Safety and efficacy of transitioning from selexipag to oral treprostinil in pulmonary arterial hypertension: Findings from the ADAPT registry.

PURPOSE: Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or tolerability issues while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil. METHODS: ADAPT was a prospective, real-world, multicenter, United States-based registry of patients with PAH newly started on oral treprostinil, with a cohort of patients (n = 10) transitioning from selexipag to oral treprostinil. PAH variables of interest were collected from standard-of-care clinic visits. Clinical improvement was defined by modified REPLACE criterion, and risk was assessed by REVEAL Lite 2 from baseline to last follow-up. Real world transition strategies were recorded. Healthcare utilization or worsening PAH was evaluated within 30 days of transitions. RESULTS: Seven patients transitioned due to worsening PAH or lack of efficacy on selexipag, and three patients transitioned due to tolerability issues. Based on the modified REPLACE criterion, five patients demonstrated clinical improvement after transition from selexipag to oral treprostinil. Using REVEAL Lite 2 to assess risk, three patients improved and five patients maintained risk category from baseline to last follow-up. All transitions occurred in an outpatient setting either as abrupt stop/start or cross-titration, without parenteral treprostinil bridging. CONCLUSION: Transition from selexipag to oral treprostinil was safe, performed without parenteral prostacyclin bridging, and resulted in clinical and categorical risk improvements in some patients.

Development and validation of prognostic scoring system for COVID-19 severity in South India.

BACKGROUND: Development of a prediction model using baseline characteristics of COVID-19 patients at the time of diagnosis will aid us in early identification of the high-risk groups and devise pertinent strategies accordingly. Hence, we did this study to develop a prognostic-scoring system for predicting the COVID-19 severity in South India. METHODS: We undertook this retrospective cohort study among COVID-19 patients reporting to Hindu Mission Hospital, India. Multivariable logistic regression using the LASSO procedure was used to select variables for the model building, and the nomogram scoring system was developed with the final selected model. Model discrimination, calibration, and decision curve analysis (DCA) was performed. RESULTS: In total, 35.1% of the patients in the training set developed severe COVID-19 during their follow-up period. In the basic model, nine variables (age group, sex, education, chronic kidney disease, tobacco, cough, dyspnea, olfactory-gustatory dysfunction [OGD], and gastrointestinal symptoms) were selected and a nomogram was built using these variables. In the advanced model, in addition to these variables (except OGD), C-reactive protein, lactate dehydrogenase, ferritin, D-dimer, and CT severity score were selected. The discriminatory power (c-index) for basic model was 0.78 (95%CI: 0.74-0.82) and advanced model was 0.83 (95%CI: 0.79-0.87). DCA showed that both the models are beneficial at a threshold probability around 10-95% than treat-none or treat-all strategies. CONCLUSION: The present study has developed two separate prognostic-scoring systems to predict the COVID-19 severity. This scoring system could help the clinicians and policymakers to devise targeted interventions and in turn reduce the COVID-19 mortality in India.

Perceptions and preparedness of veterinarians to combat brucellosis through Brucellosis Control Programme in India.

BACKGROUND AND AIM: Brucellosis caused by bacteria belongs to the genus Brucella is an important zoonosis and constitutes a serious public health hazard worldwide including India. The present study aimed to estimate the knowledge of veterinarians on brucellosis, its public health threat, diagnosis, and vaccination. MATERIALS AND METHODS: This cross-sectional study was conducted during 2013-2015 and 453 veterinarians representing 11 states/Union Territories (UT) of India (Assam, Tripura, Meghalaya, Goa, Karnataka, Madhya Pradesh, Uttar Pradesh, Delhi, Jammu and Kashmir, Tamil Nadu, and Punjab) were interviewed using self-administered questionnaire. RESULTS: Out of 453 veterinarians, 71.74% stated handling of the animals on day-to-day basis and 28.25% were engaged in administration activities. The veterinarians ranked foot-and-mouth disease and brucellosis at the first and fourth ranks among the list of ten economic impacted diseases in the country. A significant association was observed between laboratory confirmation with those who handled brucellosis-suspected cases (p=0.000). Similarly, significant association was noted for the availability of vials/slides (p=0.114), vacutainers (p=0.008), icebox (p=0.103), and refrigerator (p=0.106) for those who preferred laboratory diagnosis. Only 20% of the veterinarians recommended vaccination against bovine brucellosis, and 17% obtained laboratory confirmation for the brucellosis-suspected cases. CONCLUSION: The study highlighted the need for awareness programs, laboratory facilities, veterinary doctors, and protective measures for the veterinarians for combating brucellosis through the control program in the country.

