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Pontocerebellar hypoplasia (PCH) type 12 is a rare, perinatal lethal neurodegenerative genetic disorder caused by biallelic mutations in the COASY gene. Herein, we describe the clinical and neuroradiological profile of nine affected fetuses/neonates from five families identified with a common COASY: c.1486-3C>G biallelic variant. Four of the five families were identified after data reanalysis of unresolved, severe PCH like phenotype and the fifth family through collaboration. The common antenatal phenotype was cerebellar hypoplasia. Microcephaly, arthrogryposis, and intrauterine growth restriction were the shared postnatal findings. The neurological manifestations included seizures, poor sucking, and spasticity. Novel findings of corpus callosum agenesis, simplified gyral pattern, normal sized pons, optic neuropathy, and a small thorax are reported in this series. The allele frequency of the COASY: c.1486-3C>G variant was 0.62% in the available Asian Indian database. We describe this as a possible common Indian origin variant. To the best of our knowledge, this is the largest PCH12 series reported., (© 2022 Wiley Periodicals LLC.)

A vast amount of real-world data, such as pathology reports and clinical notes, are captured as unstructured text in electronic health records (EHRs). However, this information is both difficult and costly to extract through human abstraction, especially when scaling to large datasets is needed. Fortunately, Natural Language Processing (NLP) and Machine Learning (ML) techniques provide promising solutions for a variety of information extraction tasks such as identifying a group of patients who have a specific diagnosis, share common characteristics, or show progression of a disease. However, using these ML-extracted data for research still introduces unique challenges in assessing validity and generalizability to different cohorts of interest. In order to enable effective and accurate use of ML-extracted real-world data (RWD) to support research and real-world evidence generation, we propose a research-centric evaluation framework for model developers, ML-extracted data users and other RWD stakeholders. This framework covers the fundamentals of evaluating RWD produced using ML methods to maximize the use of EHR data for research purposes.

Introduction: Younger age at diagnosis is a risk factor for poor health-related quality of life (HRQOL) in long-term breast cancer survivors. However, few studies have specifically addressed HRQOL in young adults with breast cancer (i.e., diagnosed prior to age 40), nor have early changes in HRQOL been fully characterized., Methods: Eligible female patients with breast cancer were identified through our local cancer center. To establish HRQOL, patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) around diagnosis and 12 months later. Sociodemographic factors, genetic susceptibility to cancer, tumor- and treatment-related factors, and comorbidities (e.g., depression/anxiety) were abstracted from medical records and the local oncology registry. Mixed-effects models were used to identify changes in FACT-B scores during the first year of treatment and to determine whether any demographic/treatment-related factors modulated changes in scores., Results: Health-related quality of life in young patients with breast cancer was within normal limits at baseline, with a FACT-B overall well-being score of 108.5 (95% confidence limits [CI] = 103.7, 113.3). Participants reported slight improvements over a 12-month period: FACT-B overall well-being scores increased 6.6 points (95% CI = 2.1, 11.1, p < 0.01), functional well-being improved 3.0 points (95% CI = 2.0, 4.1, p < 0.01), emotional well-being improved 1.9 points (95% CI = 0.9, 2.8, p < 0.01), and physical well-being improved 1.5 points (95% CI = 0.2, 2.8, p = 0.03), on average. Participants with anxiety/depression at baseline reported greater improvements in FACT-B overall well-being (change: 12.9, 95% CI = 6.4, 9.5) and functional well-being (change: 5.2, 95% CI = 3.5, 6.9) than participants who did not have anxiety/depression at baseline (change in FACT-B overall well-being: 4.9, 95% CI = 0.2, 9.7; change in functional well-being: 2.3, 95% CI = 1.1, 3.4). Marital status, reconstructive surgery, and baseline clinical staging were also significantly associated with changes in aspects of HRQOL, although their impact on change was relatively minimal., Conclusion: Young women with breast cancer do not report HRQOL concerns during the first year of treatment. Improvements in HRQOL during the first year of treatment may be attributable to a sense of relief that the cancer is being treated, which, in the short run, may outweigh the negative late effects of treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Al-Kaylani, Loeffler, Mott, Curry, Phadke and van der Plas.)

Purpose: Anemia is common in adolescent girls. Apprehension while drawing blood to estimate hemoglobin concentration is a barrier for confirming anemia. ToucHb, a noninvasive instrument that estimates the hemoglobin by taking an image of the exposed conjunctiva, was used during eye screening to help diagnose and treat anemia., Methods: ToucHb was used during secondary school eye screening and during house-to-house eye screening to estimate the hemoglobin concentration in the body. Each of the girls was distributed a packet of 60 tablets of ferrous and folate and a tablet of albendazole. They were followed up after 3 months., Results: Exactly 1511 municipal school girls aged 10-19 years (mean 12.9; standard deviation [SD] 1.64) were examined. Of them, 949 (62.8%) had hemoglobin of ≤9 mg%. Among those girls with hemoglobin ≤9 mg%, the mean (SD) during the initial and follow-up examinations was 6.1 (1.4) and 9.6 (1.03), respectively, by paired t-test (P < 0.001). Another 588 girls (average age 14.4 years, SD 1.2) had their eyes examined and hemoglobin estimated during a house-to-house eye screening. Of them, 116 (19.7%) had hemoglobin level of ≤9 mg%. Their pre-Hb was 7.9 (SD 1.05) on average and after 3 months, it was 9.6 (SD 1.02). Among those girls with hemoglobin ≤9 mg%, the mean (SD) during the initial and follow-up examinations was 6.2 (1.4) and 7.9 (1.1), respectively, by paired t-test (P < 0.001)., Conclusion: ToucHb was useful to diagnose anemia while doing eye screening and to ensure its treatment. Anemia diagnosis and management would enhance the health of adolescent girls., Competing Interests: None

Small molecule kinase inhibitors have shown immense clinical utility for diverse indications. While >60 kinase inhibitors have been approved (and many more in clinical trials), it remains unclear whether the clinical efficacy of a kinase inhibitor is solely dependent on enzymatic inhibition, or whether non-catalytic functions play a role in the efficacy of some kinase inhibitors. Here, we designed and synthesized a series of pyrazolopyrimidine kinase inhibitors that modulate the global kinase conformation of c-Src kinase. Expanding upon our findings from the pyrazolopyrimidine inhibitor series, we designed, synthesized, and evaluated three pair of conformation-selective kinase inhibitors, each with a unique hinge-binding scaffold. We profiled each pair of kinase inhibitors across 468 kinases and identified 38 kinases that could be studied using these pair of conformation-selective inhibitors. We also explore the binding of conformation-selective kinase inhibitors to mutant kinases of EGFR, FLT3, and KIT. Together, these studies yield important insight into the design of conformation-tunable kinase inhibitors and provide a toolset of compounds to study the role of protein conformation on kinase signaling.

