KI mediated one-pot cascade reaction for synthesis of 1,3,4-selenadiazoles.

An efficient catalytic system consisting of KI and K2S2O8 for a one-pot pseudo three-component cascade reaction in the preparation of a diverse array of 1,3,4-selenadiazole derivatives from easily accessible precursors aldehydes, hydrazine and elemental selenium is demonstrated in this paper. Here, KI is used as the surrogate of iodine and K2S2O8 as the oxidant. The key advantages of this protocol include an easy reaction set up, operational simplicity, high functional group tolerance and utilisation of low toxicity chemicals. Further, a radical quenching reaction was also performed to confirm the mechanistic pathway.

Review of soil environment quality in India near coal mining regions: current and future predictions.

Production and utilization of coal are one of the primary routes of accumulation of Toxic Elements (TEs) in the soil. The exploration of trends in the accumulation of TEs is essential to establishing a soil pollution strategy, implementing cost-effective remediation, and early warnings of ecological risks. This study provides a comprehensive review of soil concentrations and future accumulation trends of various TEs (Cr, Ni, Pb, Co, Cu, Cd, Zn, Fe, Mn, and As) in Indian coal mines. The findings revealed that average concentrations of Cr, Mn, Ni, Cu, Zn, Pb, and Co surpass India's natural background soil levels by factors of 2, 4.05, 5.32, 1.77, 9.6, and 6.15, respectively. Geo-accumulation index values revealed that 27.3%, 14.3%, and 7.7% of coal mines are heavily polluted by Ni, Co, and Cu, respectively. Also, the Potential Ecological Risk Index indicates that Cd and Ni are primary contaminants in coal mines. Besides, the health risk assessment reveals oral ingestion as the main exposure route for soil TMs. Children exhibit a higher hazard index than adults, with Pb and Cr being major contributors to their non-carcinogenic risk. In addition, carcinogenic risks exist for females and children, with Cr and Cu as primary contributors. Multivariate statistical analysis revealed that TEs (except Cd) accumulated in the soil from anthropogenic sources. The assessment of future accumulation trends in soil TE concentrations reveals dynamic increases that significantly impact both the ecology and humans at elevated levels. This study signifies a substantial improvement in soil quality and risk management in mining regions.

Brepocitinib, Zimlovisertib, and Ropsacitinib in Hidradenitis Suppurativa.

Kinase Inhibitors for Hidradenitis SuppurativaThree kinase inhibitor immunomodulators (daily oral brepocitinib, zimlovisertib, and ropsacitinib) were evaluated in this randomized, placebo-controlled trial of 194 patients with hidradenitis suppurativa. At 16 weeks, only brepocitinib, a JAK1/TYK2 inhibitor, achieved a higher clinical response than placebo (52% vs. 33%). The other two agents were no better than placebo.

Molecular iodine catalyzed C(sp2)-H sulfenylation of biologically active enaminone compounds under mechanochemical conditions and studies on their biocidal activity including molecular docking and DFT.

Here we demonstrated a solvent free, mechanochemical I2 catalyzed C(sp2)-H sulfenylation of enaminones under grinding condition. Only catalytic amount of I2 is required on silica surface without any external heating. The reaction time has reduced to a great extent in comparison to their solution based counterpart. The frictional energy created by ball-mill on mesoporous silica materials has attracted much attention towards this mechanochemical approach for molecular heterogeneous catalysis. Their large surface area and well defined porous architecture certainly increase the catalytic ability of iodine in this developed protocol. Anti-microbial activities of our synthesized compounds were investigated against two gram positive (Staphylococcus aureus and Bacillus cereus) and two gram negative (Escherichia coli and Klebsiella pneumonia) bacteria. To understand the potency of these compounds (3a-3m) as antimalarial agents, molecular docking studies were also performed. Density functional theory was also used to investigate the chemical reactivity and kinetic stability of the compound 3a-3m.

