Modelling alternately recurring events using subject specific hazard estimation approach.

The motivation for this paper is to account for subject specific variations in a Cox proportional hazard model for alternating recurrent events. This is done through two sets of frailty components, whose marginal distributions are bound together by a copula function. The likelihood function involves unobservable variables, which requires the use of the EM algorithm. This leads to intractable integrals, which after some approximations, are solved using computationally intensive techniques. The results are applied to a real-life data. A simulation study is also carried out to check for consistency.

Comparative Effectiveness of Tofacitinib and Adalimumab in Axial Spondyloarthritis: A Real-World Clinical Context Multicenter Study.

INTRODUCTION: Tofacitinib, an oral Janus kinase inhibitor, is a putative choice in the treatment of axial spondyloarthritis (AxSpA). The objective of this study was to compare the effectiveness and tolerability of tofacitinib with adalimumab, in AxSpA, in a real-world clinical setting. METHODS: In this multicentric medical records review study, adult patients with active AxSpA treated with either tofacitinib 5 mg twice daily or adalimumab 40 mg subcutaneously fortnightly were recruited. Effectiveness was measured with Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Drug-cost analysis was calculated with Incremental Cost-Effectiveness Ratio (ICER drug ). RESULTS: Among the 266 patients, 135 were treated with tofacitinib and 131 with adalimumab (follow-up: 6.5 ± 1.6 months). Mean improvement of BASDAI (3.39 ± 0.09 vs. 3.14 ± 1.16, respectively) and that of ASDAS (1.78 ± 0.68 vs. 2.07 ± 2.08, respectively) were comparable between the adalimumab and tofacitinib groups. A higher proportion of patients achieved BASDAI50 response in the second (49.5% vs. 31.6%) and fourth month (83.9% vs. 62.8%) and ASDAS low disease activity in the fourth month (71.6% vs. 47.9%) in the adalimumab group. All disease activity measurements were similar by the sixth month in both groups. A higher proportion of patients in the tofacitinib group than in the adalimumab group required change in therapy (14.8% vs. 7.6%, respectively). ICER drug for adalimumab compared with tofacitinib was US $188.8 per patient in the adalimumab group for each person-month with BASDAI <4. CONCLUSIONS: Tofacitinib showed comparable effectiveness with adalimumab in patients with AxSpA at the sixth month, despite lesser response in the initial months, with favorable ICER drug .

Oncogenic KRAS drives radioresistance through upregulation of NRF2-53BP1-mediated non-homologous end-joining repair.

KRAS-activating mutations are oncogenic drivers and are correlated with radioresistance of multiple cancers, including colorectal cancer, but the underlying precise molecular mechanisms remain elusive. Herein we model the radiosensitivity of isogenic HCT116 and SW48 colorectal cancer cell lines bearing wild-type or various mutant KRAS isoforms. We demonstrate that KRAS mutations indeed lead to radioresistance accompanied by reduced radiotherapy-induced mitotic catastrophe and an accelerated release from G2/M arrest. Moreover, KRAS mutations result in increased DNA damage response and upregulation of 53BP1 with associated increased non-homologous end-joining (NHEJ) repair. Remarkably, KRAS mutations lead to activation of NRF2 antioxidant signaling to increase 53BP1 gene transcription. Furthermore, genetic silencing or pharmacological inhibition of KRAS, NRF2 or 53BP1 attenuates KRAS mutation-induced radioresistance, especially in G1 phase cells. These findings reveal an important role for a KRAS-induced NRF2-53BP1 axis in the DNA repair and survival of KRAS-mutant tumor cells after radiotherapy, and indicate that targeting NRF2, 53BP1 or NHEJ may represent novel strategies to selectively abrogate KRAS mutation-mediated radioresistance.

A systematic review and meta-analysis of mycobacterial infections in patients with idiopathic inflammatory myopathies.