We developed a computer-assisted platform using laser scanning confocal microscopy to 3D reconstruct in real-time interactions between metastatic breast cancer cells and human umbilical vein endothelial cells (HUVECs). We demonstrate that MB-231 cancer cells migrate toward HUVEC networks, facilitated by filopodia, migrate along the network surfaces, penetrate into and migrate within the HUVEC networks, exit and continue migrating along network surfaces. The system is highly amenable to 3D reconstruction and computational analyses, and assessments of the effects of potential anti-metastasis monoclonal antibodies and other drugs. We demonstrate that an anti-RHAMM antibody blocks filopodium formation and all of the behaviors that we found take place between MB-231 cells and HUVEC networks.

Scaffold hopping is a common strategy for generating kinase inhibitors that bind to the DFG-out inactive conformation. Small structural differences in inhibitor scaffolds can have significant effects on potency and selectivity across the kinome, however, these effects are often not studied in detail. Herein, we outline a design strategy to generate an array of DFG-out conformation inhibitors with three different hinge-binders and two DFG-pocket groups. We studied inhibitor selectivity across a large segment of the kinome and elucidated binding preferences that can be used in scaffold hopping campaigns. Using these analyses, we identified two selective inhibitors that display low nanomolar potency against Axl or wild-type and clinically relevant mutants of Abl., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Profilins (PFNs) are key regulatory proteins for the actin polymerization in cells and are encoded in mouse and humans by four Pfn genes. PFNs are involved in cell mobility, cell growth, neurogenesis, and metastasis of tumor cells. The testes-specific PFN3 is localized in the acroplaxome-manchette complex of developing spermatozoa. We demonstrate that PFN3 further localizes in the Golgi complex and proacrosomal vesicles during spermiogenesis, suggesting a role in vesicle transport for acrosome formation. Using CRISPR/Cas9 genome editing, we generated mice deficient for Pfn3 . Pfn3 -/- males are subfertile, displaying a type II globozoospermia. We revealed that Pfn3 -/- sperm display abnormal manchette development leading to an amorphous sperm head shape. Additionally, Pfn3 -/- sperm showed reduced sperm motility resulting from flagellum deformities. We show that acrosome biogenesis is impaired starting from the Golgi phase, and mature sperm seems to suffer from a cytoplasm removal defect. An RNA-seq analysis revealed an upregulation of Trim27 and downregulation of Atg2a . As a consequence, mTOR was activated and AMPK was suppressed, resulting in the inhibition of autophagy. This dysregulation of AMPK/mTOR affected the autophagic flux, which is hallmarked by LC3B accumulation and increased SQSTM1 protein levels. Autophagy is involved in proacrosomal vesicle fusion and transport to form the acrosome. We conclude that this disruption leads to the observed malformation of the acrosome. TRIM27 is associated with PFN3 as determined by co-immunoprecipitation from testis extracts. Further, actin-related protein ARPM1 was absent in the nuclear fraction of Pfn3 -/- testes and sperm. This suggests that lack of PFN3 leads to destabilization of the PFN3-ARPM1 complex, resulting in the degradation of ARPM1. Interestingly, in the Pfn3 -/- testes, we detected increased protein levels of essential actin regulatory proteins, cofilin-1 (CFL1), cofilin-2 (CFL2), and actin depolymerizing factor (ADF). Taken together, our results reveal the importance for PFN3 in male fertility and implicate this protein as a candidate for male factor infertility in humans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Umer, Arévalo, Phadke, Lohanadan, Kirfel, Sons, Sofia, Witke and Schorle.)

Acute cholecystitis is a common cause of right upper quadrant pain in patients presenting to the emergency department. Ultrasound, computed tomography, HIDA scans, and magnetic resonance imaging are increasingly utilized to evaluate suspected cases. The prognosis of acute cholecystitis is usually excellent with timely diagnosis and management. However, complications associated with cholecystitis pose a considerable challenge to the clinician and radiologist. Complications of acute cholecystitis may result from secondary bacterial infection or mural ischemia secondary to increased intramural pressure. The recognized subtypes of complicated cholecystitis are hemorrhagic, gangrenous, and emphysematous cholecystitis, as well as gallbladder perforation. Acute acalculous cholecystitis is a form of cholecystitis that occurs as a complication of severe illness in the absence of gallstones or without gallstone-related inflammation. Complicated cholecystitis may cause significant morbidity and mortality, and early diagnosis and recognition play a pivotal role in the management and early surgical planning. As appropriate utilization of imaging resources plays an essential role in diagnosis and management, the emergency radiologist should be aware of the spectrum of complications related to cholecystitis and the characteristic imaging features. This article aims to offer a comprehensive contemporary review of clinical and cross-sectional imaging findings of complications associated with cholecystitis. In conclusion, cross-sectional imaging is pivotal in identifying the complications related to cholecystitis. Preoperative detection of this complicated cholecystitis can help the care providers and operating surgeon to be prepared for a potentially more complicated procedure and course of recovery., (© 2021. American Society of Emergency Radiology.)

