Communal interaction of glycation and gut microbes in diabetes mellitus, Alzheimer's disease, and Parkinson's disease pathogenesis.

Diabetes and its complications, Alzheimer's disease (AD), and Parkinson's disease (PD) are increasing gradually, reflecting a global threat vis-à-vis expressing the essentiality of a substantial paradigm shift in research and remedial actions. Protein glycation is influenced by several factors, like time, temperature, pH, metal ions, and the half-life of the protein. Surprisingly, most proteins associated with metabolic and neurodegenerative disorders are generally long-lived and hence susceptible to glycation. Remarkably, proteins linked with diabetes, AD, and PD share this characteristic. This modulates protein's structure, aggregation tendency, and toxicity, highlighting renovated attention. Gut microbes and microbial metabolites marked their importance in human health and diseases. Though many scientific shreds of evidence are proposed for possible change and dysbiosis in gut flora in these diseases, very little is known about the mechanisms. Screening and unfolding their functionality in metabolic and neurodegenerative disorders is essential in hunting the gut treasure. Therefore, it is imperative to evaluate the role of glycation as a common link in diabetes and neurodegenerative diseases, which helps to clarify if modulation of nonenzymatic glycation may act as a beneficial therapeutic strategy and gut microbes/metabolites may answer some of the crucial questions. This review briefly emphasizes the common functional attributes of glycation and gut microbes, the possible linkages, and discusses current treatment options and therapeutic challenges.

Timing of development of osteoradionecrosis post head and neck radiotherapy: does a safe time interval exist for dental extraction?

INTRODUCTION: Risk factors for developing osteoradionecrosis (ORN) are well known, but less is known about factors influencing the interval between radiotherapy and the onset of ORN. Also, it is unknown whether there is any specific period post-radiotherapy with a reduced probability of ORN when irradiated teeth require extraction. PURPOSE: The primary aim of this study was to identify factors influencing the interval in developing ORN in the following subgroups of patients: (1) patients who spontaneously developed ORN, (2) surgical-intervention-related ORN with a particular focus on patients after mandibulectomy. The secondary aim was to attempt to identify a possible time for safer dental intervention after primary treatment. MATERIALS AND METHODS: The authors retrospectively analysed 1608 head and neck cancer (HNC) patients treated in a single centre. Time intervals were measured from the end of radiotherapy to the development of ORN and further analysed in the subgroups listed above. RESULTS: In all, 141 patients (8.8%) developed intra-oral ORN. Median time from radiotherapy to ORN development in the whole cohort was 9 months. Median interval for spontaneous ORN was 8 months, 6.5 months for intervention-related ORN, and 15 months for patients post-mandibulectomy. In patients who required dental extraction preradiotherapy, median interval of ORN onset was 5 months. CONCLUSION: In our study, a slightly higher proportion of patients with intervention developed ORN earlier in comparison with spontaneous ORN. The period from 12-18 months after radiotherapy was identified as having the highest probability of developing ORN in patients after mandibulectomy. A time for safer dental intervention after primary treatment was not identified.

Electronic and Structural Engineering of Atomically Dispersed Isolated Single-Atom and Alloy Architectures.

Precise configurations of isolated metal atoms in nitrogen-doped carbon materials with 2D single or multilayers and 3D nanoarchitectures are gaining attention owing to their good stability and activity at high current densities. Atomic metal-Nx moieties, which utilize maximum atoms to attain high intrinsic activity and novel electronic architecture of support materials, facilitate strong interaction between the central metal atom and support matrix. However, resource consumption is considerably high due to the inferior atomic utilization of active sites. Therefore, energy-efficient electrochemical processes are needed to develop advanced isolated single-atom architecture, which would provide high atom-utilization and good durability. Herein, the concepts of atomically dispersed metal sites in single-atom and alloy architectures and their electronic features associated with structural evolution are discussed. Opportunities and challenges associated with the use of isolated single-atoms in 2D materials are discussed based on their unique electronic defects, low-valence central metals, mechanical flexibility, and maximum access to metal sites. This insightful revisit into the engineering of single-atom and alloy architectures would provide a profound understanding of electronic modulations and regulation of geometric characteristics, and unravels potential directions for electrochemical energy conversion, charge storage, and sensing processes.

Impact of Faradaic Interlayer Confinement and Carbon-Centered Macrostructure Designs for Ion Capture and the Recovery of Elements.