OBJECTIVES: Infections including tuberculosis (TB) are a leading cause of morbidity and mortality in idiopathic inflammatory myopathies (IIM). We systematically reviewed the prevalence of mycobacterial infections in patients with IIM. METHODS: We screened PUBMED, EMBASE and SCOPUS databases and conference abstracts (2015-20) for original articles using Covidence. Pooled estimates of prevalence were calculated. RESULTS: Of 83 studies (28 cohort studies, two case control and 53 case reports), 19 were analysed. Of 14 043 IIM patients, DM (54.41%) was the most common subset among TB. Most studies were from Asia with high prevalence (5.86%, 2.33%-10.60%). Pooled prevalence of mycobacterial infections among IIM was 3.58% (95% CI: 2.17%, 5.85%, P < 0.01). Disseminated and extrapulmonary forms (46.58%; 95% CI: 39.02%, 54.31%, P = 1.00) were as common as pulmonary TB (49.07%; 95% CI: 41.43%, 56.75%, P =0.99) both for I2=0. Muscle involvement, an otherwise rare site, was frequently seen in case reports (24.14%). M. tuberculosis (28.84%) was the most common pathogen followed by Mycobacterium avium complex (3.25%). Non-tuberculous mycobacteria were less common overall (6.25; 95% CI: 3.49%, 10.93%) I2=0, P =0.94. Subgroup analysis and meta-regression based on high vs low TB regions found prevalence 6.61% (2.96%, 11.33%) in high TB regions vs 2.05% (0.90%, 3.56%) in low TB regions. While death due to TB was occasionally reported (P =0.82), successful anti-tubercular treatment was common (13.95%). CONCLUSION: TB is common in IIM, particularly in endemic regions though current data is largely heterogeneous. Extra-pulmonary forms and atypical sites including the muscle are frequent. Limited data suggests fair outcomes, although larger prospective studies may offer better understanding.

Endemic infections, vaccinations, and variability of SARS-COV2 worldwide epidemiology: A cross-sectional study.

The present article aims to analyze epidemiologic aspects of the novel coronavirus pandemic (COVID-19) over different countries across the globe. While analyzing the overall spread of the disease, clusters of countries could be identified where the population-adjusted number of cases and mortality rates (MRs) were significantly different from the others. To draw a comparison over the countries at the same stage of infection, the nature and spread of the infection was evaluated at the 90th day of the pandemic for each country. It was observed that the countries with prevalent malarial transmission tended to have lesser population-adjusted COVID-19 caseloads. It was further observed that high population coverage of the Bacillus Calmette-Guérin vaccination was negatively associated with population-adjusted caseloads and MRs due to COVID-19. The present cross-sectional study is an attempt to bring in several social, economic, and structural confounders into understanding of the nature and spread of this novel pandemic globally.

Rituximab in the treatment of systemic sclerosis-related interstitial lung disease: a systematic review and meta-analysis.

OBJECTIVES: To assess the effect of rituximab (RTX) on the lung function parameters in SSc interstitial lung disease (SSc-ILD) patients. METHODS: PubMed and Embase were searched to identify studies on SSc-ILD treated with RTX, confined to a predefined inclusion and exclusion criteria. A systematic review and meta-analysis were performed on the included studies on changes in forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO) from baseline to 6 and 12 months of follow-up. RESULTS: A total of 20 studies (2 randomized controlled trials, 6 prospective studies, 5 retrospective studies and 7 conference abstracts) were included (n = 575). RTX improved FVC from baseline by 4.49% (95% CI 0.25, 8.73) at 6 months and by 7.03% (95% CI 4.37, 9.7) at 12 months. Similarly, RTX improved DLCO by 3.47% (95% CI 0.99, 5.96) at 6 months and 4.08% (95% CI 1.51, 6.65) at 12 months. In the two studies comparing RTX with other immunosuppressants, improvement of FVC by 6 months in the RTX group was 1.03% (95% CI 0.11, 1.94) greater than controls. At the 12 month follow-up, RTX treatment was similar to controls in terms of both FVC and DLCO. Patients treated with RTX had a lower chance of developing infections compared with controls [odds ratio 0.256 (95% CI 0.104, 0.626), I2 = 0%, P = 0.47). CONCLUSIONS: Treatment with RTX in SSc-ILD was associated with a significant improvement of both FVC and DLCO during the first year of treatment. RTX use was associated with lower infectious adverse events.