Allosteric inhibitors of Abl kinase are being explored in the clinic, often in combination with ATP-site inhibitors of Abl kinase. However, there are conflicting data on whether both ATP-competitive inhibitors and myristoyl-site allosteric inhibitors can simultaneously bind Abl kinase. Here, we determine whether there is synergy or antagonism between ATP-competitive inhibitors and allosteric inhibitors of Abl. We observe that clinical ATP-competitive inhibitors are not synergistic with allosteric ABL inhibitors, however, conformation-selective ATP-site inhibitors that modulate the global conformation of Abl can afford synergy. We demonstrate that kinase conformation is the key driver to simultaneously bind two compounds to Abl kinase. Finally, we explore the interaction of allosteric and conformation selective ATP-competitive inhibitors in a series of biochemical and cellular assays., (© 2021 Wiley-VCH GmbH.)

Objective: We aimed to determine the ocular manifestation and refractive error prevalences among people living with HIV (PLHIV) in Pune, India., Methods: This cross-sectional study included HIV-infected adults attending a National AIDS Research Institute clinic. Ophthalmologic examination included visual acuity estimation, refraction, orthoptic evaluation, slit lamp and fundus examination, and photography., Results: In total, 441 HIV-infected individuals were enrolled. The participants' median age was 44 (interquartile range 38-49) years and 227 (51.5%) were men. Refractive errors occurred in 132 (29.9%) individuals. Ocular manifestations were present in 93 (21.1%) participants and the most frequent was cataract in 59 (13.4%) participants. Multivariate logistic regression analysis showed that participants who were illiterate (adjusted odds ratio [AOR] 2.80, 95% confidence interval [CI] 1.47-5.33) and those aged greater than 40 years (AOR 5.59, 95% CI 2.69-11.61) were more likely to have ocular manifestations. The odds of having ocular manifestations were greater in participants with treatment substitution or changes (AOR 2.11, 95% CI 1.16-3.82)., Conclusions: Cataract and refractive errors were prevalent among PLHIV. PLHIV should be encouraged to have regular ophthalmic checkups. Individuals with lower education levels and older age should be counseled regarding eye care and timely reporting of ocular symptoms.

Background: Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation. Objective: To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India. Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed. Results: Data on 107 patients with SAID were collated-of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 ( DADA2) (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 ( NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG 2 -associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness. Conclusions: This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Suri, Rawat, Jindal, Vignesh, Gupta, Pilania, Joshi, Arora, Kumrah, Anjani, Aggarwal, Phadke, Aboobacker, George, Edison, Desai, Taur, Gowri, Pandrowala, Bhattad, Kanakia, Gottorno, Ceccherini, Almeida de Jesus, Goldbach-Mansky, Hershfield and Singh.)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating disease characterized by severe and disabling fatigue that fails to improve with rest; it is commonly accompanied by multifocal pain, as well as sleep disruption, and cognitive dysfunction. Even mild exertion can exacerbate symptoms. The prevalence of ME/CFS in the U.S. is estimated to be 0.5-1.5 % and is higher among females. Viral infection is an established trigger for the onset of ME/CFS symptoms, raising the possibility of an increase in ME/CFS prevalence resulting from the ongoing COVID-19 pandemic. Current treatments are largely palliative and limited to alleviating symptoms and addressing the psychological sequelae associated with long-term disability. While ME/CFS is characterized by broad heterogeneity, common features include immune dysregulation and mitochondrial dysfunction. However, the underlying mechanistic basis of the disease remains poorly understood. Herein, we review the current understanding, diagnosis and treatment of ME/CFS and summarize past clinical studies aimed at identifying effective therapies. We describe the current status of mechanistic studies, including the identification of multiple targets for potential pharmacological intervention, and ongoing efforts towards the discovery of new medicines for ME/CFS treatment., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Psychiatry and Endocrinology share a deep rooted, multifaceted bidirectional relationship. Both have seen a surge in cases due to change in lifestyle. Time has come where these two rapidly growing fields interact and exchange knowledge leading to emergence of Psychocrinology. This communication describes the rationale behind using the term psychocrinology, and provides an overview of it's vast spectrum.