Impact of GSTM1, GSTT1 and GSTP1 gene polymorphism and risk of ARV-associated hepatotoxicity in HIV-infected individuals and its modulation.

Glutathione S-transferase (GST) family is involved in a two-stage detoxification process of a wide range of environmental toxins, carcinogen and antiretroviral (ARV) therapy (ART) drugs. The aim of this study is to describe the impact of genetic polymorphisms of GSTM1, GSTT1 and GSTP1-313A/G in the risk of ARV-associated hepatotoxicity in HIV-infected individuals and its modulation in hepatotoxic patients. We enrolled a total of 34 patients with hepatotoxicity, 131 HIV-infected individuals without hepatotoxicity under non-nucleoside reverse transcriptase inhibitor containing ART and 153 unrelated healthy individuals. With a case-control design, polymorphisms of GSTM1, GSTT1 and GSTP1-313A/G gene were genotyped by PCR and restriction enzyme-length polymorphism. Genotypes of GSTT1 null were significantly higher in HIV-infected individuals as compared with healthy controls (P=0.01, odds ratio (OR)=1.54). HIV-infected individuals with GSTM1-null genotype showed higher risk (P=0.09, OR=1.37) for hepatotoxicity, but risk was not significant. On evaluating gene-gene interaction models, GSTM1 null and GSTT1 null showed significant association with the risk of hepatotoxicity in HIV-infected individuals (P=0.004, OR=2.67) owing to synergistic effect of these genes. Individuals with GSTT1-null and GSTM1-null genotypes showed higher risk of hepatotoxicity with advanced stage of (CD4<200) of HIV infection (P=0.18, OR=1.39; P=0.63, OR=1.13). In case-only analysis, GSTT1-null genotype among alcohol users showed elevated risk of hepatotoxicity in HIV-infected individuals (P=0.12, OR=1.36, 95% confidence interval (CI): 0.94-1.97) as compared with GSTT1 genotypes. The carriers GSTM1-null+GSTT1-null genotype among nevirapine user showed prominent risk of hepatotoxicity in HIV-infected individuals (P=0.12, OR=4.21, 95% CI: 0.60-29.54). Hence, we can conclude that GSTT1-null and GSTM1-null genotypes alone and in combination may predict the acquisition of hepatotoxicity.

MELD exceptions for portopulmonary hypertension: current policy and future implementation.

Since 2006, waitlist candidates with portopulmonary hypertension (POPH) have been eligible for standardized Model for End-Stage Liver Disease (MELD) exception points. However, there are no data evaluating the current POPH exception policy and its implementation. We used Organ Procurement and Transplantation Network (OPTN) data to compare outcomes of patients with approved POPH MELD exceptions from 2006 to 2012 to all nonexception waitlist candidates during this period. Since 2006, 155 waitlist candidates had approved POPH MELD exceptions, with only 73 (47.1%) meeting the formal OPTN exception criteria. Furthermore, over one-third of those with approved POPH exceptions either did not fulfill hemodynamic criteria consistent with POPH or had missing data, with 80% of such patients receiving a transplant based on receiving exception points. In multivariable multistate survival models, waitlist candidates with POPH MELD exceptions had an increased risk of death compared to nonexception waitlist candidates, regardless of whether they did (hazard ratio [HR]: 2.46, 95% confidence interval [CI]: 1.73-3.52; n = 100) or did not (HR: 1.60, 95% CI: 1.04-2.47; n = 55) have hemodynamic criteria consistent with POPH. These data highlight the need for OPTN/UNOS to reconsider not only the policy for POPH MELD exceptions, but also the process by which such points are awarded.

Loss of the xeroderma pigmentosum group B protein binding site impairs p210 BCR/ABL1 leukemogenic activity.

Previous studies have demonstrated that p210 BCR/ABL1 interacts directly with the xeroderma pigmentosum group B (XPB) protein, and that XPB is phosphorylated on tyrosine in cells that express p210 BCR/ABL1. In the current study, we have constructed a p210 BCR/ABL1 mutant that can no longer bind to XPB. The mutant has normal kinase activity and interacts with GRB2, but can no longer phosphorylate XPB. Loss of XPB binding is associated with reduced expression of c-MYC and reduced transforming potential in ex-vivo clonogenicity assays, but does not affect nucleotide excision repair in lymphoid or myeloid cells. When examined in a bone marrow transplantation (BMT) model for chronic myelogenous leukemia, mice that express the mutant exhibit attenuated myeloproliferation and lymphoproliferation when compared with mice that express unmodified p210 BCR/ABL1. Thus, the mutant-transplanted mice show predominantly neutrophilic expansion and altered progenitor expansion, and have significantly extended lifespans. This was confirmed in a BMT model for B-cell acute lymphoblastic leukemia, wherein the majority of the mutant-transplanted mice remain disease free. These results suggest that the interaction between p210 BCR/ABL1 and XPB can contribute to disease progression by influencing the lineage commitment of lymphoid and myeloid progenitors.