Molecular Details of Acetate Binding to a New Diamine Receptor by NMR and FT-IR Analyses.

Acetate anion plays an important role in several biochemical functions such as enzyme reaction, antibody response, and action of receptor molecules. This investigation reports the synthesis and molecular details of a unique receptor, 2-amino-N-(2-amino-benzyl)-benzamide (R) that senses selectively acetate via simultaneous involvement of one aromatic amine group and an amide proton of the receptor molecule. Solution-state NMR, steady-state fluorescence, and FT-IR examinations established that the acetate anion binds to the receptor with 1:1 ratio with high specificity. The binding was stabilized by two H-bond formations between the oxygen atoms of acetate anion and two H atoms, one from amide group and the other from the amine group of the receptor. The binding interaction caused significant changes in the chemical shift of the receptor protons, and the evaluated affinity constant, from the NMR measurements, was found to be 1.87 × 10(4) M(-1). Density functional theory (DFT) analysis further showed a significant rotation of one of the two aromatic rings leading to formation of a 10-member ring involving the acetate anion, amide proton, and the one amine group attached to aromatic ring. The H-bond patterns observed in the crystal structure were significantly changed due to complex formation. However, the changes in the geometrical arrangement in the complex caused a small but significant increase of the fluorescence emission. Acetate geometry and unique positioning of the amide and amine groups of the receptor render the recognition feasible, and DFT analysis estimated ∼30 kJ M(-1) stabilization due to 1:1 complexation. Such positioning and geometrical arrangement may make the receptor very specific to bind acetate anion, and as such R became a very relevant molecule in detection and function of the acetate anion present in complex biochemical systems.

Envisaging Structural Insight of a Terminally Protected Proline Dipeptide by Raman Spectroscopy and Density Functional Theory Analyses.

The proline residue in a protein sequence generates constraints to its secondary structure as the associated torsion angles become a part of the heterocyclic ring. It becomes more significant when two consecutive proline residues link via amide linkage and produce additional configurational constraint to a protein's folding and stability. In the current manuscript we have illustrated conformation preference of a novel dipeptide, (R)-tert-butyl 2-((S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate. The dipeptide crystallized in the orthorhombic crystalline state and produced rod-shaped macroscopic material. The analysis of the crystal coordinates showed dihedral angles (φ, ψ) of the interlinked amide groups as (+72°, -147°) and the dihedral angles (φ, ψ) produced with the next carbonyl were (-68°, +151°), indicating polyglycine II (PGII) and polyproline II (PPII)-like helix states at the N- and C-terminals, respectively. These two states, PGII and PPII, are mirror image configurations and are expected to produce similar vibration bands from the associated carbonyl groups. However, the unique atomic arrangement in the molecule produces three carbonyl groups and one of them was very specific, being part of the main peptide linkage that connects both the pyrrolidine rings. The carbonyl group in the peptide bond exhibited a Raman vibration frequency at ∼1642 cm-1 and is considered a signatory Raman marker band for the peptide bond linking two heterochiral proline residues. The carbonyl group (t-Boc) at the N-terminal of the peptide showed a characteristic vibration at ∼1685 cm-1 and the C-terminal carbonyl group as a part of the ester showed a vibration signature at a significantly high frequency (1746 cm-1). Conformation analyses performed with density functional theory (DFT) calculations depicted that the dipeptide was stabilized in vacuum with dihedral angles (+72°, -154°) and (-72°, +151°) at the N- and C-terminals, respectively. Molecular dynamics (MD) simulation also showed that the peptide conformation having dihedral angles around (+75°, -150°) and (-75°, +150°) at the N- and C-terminals, respectively, was reasonably stable in water. Due to unique absence of the amide N-H, the peptide was ineffective in forming any intramolecular hydrogen bonding. MD investigation, however, revealed an intermolecular hydrogen bonding interaction with the water molecules, leading to its stability in aqueous solution. Metadynamics simulation analysis of the dipeptide in water also supported the PGII-PPII-like conformation at the N- and C-terminals, respectively, as the energetically stable conformation among the other possible combinations of conformations. The possible electronic transitions along with the HOMO-LUMO analysis further depicted the stability of the dipeptide in water and their possible absorption pattern. Time-dependent density functional theory (TDDFT) analysis showed strong negative rotatory strength of the dipeptide around 210 nm in water and acetonitrile, and it could be the source of experimentally observed high-amplitude negative absorption in the circular dichroism (CD) spectra around 200-203 nm. The very weak positive band (signature) in the region at ∼228 nm in CD spectra could also be correlated to the positive rotatory strength at 228 nm observed in ECD. To test the effect of such a dipeptide on a living cell, an MTT assay was performed and the result indicated no cytotoxic effect toward human hepatocellular carcinoma Hep G2 cancer cell lines.

Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (nab) paclitaxel (Abraxane(®)) by the Pediatric Preclinical Testing Program (PPTP).

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane(®)) is FDA approved for the treatment of several adult cancers. Antimitotic agents are essential components for curative therapy of pediatric solid tumors, although taxanes have shown limited activity. Because of the novel formulation, nab-paclitaxel was evaluated against a limited series of Pediatric Preclinical Testing Program (PPTP) solid tumors. PROCEDURES: Nab-paclitaxel was tested against a limited subset of PPTP solid tumor xenograft models at a dose of 50 mg/kg using a q4d × 3 schedule intravenously. RESULTS: Nab-paclitaxel was well tolerated in vivo, producing maximum weight loss of approximately 10% with recovery to baseline weight in the week following the third dose. All 20 xenograft models tested were considered evaluable for efficacy. Nab-paclitaxel induced statistically significant differences in event-free survival (EFS) distribution compared to control in 19 of 20 (95%) of the solid tumors. Objective responses were observed in 12 of 20 (60%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in 5 of 8 Ewing sarcoma models and 6 of 8 rhabdomyosarcomas. There were no objective regressions in either neuroblastoma (n = 2) or osteosarcoma (n = 2) xenograft panels. At the dose tested, systemic exposures of nab-paclitaxel in mice were somewhat greater than those tolerated in humans. CONCLUSIONS: The high level of activity observed against the rhabdomyosarcoma and Ewing sarcoma PPTP preclinical models makes nab-paclitaxel an interesting agent to consider for pediatric evaluation.

Tunable Coassembly of Octaarginine with Thiazolyl Benzenesulfonamides Exerts Variable Antibacterial Activity.

The cationic peptide octaarginine (R8) is a prominent cell-penetrating peptide and has been extensively researched as a carrier of diverse cell-destined cargo. In this work, we describe the coassembly of R8 with small molecule thiazolyl benzenesulfonamide (TBS) derivatives. Physical complexation of R8 with three TBS derivatives across a range of weight ratios results in the formation of a distinctive set of nano- and microstructures. A detailed structural characterization of the R8:TBS-derivative coassemblies has been performed by a combination of FTIR, XRD, SEM, and DSC. The major functional groups that facilitate coassembly include sulfonamide SO2 and NH groups of the TBS derivatives, and the guanidinium of R8, via a combination of cation-π and hydrogen-bonding interactions. The R8:4F-TBS coassembly displays singular topological features compared to R8:4Br-TBS and R8:4CH3-TBS complexes. These differences are attributed to the changes in the preferred orientation of the guanidino groups of R8 with respect to the π-surface of TBS derivatives. The modulation of forces of interaction across the R8:TBS-derivative coassemblies aligns with their respective thermal stabilities. The single-crystal structure of bare 4F-TBS has been subjected to Hirshfeld and 2D fingerprinting analysis and indicates notable variations from the crystal packing of the R8:4F-TBS coassembly. The structural differences among the R8:TBS-derivative coassemblies correlate with distinctive profiles of antibacterial activity in each case. The coassembled structures exert a variable extent of bacterial membrane disruption and damage based on the unique disposition of R8 and the potency of small molecule in each case. The aqueous suspension of R8:4F-TBS displays significant outer membrane disruption and bacterial killing compared with the other complexes. This work successfully demonstrates the hitherto unreported potential for coassembly of cell-penetrating peptides with other entities. The coassembly of R8 with small molecules highlights an attractive strategy for tuning the functional properties of each component.