Fabry disease (FD) is a treatable X linked lysosomal storage disorder with a wide phenotypic spectrum. There is a scarcity of published data on the burden of FD in India. This study evaluates the clinical and molecular spectrum of Indian patients with FD. In this multicentric study involving 10 tertiary referral centers in India, we analyzed the clinical course and genotype of 54 patients from 37 families. Family screening identified 19 new patients (35%) from 12 index cases. Then, 33 GLA gene variants were identified in 49/54 (90.7%) which included 11 novel and 22 known pathogenic variants. Of the 54 patients in our cohort, 40 patients had "classical" and 10 patients had a "nonclassical" presentation. The symptoms and signs included kidney dysfunction in 38/54 (70.3%), neuropathic pain in 34/54 (62.9%), left ventricular hypertrophy in 22/49 (44.8%) and stroke in 5/54 (9.2%). Female heterozygotes were 10/54 (18.5%) of whom 2 were index cases. There was a significant delay in reaching the diagnosis of 11.7 years. Enzyme replacement therapy was initiated in 28/54 (51.8%) patients with significant improvement of neuropathic pain and gastrointestinal symptoms. This study highlights the clinical presentation and mutational spectrum of FD in India and suggests that family screening and screening of high-risk groups (hypertrophic cardiomyopathy, idiopathic chronic renal failure and cryptogenic stroke) could be the most cost-effective strategies for early identification of FD., Competing Interests: S. N. is an advisory member of INCAP. S. N. has received travel grants for INCAP advisory board meetings. S. N. has no conflict of interest related to this manuscript. D. Y. does not have any conflict of interest for the study/paper. A. B. does not have any conflict of interest for the study/paper. H. A. has no conflicts of interest related to this manuscript. R. D. P. access to ERT is provided under the Indian Charitable Access Program (INCAP) of Sanofi Genzyme for patients of authors R. D. P. The association is purely academic, and no financial compensation is provided. The author is also committee members of the INCAP /CAP, Takeda programme. The author declares no other conflicts of interest. N. G. has no conflicts of interest related to this manuscript. M. K. does not have any conflict of interest for the study/paper. P. R. has no competing interests or conflict of interest to declare with reference to the paper on FD submitted to JIMD Reports M. B. is an honorary member of Indian Medical Advisory Board, Sanofi‐Genzyme, India. M. B. has no conflict of interest related to this manuscript. S. P. does not have any conflict of interest, except that her patients had received and have been receiving ERT for FD under India Charitable Access Program of Sanofi‐Genzyme and Shire Charitable Access Program. R. R. D. does not have any conflict of interest for the study/paper. S. J. is an advisory member of INCAP. S. J. has no conflict of interest related to this manuscript. S. D. is a member of the Indian Medical Advisory Board Member (IMAB) and has no conflict of interest with regard to this manuscript. P. S. does not have any conflict of interest for the study/paper. K. M. does not have any conflict of interest for the study/paper. S. B. M. does not have any conflict of interest for the study/paper. R. M. is the Medical director and employee at Sanofi Genzyme India. I. C. V. does not have any conflict of interest for the study/paper. A. D. is a nonpaid member of the Scientific Advisory Committee of Sanofi Genzyme. A. D. has no conflict of interest related to this manuscript. U. R. is an International advisory member of INCAP and Medical Expert Committee member for Takeda's Compassionate Access Programme (CAP). U. R. has received travel grants for INCAP advisory board meetings. U. R. has no conflict of interest related to this manuscript., (© 2020 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Breast cancer (BC) patients undergoing surveillance often fear recurrence. Given that routine imaging is not recommended, recognizing metastatic disease early requires a knowledge of recurrence patterns. The aim of this study was to analyze the most common presentations of metastatic disease., Patients and Methods: A retrospective review was conducted of patients who were initially diagnosed with early-stage BC and who later developed metastatic disease. Data collected included method of metastatic disease diagnosis, types of symptoms at diagnosis, and survival. Chi-square tests as well as logistic and Cox regression models were used., Results: Metastatic diagnoses were made from reported symptoms in 77.6% of patients, clinical examination in 3.2%, and 7.8% incidentally on imaging. Among those with symptoms, musculoskeletal pain was the most common (33.7%) and was more frequently noted at scheduled (48.9%) compared to acute-care visits (26.0%, P < .01). Receptor status was associated with nervous system symptoms at metastasis (P = .01), with higher odds of nervous system symptoms in triple-negative (odds ratio = 3.02) compared to estrogen receptor/progesterone receptor-positive, HER2 - cases. On multivariable analysis, initial stage (P = .03), receptor status (P < .01), age (P < .01), and time to recurrence (P < .01) were significantly associated with 10-year survival after diagnosis of metastasis, whereas the presence of symptoms was not (P = .27). Providers of BC patients undergoing surveillance should modify their threshold of suspicion for recurrence depending on the characteristics of the initial diagnosis and the symptoms subsequently reported., Conclusion: In this retrospective study, patients who presented with symptoms did not have shorter survival compared to those who were diagnosed in other ways., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Childhood blindness and visual impairment accounts for enormous burden of blindness. This study aimed to analyze the causes of severe visual impairment and blindness in students attending schools for the blind and to identify those whose vision could be improved by optical aids. On dispensing such aids, the study also aimed to analyze the improvement in their vision function., Methods: This was a prospective interventional study of 428 certified students from four special schools for blind. All the students underwent a comprehensive ophthalmic examination by a team of four ophthalmologists and four optometrists. The World Health Organization-Prevention of Blindness forms were used to record history and examination details. Spectacles and low-vision aids (LVAs) were dispensed to those whose vision could be improved. The main outcome measure was L V Prasad- Functional Vision Questionnaire (LVP-VFQ), which was used to compare the vision function before and 6 months after the intervention., Results: Two hundred and thirteen (49.5%) students were girls. The causes of blindness in 370 children (<18 years) with vision <6/60 were whole globe involvement in 117 (31.6%) students (this included anophthalmos 47 [12.7%], microphthalmos 61 [16.4%], both 9 [2.4%]), nystagmus 29 (7.8%), optic atrophy 22 (5.9%), retinal causes 42 (11.3%), cataract 18 (4.9%), phthisis bulbi 24 (6.4%), corneal scarring in 40 (10.8%), and retinopathy of prematurity in 4 (1.1%). Fifty-four (12.6%) students were given spectacles and 41 (9.57%) LVA. There was a statistically significant difference in all questions ( P < 0.01) of LVP-VFQ for the students dispensed with optical aids 6 months after the intervention. Twenty-four students had their vision improved to 6/60 or better, whereas 26 could now identify letters and print., Conclusion: A significant proportion of students in schools for the blind can be helped to improving vision function using optical aids. Students in schools for the blind, nay all visually impaired individuals, need periodic ocular examination and ophthalmic care., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Middle East African Journal of Ophthalmology.)

Recent pandemic caused by COVID-19 has motivated lockdown in several countries for long duration and will have a long lasting impact on the social life and economics world wide. India is no exception although showing relatively delayed increase in number of cases. Multilayered diagnostics for mass scaled screening is inevitable during and especially after the peak is passed and life is moving towards normalcy. First level of screening currently used in India is mainly based on temperature and has possibility of false positives and false negative (fever as a symptom has not yet been developed although infected). We propose here another augmentation or an intermediate level of screening, depending on the usage, based on assessing olfactory functions. It is established with multiple publications reporting degrading (hyposmia) or loss of sense (anosmia) of smell for infected patients. This paper presents a recently developed technology and device that uses olfactory sense detection using a novel device that is capable of generating precise level of smell digitally, and repeatedly in contactless manner. The device is designed to work with a mobile app that can trigger selected smell or combinations and further can be programmed to give standard or customised smell tests. Estimated capital and running cost are low since one (out of 25) canister filled with of 0.1 ml volume of essential smell oil can serve hundreds of tests. The prototype is tested to work for a desired smell generation and is available for further tweaking for rapid screening of subjects as per the requirements., (© Indian National Academy of Engineering 2020.)