Efficacy and safety of topical brepocitinib cream for mild-to-moderate chronic plaque psoriasis: a phase IIb randomized double-blind vehicle-controlled parallel-group study.

BACKGROUND: Plaque psoriasis (PsO) is an inflammatory skin disease driven, in part, by the activation of Janus kinase (JAK) signalling pathways. OBJECTIVES: To assess the efficacy and safety of multiple doses of topical brepocitinib, a tyrosine kinase 2/JAK1 inhibitor, in participants with mild-to-moderate PsO. METHODS: This phase IIb multicentre randomized double-blind study was conducted in two stages. In stage 1, participants received one of eight treatments for 12 weeks: brepocitinib 0.1% once daily, 0.3% once or twice daily, 1.0% once or twice daily, 3.0% once daily, or vehicle once or twice daily. In stage 2, participants received brepocitinib 3.0% twice daily or vehicle twice daily. The primary endpoint was the change from baseline in Psoriasis Area and Severity Index (PASI) score at week 12, analysed using analysis of covariance. The key secondary endpoint was the proportion of participants who achieved a Physician Global Assessment response [score of clear (0) or almost clear (1) and an improvement of ≥ 2 points from baseline] at week 12. Additional secondary endpoints included the difference vs. vehicle in change from baseline in PASI, using mixed-model repeated measures, and the change from baseline in Peak Pruritus Numerical Rating Scale at week 12. Safety was monitored. RESULTS: Overall, 344 participants were randomized. Topical brepocitinib did not result in statistically significant changes compared with respective vehicle controls in the primary or key secondary efficacy endpoints for any dose group. At week 12, least squares mean change from baseline in PASI score ranged from -1.4 to -2.4 for the brepocitinib once-daily groups vs. -1.6 for vehicle once daily, and from -2.5 to -3.0 for the brepocitinib twice-daily groups vs. -2.2 for vehicle twice daily. From week 8, change from baseline in PASI score separated from vehicle in all brepocitinib twice daily groups. Brepocitinib was well tolerated, with adverse events (AEs) occurring at similar rates across groups. One participant in the brepocitinib 1.0% once-daily group developed a treatment-related AE of herpes zoster in the neck area. CONCLUSIONS: Topical brepocitinib was well tolerated but did not result in statistically significant changes compared with vehicle when administered at the doses evaluated to treat signs and symptoms of mild-to-moderate PsO.

ß-Cyclodextrin: a green supramolecular catalyst assisted eco-friendly one-pot three-component synthesis of biologically active substituted pyrrolidine-2-one.

A green, novel and eco-efficient synthetic route towards the synthesis of highly substituted bio-active pyrrolidine-2-one derivatives was demonstrated using ß-cyclodextrin, a water-soluble supramolecular solid as a green and eco-benign catalyst at room temperature under water-ethanol solvent medium. The exploration of the green catalyst ß-cyclodextrin for the metal-free one-pot three-component synthesis of a wide range of highly functionalized bio-active heterocyclic pyrrolidine-2-one moieties from easily available aldehydes and amines explains the superiority and uniqueness of this protocol.

Performance of Modified ALMS and BLISS Criteria with Standard of Care Treatment in Two US Health Care Systems.

