Cystic fibrosis: current treatment and future direction

Cystic fibrosis is an autosomal recessive genetic disorder, characterized by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to abnormality in the chloride channels of the mucus and sweat producing glands. Multiple organs systems are affected in this disorder, like respiratory system and gastrointestinal tract, severely impacting the patient’s quality of life, eventually leading on to several complications and death. Since the uncovering of the underlying genetic defect in cystic fibrosis (CF), our knowledge of the disease process has increased substantially, but we still lack a holistic approach to its management, which comprises of multiple facades, requiring both pharmacological and non-pharmacological or rehabilitatory approaches. So far, the therapeutic options were limited to targeting the consequences and complications of the disease, such as respiratory infection, mucus retention, pancreatic insufficiency, etc., but now several promising therapies may be able to address the underlying pathology rather than its long-term effects. This review summarizes the current and upcoming pharmacological options for CF, such as those targeting the CFTR gene defect directly, including gene editing, CFTR correctors and potentiators; drugs targeting the epithelial sodium channels (ENaC inhibitors); repositioning of some existing drugs and evaluating their role in CF; and understanding the disease better by transcriptomic approaches and the role of gut microbiota in the disease process and severity

Clomiphene citrate: the changing landscape

Ovulatory dysfunction is one of the leading causes of female infertility. Clomiphene citrate has emerged as a boon in the induction of ovulation in the human female. Clomiphene results in many adverse effects some of which are documented, and some reported spontaneously. Clomiphene citrate is a non-racemic mixture of two isomers, zuclomiphene and enclomiphene, having individual and opposite biological actions. It is accepted that cis isomer (zuclomiphene) is estrogenic and trans isomer (enclomiphene) is anti-estrogenic. Zuclomiphene does not have any ovulation-induction propertybut gets accumulated for a longer time in the human body and it has more agonistic activity than enclomiphene. Thus, Zuclomiphene may be responsible for the adverse effects by clomiphene citrate. Enclomiphene is being explored for its potential use in male as well as female infertility. Trails are underway to explore its effectiveness and safety in various disorders. This article highlights the pharmacology of Clomiphene with respect to its isomers and the potential uses of enclomiphene based on evidences available

A Conflict Resolution Tool for Project Managers: Evaporating Cloud

Today’s ever changing business environment requires managers to interact globally with people across functional areas with conflicting points of view. A preliminary literature review suggests that a generic tool to understand and resolve conflicts is desirable. This paper demonstrates how a theory of constraints-based logical tool, an evaporating cloud, can enable IT managers to better understand conflicts underlying most problems. Using a commonly encountered conflict as an example, we show how this tool verbalizes a problem through the logic of cause and effect, surfaces the assumptions causing the conflicting actions and decisions, and presents injections – potential solutions – that can cause the conflict to evaporate (i.e., disappear or be resolved). Using a real-world IT project management case study, we also explain the usefulness and versatility of this intuitive tool via a web app for novice users. We conclude this paper acknowledging its limitations and providing some future research directions

Patients’ sensory perception and satisfaction with use of metered dose inhalers and dry powder inhalers in moderate persistent asthma

Background: Inhalers containing corticosteroid and a long acting β2 agonist (LABA) are widely used in asthma treatment. This study assessed the patient sensory perception and satisfaction of budesonide/formoterol fixed dose combination by pressurized metered dose inhalers (pMDI) with spacer and dry powder inhalers (DPI) in patients of moderate persistent asthma.Methods: This was a 6 week prospective, randomized, open label, comparative, parallel group clinical study. All patients had a forced expiratory volume in 1 second (FEV1) of 60-80% predicted normal. The patients were assessed for sensory perception and satisfaction in group I (pMDIs with spacers) and group II (DPIs) using patient evaluation questionnaire (PEQ) and patient satisfaction and preference questionnaire (PASAPQ) at the end of 6th week.Results: In PEQ, statistical analysis of the mean attribute ratings showed that both the devices were easy to use by patients. More medication was felt reaching throat using DPIs. Patients on DPI liked the taste and felt it to be less strong than patients on pMDIs. The overall liking was statistically comparable in two groups. In PASAPQ, the patients on DPI group were very satisfied with the treatment than pMDI (p<0.05).Conclusion: Overall liking of both DPIs and pMDIs was comparable and patients on DPI were satisfied more with the treatment device. Patient sensory perception and satisfaction may be taken into account in selecting device to improve compliance to treatment