Evaluation of pectinolytic activities for oenological uses from psychrotrophic yeasts.

UNLABELLED: Of the twenty-three morphotypes of yeasts isolated from soil capable of utilizing pectin as sole carbon source at 6°C, two yeast isolates, one psychrotolerant (PT1) and one psychrophilic (SPY11), were selected according to their ability to secrete pectinolytic enzymes under some oenological conditions (temperature 6 and 12°C and pH 3.5) and ability or inability to grow above 20°C, respectively. As compared to their optimal activity, the three pectinolytic enzymes viz., pectin methyl esterase (PME), endopolygalacturonase (endo-PG) and exopolygalacturonase (exo-PG) isolated and assayed at pH 3.5 from PT1 were found to retain 39, 60 and 60% activity at 12°C and 40, 79 and 74% activity at 28°C, respectively. Likewise, the enzymes PME and endo-PG at pH 3.5 from SPY11 displayed 46 and 86% activity at 12°C and 50 and 60% activity at 28°C, respectively. All these enzymes showed 20-90% of residual activity at pH 3.5 and 6°C. The yeast isolates PT1 and SPY11 were identified as Rhodotorula mucilaginosa and Cystofilobasidium capitatum, respectively, on the basis of morphological, physiological and molecular characteristics. This study presents the first report on pectinolytic activities under major oenological conditions from psychrotolerant isolate R. mucilaginosa PT1 and psychrophilic isolate C. capitatum SPY11. SIGNIFICANCE AND IMPACT OF THE STUDY: The cold-active pectinolytic enzymes (PME, endo-PG and exo-PG) from the newly isolated and identified psychrophilic yeast Cystofilobasidium capitatum SPY11 and psychrotolerant yeast Rhodotorula mucilaginosa PT1that exhibited 50-80% of their optimum activity under some major oenological conditions pH (3.5) and temperatures (6 and 12°C) could be applied to wine production and juice clarification at low temperature. The psychrotrophic yeasts themselves could be applied to cold process for the production of enzymes thus saving cost of energy and protecting process from contamination.

Systematic review and meta-analysis of intraoperative versus preoperative endoscopic sphincterotomy in patients with gallbladder and suspected common bile duct stones.

BACKGROUND: Most patients with gallbladder and common bile duct stones are treated by preoperative endoscopic sphincterotomy (POES) followed by laparoscopic cholecystectomy. Recently, intraoperative endoscopic sphincterotomy (IOES) during laparoscopic cholecystectomy has been suggested as an alternative treatment. METHODS: Data from randomized clinical trials related to safety and effectiveness of IOES versus POES were extracted by two independent reviewers. Risk ratios (RRs) or mean differences were calculated with 95 per cent confidence intervals based on intention-to-treat analysis whenever possible. RESULTS: Four trials with 532 patients comparing IOES with POES were included. There were no deaths. There was no significant difference in rates of ampullary cannulation (RR 1·01, 0·97 to 1·04; P = 0·70) or stone clearance by ES (RR 0·99, 0·96 to 1·02; P = 0·58) between the groups. The proportion of patients with at least one post-ES complication, including pancreatitis, bleeding, perforation, cholangitis, cholecystitis or gastric ulcer, was significantly lower in the IOES group (RR 0·37, 0·18 to 0·78; P = 0·009). There was no significant difference in morbidity after laparoscopic cholecystectomy or requirement for open operation between the groups. Mean hospital stay was 3 days shorter in the IOES group: mean difference - 2·83 (-3·66 to - 2·00) days (P < 0·001). CONCLUSION: In patients with gallbladder and common bile duct stones, IOES is as effective and safe as POES and results in a significantly shorter hospital stay.

Barriers to ART adherence & follow ups among patients attending ART centres in Maharashtra, India.