Environmental protection associated with renewable energy is among the most critical challenges for translational ion-capture based on capacitive storage of ions in electrical double layers at the interface of electrode and electrolyte. Electric double-layer capacitance with charge induction and faradaic pseudo-capacitance with charge transfer classifies the capacitance of the electrochemical interface. The electrochemical interface in most energy technologies involves porous and pseudocapacitive redox materials that offer varying degrees of electrolyte confinement. In this review, we discuss the factors affecting water desalination, such as the effect of nanopores for ion capture, the ion sieving effect, the effect of hydration energy, and hydration radius in the carbon sub-nanometer pore. Moreover, the surface phenomena of electrodes, including carbon corrosion, and the potential of zero charge to control the oxidation of carbon electrodes are explained along with protection mechanisms. The various capacitive deionization (CDI) operations and the corresponding electrochemical cell technologies are briefly introduced, including the significance of double-layer charging materials with faradaic intercalation, which suffer less from co-ion expulsion. Finally, we revisit the effects of various nanoarchitectures and the construction of capacitive deionization electrodes for clean water technology.

Elevated translationally controlled tumour protein promotes oral cancer progression and poor outcome.

BACKGROUND: Translationally controlled tumour protein (TCTP) is a multifunctional protein elevated in multiple cancers. However, studies on its role in oral carcinogenesis and prognosis are rare. We recently reported the role of its interacting partner, MCL1, in oral cancer progression and outcome. Hence, the present study aimed to assess TCTP expression in oral tumorigenesis and its association with patient outcomes alone and in combination with MCL1. METHODS: TCTP expression was assessed by immunohistochemistry and immunoblotting in oral tissues and cells, respectively. Cell viability post siRNA/dihydroartemisinin treatment was analysed by tetrazolium salt assay. Cell survival, invasion and tumorigenic potential post TCTP knockdown were assessed by clonogenic, Matrigel and soft-agar assays, respectively. The association of TCTP with patient outcome was analysed by Kaplan-Meier and Cox regression. RESULTS: TCTP was significantly overexpressed in oral premalignant lesions (p < 0.0001), oral tumours (p < 0.0001) and oral dysplastic and cancer cells versus normal oral mucosa and also in recurrent (p < 0.05) versus non-recurrent oral tumours. Further, elevated TCTP was significantly (p < 0.05) associated with poor recurrence free survival (RFS) and poor overall survival (OS; hazard ratio = 2.29; p < 0.05). Intriguingly, the high co-expression of TCTP and MCL1 further reduced the RFS (p < 0.05) and OS (p < 0.05; hazard-ratio = 3.49; p < 0.05). Additionally, TCTP knockdown decreased survival (p < 0.05), invasion (p < 0.01) and in vitro tumorigenic potential (p < 0.0001). Dihydroartemisinin treatment reduced TCTP levels and viability of oral cancer cells. CONCLUSION: Our studies demonstrate an oncogenic role of TCTP in oral cancer progression and poor outcome. Thus, TCTP may be a potential prognostic marker and therapeutic target in oral cancers.

Superstructures of Zeolitic Imidazolate Frameworks to Single- and Multiatom Sites for Electrochemical Energy Conversion.

The exploration of electrocatalysts with high catalytic activity and long-term stability for electrochemical energy conversion is significant yet remains challenging. Zeolitic imidazolate framework (ZIF)-derived superstructures are a source of atomic-site-containing electrocatalysts. These atomic sites anchor the guest encapsulation and self-assembly of aspheric polyhedral particles produced using microreactor fabrication. This review provides an overview of ZIF-derived superstructures by highlighting some of the key structural types, such as open carbon cages, 1D superstructures, hollow structures, and the interconversion of superstructures. The fundamentals and representative structures are outlined to demonstrate the role of superstructures in the construction of materials with atomic sites, such as single- and dual-atom materials. Then, the roles of ZIF-derived single-atom sites for the electroreduction of CO2 and electrochemical synthesis of H2 O2 are discussed, and their electrochemical performance for energy conversion is outlined. Finally, the perspective on advancing single- and dual-atom electrode-based electrochemical processes with enhanced redox activity and a low-impedance charge-transfer pathway for cathodes is provided. The challenges associated with ZIF-derived superstructures for electrochemical energy conversion are discussed.

