A Real-World Effectiveness Study Using a Mobile Application to Evaluate Early Outcomes with Upadacitinib in Rheumatoid Arthritis.

INTRODUCTION: The impact of upadacitinib on rheumatoid arthritis (RA) symptoms was evaluated during the first 12 weeks of treatment via patient-reported outcomes (PROs) using a mobile health application (app). METHODS: Participating rheumatologists from the CorEvitas RA Registry (prospective, observational cohort) recruited patients with RA initiating upadacitinib treatment. A modified version of the ArthritisPower® app was used to collect PROs, including the Routine Assessment of Patient Index Data 3 (RAPID3), duration of morning joint stiffness, and the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue 7a Short Form at baseline and weeks 1-4, 8, and 12. RAPID3 responses over time were assessed using Kaplan-Meier estimation to determine the proportion of patients achieving disease activity improvement and minimal clinically important difference (MCID). Results were analyzed for all patients initiating upadacitinib and a subsample of TNF inhibitor (TNFi)-experienced patients with moderate to severe disease at baseline. RESULTS: A total of 103 patients with RA initiating upadacitinib (62.1% TNFi-experienced) were included. At week 12, 53 patients (51.4%) completed the study and provided PRO data via the app. Among all patients, improvements in RAPID3, pain, morning stiffness, and fatigue were observed at week 1 and were maintained or further improved through week 12. At week 12, 37.5% of patients achieved RAPID3 low disease activity. Starting at week 1, improvements in RAPID3 disease activity category (19.4% of patients) and achievement of MCID (16.3%) were reported, with nearly 50% of patients achieving these outcomes by week 4 (RAPID3 category: 48.8%; MCID: 49.2%) and 60% by week 12 (RAPID3 category: 59.6%; MCID: 59.8%). TNFi-experienced patients generally reported similar outcomes. Patient-reported medication convenience and compliance were generally high. CONCLUSIONS: In this real-world cohort of patients with RA, treatment with upadacitinib was associated with early and significant improvement in RAPID3, pain, morning stiffness, and fatigue regardless of prior TNFi experience. Clinically meaningful improvement in RAPID3 patient-reported disease activity was observed as early as week 1, with continued improvement reported through week 12.

Comparative microplastic load in two decapod crustaceans Palinurus elephas (Fabricius, 1787) and Nephrops norvegicus (Linnaeus, 1758).

The present work compares microplastics (MPs) contamination in two charismatic crustaceans: European spiny lobster Palinurus elephas and langoustine Nephrops norvegicus. Samples (P. elephas n = 14; N. norvegicus n = 15) were collected between 76 and 592 m depth, from four sites in west Sardinia, Italy. An extraction protocol was applied on stomachs and intestines, separately, and over 500 particles were further characterized through µFT-IR. We document 100 % occurrence in specimens from both species, with P. elephas being significantly more contaminated (9.1 ± 1.75 vs. 3.2 ± 0.45 MPs individual-1), ingesting larger MPs with different polymeric composition. The scavenging-based feeding strategy of both species could explain such exposure to MPs, mostly derived by single-use plastic. The overall results highlight that both species are clearly affected by plastic pollution, being valuable bioindicators and charismatic species that could thus represent excellent flagship species for raising awareness toward the global issue of plastic in the marine environment.

Whole genome sequencing and characteristics of extended-spectrum beta-lactamase producing Escherichia coli isolated from poultry farms in Banaskantha, India.

Worldwide dissemination of extended-spectrum -lactamase (ESBL)-producing Escherichia coli constitutes an emerging global health issue, with animal food products contributing as potential reservoirs. ESBL E. coli infection is associated with the high mortality and mobility rate in developing countries due to less susceptibility to antibiotics. The present study aimed to elucidate the molecular characteristics and sequence-based analysis of ESBL E. coli in the Gujarat state of India. This study included 108 E. coli strains were isolated from different poultry farms (broiler and layer) in the Banaskantha District. PCR was employed to identify genotypic ESBL-producing antimicrobial resistance genes. Overall, a high occurrence of ESBL genes was found in poultry farms due to the high usage of antimicrobials. The PCR analysis revealed that 79.62% of isolates were detected positive with one or more ESBL genes. Among them, bla TEM (63.88%) was found to be the predominant genotype, followed by bla SHV (30.55%) and bla OXA (28.70%). In the bla CTX-M group, a higher occurrence was observed in bla CTX-M-9 (23.14%), followed by bla CTX-M-2 (24.07%) and bla CTX-M-1 (22.22%). We used the whole-genome sequencing (WGS) method to evaluate the antimicrobial resistance genes, virulence factors, single nucleotide polymorphisms (SNPs), plasmid replicons, and plasmid-mediated AMR genes of one ESBL E. coli isolated. We examined the genetic relatedness of a human pathogenic E. coli strain by comparing its sequence with the broad geographical reference E. coli sequences. Escherichia coli ST 681 was determined using multi-locus sequence typing. We compared our findings to the reference sequence of Escherichia coli str. K- 12 substr. MG1655. We found 24,937 SNPs with 21,792 in the genic region, 3,145 in the intergenic region, and six InDels across the genome. The WGS analysis revealed 46 antimicrobial resistance genes and seven plasmid-mediated AMR genes viz., tetA, qnrS1, dfrA14, sul2, aph(3")-lb, aph(6)-ld, and Aph(3')-la. The ST 681 was found to have Cib, traT, and terC virulence factors and two plasmid replicons, IncFII(pHN7A8) and IncI1-I(Alpha). This study revealed a higher occurrence of ESBL E. coli detected in poultry.