COPD and glycopyrronium responsiveness assessment: An appraisal.

Clinical Trial Registration: ECR/159/Inst/WB/2013/RR-20. Background: Glycopyrronium bromide (a long-acting antimuscarinic agent: LAMA) appears pharmacokinetically suitable for testing bronchodilator responsiveness as salbutamol (short-acting ß2-agonist: SABA). Exploring the feasibility, acceptability, degree of reversibility with glycopyrronium, and its comparison with that of salbutamol may be intriguing. Methods: New, consecutive, and willing outpatient attendees in the same season of the two consecutive years with chronic obstructive pulmonary disease (FEV1/FVC <0.07; FEV1 <80% of predicted) were subjected to serial responsiveness with inhalation of salbutamol first followed by 50 µg dry powder glycopyrronium [Salbutamol- Glycopyrronium] (phase-1) in the first year and glycopyrronium followed by salbutamol [Glycopyrronium- Salbutamol] (phase-2) in the following year. We looked for the acceptability, adverse reactions, and degree of changes in FEV1, FVC, FEV1/FVC, and FEF25-75 with comparison between the two groups. Results: The [Salbutamol- Glycopyrronium] group (n = 86) were similar in age, body mass index, and FEV1 to the [Glycopyrronium- Salbutamol] group (n = 88). Both the agents could make a significant (P <.0001) improvement in the parameters independently or as add-on when used serially in alternate orders. The intergroup difference at no stage was significant. The sensitive patients to salbutamol (n = 48), glycopyrronium (n = 44), and both (n = 12) have improvement of 165, 189, and 297 mL while a both-insensitive group (n = 70) had barely 44 mL of improvement. The protocol was universally accepted without any adverse events. Conclusion: Serial testing of salbutamol and glycopyrronium responsiveness in alternate orders provides an insight regarding the independent and the add-on effects of these two agents. About 40% of our chronic obstructive pulmonary disease patients had no clinically appreciable difference in FEV1 with the salbutamol + glycopyrronium combination inhalation.

The impact of lockdown on symptoms and health status of patients with chronic airway diseases: An appraisal of patient perceived impressions.

Background: The pandemic-specific lockdown may influence the health status of patients with chronic airflow obstruction (CAO) as COPD, COPD-PH, and chronic asthma. Objectives: To find the impact of the lockdown on symptoms, and the degree of perceived change in physical activity and emotional health with possible reasons including the indicators of ambient air pollution. Methods: A cohort of CAO patients was telephonically enquired regarding their perceived well-being in symptom status, physical activity, and emotional health with the perceived contribution from plausible reasons (regular medication, simple food, no pollution, and family attention) for the change; all being expressed in percentages. The change in symptom scores as 0-39, 40-79, and 80-100 were regarded as 'low', 'medium', and 'high' respectively. The impact of the individual contributing factor was calculated statistically. The assessment of the CAT (COPD assessment test) score and the ambient air pollution (PM2.5 and PM10) was also done for their association with well-being. Results: There was a universal improvement (p < 0.5) in COPD (n = 113), COPD-PH, (n = 40), and chronic asthma, (n = 19) as regards symptoms, physical activity, and emotional health that tallies to overall and individual change in CAT score. There were concomitant reductions in PM10 and PM2.5 levels during the lockdown compared to the same period of the previous year. All the four listed factors contributed with the 'no/low pollution' and 'simple food being the most important; on acting together, they reduced the moderate and severe symptoms impressively. Conclusion: Reduced air pollution and simple food appear most important for the improvement of CAO patients during the lockdown period.

Monitoring Fine and Associative Motor Learning in Mice Using the Erasmus Ladder.