Ruthenium(II)-Catalyzed Hydrogenation and Tandem (De)Hydrogenation via Metal-Ligand Cooperation: Base- and Solvent-Assisted Switchable Selectivity.

A versatile, selective, solvent (methanol vs ethanol)- and base (potassium vs lithium carbonate)-assisted switchable synthesis of saturated ketone and α-methyl saturated ketone from α,ß-unsaturated ketone is developed. Mechanistic aspects, evaluated from spectroscopic studies, in situ monitoring of the reaction progress, control studies, and labeling studies, further indicate the involvement of a tandem dehydrogenation-condensation-hydrogenation sequence in the reaction, in which the interconvertible coordination mode (imino N → Ru and amido N-Ru) of coordinated imidazole with Ru(II)-para-cymene is crucial, without which the efficiency and selectivity of the catalyst are completely lost. The catalyst demonstrates good efficiency, selectivity, and functional group tolerance and displays a broad scope (69 examples) for monomethylation and hydrogenation of unsaturated chalcones, double methylation of ketones, and N-methylation of amines.

The predictive role of neutrophil-to-lymphocyte ratio in the outcomes of patients with sarcomatoid carcinoma of oral cavity.

INTRODUCTION: The aim of the present study was to evaluate the prognostic value of the inflammatory response biomarkers and their impact on survival outcomes in the patients with sarcomatoid carcinoma (SC) of oral cavity, a rare variant of squamous cell carcinoma (SqC). MATERIALS AND METHODS: Seventeen patients diagnosed with SC of oral cavity without metastases treated between Jan 2017 to June 2020 were identified and included in the present study. Pre- and post-operative inflammatory biomarkers and other prognostic markers were evaluated and their impact on disease-free survival (DFS) and overall survival (OS) was studied. RESULTS: Seventeen patients (16 males and one female) were included in the present study with a median age of 42 years (IQR: 26-76 years). With the median follow-up of 15 months, nine of 17 patients had developed recurrence and were succumbed to either locoregional recurrence or distant progression. One-year Kaplan-Meier estimates of DFS and OS were 57% and 58.3% respectively. On univariate analysis, baseline NLR, PLR, and pathological bone/skin involvement were identified to be significant prognostic factors affecting the patient's DFS and OS. On multi-variate analysis, baseline NLR > 3 and pathological bone or skin involvement by tumour were emerged as some independent significant predictors. CONCLUSION: For the first time, the predictive role of inflammatory markers is studied and proven significant affecting patients' survival outcomes. Hence, these inflammatory biomarkers may be considered for routine clinical use as reliable and low-cost prognostic markers to tailor the management of SC of oral cavity.

Study of Thyroid Functions in critically ill Patients admitted in Medical Intensive Care Unit and its Correlation with Critical Care Scoring Acute Physiology and Chronic Health Evaluation III.

BACKGROUND: Thyroid hormones have a crucial role in adapting the metabolic functions during stress and critical illness. Patients who are critically ill may have profound changes in thyroid hormone metabolism. Non-thyroidal Illness Syndrome (NTIS) is one among them, in which there is marked abnormality seen in the thyroid hormone levels. Hence this study is to understand the alterations of the thyroid function tests (TFTs) encountered in critically ill patients admitted in medical intensive care unit (MICU) without primary thyroid disease and to correlate with the severity of Acute Physiology and Chronic Health Evaluation (APACHE III) scoring. METHODS: The study was conducted on 100 critically ill patients with no previous thyroid disorders, admitted in MICU in the Department of General Medicine in a tertiary care hospital between September 2017 and August 2019 who fulfilled the inclusion and exclusion criteria. RESULTS: Out of 100 critically ill patients the abnormal thyroid function prevalence was seen in 78% patients. The most common abnormality seen in our study was low total triiodothyronine (TT3) (61%) followed by low free triiodothyronine (FT3) (36%), low total thyroxine (TT4) (29%), high thyroid-stimulating hormone (TSH) (18%), and low free thyroxine (FT4) (12%). Low TT3, TT4, and FT3 values had a significant correlation with increasing critical severity score of APACHE III with a p value which was statistically significant (p<0.05). CONCLUSIONS: With increase in severity of critical illness assessed by APACHE III, TFT, that is, TT3, TT4, and FT3 levels were decreasing, suggestive of increasing non-thyroidal illness in critically ill patients.