OBJECTIVE: A retrospective cohort study was undertaken in a predominantly Black population undergoing standard treatment for lupus nephritis (LN) to estimate the incidence of, and risk factors for, complete response (CR) according to modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Study in Lupus Nephritis (mBLISS) criteria by 12 months. METHODS: Patients with biopsy-proven LN class III or IV ± V, urine protein-to-creatinine ratio of ≥1gm/gm and estimated glomerular filtration rate of >50 ml/minute/1.73 m2 at the time of the incident LN flare were included. The clinical, treatment, and laboratory factors associated with CR were identified using multivariable Cox regression. RESULTS: Of 173 patients, 86.1% were women, 77.5% were Black, and over half (59.5%) had non-commercial insurance. By 12 months, 20.6% (95% confidence interval (95% CI) 14.6-28.6%) achieved mALMS CR and 33.7% (95% CI 26.4-42.4%) achieved mBLISS CR. Factors associated with mBLISS CR were commercial insurance (adjusted CR ratio = 3.5 [95% CI 1.9-6.7]; P < 0.001), albumin (adjusted CR ratio = 1.8 per 1 gm/dl increase in albumin; P = 0.02), and low C4 (adjusted CR ratio = 2.6; P = 0.03). Cumulative incidence of end-stage renal disease (ESRD) at 3 years was 23.1% (95% CI 15.7-31.3%) and 6.1% (95% CI 2.8-11.1%) for death. Patients with non-commercial insurance were more likely to develop ESRD, with cumulative incidence of 30.4% (95% CI 19.6-41.9%) compared to 12.7% (95% CI 5.0-24.2%) for patients with commercial insurance (P = 0.024). CONCLUSION: In a primarily Black, uninsured LN population, despite achieving similar CR rates at 12 months, the incidence of ESRD and death exceeded those observed in controlled clinical trials with placebo arms.

Whole-Genome Shotgun (WGS) Sequence of cis-Isoprene Polymer-Degrading Nocardia sp. strain BSTN01.

Species belonging to the genus Nocardia are known to be facultative human pathogens. There are also reports of Nocardia species capable of degrading various forms of rubber. Here, we report the whole-genome shotgun (WGS) sequence of Nocardia sp. strain BSTN01, isolated from stored water in latex-collecting cups thrown away near a local rubber processing unit in Tripura, India.

Environmentally benign approach towards C-S cross-coupling reaction by organo-copper(II) complex.

C-S cross-coupling reaction in water giving an excellent yield of the desired C-S coupled product by using a newly developed Bis[2-(4,5-diphenyl-1H-imidazol-2-yl)-4-nitrophenolato] copper(II) dehydrate complex as catalyst. Although it was the first report of the synthesis of such a novel organo-copper complex from our laboratory, its potential catalytic application was not tested so far. Keeping this in mind and based on our anticipation, we developed a greener route for the C-S coupling reaction. The result is very interesting and comprises the subject matter of this report.

Robust group sequential designs for trials with survival endpoints and delayed response.

Randomized clinical trials in oncology typically utilize time-to-event endpoints such as progression-free survival or overall survival as their primary efficacy endpoints, and the most commonly used statistical test to analyze these endpoints is the log-rank test. The power of the log-rank test depends on the behavior of the hazard ratio of the treatment arm to the control arm. Under the assumption of proportional hazards, the log-rank test is asymptotically fully efficient. However, this proportionality assumption does not hold true if there is a delayed treatment effect. Cancer immunology has evolved over time and several cancer vaccines are available in the market for treating existing cancers. This includes sipuleucel-T for metastatic hormone-refractory prostate cancer, nivolumab for metastatic melanoma, and pembrolizumab for advanced nonsmall-cell lung cancer. As cancer vaccines require some time to elicit an immune response, a delayed treatment effect is observed, resulting in a violation of the proportional hazards assumption. Thus, the traditional log-rank test may not be optimal for testing immuno-oncology drugs in randomized clinical trials. Moreover, the new immuno-oncology compounds have been shown to be very effective in prolonging overall survival. Therefore, it is desirable to implement a group sequential design with the possibility of early stopping for overwhelming efficacy. In this paper, we investigate the max-combo test, which utilizes the maximum of two weighted log-rank statistics, as a robust alternative to the log-rank test. The new test is implemented for two-stage designs with possible early stopping at the interim analysis time point. Two classes of weights are investigated for the max-combo test: the Fleming and Harrington (1981) Gρ,γ$G^{\rho , \gamma }$ weights and the Magirr and Burman (2019) modest (τ∗)$ (\tau ^{*})$  weights.

One-pot three-component tandem annulation of 4-hydroxycoumarine with aldehyde and aromatic amines using graphene oxide as an efficient catalyst.

