsing-remitting MS, the DHQ total significantly predicted a lower relapse rate and reduced odds of increasing disease activity, but the model fit was poor and the predicted change only marginal. DISCUSSION: This study supports significant associations of healthy dietary habits with better physical and mental HRQOL and a lower level of disability. Further research is urgently required to explore these associations including randomized controlled trials of dietary modification for people with MS.

Accuracy of Handheld Continuous - Wave Doppler Ultrasound in the Assessment of Varicose Veins

The incidence of varicose veins and the need for treatment has shown a tremendous increase over the years. Debilitating venous ulcers and dragging edemas of the lower limb with overall improvement in cosmetic results and availability of endovenous procedures has brought many patients forward for treatment. Continuous-wave handheld Doppler usage is limited by its diagnostic capabilities, thus the need to determine its real effectiveness. Benefits of using hand-held dopplers lies in its rapidity in assessment of patients, it's low running cost and short learning curve. This is important as duplex ultrasounds are not readily available in district hospitals. This study aims to determine the clinical effectiveness of hand-held continuous wave dopplers in the local setting especially in primary uncomplicated varicose articles veins. All electively referred patients with primary uncomplicated varicose veins who were referred to the Varicose Vein Clinic were evaluated with continuous-wave handheld Doppler (CWD) and duplex ultrasound (DUS) examination. The study duration was from the 1st of July to 31st of August 2013 (2 months). All patients in the study were independently evaluated with CWD and DUS in the clinic on the same day after adequate rest time. DUS was taken as the gold standard for evaluation of CWD specificity and sensitivity. The Chi-square and T-test was used to test for statistical significance. A total of 41 patients were evaluated in this study. The specificity of CWD when compared to DUS for diagnosing Sapheno-femoral junction (SFJ) was 100% and at the Sapheno-popliteal junction (SPJ) was 87%. Meanwhile sensitivity of CWD for SFJ was 75% and SPJ was 60%. The examination time with CWD was significantly faster than when compared with DUS examination with significant faster tracing times that can be achieved with CWD. CWD also significantly shorter reflux times when compared to DUS. Continuous-wave handheld doppler proves to be an indispensable clinical tool in the evaluation of SFJ and SPJ reflux in varicose veins. CWD assessment in this study was shown to be equal if not better for evaluating reflux when compared to DUS assessment for SFJ reflux. Main advantages for CWD also lie in its low running cost, rapidity in assessment and short learning curve when compared to duplex ultrasound examinations.

Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.

BACKGROUND: Depression is the most common co-morbidity for people with Multiple Sclerosis (MS); irrespective of disease severity, depression has the greatest impact on quality of life. An emerging paradigm in the treatment of depression is lifestyle medicine. There is significant potential to prevent and treat depression through modification of lifestyle risk factors for people with MS. This study sought to understand the association between lifestyle risk factors, medication and depression risk through the analysis of self-reported data from a large international sample of people with MS. METHODS: This cross-sectional analysis recruited a total of 2459 participants via Web 2.0 platforms. Survey data included socio-demographics; a range of lifestyle risk factors; medication; disease variables and depression risk using the Patient Health Questionnaire-2 (PHQ-2). RESULTS: In total approximately one fifth (19.3%) of our sample screened positive for depression (PHQ-2 score ≥3). Several demographic factors were significantly associated with this depression risk in bivariate analysis. Regression analyses showed that poor diet, low levels of exercise, obesity, smoking, marked social isolation and taking interferon were associated with greater depression risk. Participants who supplemented with omega 3s, particularly flaxseed oil, had frequent fish consumption, supplemented with vitamin D, meditated, and had moderate alcohol consumption had significantly reduced depression risk. CONCLUSIONS: This study demonstrates a significant association between modifiable lifestyle factors and depression risk. Planned longitudinal follow up may clarify causality. Clinicians and people with MS should be aware of the wide range of modifiable lifestyle factors that may reduce depression risk as part of a comprehensive secondary and tertiary preventive medical approach to managing MS.

Can meditation influence quality of life, depression, and disease outcome in multiple sclerosis? Findings from a large international web-based study.