BACKGROUND & OBJECTIVES: Adherence to ART is a patient specific issue influenced by a variety of situations that a patient may encounter, especially in resource-limited settings. A study was conducted to understand factors and influencers of adherence to ART and their follow ups among patients attending ART centres in Maharashtra, India. METHODS: Between January and March 2009, barriers to ART adherence among 32 patients at three selected ART centres functioning under national ART roll-out programme in Maharashtra, India, were studied using qualitative methods. Consenting patients were interviewed to assess barriers to ART adherence. Constant comparison method was used to identify grounded codes. RESULTS: Patients reported multiple barriers to ART adherence and follow up as (i) Financial barriers where the contributing factors were unemployment, economic dependency, and debt, (ii) social norm of attending family rituals, and fulfilling social obligations emerged as socio-cultural barriers, (iii) patients' belief, attitude and behaviour towards medication and self-perceived stigma were the reasons for sub-optimal adherence, and (iv) long waiting period, doctor-patient relationship and less time devoted in counselling at the center contributed to missed visits. INTERPRETATION & CONCLUSIONS: Mainstreaming ART can facilitate access and address 'missed doses' due to travel and migration. A 'morning' and 'evening' ART centre/s hours may reduce work absenteeism and help in time management. Proactive 'adherence probing' and probing on internalized stigma might optimize adherence. Adherence probing to prevent transitioning to suboptimal adherence among patients stable on ART is recommended.

The RhoGEF domain of p210 Bcr-Abl activates RhoA and is required for transformation.

The BCR-ABL oncogene encodes an in-frame fusion protein containing N-terminal sequences derived from Bcr and C-terminal sequences derived from Abl. Bcr contains a centrally located Rho-specific guanine nucleotide exchange factor (RhoGEF) domain that is retained within p210 Bcr-Abl. Although this domain is subject to autoinhibition in the context of Bcr, here we show that it is constitutively activated in p210 Bcr-Abl. p210 Bcr-Abl can stimulate RhoA activation independently of its tyrosine kinase activity, and mutations within the RhoGEF domain that are predicted to eliminate RhoGEF activity inhibit RhoA activation. The RhoGEF mutant of p210 Bcr-Abl does not affect the tyrosine kinase activity of the molecule, nor the ability of p210 Bcr-Abl to interact with XPB through the RhoGEF domain. Despite retaining normal levels of tyrosine kinase activity, the RhoGEF mutant of p210 Bcr-Abl is impaired in transforming activity as measured by anchorage-independent growth. However, the mutant is still able to confer the phenotype of growth factor independence in myeloid cells, suggesting that some, but not all parameters of p210 Bcr-Abl transformation, are dependent upon a catalytically active RhoGEF domain. Collectively, these observations identify a gain-of-function activity attributable to the RhoGEF domain of p210 Bcr-Abl that is required to support the transformed phenotype.

Community perspectives on care options for HIV prevention trial participants.

There is on-going global debate and policy-setting concerning researchers' obligations to meet the health needs of people participating in HIV prevention trials in resource-poor settings. The perspectives of local community stakeholders on this issue are poorly understood as most of what is presented on behalf of communities where research takes place is anecdotal commentary. Using qualitative methods (130 in-depth interviews and 20 focus groups) we assessed perceived fairness of different strategies to meet the health needs of women who become HIV-infected during a hypothetical vaginal microbicide trial. Respondents included HIV prevention research participants, community stakeholders and health-care service providers in ten sites in seven countries (South Africa, Malawi, Tanzania, Zimbabwe, Zambia, India, US). Many respondents perceived referrals to be a potentially fair way to address care and treatment needs but concerns were also voiced about the adequacy of local health-care options and the ability of trial participants to access options. Most respondents viewed the provision of antiretroviral treatment by researchers to HIV-infected trial participants as unfair if treatment was not sustained beyond the end of the trial. The results underscore the importance of effectively linking trial participants to sustainable, community-based treatment and care.

Low HIV-1 incidence among married serodiscordant couples in Pune, India.

Unlike commercial sex workers and patients attending sexually transmitted infection (STI) clinics, married couples are not typically targeted for HIV risk reduction programs in India. Thus, married partners of HIV-infected persons are at particularly high risk for HIV infection. Between September 2002 and November 2004, 457 HIV-1 sero-discordant, married couples were enrolled in a one-year prospective study of HIV transmission in Pune, India. The HIV incidence among uninfected partners was 1.22 per 100 person-years (95% CI 0.45-2.66), which is much lower than what has been previously reported among discordant couples in Africa. This may be due to higher rates of condom use, lower rates of STIs and higher CD4 T lymphocyte counts, among the Indian HIV sero-discordant couples.

High-risk behaviour in young men attending sexually transmitted disease clinics in Pune, India.