COVID-Inflicted Coagulopathy: Expert Consensus on Management with Novel Oral Anticoagulants in India.

Coronavirus disease 2019 (COVID-19) is a highly hypercoagulable viral infection complicated as COVID-inflicted coagulopathy (CIC), that is associated with increased risk of morbidity and mortality. International guidelines recommend low molecular weight heparin (LMWH) to treat CIC in both in-hospital and in-home settings. However, in India, using subcutaneous LMWH may not be a feasible option for a vast majority of patients under home management. Additionally, while some evidence advocates the use of novel oral anticoagulants (NOACs), in hospitalized settings, most guidelines find no role of NOACs in hospital settings. On the other hand, the resource crunch faced in recent COVID-19 pandemic in India forced physicians to treat many patients in home settings. These patients had been usually prescribed NOACs for ease of administration and adherence. Therefore, there is a need to form a consensus on the use of NOACs to manage CIC in India.

Non-ionic Surfactants as a P-Glycoprotein(P-gp) Efflux Inhibitor for Optimal Drug Delivery-A Concise Outlook.

Significant research efforts have been devoted to unraveling the mystery of P-glycoprotein(P-gp) in drug delivery applications. The efflux membrane transporter P-gp is widely distributed in the body and accountable for restricting drug absorption and bioavailability. For these reasons, it is the primary cause of developing multidrug resistance (MDR) in most drug delivery applications. Therefore, P-gp inhibitors must be explored to address MDR and the low bioavailability of therapeutic substrates. Several experimental models in kinetics and dynamic studies identified the sensitivity of drug molecules and excipients as a P-gp inhibitor. In this review, we aimed to emphasize nonionic surface-active agents for effective reversal of P-gp inhibition. As it is inert, non-toxic, noncharged, and quickly reaching the cytosolic lipid membrane (the point of contact with P-gp efflux protein) enables it to be more efficient as P-gp inhibitors. Moreover, nonionic surfactant improves drug absorption and bioavailability through the various mechanism, involving (i) association of drug with surfactant improves solubilization, facilitating its cell penetration and absorption; (ii) weakening the lateral membrane packing density, facilitating the passive drug influx; and (iii) inhibition of the ATP binding cassette of transporter P-glycoprotein. The application of nonionic surfactant as P-gp inhibitors is well established and supported by various experiments. Altogether, herein, we have primarily focused on various nonionic surfactants and their development strategies to conquer the MDR-causing effects of P-gp efflux protein in drug delivery. Graphical Abstract.

Survival outcomes for patients with nasopharyngeal carcinoma in non-endemic region in the UK treated with intensity modulated based radiotherapy 65 Gy in 30 fractions ± weekly cisplatin chemotherapy.

Background: Nasopharyngeal carcinoma (NPC) is rare in the UK. The aim of the current study was to investigate survival outcomes for patients with NPC treated with (chemo)radiotherapy using 65 Gy in 30 fractions in a non-endemic region. Materials and methods: All consecutive 62 patients with histology proven non-metastatic nasopharyngeal carcinoma diagnosed between January 2009 to June 2019 were included in this retrospective analysis. Results: Median age was 59 years (range:19-81). The majority of patients had stage III disease (66.1%). Induction chemotherapy was given in 21% of patients and 82.3% of patients received concomitant systemic therapy. All patients were treated with 65 Gy in 30 fractions. There was disease recurrence in 17.4% patients. The 5-year disease-free, disease-specific and overall survival were 81.9%, 79.2% and 76.4%, respectively. On univariate analysis, disease recurrence was associated with N-stage (p = 0.047) and overall stage group (p = 0.023). Conclusion: To the best of authors' knowledge, this is the first report of the use of 65 Gy in 30 fractions of radiotherapy ± weekly cisplatin chemotherapy in NPC in a real-world setting. Our results are comparable to that from other non-endemic regions of the world using different dose fractionation of (chemo)radiotherapy. Future randomised control trials are warranted to compare various dose fractionations in these settings.

Elevated USP9X drives early-to-late-stage oral tumorigenesis via stabilisation of anti-apoptotic MCL-1 protein and impacts outcome in oral cancers.

