Whole Exome Sequencing Reveals Novel Variants in Unexplained Erythrocytosis.

Erythrocytosis is characterized by an increase in red cells in peripheral blood. Polycythemia vera, the commonest primary erythrocytosis, results from pathogenic variants in JAK2 in ∼98% of cases. Although some variants have been reported in JAK2-negative polycythemia, the causal genetic variants remain unidentified in ∼80% of cases. To discover genetic variants in unexplained erythrocytosis, we performed whole exome sequencing in 27 patients with JAK2-negative polycythemia after excluding the presence of any mutations in genes previously associated with erythrocytosis (EPOR, VHL, PHD2, EPAS1, HBA, and HBB). We found that the majority of patients (25/27) had variants in genes involved in epigenetic processes, including TET2 and ASXL1 or in genes related to hematopoietic signaling such as MPL and GFIB. Based on computational analysis, we believe that variants identified in 11 patients in this study could be pathogenic although functional studies will be required for confirmation. To our knowledge, this is the largest study reporting novel variants in individuals with unexplained erythrocytosis. Our results suggest that genes involved in epigenetic processes and hematopoietic signaling pathways are likely associated with unexplained erythrocytosis in individuals lacking JAK2 mutations. With very few previous studies targeting JAK2-negative polycythemia patients to identify underlying variants, this study opens a new avenue in evaluating and managing JAK2-negative polycythemia.

Comprehension of Prescriptions and Errors in Taking Prescribed Medicines by Veterans - Polypharmacy a Problem Underrated.

BACKGROUND: Polypharmacy is a significant problem in the elderly. The veteran population is unique in terms of better access to health-care services and higher educational qualifications. However, the studies to assess the burden and effects of polypharmacy in this cohort are rare. Hence, the research was done to find the prevalence of polypharmacy in the veteran population. METHODS: In this cross-sectional observational study, we included veterans with more than 35 years visiting the medical outpatient department. All participants were interviewed about polypharmacy after taking informed consent. RESULTS: Out of 394 patients included in the study, 110 were prescribed five or more medicines for their illnesses (27.91%: 95% confidence interval [CI] 21.1%-30%). More than 95% (377/394) of the study participants were unaware of the concept of polypharmacy. There was high compliance to treatment in veterans (97.46%, 95% CI 95.1%-98.6%). CONCLUSION: This study shows that the prevalence of polypharmacy is significant in veterans, including patients in their fourth and fifth decades of life, despite fewer morbidities.

Chemotherapy-Associated Pulmonary Toxicity-Case Series from a Single Center.

Background Pulmonary toxicity due to chemotherapeutic agents can occur with many established and new drugs. Strong clinical suspicion is important as the clinical presentation is usually with nonspecific symptoms like cough, dyspnea, fever, and pulmonary infiltrates. Timely discontinuation of the offending agent alone can improve the condition. Methods A prospective observational study on patients receiving chemotherapy at an 800-bedded tertiary care hospital was performed from 2014 to 2016. Consecutive patients on chemotherapy, presenting with nonresolving respiratory symptoms were evaluated with contrast-enhanced computerized tomography of chest, diffusion lung capacity for carbon monoxide (DLCO), fiberoptic bronchoscopy with lavage, and biopsy, after excluding all causes for pulmonary infections. Descriptive data has been depicted. Results A total of 18 patients were evaluated for persistent symptoms of dry cough, dyspnea, and fever among 624 who received chemotherapy during the study period. Ground-glass opacities on high-resolution CT was the most common imaging finding, others being patchy subpleural consolidation and pleural effusion. Lymphocyte-predominant bronchoalveolar lavage was detected in nine. Eight of the 15 patients who underwent DLCO, had abnormal results. Seven had significant histopathological findings on bronchoscopic lung biopsy, which revealed organizing pneumonia as the most common pattern. Paclitaxel, fluorouracil, gemcitabine, and tyrosine kinase inhibitors were the common culprit drugs. Discontinuation alone of the culprit drug was effective in 15 and 3 needed oral corticosteroids for relief of symptoms. None of the patients died due to the toxicity. Conclusion An incidence of 2.8% for chemotherapy-induced lung injury was seen in our observational study of 3 years, with parenchymal, interstitial, and pleural involvement due to various chemotherapeutic agents. Oral steroids maybe required in a subset of patients not responding to discontinuation of the culprit agent.

ClassyFire: automated chemical classification with a comprehensive, computable taxonomy.

BACKGROUND: Scientists have long been driven by the desire to describe, organize, classify, and compare objects using taxonomies and/or ontologies. In contrast to biology, geology, and many other scientific disciplines, the world of chemistry still lacks a standardized chemical ontology or taxonomy. Several attempts at chemical classification have been made; but they have mostly been limited to either manual, or semi-automated proof-of-principle applications. This is regrettable as comprehensive chemical classification and description tools could not only improve our understanding of chemistry but also improve the linkage between chemistry and many other fields. For instance, the chemical classification of a compound could help predict its metabolic fate in humans, its druggability or potential hazards associated with it, among others. However, the sheer number (tens of millions of compounds) and complexity of chemical structures is such that any manual classification effort would prove to be near impossible. RESULTS: We have developed a comprehensive, flexible, and computable, purely structure-based chemical taxonomy (ChemOnt), along with a computer program (ClassyFire) that uses only chemical structures and structural features to automatically assign all known chemical compounds to a taxonomy consisting of >4800 different categories. This new chemical taxonomy consists of up to 11 different levels (Kingdom, SuperClass, Class, SubClass, etc.) with each of the categories defined by unambiguous, computable structural rules. Furthermore each category is named using a consensus-based nomenclature and described (in English) based on the characteristic common structural properties of the compounds it contains. The ClassyFire webserver is freely accessible at http://classyfire.wishartlab.com/. Moreover, a Ruby API version is available at https://bitbucket.org/wishartlab/classyfire_api, which provides programmatic access to the ClassyFire server and database. ClassyFire has been used to annotate over 77 million compounds and has already been integrated into other software packages to automatically generate textual descriptions for, and/or infer biological properties of over 100,000 compounds. Additional examples and applications are provided in this paper. CONCLUSION: ClassyFire, in combination with ChemOnt (ClassyFire's comprehensive chemical taxonomy), now allows chemists and cheminformaticians to perform large-scale, rapid and automated chemical classification. Moreover, a freely accessible API allows easy access to more than 77 million "ClassyFire" classified compounds. The results can be used to help annotate well studied, as well as lesser-known compounds. In addition, these chemical classifications can be used as input for data integration, and many other cheminformatics-related tasks.