Behavior is shaped by actions, and actions necessitate motor skills such as strength, coordination, and learning. None of the behaviors essential for sustaining life would be possible without the ability to transition from one position to another. Unfortunately, motor skills can be compromised in a wide array of diseases. Therefore, investigating the mechanisms of motor functions at the cellular, molecular, and circuit levels, as well as understanding the symptoms, causes, and progression of motor disorders, is crucial for developing effective treatments. Mouse models are frequently employed for this purpose. This article describes a protocol that allows the monitoring of various aspects of motor performance and learning in mice using an automated tool called the Erasmus Ladder. The assay involves two phases: an initial phase where mice are trained to navigate a horizontal ladder built of irregular rungs ("fine motor learning"), and a second phase where an obstacle is presented in the path of the moving animal. The perturbation can be unexpected ("challenged motor learning") or preceded by an auditory tone ("associative motor learning"). The task is easy to conduct and is fully supported by automated software. This report shows how different readouts from the test, when analyzed with sensitive statistical methods, allow fine monitoring of mouse motor skills using a small cohort of mice. We propose that the method will be highly sensitive to evaluate motor adaptations driven by environmental modifications as well as early-stage subtle motor deficits in mutant mice with compromised motor functions.

Efficacy and safety of intravenous and subcutaneous immunoglobulin therapy in idiopathic inflammatory myopathy: A systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis on the efficacy and safety of intravenous (IVIg) and subcutaneous (SCIg) immunoglobulin (Ig) therapy in the treatment of idiopathic inflammatory myopathy (IIM) and juvenile dermatomyositis (JDM). METHODS: PubMed, Embase and SCOPUS were searched to identify studies on Ig therapy in patients with IIM and/or JDM (2010-2020). Outcome measures were complete response (CR) or partial response (PR) in terms of muscle power and extramuscular disease activity measures on the International Myositis Assessment and Clinical Studies Group (IMACS) core set domains. RESULTS: Twenty-nine studies were included (n = 576, 544 IIM, 32 JDM). Muscle power PR with pooled Ig therapy was 88.5% (95% confidence interval (CI): 80.6-93.5, n = 499) and PR with SCIg treatment was 96.61% (95% CI: 87.43-99.15, n = 59). Pooled PR with first-line use of IVIg was 77.07% (95% CI: 61.25-92.89, n = 80). Overall, mean time to response was 2.9 months (95% CI: 1.9-4.1). Relapse was seen in 22.76% (95% CI: 14.9-33). Studies on cutaneous disease activity and dysphagia showed significant treatment responses. Glucocorticoid and immunosuppressant sparing effect was seen in 40.9% (95% CI: 20-61.7) and 42.2% (95% CI: 20.4-64.1) respectively. Ig therapy was generally safe with low risk of infection (1.37%, 95% CI: 0.1-2.6). CONCLUSIONS: Add-on Ig therapy improves muscle strength in patients with refractory IIM, but evidence on Ig therapy in new-onset disease and extramuscular disease activity is uncertain.

Farnesyl transferase inhibitor treatment of breast cancer cells leads to altered RhoA and RhoC GTPase activity and induces a dormant phenotype.

Farnesyl transferase inhibitors (FTIs) were shown to be effective in modulating tumor growth in Ras-transformed tumor cells. Recent studies have focused on Rho GTPases as putative targets of FTI action. Previously, we demonstrated that FTIs were effective in inhibiting the growth and invasiveness of RhoC GTPase-overexpressing inflammatory breast cancer (IBC) cells however, RhoC activity was increased. In this study, we examine the mechanisms of FTI action on breast cancer cells in culture through modulation of RhoC and RhoA GTPases. We found that FTI inhibition of breast cancer cell growth was reversible and resembled what has been described for an in vitro model of tumor cell dormancy. On FTI treatment, levels of active RhoA decreased significantly, whereas levels of active RhoC increased 3.8-fold. We studied the role of these two GTPases in a fibronectin and basic FGF-induced model of breast cancer cell dormancy. Hypoactivation of RhoA and hyperactivation of RhoC were seen to induce morphology and growth changes consistent with tumor cell dormancy in culture. In addition, the JNK/SAPK pathway was induced on FTI treatment. A pharmacologic inhibitor of the JNK/SAPK pathway significantly reduced the number of dormant cells. This study has implications for the use of FTIs as therapeutic agents as well as potential mechanisms for breast cancer cell dormancy.