An evaluation of adverse drug reactions monitoring at a pharmacovigilance unit under pharmacovigilance program of India in a tertiary care hospital of Haryana

Background: Adverse drug reactions (ADRs) are among top 10 causes of mortality in patients. Pharmacovigilance programme of India (PvPI) is a step towards participation in the WHO programme for International Drug Safety Monitoring. The present article is an evaluation of the incidence and the patterns of ADRs from the reports collected from various clinical departments of this hospital.Methods: A total of 859 suspected ADR reports submitted to the pharmacovigilance unit at Department of Pharmacology under PvPI were evaluated for 6 months with respect to demographics, causative drug, organ system involvement, severity and seriousness of ADRs. The causality assessment was carried out by using WHO assessment method and Naranjo’s scale.Results: Males experienced more (66.33%) ADRs. The highest percentage (45.83%) of ADRs was seen in the age group of 46-60 years (35.33%), followed by 16-30 years (25.5%). The most common drug group causing ADRs was antimicrobials (43.37%), followed by anticancer and immunosuppressive agents (29.02%). The gastrointestinal system (31.43%) was most prone system, followed by generalized body reactions (22.93%) and cutaneous reactions (17.11%). 662 (77%) ADRs were non-serious, 197 (22.9%) were serious. On severity scale, 682 (79.39%) were mild, 168 (19.65%) moderate and only 9 (1.05%) ADRs were severe out of which three were fatal. As per WHO assessment method 66.94% ADRs were probable and 33.06% possible. The probability was comparable with Naranjo’s scale.Conclusion: ADRs to drugs happen commonly, and their reporting is important for the early recognition and prevention of ADRs and will also help in generating signals. ADR monitoring not only acts as an alerting mechanism for physicians, but helps the regulatory authorities in making the policy decision

Carrier relaxation dynamics in defect states of epitaxial GaN/AlN/Si using ultrafast transient absorption spectroscopy

The relaxation dynamics of the carriers through the defect levels in an epitaxial GaN film grown with an AlN buffer layer on Si has been performed on the femto-picosecond timescale, using ultrafast transient absorption spectroscopy (UFTS). The sample was pumped above and below the band gap and probed with a white light continuum (480-800 nm). A combination of bi and triple exponential decay functions at different probe wavelengths were used to fit the kinetic profile of the carriers in the defect continuum. Based on the UFTS measurements, a model is proposed which explains the dynamics in the shallow traps and deep level defects. Furthermore, to determine the role of the lattice in the relaxation dynamics, the experiment was conducted at a low lattice temperature of 4.2 K. The relaxation constants from the UFTS measurements confirm not only the presence of shallow and deep level defects but also the involvement of phonons in one of the relaxation processes

An agent-based simulator for quantifying the cost of uncertainty in production systems

Product-mix problems, where a range of products that generate different incomes compete for a limited set of production resources, are key to the success of many organisations. In their deterministic forms, these are simple optimisation problems; however, the consideration of stochasticity may turn them into analytically and/or computationally intractable problems. Thus, simulation becomes a powerful approach for providing efficient solutions to real-world productmix problems. In this paper, we develop a simulator for exploring the cost of uncertainty in these production systems using Petri nets and agent-based techniques. Specifically, we implement a stochastic version of Goldratt’s PQ problem that incorporates uncertainty in the volume and mix of customer demand. Through statistics, we derive regression models that link the net profit to the level of variability in the volume and mix. While the net profit decreases as uncertainty grows, we find that the system is able to effectively accommodate a certain level of variability when using a Drum-Buffer-Rope mechanism. In this regard, we reveal that the system is more robust to mix than to volume uncertainty. Later, we analyse the cost-benefit trade-off of uncertainty reduction, which has important implications for professionals. This analysis may help them optimise the profitability of investments. In this regard, we observe that mitigating volume uncertainty should be given higher consideration when the costs of reducing variability are low, while the efforts are best concentrated on alleviating mix uncertainty under high costs.This article was financially supported by the State Research Agency of the Spanish Ministry of Science and Innovation (MCIN/AEI/ 10.13039/50110 0 011033), via the project SPUR, with grant ref. PID2020–117021GB-I00. In addition, the authors greatly appreciate the valuable and constructive feedback received from the Editorial team of this journal and two anonymous reviewers in the different stages of the review process