Microbial fuel cells (MFCs) have long held the promise of being a cost-effective technology for the energy-neutral treatment of wastewater. However, successful pilot-scale demonstrations for this technology are still limited to very few. Here, we present a large-scale MFC system, composed of 12 MFCs with a total volume of 110 L, successfully treating swine wastewater at a small educational farm. The system was operated for over 200 days in continuous mode with hydraulic residence time of 4 hr. Very stable electrochemical and waste treatment performance was observed with up to 65% of chemical oxygen demand (COD) removed and a maximum treatment rate of 5.0 kg COD/m 3 .day. Robust microbial enrichment was performed and adapted to metabolize and transform a diversity of compounds present. The Net Energy Recovery (NER = 0.11 kWhr/kg COD) is not only competitive with conventional cogeneration processes, but is in fact sufficient to sustain the operational energy requirements of the system. PRACTITIONER POINTS: This study demonstrates the design and operation of a large-scale microbial fuel cells (MFC) system for continuous treatment of swine wastewater. The system achieved a high chemical oxygen demand removal rate within a short hydraulic residence time. This study moves one-step closer to applying MFC technology for real wastewater treatment., (© 2019 Water Environment Federation.)

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.

Aim: Simplex lattice design was applied to predict extent of drug release from extended release diclofenac sodium tablets. Methods: The effects of composition on dissolution rate were evaluated by varying the levels of hydroxypropyl methylcellulose, dicalcium phosphate and cornstarch via three component design. Results: The rate of drug release was primarily dictated by the proportion of hydroxypropyl methylcellulose and was also affected by the proportion of dicalcium phosphate and the method of processing (direct compression/wet granulation). Polynomial equations constructed for directly compressed and wet-granulated formulations could successfully predict the extent of drug release at an arbitrary time point of 3 h. Conclusion: Simplex lattice design is a viable tool to predict the drug release patterns of extended release formulations.

Careful handling of the nanomaterials (NMs) in research labs is crucial to ensure a safe working environment. As the largest university in Ireland, University College Dublin (UCD) has invested significant resources to update researchers working with NMs. Due to sizes often <100 nm, the NMs including nanoparticles, harbor unprecedented materialistic properties, for example, enhanced reactivity, conductivity, fluorescence, etc. which albeit conferring the NMs an edge over bulk materials regarding the applied aspects; depending on the dose, also render them to be toxic. Thus, a set of regulatory guidelines have emerged regarding safe handling of the NMs within occupational set-ups. Unfortunately, the current regulations based on the toxic chemicals and carcinogens are often confusing, lack clarity, and difficult to apply for the NMs. As a research-intensive university, a diverse range of research activities occur within the UCD labs, and it is difficult, at times impossible, for the UCD Safety, Insurance, Operational Risk & Compliance (SIRC) office to develop a set of common guidelines and cater throughout all its labs conducting research with the NMs. Hence, a necessity for dialog and exchange of ideas was felt across the UCD which encouraged the researchers including early stage researchers (e.g. PhDs, Postdocs) from multiple schools to participate in a workshop held on the 03 December 2018. The workshop tried to follow a pragmatic approach, where apart from discussing both the in vitro and in vivo scenarios, practical cases simulating situations faced frequently in the labs were discussed. This report summarizes the findings made during the workshop by this emerging critical mass in UCD.

Protein kinase pathways are traditionally mapped by monitoring downstream phosphorylation. Meanwhile, the noncatalytic functions of protein kinases remain under-appreciated as critical components of kinase signaling. c-Src is a protein kinase known to have noncatalytic signaling function important in healthy and disease cell signaling. Large conformational changes in the regulatory domains regulate c-Src's noncatalytic functions. Herein, we demonstrate that changes in the global conformation of c-Src can be monitored using a selective proteolysis methodology. Further, we use this methodology to investigate changes in the global conformation of several clinical and nonclinical mutations of c-Src. Significantly, we identify a novel activating mutation observed clinically, W121R, that can escape down-regulation mechanisms. Our methodology can be expanded to monitor the global conformation of other tyrosine kinases, including c-Abl, and represents an important tool toward the elucidation of the noncatalytic functions of protein kinases.

Pre-clinical data has shown that beta adrenergic stimulation can affect the development and progression of many types of cancer. The use of beta blockers as an anti-neoplastic therapy has been studied in retrospective trials and observational trials, but no definitive conclusions about efficacy have been made. Within the realm of breast cancer, significant advances in therapy have led to improved survival outcomes, yet there is room for improvement. Beta adrenergic blockade may prove an effective adjunct to standard breast cancer therapy, with little associated toxicity. This article provides a review of the published literature on beta blockade as an adjunctive cancer therapy, with a focus on breast cancer., (Published by Elsevier B.V.)

Background: Gaucher disease is a rare pan-ethnic, lysosomal storage disorder resulting due to beta-Glucosidase (GBA1) gene defect. This leads to the glucocerebrosidase enzyme deficiency and an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. To date, nearly 460 mutations have been described in the GBA1 gene. With the aim to determine mutations spectrum and molecular pathology of Gaucher disease in India, the present study investigated one hundred unrelated patients (age range: 1 day to 31 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality in some of the patients., Methods: The biochemical investigation for the plasma chitotriosidase enzyme activity and β-Glucosidase enzyme activity confirmed the Gaucher disease. The mutations were identified by screening the patients' whole GBA gene coding region using bidirectional Sanger sequencing., Results: The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all patients. Sanger sequencing established 71 patients with homozygous mutation and 22 patients with compound heterozygous mutation in GBA1 gene. Lack of identification of mutations in three patients suggests the possibility of either large deletion/duplication or deep intronic variations in the GBA1 gene. In four cases, where the proband died due to confirmed Gaucher disease, the parents were found to be a carrier. Overall, the study identified 33 mutations in 100 patients that also covers four missense mutations (p.Ser136Leu, p.Leu279Val, p.Gly383Asp, p.Gly399Arg) not previously reported in Gaucher disease patients. The mutation p.Leu483Pro was identified as the most commonly occurring Gaucher disease mutation in the study (62% patients). The second common mutations identified were p.Arg535Cys (7% patients) and RecNcil (7% patients). Another complex mutation Complex C was identified in a compound heterozygous status (3% patients). The homology modeling of the novel mutations suggested the destabilization of the GBA protein structure due to conformational changes., Conclusions: The study reports four novel and 29 known mutations identified in the GBA1 gene in one-hundred Gaucher patients. The given study establishes p.Leu483Pro as the most prevalent mutation in the Indian patients with type 1 Gaucher disease that provide new insight into the molecular basis of Gaucher Disease in India.