Network theoretic analysis of JAK/STAT pathway and extrapolation to drugs and viruses including COVID-19.

Whenever some phenomenon can be represented as a graph or a network it seems pertinent to explore how much the mathematical properties of that network impact the phenomenon. In this study we explore the same philosophy in the context of immunology. Our objective was to assess the correlation of "size" (number of edges and minimum vertex cover) of the JAK/STAT network with treatment effect in rheumatoid arthritis (RA), phenotype of viral infection and effect of immunosuppressive agents on a system infected with the coronavirus. We extracted the JAK/STAT pathway from Kyoto Encyclopedia of Genes and Genomes (KEGG, hsa04630). The effects of the following drugs, and their combinations, commonly used in RA were tested: methotrexate, prednisolone, rituximab, tocilizumab, tofacitinib and baricitinib. Following viral systems were also tested for their ability to evade the JAK/STAT pathway: Measles, Influenza A, West Nile virus, Japanese B virus, Yellow Fever virus, respiratory syncytial virus, Kaposi's sarcoma virus, Hepatitis B and C virus, cytomegalovirus, Hendra and Nipah virus and Coronavirus. Good correlation of edges and minimum vertex cover with clinical efficacy were observed (for edge, rho = - 0.815, R2 = 0.676, p = 0.007, for vertex cover rho = - 0.793, R2 = 0.635, p = 0.011). In the viral systems both edges and vertex cover were associated with acuteness of viral infections. In the JAK/STAT system already infected with coronavirus, maximum reduction in size was achieved with baricitinib. To conclude, algebraic and combinatorial invariant of a network may explain its biological behaviour. At least theoretically, baricitinib may be an attractive target for treatment of coronavirus infection.

High-resolution ultrasonography in carpal tunnel syndrome: role of ancillary criteria in diagnosis and response to steroid injection.

OBJECTIVES: (1) Development and validation of a composite ultrasound score (cUSS) for the diagnosis of carpal tunnel syndrome (CTS). (2) To predict treatment response after local corticosteroid injection. METHODS: Wrists of CTS patients and controls were evaluated with high-resolution ultrasound and cross-sectional area of median nerve at carpal tunnel inlet (CSAp) and outlet (CSAd) and bowing of flexor retinaculum (FRB), flexor tenosynovitis, and intraneural vascularity and echogenicity changes were noted. Patients were prospectively followed after ultrasound-guided corticosteroid injection. RESULTS: We studied 479 wrists of 141 patients and 99 controls. Optimal cut-offs for diagnosing CTS were 9.5 mm2 and 10.5 mm2, respectively, for CSAp and CSAd. A cUSS consisting of the following parameters was developed: age, CSAp, CSAd, FRB, and flexor tenosynovitis and echogenicity changes. External validation of cUSS yielded sensitivity, specificity, and diagnostic accuracy of 91.7%, 87.1%, and 89.8%, respectively. Treatment responses from 88 injections (median duration of follow-up of 6 months) were available with satisfactory initial responses in 69.32% (61/88) and relapses in 30.86% (25/81). Median time to relapse was 2 months. Initial response was predicted by FRB (odds ratio (OR): 5.43, 95% confidence interval (CI): 1.45-20.3, p = 0.012). Relapse was predicted by age (hazard ratio (HR) 1.168, 95% CI: 1.076-1.268, p = 0.0002), male gender (HR: 8.1.02, 95% CI: 2.394-27.422, p = 0.0007), FRB, (HR: 46.982, 95% CI: 5.048-437.293, p = 0.0008), and higher body mass index (HR: 0.238, 95% CI: 0.064-0.892, p = 0.0332). CONCLUSIONS: The developed cUSS has a diagnostic accuracy of 88% for diagnosing CTS. Ultrasound parameters could predict both initial treatment response and relapse. KEY POINTS: • Anatomical ultrasound parameters in addition to nerve cross-sectional area is important for diagnosis of CTS. • A composite US score for diagnosis of CTS was developed with accuracy 88.6%. • Bowing of flexor retinaculum predicts short and long term response to local steroid injection.