A convenient and efficient solvent-free, facile, one-pot three-component graphene oxide catalysed approach has been described for the synthesis of chromeno-[4,3-b]quinolin-6-one derivatives from 4-hydroxycoumarin with aldehydes and aromatic amines. Graphene oxide (GO) has proved to be a new class of heterogeneous carbocatalyst which could be easily recovered and reused up to 5th run without significant loss of its catalytic activity. A broad scope of substrate applicability is offered and a plausible mechanism is also suggested for this developed protocol.

A Short Review on Polymeric Biomaterials as Additives for Lubricants.

With increasing environmental concerns and the depletion of petroleum resources, the development of lubricant additives from bioresources has attracted much attention recently. In this review, we reported a few polymers and polymer composites that are synthesized from vegetable oils (soybean oil, sunflower oil, rice bran oil, and castor oil) and used as multifunctional additives in the formulation of eco-friendly lubricant compositions. We mentioned the preparation of vegetable oil-based homo- and copolymers and their characterization by different spectral techniques (FTIR/NMR). The average molecular weights of the polymers are determined by gel permeation chromatography (GPC). Performance evaluations of the polymeric materials mainly as a viscosity index improver (VII), pour point depressant (PPD), and most importantly antifriction additives when blended with lubricating base oils are indicated. Standard ASTM methods have been applied to evaluate their performances. The findings have shown that all the additives discussed are non-toxic, biodegradable, and showed excellent performances compared to commercial petroleum-based additives.

ß-Cyclodextrin: a supramolecular catalyst for metal-free approach towards the synthesis of 2-amino-4,6-diphenylnicotinonitriles and 2,3-dihydroquinazolin-4(1H)-one.

ß-Cyclodextrin, a green and widespread supramolecular catalyst, has been explored as a highly proficient promoter for the metal-free one-pot multi-component synthesis of a vast range of highly functionalized bioactive heterocyclic moiety, 2-amino-4,6-diphenylnicotinonitriles and 2,3-dihydroquinazolin-4(1H)-one, from easily available precursor aldehydes. The main endeavor of these protocols is to explore this organic supramolecule in one-pot multi-component synthesis. Absence of metal catalyst or toxic acid and harsh reaction conditions, excellent functional group tolerance, inexpensive, greener and environmentally safe protocol are the key advantages of this work.

Convenient one-pot synthesis of 1,2,4-oxadiazoles and 2,4,6-triarylpyridines using graphene oxide (GO) as a metal-free catalyst: importance of dual catalytic activity.

A convenient and efficient process for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles and 2,4,6-triarylpyridines has been described using an inexpensive, environmentally benign, metal-free heterogeneous carbocatalyst, graphene oxide (GO). GO plays a dual role of an oxidizing agent and solid acid catalyst for synthesizing 1,2,4-oxadiazoles and triarylpyridines. This dual catalytic activity of GO is due to the presence of oxygenated functional groups which are distributed on the nanosheets of graphene oxide. A broad scope of substrate applicability and good sustainability is offered in this developed protocol. The results of a few control experiments reveal a plausible mechanism and the role of GO as a catalyst was confirmed by FTIR, XRD, SEM, and HR-TEM analysis.

Biological attenuation of arsenic and nitrate in a suspended growth denitrifying-sulphidogenic bioreactor and stability check of arsenic-laden biosolids.

Co-occurrence of arsenic and nitrate in groundwater sources at a wide range of concentrations is reported. In this work, performance of suspended growth semi-batch reactor was assessed for co-removal of arsenic and nitrate from simulated groundwater to meet the drinking water standards in the absence of iron. The bioreactor was inoculated with mixed bacterial culture and operated in the absence of oxygen for more than 450 days under varying influent arsenate (200-800 µg/L), nitrate concentrations (50-250 mg/L), and hydraulic retention time of 3-6 days. Complete nitrate removal was observed at all tested concentrations. Arsenic removal was found to meet drinking water standards from initial concentrations and up to 600 µg/L. The extended toxicity characteristic leaching procedure leaching experiments indicated that arsenic-laden biosolids would not constitute a hazardous waste. The arsenic leaching was found to increase with an increase in dissolved oxygen and the final leachate concentrations of arsenic were below 150 µg/L. The leaching experiments suggested maintaining non-alkaline conditions for minimum arsenic release from arsenic biosolids formed under sulphidogenic conditions. This study is the first to report that nitrate and arsenic can be simultaneously removed to meet drinking standards in a suspended growth bioreactor.