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide., (© 2019 Wiley Periodicals, Inc.)

We report an unusual 3-substituted pyridine polyketide, onydecalin A (1), which was obtained along with 2 as a major constituent from the fungus Aioliomyces pyridodomos (order: Onygenales) following a two-month fermentation. Feeding studies demonstrated that the pyridine subunit originates via an unprecedented biosynthetic process in comparison to other polyketide-linked pyridines or derivatives such as pyridones. The slow growth of the fungus led us to perform a one-year fermentation, leading to production of compounds 2-4 as the major constituents. These compounds showed modest but selective inhibition against a variety of transient receptor potential channels, as well as against the human pathogenic fungus Histoplasma capsulatum.

Background: Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. A beta-Glucosidase (GBA) gene defect results in glucocerebrosidase enzyme deficiency. Though the disease is mainly diagnosed in childhood, the adult manifestation is often missed or identified late due to the failure to recognize the heterogeneous clinical presentation. The present study includes seven unrelated Indian adult patients (age range: 20-40 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality., Methods: The biochemical investigation implicated measuring plasma chitotriosidase enzyme activity followed by confirmatory test of β-Glucosidase enzyme activity from the leukocytes. The molecular characterization involved patients' initial screening for the common Gaucher mutation (Leu444Pro). Later, all patients were subjected to whole GBA gene coding region study using bidirectional Sanger sequencing. The population screening for common Gaucher disease mutation (Leu444Pro) was executed in 1200 unrelated and healthy Indian subjects by Restriction Fragment Length Polymorphism-Polymerase Chain Reaction technique. The allele frequency was calculated using Hardy-Weinberg formula., Results: The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all the patients. Also, an elevated level of plasma Chitotriosidase activity in five patients supported their diagnosis of Gaucher disease. Sanger sequencing established four patients with homozygous variation and three patients with compound heterozygous variation in GBA gene. This study uncovers two missense variants (Ala448Thr and Val17Gly) not previously reported in Gaucher disease patients. Also the known mutations like Leu444Pro, Arg329Cys, Asp315Asn, Ser125Arg, and Arg395Cys were identified in these patients. The homology modeling suggested the destabilization of the protein structure due to novel variants. The Leu444Pro mutation screening in the Indian population spotted two people as a carrier. This emerged the carrier frequency of 1:600 along with wild-type allele frequency 0.97113 and mutant allele frequency 0.02887., Conclusions: The study reports novel and known variants identified in the GBA gene in seven adult patients. The given study is the first report on the carrier frequency of the Leu444Pro mutant allele in an Indian population which will help understanding the burden and susceptibility of Gaucher disease to affect next generation in India.

Surfactants are commonly incorporated in conventional and enabled formulations to enhance the rate and extent of dissolution of drugs exhibiting poor aqueous solubility. Generally the interactions between the drug and excipients are systematically evaluated, however, limited attention is paid towards understanding the effect of interaction between functional excipients and its impact on the performance of the product. In the current study, the effect of potential interaction between a nonionic polymer binder, povidone, and anionic surfactant docusate sodium on the rate and extent of dissolution of a drug exhibiting poor aqueous solubility was evaluated by varying the proportions of the binder and the surfactant in the formulation. Potential complexation or aggregation between the excipients was investigated by fluorescence spectroscopy and zeta potential measurements of the aqueous solutions of docusate sodium, povidone, and sodium lauryl sulfate (SLS). The rate and extent of drug release was found to decrease with an increase in the proportion of docusate sodium and povidone in the formulations. Difference in magnitude of surface charge (zeta potential) of docusate sodium in presence of povidone indicated potential surfactant-polymer aggregation during dissolution which was corroborated by CAC/CMC values derived from fluorescence spectroscopic measurements. The decrease in the rate of drug release was attributed to an increase in the viscosity of the microenvironment of dissolving particles due to the interaction of docusate sodium and povidone in the aqueous media during dissolution. These findings highlight the importance of systematic evaluation of the interaction of ionic surfactants with the polymeric components within the formulation to ensure the appropriate selection of the type of surfactant as well as its proportion in the formulation.

Case: Congenital aplasia or hypoplasia of the patella by itself is a rare condition; to our knowledge, it has been associated with aplasia of the quadriceps mechanism only 3 times in the literature. We describe a 5-year-old boy who had bilateral fixed flexion deformity of the knee as well as bilateral hypoplasia of the patella and quadriceps mechanism; he never had been able to stand upright and walk. We present the clinical and radiographic features, the surgical details, and the successful outcome after treatment., Conclusion: Corrective femoral osteotomies with soft-tissue reconstruction to provide active knee extension provided a satisfactory outcome. At the last follow-up, the child was walking without support and had good active knee extension.