Psychological impact of COVID-19 pandemic on general population in West Bengal: A cross-sectional study.

BACKGROUND: COVID-19 pandemic poses a unique medical challenge to the humanity in recent times. The psychological impact of the pandemic itself and the lockdown in particular is likely to be huge. AIM: To assess the psychological impact of COVID-19 pandemic on general population in West Bengal. MATERIALS AND METHODS: It was an online survey which was conducted using Google Forms with link sent using WhatsApp. A 38-item self-designed questionnaire was used for the study. The survey questionnaire would take around 5-7 min to complete. Total 507 responses were received by the stipulated time. RESULTS: Near about five-seventh (71.8%) and one-fifth (24.7%) of the respondents felt more worried and depressed, respectively, in the past 2 weeks. Half of the respondents (52.1%) were preoccupied with the idea of contracting COVID-19 and one-fifth (21.1%) of the respondents were repeatedly thinking of getting themselves tested for the presence of COVID-19 despite having no symptoms. Majority (69.6%) of the respondents were worried about the financial loss they were incurring during the period of lockdown. One-fourth (25.6%) and one-third (30.8%) of the respondents found that COVID-19 pandemic had threatened their existence and they found it difficult to adjust to the new routine during 21-day lockdown period, respectively. CONCLUSION: The index survey suggested that worry and sleep disturbances were common among the respondents in the past 2 weeks. The pandemic threatened the existence of the respondents to a great extent and affected their mental status negatively.

Effects of covariates on alternating recurrent events in accelerated failure time models.

In this article, we model alternately occurring recurrent events and study the effects of covariates on each of the survival times. This is done through the accelerated failure time models, where we use lagged event times to capture the dependence over both the cycles and the two events. However, since the errors of the two regression models are likely to be correlated, we assume a bivariate error distribution. Since most event time distributions do not readily extend to bivariate forms, we take recourse to copula functions to build up the bivariate distributions from the marginals. The model parameters are then estimated using the maximum likelihood method and the properties of the estimators studied. A data on respiratory disease is used to illustrate the technique. A simulation study is also conducted to check for consistency.

Solvent-Assisted Tyrosine-Based Dipeptide Forms Low-Molecular Weight Gel: Preparation and Its Potential Use in Dye Removal and Oil Spillage Separation from Water.

Low-molecular weight gelators (supramolecular, or simply molecular gels) are highly important molecular frameworks because of their potential application in drug delivery, catalysis, pollutant removal, sensing materials, and so forth. Herein, a small dipeptide composed of N-(tert-butoxycarbonyl)pentafluoro-l-phenylalanine and O-benzyl-l-tyrosine methyl ester was synthesized, and its gelation ability was investigated in different solvent systems. It was found that the dipeptide was unable to form gel with a single solvent, but a mixture of solvent systems was found to be suitable for the gelation of this dipeptide. Interestingly, water was found to be essential for gelation with the polar protic solvent, and long-chain hydrocarbon units such as, petroleum ether, kerosene, and diesel, were important for gelation with aromatic solvents. The structural insights of these gels were characterized by field-emission scanning electronic microscopy, atomic force microscopy, Fourier transform infrared analysis, and X-ray diffraction studies, and their mechanical strengths were characterized by rheological experiments. Both of the gels obtained from these two solvent systems were thermoreversible in nature, and these translucent gels had potential application for the treatment of waste water. The gel obtained from dipeptides with methanol-water was used to remove toxic dyes (crystal violet, Eriochrome Black T, and rhodamine B) from water. Furthermore, the gel obtained from dipeptide with assistance from toluene-petroleum ether was used as a phase-selective gelator for oil-spill recovery.