BACKGROUND: Overexpression of anti-apoptotic MCL-1 protein in oral squamous cell carcinoma (OSCC) is linked to disease progression, therapy resistance and poor outcome. Despite its characteristic short half-life owing to ubiquitin-proteasome-dependent degradation, oral tumours frequently show elevated MCL-1 protein expression. Hence, we investigated the role of deubiquitinase USP9X in stabilising MCL-1 protein and its contribution to oral tumorigenesis. METHODS: Expression of MCL-1 and USP9X was assessed by immunoblotting and immunohistochemistry in oral cancer cell lines and tissues. The association between MCL-1 and USP9X was confirmed by coimmunoprecipitation and immunofluorescence. Cell death assessment was performed by MTT, flow cytometry and clonogenic assays. RESULTS: Both USP9X and MCL-1 are significantly elevated in oral premalignant lesions and oral tumours versus normal mucosa. USP9X interacts with and deubiquitinates MCL-1, thereby stabilising it. Pharmacological inhibition of USP9X potently induced cell death in OSCC cells in vitro and in vivo. The elevated expression of USP9X and MCL-1 correlated with poor prognosis in OSCC patients. CONCLUSION: We demonstrate the oncogenic role of USP9X in driving early-to-late stages of oral tumorigenesis via stabilisation of MCL-1, suggesting its potential as a prognostic biomarker and therapeutic target in oral cancers.

Glycation of gut proteins initiates microbial dysbiosis and can promote establishment of diabetes in experimental animals.

Diabetes and obesity is associated with change in the gut microbiota, however, the reason for such transition is still unknown. The secondary complications in diabetes mainly stem from protein glycation, oxidative stress and inflammatory response. It is intended to study the correlation between gut proteins glycation and microbial dysbiosis and thereby progression to diabetes. The study was carried out through feeding high fructose to male Wistar rats and evaluating their gut microbiota. The rate of gut flora excretion via faecal matter was found to decrease on fructose feed for 7 days. Intestinal flora was drastically reduced and pathogenic succession observed. Intestinal fluorescence studies confirmed that there is heavy glycation of gut proteins. Microbes obtained from fructose fed animals could grow on glycated BSA. There was significant increase in level of TNF-α and IFN-γ providing evidence of inflammation. Though microbial dysbiosis was observed in diabetes, the cause for this remained elusive. In the present study we prove that high fructose feed and glycation of the gut proteins probably prevent adherence/survival of the gut microflora in control animals and promotes transition to a changed microflora which is capable of adhering/utilizing glycated proteins as well as high fructose. The changed microbiota, enhanced protein glycation and inflammation help in establishing insulin resistance.

Adsorption of P103 Nanoaggregates on Graphene Oxide Nanosheets: Role of Electrostatic Forces in Improving Nanosheet Dispersion.

Graphene oxide (GO) nanosheet suspension is not stable in physiological ionic fluids. To improve stability, surfactants such as Pluronic 103 (P103) have been tested. Going further, this work investigated whether conferring positive surface charge to the surfactant may improve the adsorption ability of P103 micelles on GO sheets. Positive charge on the surfactant was induced by adding dodecyltrimethylammonium bromide (DTAB, a cationic surfactant) in P103 micelles. Subsequent changes in aggregation parameters were investigated through dynamic light scattering and small-angle neutron scattering studies. DTAB incorporation was accompanied by a steady increase in the ζ potential and mixed micelle formation. At high surface charge density, the interaction between adjacent head groups was distorted, which led to dissociation of mixed micelles. Structural developments during the adsorption of mixed micelles on the sheet surface (mass fractal formation) were monitored in terms of changes in the scattering features of aggregates. These fractals emerged as a result of electrostatic interactions. Our observations point toward the existence of small-sized building blocks at low DTAB concentration (≤4 mM). With a superior adsorption, mixed micelles are expected to occupy the intersheet space and maintain a hydration layer. However, at a higher DTAB concentration (≥10 mM), micelles dissociate to produce DTAB-rich unimers and P103-rich loose aggregates. At this point, sheets tend to aggregate in the solvent, regardless of fractal formation.

Assessing the Usability of Flexor Digiti Minimi Muscle for Opponensplasty: An Anatomic Study.