OBJECTIVES: To explore the association between meditation and health related quality of life (HRQOL), depression, fatigue, disability level, relapse rates, and disease activity in a large international sample of people with multiple sclerosis (MS). METHODS: Participants were invited to take part in an online survey and answer questions relating to HRQOL, depression, fatigue, disability, relapse rates, and their involvement in meditation practices. RESULTS: Statistically and potentially clinically significant differences between those who meditated once a week or more and participants who never meditated were present for mean mental health composite (MHC) scores, cognitive function scale, and health perception scale. The MHC results remained statistically significant on multivariate regression modelling when covariates were accounted for. Physical health composite (PHC) scores were higher in those that meditated; however, the differences were probably not clinically significant. Among those who meditated, fewer screened positive for depression, but there was no relationship with fatigue or relapse rate. Those with worsened disability levels were more likely to meditate. DISCUSSION: The study reveals a significant association between meditation, lower risk of depression, and improved HRQOL in people with MS.

Locust bean gum in the development of sustained release mucoadhesive macromolecules of aceclofenac.

The study shows the development and optimization of locust bean gum (LBG)-alginate mucoadhesive macromolecules containing aceclofenac through ionotropic-gelation using 3(2) factorial design. The effect of amount of LBG and sodium alginate on drug entrapment efficiency (%DEE), % mucoadhesion at 8h (M8) and % in vitro drug release at 10h (%Q10h) were optimized. The percentage yield, average size and DEE of macromolecules were found within the range of 93.19 to 96.65%, 1.328 ± 0.11 to 1.428 ± 0.13 µm, and 56.37 to 68.54%, respectively. The macromolecules were also characterized by SEM, FTIR and DSC. The in vitro drug release from these macromolecules (84.95 ± 2.02 to 95.33 ± 1.56% at 10h) exhibited sustained release (first-order) pattern with super case-II transport mechanism. The swelling and mucoadhesivity of these macromolecules were affected by pH of the medium. The design established the role of derived polynomial equations and plots in predicting the values of dependent variables for the preparation and optimization.

Potential probiotic Escherichia coli 16 harboring the Vitreoscilla hemoglobin gene improves gastrointestinal tract colonization and ameliorates carbon tetrachloride induced hepatotoxicity in rats.

The present study describes the beneficial effects of potential probiotic E. coli 16 (pUC8:16gfp) expressing Vitreoscilla hemoglobin (vgb) gene, associated with bacterial respiration under microaerobic condition, on gastrointestinal (GI) colonization and its antioxidant activity on carbon tetrachloride (CCl4) induced toxicity in Charles Foster rats. In vitro, catalase activity in E. coli 16 (pUC8:16gfp) was 1.8 times higher compared to E. coli 16 (pUC-gfp) control. In vivo, E. coli 16 (pUC8:16gfp) not only was recovered in the fecal matter after 70 days of oral administration but also retained antibacterial activities, whereas E. coli 16 (pUC-gfp) was not detected. Oral administration of 200 and 500 µL/kg body weight of CCl4 to rats at weekly interval resulted in elevated serum glutamyl pyruvate transaminase (SGPT) and serum glutamyl oxalacetate transaminase (SGOT) levels compared to controls. Rats prefed with E. coli 16 (pUC8:16gfp) demonstrated near to normal levels for SGPT and SGOT, whereas the liver homogenate catalase activity was significantly increased compared to CCl4 treated rats. Thus, pUC8:16gfp plasmid encoding vgb improved the growth and GI tract colonization of E. coli 16. In addition, it also enhanced catalase activity in rats harboring E. coli 16 (pUC8:16gfp), thereby preventing the absorption of CCl4 to GI tract.

Probing transverse coherence of x-ray beam with 2-D phase grating interferometer.

Transverse coherence of the x-ray beam from a bending magnet source was studied along multiple directions using a 2-D π/2 phase grating by measuring interferogram visibilities at different distances behind the grating. These measurements suggest that the preferred measuring orientation of a 2-D checkerboard grating is along the diagonal directions of the square blocks, where the interferograms have higher visibility and are not sensitive to the deviation of the duty cycle of the grating period. These observations are verified by thorough wavefront propagation simulations. The accuracy of the measured coherence values was also validated by the simulation and analytical results obtained from the source parameters. In addition, capability of the technique in probing spatially resolved local transverse coherence is demonstrated.

Physical activity and associated levels of disability and quality of life in people with multiple sclerosis: a large international survey.