The location and/or type of variants in FLNB result in a spectrum of osteochondrodysplasias ranging from mild forms, like spondylocarpotarsal synostosis syndrome and Larsen syndrome, to severe perinatal lethal forms, such as atelosteogenesis I and III and Boomerang dysplasia. Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones. Biallelic loss-of-function variants in FLNB are known to cause spondylocarpotarsal synostosis syndrome and 9 families and 9 pathogenic variants have been reported so far. We report clinical features of 10 additional patients from 7 families with spondylocarpotarsal synostosis syndrome due to 7 novel deleterious variants in FLNB, thus expanding the clinical and molecular repertoire of spondylocarpotarsal synostosis syndrome. Our report validates key clinical (fused thoracic vertebrae and carpal and tarsal coalition) and molecular (truncating variants in FLNB) characteristics of this condition., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Hemoglobin E beta-thalassemia is one of the leading forms of severe thalassemia world wide. This disorder is more commonly found in South East Asia including north eastern states of India. Patients suffering from this disorder show marked clinical heterogeneity., Materials and Methods: Referred cases of hemoglobin disorders from north India were evaluated prospectively. Details of clinical history and haematological findings including HPLC as well as mutation analysis were obtained., Results: Twenty cases of E beta-thalassemia with widely variable clinical profile were included. The hematological parameters were also extremely variable with a wide range of hemoglobin (1.8-9.9 g/dl). Applying a severity scoring system all patients were classified the patients into mild (n=6), moderate (n=7) and severe (n=7) subclasses. We also correlated red cell Indies with HB E and HB F as well as age of onset of symptoms with HB E and HB F. IVS1-5(G-C) was found to be the most common thalassemia mutation associated with Hemoglobin E beta-thalassemia., Conclusion: Extremely variable clinical and haematological findings were observed in Hemoglobin E beta-thalassemia patients. These findings are comparable to other Indian studies. Appropriate knowledge of the clinical variability and unpredictable natural history can help better management of this group of patients., (© Journal of the Association of Physicians of India 2011.)

Introduction: The use of antibiotic impregnated biodegradable synthetic high purity calcium sulfate (SHPCS) beads is frequently reported as they offer increased concentration of antibiotics locally, without need for removal. However some wound discharge following their use has been noted. The purpose of this study was to determine any correlation between wound discharge and infection remission. Methodology: Retrospective study of 39 cases of Osteoarticular infections from April 2013 to November 2016 in whom SHPCS beads were used. All patients underwent the standard staged protocol of aggressive debridement, deep tissue biopsy, implant removal where indicated and early soft tissue cover. SHPCS beads were used locally in the second stage combined with appropriate antibiotics based on tissue culture. All patients received systemic antibiotics for a period of 6 weeks and followed up for a minimum period of six months. The study analysed the patient demographics, etiology, surgical procedures, culture patterns, local antibiotics used, radiological status of beads, incidence and characteristics of wound discharge and outcome. Results: There were 25 cases of chronic osteomyelitis, eight infected non unions, three peri prosthetic joint infections, two soft tissue infections and one case of acute osteomyelitis. 17 of these infections were following osteosynthesis. The cultures were negative on eight occasions in seven patients. A total of 40 organisms were isolated in the other patients; commonest being Staphylococcus aureus (n=16) and E coli (n=7). SHPCS beads were mixed with vancomycin in 17 cases, colistin in 11, vancomycin with colistin in eight and vancomycin with gentamicin in four. Voriconazole was used in one case with fungal infection. Eight cases (20.51 %) developed discharge from the wound at an average of 6 days after inserting the beads. The discharge was serous with no foul smell in six and purulent in two inflamed wounds. Four cases underwent re-debridement; two cases with purulent discharge and subsequent positive cultures; two with serous discharge early in the series and no evidence of infection on re-exploration with negative cultures. The remaining four patients with serous wound discharge were observed without any further surgical intervention, with the discharge stopping spontaneously between 15 to 36 days post operatively. There was no correlation between antibiotic used and wound discharge. Radiographic analysis showed dissolution of all the beads at an average of 36 days in the 39 cases. Heterotrophic ossification was not observed. Clinical and radiological remission of infection was observed in 37 cases (94.9%). Two patients died during the course of hospitalization, secondary to septicaemia and multi organ failure. Three patients had an infection recurrence within six months, managed successfully by re-debridement and appropriate antibiotics. Radiological union was achieved in seven of the eight infected non unions. Conclusions: With the encouraging rates of infection remission we have observed, we continue to use antibiotic loaded SHPCS as an alternative for local antibiotic delivery in the treatment of osteoarticular infections. However, wound discharge is a known potential observation following implantation of calcium sulfate beads, subsiding typically within four to six weeks. The appearance of wound discharge can vary, ranging from purulent discharges to non-purulent, serous/ sero sanguineous fluid wound discharges. The presence of a wound discharge alone does not necessarily imply a failure to treat the infection. It is important to be aware of this side effect and guard against unnecessary re- operations, by careful consideration and monitoring all of the available clinical signs of infection, in addition to blood test results and radiographic evidence. Further research is needed to determine the relationship between the implantation of antibiotic loaded calcium sulfates and the incidence and duration of drainage., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Organic materials such as polyanthraquinone sulfide (PAQS) are receiving increased attention as electrodes for energy storage systems owing to their good environmental compatibility, high rate capability, and large charge-storage capacity. However, one of their limitations is the solubility in organic solvents typically composing the electrolytes. Here, the solubility of PAQS was tested in 17 different solvents using UV/Vis spectroscopy. The results show that PAQS exhibits a very wide range of solubility according to the nature of the solvent and the obtained trend agrees well with the predictions from Hansen solubility analysis. Furthermore, the transport properties (conductivity, σ, and viscosity, η) of selected electrolytes composed of non-solubilising solvents with 1 m LiTFSI are compared and discussed in the temperature range from -40 °C to 80 °C. In the second part of this study, the electrochemical characterization of PAQS as electrode material in selected pure or mixture of solvents with 1 m LiTFSI as salt was made in half-cells by a galvanostatic method. In a methylglutaronitrile (2MeGLN)-based electrolyte that exhibits low solubility of PAQS, it appears that the capacity fade is intricately linked to the large irreversibility of the second step of the redox process. Although the standard cyclic carbonate solvents mixture (ethylene carbonate and propylene carbonate) led to rapid capacity fade in the initial 10-15 cycles owing to their high solubilising ability. Finally, it is shown that a pure linear alkylcarbonate (dimethyl carbonate) or binary mixture of ether-based (dioxolane/dimethoxy ethane) electrolyte is much more compatible for enhanced capacity retention in PAQS with more than 120 mAh g -1 for 1000 cycles at 4 C., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The sulfur electrode in LiS batteries suffers from rapid capacity loss and low efficiency due to the solubility of long chain polysulfides formed during discharge. Herein, we demonstrate the beneficial effect of original catholyte formulations containing redox active organyl disulfides (PhS 2 Ph) on the capacity utilization and retention as well as the efficiency in LiS batteries. Resulting from the chemical equilibria in the electrolyte between the sulfur/polysulfides (S 8 /S x 2- ) and disulfide/thiolates (PhS 2 ), the polysulfide redox shuttle phenomenon is minimized due to the suppression of formation of soluble polysulfides (S x - S x 2- , x > 4). Using the catholyte containing 0.4 M Ph 2 S 2 as an additive in a standard base electrolyte (DOL/DME + LiTFSI/LiNO 3 ), a stable capacity of 1050 mAh·g -1 is obtained under galvanostatic cycling at C/5 with a Coulombic efficiency of >99.5%. At 45 °C, it is shown that the formulated catholyte enables galvanostatic cycling at a high c-rate of 1C over 500 cycles with a capacity above 900 mAh·g -1 and a high energy efficiency of 82%.