Polyacrylate-magnetite nanocomposite as a potential multifunctional additive for lube oil.

The application of polymer nanocomposites (PNCs) in lubricant industry has attracted considerable interest due to their much enhanced properties compared to neat polymers. In this study, magnetite (Fe3O4) nanoparticles (NPs) were synthesized. Then PNCs were prepared by reinforcing these NPs in the homopolymer of dodecyl acrylate in different percentages. The characterization of the prepared NPs and PNCs was done by different analytical techniques. Thermal stability is determined through thermogravimetric analysis (TGA). Performance evaluation of the PNCs as viscosity index improver, pour point depressant and antiwear additive was carried out by blending them with a mineral base stock at different percentage ratios. Standard ASTM methods are followed to carry out the evaluations. It is found that with increasing the percentage of nanocomposites in the base stock, the overall performance of the furnished lubricant is enhanced.

Formulation of Extended-Release Beads of Lamotrigine Based on Alginate and Cassia fistula Seed Gum by QbD Approach.

AIM: This study was focused on the formulation of the multi-unit extended-release peroral delivery device of lamotrigine for better management of epilepsy. BACKGROUND: The single-unit extended-release peroral preparations often suffer from all-or-none effect. A significant number of multi-unit delivery systems have been reported as a solution to this problem. But most of them are found to be composed of synthetic, semi-synthetic or their combination having physiological toxicity as well as negative environmental impact. Therefore, fabrication and formulation of multi-unit extended-release peroral preparations with natural, non-toxic, biodegradable polymers employing green manufacturing processes are being appreciated worldwide. OBJECTIVE: Lamotrigine-loaded extended-release multi-unit beads have been fabricated with the incorporation of a natural polysaccharide Cassia fistula seed gum in calcium-cross-linked alginate matrix employing a simple green process and 23 full factorial design. METHODS: The total polymer concentration, polymer ratio and [CaCl2] were considered as independent formulation variables with two different levels of each for the experiment-design. The extended-release beads were then prepared by the ionotropic gelation method using calcium chloride as the crosslinkerions provider. The beads were then evaluated for drug encapsulation efficiency and drug release. ANOVA of all the dependent variables such as DEE, cumulative % drug release at 2h, 5h, 12h, rate constant and dissolution similarity factor (f2) was done by 23 full factorial design using Design-Expert software along with numerical optimization of the independent variables in order to meet USP-reference release profile. RESULTS: The optimized batch showed excellent outcomes with DEE of 84.7 ± 2.7 (%), CPR2h of 8.41± 2.96 (%), CPR5h of 36.8± 4.7 (%), CPR12h of 87.3 ± 3.64 (%) and f2 of 65.9. CONCLUSION: This approach of the development of multi-unit oral devices utilizing natural polysaccharides might be inspiring towards the world-wide effort for green manufacturing of sustained-release drug products by the QbD route.

Adaptive multiarm multistage clinical trials.