BACKGROUND: Multiple Sclerosis (MS) is a common neurodegenerative disease, which often has a devastating effect on physical and emotional wellbeing of people with MS (PwMS). Several studies have shown positive effects of physical activity (PA) on disability, health related quality of life (HRQOL), and other outcomes. However, many studies include only people with mild disability making it difficult to generalize findings to those with moderate or severe disability. This study investigated the associations between PA and HRQOL, relapse rate (RR), disability, and demographic variables in PwMS with varying disability. METHODS: Through online platforms this large international survey recruited 2232 participants with MS who completed items regarding PA, MS and other health characteristics. RESULTS: PwMS who were younger (p < .001), male (p = 0.006), and with lower body mass index (BMI) (p < .001) undertook more PA, which was associated with decreased disability (p < 0.001) and increased HRQOL measures (all p < 0.001). For the subsample of people with relapsing-remitting MS, PA was associated with a decreased RR (p = 0.009). Regression analyses showed that increased PA predicted clinically significant improvements in HRQOL while controlling for level of disability, age and gender. More specifically, increasing from low to moderate and to high PA increased estimated mean physical health composite from 47.7 to 56.0 to 59.9 respectively (25.6% change), mental health composite from 60.6 to 67.0 to 68.8 (13.5% change), energy subscale from 35.9 to 44.5 to 49.8 (38.7% change), social function subscale from 57.8 to 66.1 to 68.4 (18.3% change), and overall QOL subscale from 58.5 to 64.5 to 67.7 (15.7% change). CONCLUSIONS: For PwMS, regardless of disability level, increased PA is related to better HRQOL in terms of energy, social functioning, mental and physical health. These are important findings that should be taken into consideration by clinicians treating PwMS.

The association of alcohol consumption and smoking with quality of life, disability and disease activity in an international sample of people with multiple sclerosis.

BACKGROUND: Modifiable lifestyle factors represent important targets for preventive intervention in multiple sclerosis (MS). We aimed to explore the association of cigarette smoking and alcohol consumption with major MS morbidity outcomes. METHODS: We surveyed a large, international sample of people with MS recruited via Web 2.0 platforms about type of MS, relapse rates, disability, disease activity, health-related quality of life (HRQOL), alcohol use and smoking. RESULTS: Of 2469 respondents with confirmed MS, 11.7% were current and 40.3% former smokers. Most (61.5%) consumed less than 15 g alcohol weekly; few (0.8%) drank large amounts. Moderate alcohol consumption was associated with increased HRQOL; and after controlling for age and gender, was associated with lower odds of significant disability (41% decrease). After controlling for age, gender and alcohol use, smokers had an increased likelihood of major mobility requirements by 90% compared to never smokers. There was no association between alcohol or smoking and relapse rate or disease activity after controlling for age and gender, however among former smokers, a longer duration of smoking cessation was associated with reduced disease activity. Smokers had significantly lower HRQOL than never smokers and former smokers; heavier smoking was associated with greater decreases in HRQOL. CONCLUSION: This cross-sectional study supports previous research showing a link between morbidity indicators in MS and alcohol use and smoking. While people with MS should be advised of the potential risks of smoking, any risks and benefits of alcohol consumption require validation using a prospective cohort of people with MS.

Pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in renal and hepatic impairment patients.

Hepatic and renal impairment studies were conducted with ruxolitinib, a JAK1&2 inhibitor that is cleared predominantly by metabolism. Both studies were open label, single-dose studies. Ruxolitinib area under the curve (AUC) was increased by 87%, 28%, and 65%, respectively, in subjects with mild, moderate, and severe hepatic impairment compared to healthy subjects with no correlation between exposure of ruxolitinib and the degree of hepatic impairment. The pharmacodynamics (PD) data were consistent with ruxolitinib pharmacokinetics (PK). The renal impairment study showed a surprising finding. While there was no change in ruxolitinib PK with varying degrees of renal impairment, the PD showed increasing pharmacological activity with increased severity of renal impairment. Analysis of the metabolite exposures revealed that active metabolites contributed to the observed incremental increase in PD activity. The recovery of ruxolitinib in dialysate was negligible. The starting dose of ruxolitinib in subjects with any hepatic impairment or moderate or severe renal impairment should be decreased to 10 mg twice daily (BID) if their platelet counts are between 100 × 10(9) /L and 150 × 10(9) /L. Subjects on dialysis should initiate dosing with a single dose of 15 or 20 mg, based on platelet counts, with dosing only on the days of dialysis.