One of the primary causes of aging in supercapacitors are the irreversible faradaic reactions occurring near the operating-voltage limit that lead to the production of gases resulting in device swelling, increased resistance, and lowering of the capacitance. In this study, a protic deep eutectic solvent (DES) consisting of mixture of lithium bis(fluorosulfonyl)imide (LiFSI) with formamide (FMD) as H-bond donor (x LiFSI =0.25; C=2.5 m LiFSI) is investigated as electrolyte for activated carbon (AC)-based electrical double layer capacitors (EDLCs). Characterization of the viscosity, conductivity, and the ionicity of the electrolyte in a wide range of temperatures indicates >88 % salt dissociation. In situ pressure measurements are performed to understand the effect of cycling conditions on the rate of gas generation, quantified by the in operando pressure variation dP/dt. These measurements demonstrate that about 25 % of the faradaic reactions leading to gas generation are electrochemically reversible. Cell aging studies demonstrate promising potential of the LiFSI/FMD as a protic electrolyte for AC-based EDLCs and high energy density close to 30 Wh kg -1 at 2.4 V., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Global ventricular function often remains normal in patients with beta-thalassemia major (β-TM) until late. Tissue Doppler and strain imaging may be useful to assess regional myocardial function abnormalities in these patients., Methods: Systolic (Sm), early diastolic (Em), and late diastolic (Am) (Em/Am) myocardial velocities at basal lateral and septal left ventricular (LV) segments, strain (S), and strain rate (SR) in basal and mid LV, right ventricular (RV) and septum were measured in 30 patients (β-TM, 12.4 ± 5.2 years, serum ferritin 2603.1 μg/L) and twenty controls (12.5 ± 5.2 years). Flow-mediated dilatation (FMD) vasodilatation as a measure of endothelial function was also assessed., Results: Patients had significantly higher LV mass index (169.45 ± 61.14 vs. 104.66 ± 24.42; P = 0.009) while global LV Sm and diastolic function was similar to controls. Patients had significantly lower lateral Em velocity, Em (10.12 ± 1.16 vs. 17.9 ± 2.11; P = 0.002), Em/Am ratio (0.811 ± 0.192 vs. 2.06 ± 0.62; P = 0.001) at the basal lateral LV, lower strain values at the basal lateral LV (19.5 ± 4.17 vs. 24.196 ± 1.81; P = 0.002), mid lateral LV (19.07 ± 3.98 vs. 25.56 ± 2.62; P = 0.042), basal septum (17.04 ± 3.44 vs. 25.43 ± 2.53; P = 0.001), and mid septum (20.49 ± 5.34 vs. 24.45 ± 2.20; P = 0.001) as compared to controls. SR at the basal and mid segment of the lateral LV wall and at the basal and mid septum was also significantly lower in patients. SR in basal and mid RV although lower was not significantly different from controls. Patients also had significantly lower FMD (7.57 ± 3.16 vs. 18.08 ± 1.9, P = 0.018) implying endothelial dysfunction., Conclusions: Tissue Doppler, strain and SR imaging are useful to quantify regional myocardial function in asymptomatic β-TM patients with preserved global Sm and diastolic function., Competing Interests: There are no conflicts of interest.

The advent of rapid and progressively more affordable sequencing and gene expression studies have spurred research on therapies for cancer targeted to specific gene alterations. With few exceptions, such as those cancers with either a paucity of mutations or major chromosomal rearrangements driving the neoplastic transformation, the approaches based on one mutational target-one drug have achieved only modest outcomes in cancer. Using the paradigm of aggressive breast cancers, we will show the mathematical explanation that predicts our failures and indicates a plausible way forward. An integrated network modeling approach to intracellular signaling, metabolism, and microenvironment interactions, coupled with the use of synthetic devices engineered to understand phenotypic heterogeneity of cancer lesions, may form the basis for selection of the next-generation of personalized therapies for cancer. Academia can play a larger role in bringing effective drugs to first-in-human trials in this context., Competing Interests: Potentials Conflicts of Interest: None disclosed.

Polymerase chain reaction (PCR) is central to methods in molecular ecology. Here, we describe PCR-dependent approaches useful for investigating microbial diversity and its function in various natural, human-associated, and built environment ecosystems. Protocols routinely used for DNA extraction, purification, cloning, and sequencing are included along with various resources for the statistical analysis following gel electrophoresis-based methods (DGGE) and sequencing. We also provide insights into eukaryotic microbiome analysis, sample preservation techniques, PCR troubleshooting, DNA quantification methods, and commonly used ordination techniques.

Acromesomelic dysplasia, type Maroteaux is a disorder characterized by disproportionate short stature predominantly affecting the middle and distal segments of the upper and lower limbs. It is an autosomal recessive disorder due to mutation in NPR2 gene which impairs skeletal growth. To screen the mutations in the gene NPR2, all of its coding exons and splice junction sites were PCR amplified from genomic DNA of affected individuals of four families and sequenced. Four homozygous mutations in four different families were identified. These include three novel mutations including a deletion frameshift mutation (p.Cys586Ter), one nonsense mutation (p.Arg479Ter), one missense mutation (p.Val187Asp) and one reported missense mutation (p.Tyr338Cys). The study describes phenotypes of Indian patients and expands the mutation spectrum of the disorder.