Two methods for designing adaptive multiarm multistage (MAMS) clinical trials, originating from conceptually different group sequential frameworks are presented, and their operating characteristics are compared. In both methods pairwise comparisons are made, stage-by-stage, between each treatment arm and a common control arm with the goal of identifying active treatments and dropping inactive ones. At any stage one may alter the future course of the trial through adaptive changes to the prespecified decision rules for treatment selection and sample size reestimation, and notwithstanding such changes, both methods guarantee strong control of the family-wise error rate. The stage-wise MAMS approach was historically the first to be developed and remains the standard method for designing inferentially seamless phase 2-3 clinical trials. In this approach, at each stage, the data from each treatment comparison are summarized by a single multiplicity adjusted P-value. These stage-wise P-values are combined by a prespecified combination function and the resultant test statistic is monitored with respect to the classical two-arm group sequential efficacy boundaries. The cumulative MAMS approach is a more recent development in which a separate test statistic is constructed for each treatment comparison from the cumulative data at each stage. These statistics are then monitored with respect to multiplicity adjusted group sequential efficacy boundaries. We compared the powers of the two methods for designs with two and three active treatment arms, under commonly utilized decision rules for treatment selection, sample size reestimation and early stopping. In our investigations, which were carried out over a reasonably exhaustive exploration of the parameter space, the cumulative MAMS designs were more powerful than the stage-wise MAMS designs, except for the homogeneous case of equal treatment effects, where a small power advantage was discernable for the stage-wise MAMS designs.

Bacterially-assisted recovery of cadmium and nickel as their metal sulfide nanoparticles from spent Ni-Cd battery via hydrometallurgical route.

Soaring demand for technology metals (e.g., Cd, Ni) and its ever-depleting primary resources ask for alternative recovery from secondary sources. Ni-Cd battery is one such source that can abridge the gap between demand and supply of such metals. Biogenic recovery, being environmentally benign, is explored for Cd and Ni recovery to manage the menace of spent Ni-Cd battery. Studies with 20, 40 and 60 mg/L Cd2+ initial concentrations in batch mode (in triplicates) at pH 7.0 ± 0.2, 30 ± 0.5 °C and 120 rpm were conducted using sulfate-reducing bacteria for 10 days. Analysis of extracellular polymeric substance revealed that protein secretion was enhanced, thereby forming Cd-EPS binding. Biosolids were collected and freeze-dried for morphological analysis viz. FESEM/EDX, PXRD and TEM, which revealed the formation of CdS nanoparticles (JCPDS card #00-042-1411) in range of 2-6 nm. Similarly, combined effect with 5, 10 and 20 mg/L Ni2+ at 20 mg/L Cd2+ were also investigated. Furthermore, to test the efficacy for real field application, spent Ni-Cd battery was dismantled and its powder was characterized, digested with concentrated HCl at 70 °C and was fed in batch mode after cooling, wherein nanoparticles of Ni and Cd sulfides were formed that has potential as semi-conducting material.

A practical approach on reuse of drinking water treatment plant residuals for fluoride removal.

The sustainable management of the voluminous waste from drinking water treatment plants has motivated environmental researchers towards several reuse options. Water treatment residues (WTR) are proven adsorbent for remediation of many water- and soil-borne anions (perchlorate, selenium and arsenic), and may be able to remove fluoride from contaminated water. In this study, the sustainable reuse of the freely available waste of the drinking water treatment plants, namely WTR, was explored for their fluoride removal potential to meet drinking water standards. WTR was characterized by specific surface area, Fourier transform infrared (FT-IR), scanning electron microscopy and X-ray powder diffraction (XRD). Batch adsorption experiments were conducted as a function of WTR dose, contact time, agitation speed, initial fluoride concentration, initial temperature and water pH to get best adsorption capacity. About 90% fluoride removal (from initial 5.0 mg/L) was observed within 2 h contact time at WTR dose of 28 g/L. Also, WTR effectively removed fluoride in the pH range of 5-8, whereas removal efficiency decreased at pH 9 or higher. The adsorption equilibrium was established within 120-150 min. Adsorption isotherm data were best fit to Langmuir (R 2 = 0.984) and Freundlich models (R 2 = 0.983), while adsorption kinetic study exhibited that second-order kinetic model was followed with rate constant of 0.038 g/mg min. The FT-IR and XRD analyses affirmed that the metal hydroxyl and metal oxide groups contributed to the fluoride removal. The experimental results show the promising potential of WTR as an adsorbent in fluoride removal from real contaminated groundwater.