HIV drug-resistance early-warning indicators and quality care in India: preliminary findings from a pilot study in Pune city

Background: India has rapidly scaled up its programme for antiretroviral therapy(ART). There is high potential for the emergence of HIV drug resistance (HIVDR),with an increasing number of patients on ART. It is not feasible to perform testingfor HIVDR using laboratory genotyping, owing to economic constraints. This studypiloted World Health Organization (WHO) early-warning indicators (EWIs) forHIVDR, and quality-of-care indicators (QCIs), in four ART clinics in Pune city.Methods: A retrospective study was conducted in 2015, among four ART clinicsin Pune city, India. The data on four standardized EWIs (EWI 1: On-time pill pickup, EWI 2: Retention of patients in ART care at 12 months after initiation, EWI 3:Pharmacy stock-out, EWI 4: Pharmacy dispensing practices) and three QCIs(QCI 1: Regularity in CD4 testing in patients taking ART, QCI 2: Percentage ofpatients initiating ART within 30 days of medical eligibility, QCI 3: Percentage ofpatients initiating ART within 30 days of initiation of anti-tuberculosis therapy) wereabstracted into WHO Excel HIV data abstractor tools, from the patient recordsfrom April 2013 to March 2014.Results: All four ART clinics met the EWI 4 target (100%) for ART dispensingpractices. The target for EWIs on-time pill-pick (EWI 1 >90%) and pharmacy stockouts (EWI 3: no stock-outs, 100%) were achieved in one clinic. None of the clinicsmet the EWI 2 target for retention in care at 12 months (>90%) and the overallretention was 76% (95% confidence interval: 73% to 79%). The targets for QCI 1and QCI 2 (>90% each) were achieved in one and two clinics respectively. Noneof the clinics achieved the target for QCI 3 (>90%).Conclusion: ART dispensing practices (EWI 4) were excellent in all clinics. Effortsare required to strengthen retention in care and timely pill pick-up and ensurecontinuity of clinic-level drug supply among the programme clinics in Pune city.The clinics should focus on regularity in testing CD4 count and timely initiation ofART

Shrinking lung syndrome in systemic lupus erythematosus-scleroderma overlap.

Shrinking lung syndrome (SLS) is a infrequently reported manifestation of systemic lupus erythematosus (SLE). Reported prevalence of SLS is about 0.5% in SLE patients. Pathogenesis is not fully understood and different therapeutic modalities have been employed with variable results, as only 77 cases of SLS have been documented in literature. SLS in SLE-Scleroderma overlap has not been reported yet. We report a patient of SLE - scleroderma overlap presenting with dyspnea, intermittent orthopnea and pleuritic chest pain. Evaluation revealed elevated hemidiaphragms and severe restrictive defect. She was eventually diagnosed as a case of SLS. This case report is a reminder to the medical fraternity that SLS although a rare complication must be thought of in the special subset of patients of SLE having respiratory symptoms.

Identification and functional characterization of tRNA-derived RNA fragments (tRFs) in respiratory syncytial virus infection.

The discovery of small noncoding RNAs (sncRNAs) with regulatory functions is a recent breakthrough in biology. Among sncRNAs, microRNA (miRNA), derived from host or virus, has emerged as elements with high importance in control of viral replication and host responses. However, the expression pattern and functional aspects of other types of sncRNAs, following viral infection, are unexplored. In order to define expression patterns of sncRNAs, as well as to discover novel regulatory sncRNAs in response to viral infection, we applied deep sequencing to cells infected with human respiratory syncytial virus (RSV), the most common cause of bronchiolitis and pneumonia in babies. RSV infection leads to abundant production of transfer RNA (tRNA)-derived RNA Fragments (tRFs) that are ~30 nucleotides (nts) long and correspond to the 5'-half of mature tRNAs. At least one tRF, which is derived from tRNA-Glu-CTC, represses target mRNA in the cytoplasm and promotes RSV replication. This demonstrates that this tRF is not a random by-product of tRNA degradation but a functional molecule. The biogenesis of this tRF is also specific, as it is mediated by the endonuclease angiogenin (ANG), not by other nucleases. In summary, our study presents novel information on the induction of a functional tRF by viral infection.

Penicilliosis presenting as fungating skin lesion.

A 35-year-old HIV seropositive male patient presented with fever, weight loss, papules, nodules and fungating masses all over the body. Histopathological and mycological study of the skin biopsy tissue confirmed the diagnosis of penicilliosis. Although penicilliosis is restricted to Southeast Asia, more cases are being recognized in nonendemic countries.