Performance analysis of cow dung as an eco-friendly binder and additive material for sustainable moulding and casting

Abstract: In the present work, an attempt is made to partially replace the high cost silica sand with sustainable eco-friendly material, namely cow-dung. Practical utility of cow dung as a binding and additive material in foundries has been tested in the present work. Taguchi method is used to plan and conduct nine experiments with three replicates each. Pareto analysis of variance study is done to understand the practical significance of moulding sand variables namely percent of cow dung, percent of clay, percent of water, and degree of ramming on sand mould properties. The conflicting multiple objective functions (maximize: mould hardness, and minimize: collapsibility and gas evolution) are optimized by utilizing data envelopment analysis ranking (DEAR) method. The optimal parameter levels i.e. 6% of clay, 4% of water, 5% of cow-dung and 4 numbers of ramming strokes are obtained by applying hybrid Taguchi- DEAR method. These parameters yielded the best moulding properties i.e. mould hardness 55, gas evolution 5.9 ml/gm , and collapsibility 470 g/cm2. Thereafter, Lovejoy coupling made of aluminium is cast in the sand mould prepared with cow-dung and without cow-dung. The sand mould is prepared with the optimum set of parameters and the casting produced in the mould has been tested for its quality characteristics. The mechanical properties, surface finish, and microstructure of the casting made in sand mould with cow-dung are found to be better than that obtained with sand mould without cow-dung. The present research work is found to be more useful in foundries for sustainable production of good quality casting

SIRT3 Deacetylates and Activates OPA1 To Regulate Mitochondrial Dynamics during Stress

Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. There is significant evidence suggesting a stringent association between morphology and bioenergetics of mitochondria. Morphological alterations in mitochondria are linked to several pathological disorders, including cardiovascular diseases. The consequences of stress-induced acetylation of mitochondrial proteins on the organelle morphology remain largely unexplored. Here we report that OPA1, a mitochondrial fusion protein, was hyperacetylated in hearts under pathological stress and this posttranslational modification reduced the GTPase activity of the protein. The mitochondrial deacetylase SIRT3 was capable of deacetylating OPA1 and elevating its GTPase activity. Mass spectrometry and mutagenesis analyses indicated that in SIRT3-deficient cells OPA1 was acetylated at lysine 926 and 931 residues. Overexpression of a deacetylation-mimetic version of OPA1 recovered the mitochondrial functions of OPA1-null cells, thus demonstrating the functional significance of K926/931 acetylation in regulating OPA1 activity. Moreover, SIRT3-dependent activation of OPA1 contributed to the preservation of mitochondrial networking and protection of cardiomyocytes from doxorubicin-mediated cell death. In summary, these data indicated that SIRT3 promotes mitochondrial function not only by regulating activity of metabolic enzymes, as previously reported, but also by regulating mitochondrial dynamics by targeting OPA1

Electronic Raman scattering and photoluminescence from La0.7_{0.7}Sr0.3_{0.3}MnO3_3 exhibiting giant magnetoresistance

Raman and Photoluminescence (PL) experiments on correlated metallic La$_{0.7}$Sr$_{0.3}$MnO$_{3}$ have been carried out using different excitation wavelengths as a function of temperature from 15 K to 300 K. Our data suggest a Raman mode centered at 1800 cm$^{-1}$ and a PL band at 2.2 eV. The intensities of the two peaks decrease with increasing temperature. The Raman mode can be attributed to a plasmon excitation whose frequency and linewidths are consistent with the measured resistivities. The PL involves intersite electronic transitions of the manganese ions.Comment: 10 pages + 4 eps figures, Revtex 3.0, figures available on reques