PURPOSE: The abductor digiti minimi (ADM) and flexor digiti minimi (FDM) muscles have a similar vascular and nerve supply. The purpose of this study was to assess the feasibility of transferring the FDM instead of ADM for thumb opposition. METHODS: Thirty cadaver hands were dissected under loupe magnification to assess the presence of the ADM and FDM muscles as well as their blood and nerve supply. The length of these muscles and their location in relation to the radial aspect of the thumb metacarpophalangeal joint were assessed. RESULTS: The ADM muscle was present in all cadavers whereas the FDM muscle was absent in 33% of hands. When the dimensions were suitable (53%), the more radially located FDM muscle reached the thumb metacarpophalangeal joint more easily. CONCLUSIONS: Although the dissections revealed considerable variability in FDM anatomy, when present, it can have positional advantage over the ADM for opponensplasty. CLINICAL RELEVANCE: In some cases with radial longitudinal deficiency, preservation of ADM function is essential. In these children, the FDM can potentially be explored and transferred if it is found to be suitable.

The Story of the Hand.

This review describes the Story of the Human Hand. It traces the functional needs that led to evolution of the human hand as well as its embryological development. The various in utero stages of formation of the human hand are covered along with a description of the various molecular and genetic factors that control this process.

A ligand-induced structural change in fatty acid-binding protein 1 is associated with potentiation of peroxisome proliferator-activated receptor α agonists.

Peroxisome proliferator-activated receptor α (PPARα) is a transcriptional regulator of lipid metabolism. GW7647 is a potent PPARα agonist that must reach the nucleus to activate this receptor. In cells expressing human fatty acid-binding protein 1 (FABP1), GW7647 treatment increases FABP1's nuclear localization and potentiates GW7647-mediated PPARα activation; GW7647 is less effective in cells that do not express FABP1. To elucidate the underlying mechanism, here we substituted residues in FABP1 known to dictate lipid signaling by other intracellular lipid-binding proteins. Substitutions of Lys-20 and Lys-31 to Ala in the FABP1 helical cap affected neither its nuclear localization nor PPARα activation. In contrast, Ala substitution of Lys-57, Glu-77, and Lys-96, located in the loops adjacent to the ligand-binding portal region, abolished both FABP1 nuclear localization and GW7647-induced PPARα activation but had little effect on GW7647-FABP1 binding affinity. Using solution NMR spectroscopy, we determined the WT FABP1 structure and analyzed the dynamics in the apo and GW7647-bound structures of both the WT and the K57A/E77A/K96A triple mutant. We found that GW7647 binding causes little change in the FABP1 backbone, but solvent exposes several residues in the loops around the portal region, including Lys-57, Glu-77, and Lys-96. These residues also become more solvent-exposed upon binding of FABP1 with the endogenous PPARα agonist oleic acid. Together with previous observations, our findings suggest that GW7647 binding stabilizes a FABP1 conformation that promotes its interaction with PPARα. We conclude that full PPARα agonist activity of GW7647 requires FABP1-dependent transport and nuclear localization processes.

An in vitro toolbox to accelerate anti-malarial drug discovery and development.

BACKGROUND: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. METHODS: Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC-MS/MS. RESULTS: Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. CONCLUSIONS: This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.

Reply to the Letter to Editor Regarding "An Unusual Case of Critical Illness Polyneuromyopathy".

Critical illness myopathy (CIM), critical illness polyneuropathy (CIP), and critical illness polyneuromyopathy (CIPNM) are the group of disorders that are commonly presented as neuromuscular weakness in intensive care unit (ICU) settings. They are responsible for prolonged ICU stay and failure to wean off from mechanical ventilation.1 We report one such case of young female who was admitted with undiagnosed type I diabetes mellitus with diabetic ketoacidosis with severe hypokalemia with sepsis developed acute-onset quadriplegia and diaphragmatic palsy within 72 hours of ICU admission. Detailed investigation led to the diagnosis of critical illness polyneuromyopathy. In view of high morbidity, mortality, and poor prognosis, a guided approach to diagnoses and treatment in earliest possible duration might give better improvement and outcome of the illness. Despite all the odds, our patient showed good clinical improvement and finally got discharged. HOW TO CITE THIS ARTICLE: Mahashabde M, Chaudhary GA, Kanchi G, Rohatgi S, Rao P, Patil R, et al. Reply to the Letter to Editor Regarding "An Unusual Case of Critical Illness Polyneuromyopathy". Indian J Crit Care Med 2020;24(7):604-605.