The present study reports sexual risk factors associated with HIV infection among men attending two sexually transmitted disease (STD) clinics in Pune, India and compares these behaviours between young and older men. Between April 1998 and May 2000, 1872 STD patients were screened for HIV infection. Data on demographics, medical history and sexual behaviour were collected at baseline. The overall HIV prevalence was 22.2%. HIV risk was associated with being divorced or widowed, less educated, living away from the family, having multiple sexual partners and initiation of sex at an early age. The risk behaviours in younger men were different to older men. Younger men were more likely to report early age of initiation of sex, having friends, acquaintances or commercial sex workers as their regular partners, having premarital sex and bisexual orientation. Young men were more educated and reported condom use more frequently compared with the older men. Similar high HIV prevalence among younger and older men highlights the need for focused targeted interventions aimed at adolescents and young men and also appropriate interventions for older men to reduce the risk of HIV and STD acquisition.

Sexual victimization and clinical challenges in women receiving hospital treatment for depression.

The study examined the prevalence of sexual victimization among 60 female inpatients and outpatients with depression. Sixty-five percent of the sample reported previous sexual violation in either childhood or adolescence/adulthood. Of these, 52% indicated that they had been victimized both in childhood and adolescence/adulthood. Based on the history of sexual victimization, participants were allocated to one of three groups. Body satisfaction, global self-esteem, and internality were progressively lower from Group 1 (no history), to Group 2 (childhood or adolescent/adult victimization), to Group 3 (both childhood and adolescent/adult victimization). Body satisfaction was further shown to be independently affected by sexual violation.

Phenylalanine transport in Aspergillus nidulans: demonstration of role of phenylalanine binding proteins.

Crude shock proteins extracted by two stage osmotic shock were further purified by affinity chromatography to obtain ligand (phenylalanine) specific binding protein (phebip) a component of phenylalanine (phe) transport system from wild type and a phe transport mutant fpaD11 of Aspergillus nidulans. A new eluent 0.1 M Tris-HCl containing 1.5 N NaCl and 0.5 N Na2CO3, pH 8 was used during the investigation. The elution profile of mutant phebip exhibited one simple and two compound peaks instead of three simple ones as exhibited by the wild type phebip. SDS-PAGE profile of mutant phebip showed faster electrophoretic mobility than that of wild type one. It is therefore evident that the mutant phebip has reduced molecular mass (M(r)) due to deletion of a segment that somehow has bearing on the binding capacity of the active site of phebip. The resultant erosion in the binding capacity of the mutant phebip is in turn responsible for its incapability to stimulate transport of ligand across the plasma membrane.

Skin-color preferences and body satisfaction among South Asian-Canadian and European-Canadian female university students.

Skin-color preferences and body satisfaction among 100 South Asian-Canadian and 100 European-Canadian female university students were examined. South Asian-Canadian females were found to desire lighter skin than they possessed and had lower body satisfaction compared with European-Canadian females. Among South Asian-Canadians, the desire to be lighter skinned was greater the more participants differed from the cultural White ideal. Light- and medium-skinned South Asian-Canadians had the highest and lowest levels of body satisfaction, respectively.

Coronary angioplasty in high risk patients: comparison of elective intraaortic balloon pump and percutaneous cardiopulmonary bypass support--a randomized study.

Forty patients undergoing percutaneous transluminal coronary angioplasty (PTCA) with severely impaired left ventricular ejection fraction (LVEF) < 30% were randomized between prophylactic intraaortic balloon pump (IABP) support (N = 20) and percutaneous cardiopulmonary bypass (PCPB) support (N = 20). The indications for both groups were left ventricular (LV) dysfunction and a large area of myocardium (> 50%) being perfused by the target vessel. The IABP and PCPB supported groups were comparable in LVEF (20% +/- 6.4% vs 22.8% +/- 8.1%), mean pulmonary artery pressure (46.5 +/- 10.5 mmHg vs 42.6 +/- 12.6 mmHg), average number of vessels dilated (1.4 vs 1.3), mean inflation time (2.8 +/- 0.3 min vs 3.1 +/- 0.5 min), and hospital stay after PTCA (5.6 +/- 1.2 days vs 5.2 +/- 1.4 days). The primary success rate (95% vs 95%) and hospital mortality (5% vs 5%) were also similar in the two groups. Two patients required surgical exploration of the femoral artery and eight patients required blood transfusion in the PCPB group. IABP patients had no vascular complications and did not require blood transfusion. High risk PTCA is equally effective whether using prophylactic IABP or PCPB support. PCPB support, however, has a higher rate of vascular complications and need for blood transfusions. IABP has the additional advantage of ease of insertion and the support can be used for a longer period after PTCA, if required.