Human gingival mesenchymal stem cells retain their growth and immunomodulatory characteristics independent of donor age.

Aging has been reported to deteriorate the quantity and quality of mesenchymal stem cells (MSCs), which affect their therapeutic use in regenerative medicine. A dearth of age-related stem cell research further restricts their clinical applications. The present study explores the possibility of using MSCs derived from human gingival tissues (GMSCs) for studying their ex vivo growth characteristics and differentiation potential with respect to donor age. GMSCs displayed decreased in vitro adipogenesis and in vitro and in vivo osteogenesis with age, but in vitro neurogenesis remained unaffected. An increased expression of p53 and SIRT1 with donor age was correlated to their ability of eliminating tumorigenic events through apoptosis or autophagy, respectively. Irrespective of donor age, GMSCs displayed effective immunoregulation and regenerative potential in a mouse model of LPS-induced acute lung injury. Thus, we suggest the potential of GMSCs for designing cell-based immunomodulatory therapeutic approaches and their further extrapolation for acute inflammatory conditions such as acute respiratory distress syndrome and COVID-19.

Scattered accumulation hotspots of macro-litter on the seafloor: Insights for mitigation actions.

Marine litter is an ever-increasing problem that demands immediate reduction plans and mitigation actions that should act synergically to efficiently meet ambitious goals. Since the seafloor has been recognized as the major sink for marine debris, the study of litter accumulation dynamics represent a fundamental tool to evaluate possible removal actions. We analysed a 7 years (2013-2019) standardized data series collected along Sardinian fishing grounds through MEDiterranean International Trawl Survey, for which estimates of density and weight of seafloor macro-litter were calculated for over 707 hauls. Results show the absence of any temporal trend in seafloor macro-litter density and weight, but rather indicate a spatial and bathymetric segregation of different litter categories. Our data showed how different sources and physical features of macro-litter items (i.e., plastic and fishing gear, rubber, glass, metals, and cloth) led to spatially segregated accumulation hotspots. We also point out here how the identification of seafloor macro-litter hotspots using aggregated data that include plastic items could obscure the identification of other segregated but yet relevant hotspots of other macro-litter categories accumulated in the marine environment. These hotspots often occurred at shallower depths and closer to coastlines, thus representing potential spots where eventual future litter removal action could be prioritized.

Scattered accumulation hotspots of macro-litter on the seafloor: Insights for mitigation actions.

Marine litter is an ever-increasing problem that demands immediate reduction plans and mitigation actions that should act synergically to efficiently meet ambitious goals. Since the seafloor has been recognized as the major sink for marine debris, the study of litter accumulation dynamics represents a fundamental tool to evaluate future removal actions. We analysed a 7 years (2013-2019) standardized data series collected along Sardinian fishing grounds through MEDiterranean International Trawl Survey, for which estimates of density and weight of seafloor macro-litter were calculated over 707 hauls. Results show the absence of any temporal trend in seafloor macro-litter density and weight, but rather indicate a spatial and bathymetric segregation of different litter categories. Our data showed how different sources and physical features of macro-litter items (i.e., plastic and fishing gears, rubber, glass, metal and textile) led to spatially segregated accumulation hotspots. These hotspots often occurred at shallower depths and closer to coastlines, representing spots where future litter removal action could be prioritized. We also point out here how the identification of seafloor macro-litter hotspots using aggregated data that include plastic items could indeed hide the identification of hotspots of other less abundant but yet detrimental macro-litter categories accumulated in the marine environment.

Healthcare Resource Use in Patients with Immune-Mediated Conditions Treated with Targeted Immunomodulators During COVID-19 Pandemic: A Retrospective Claims Analysis.

INTRODUCTION: The impact of the COVID-19 pandemic on routine medical care may result in altered healthcare resource use in patients with immune-mediated conditions. The aim of this study was to determine the impact of treatment interruptions in patients with and without COVID-19 infections who were treated with targeted immunomodulators (TIMs) in the USA. METHODS: Data from the IBM® MarketScan® Research Databases were analyzed in patients with immune-mediated conditions from January 1, 2018, through December 31, 2020. Healthcare resource use (HCRU) including hospitalizations, emergency department (ED) visits, in-person outpatient visits, and respiratory outcomes was assessed in a cohort of patients without COVID-19 who had uninterrupted versus interrupted TIM use. The impact of treatment interruption on HCRU and respiratory outcomes was also evaluated in a cohort of patients with COVID-19. Results from adjusted logistic regression were reported as adjusted odds ratios (aORs) with 95% confidence intervals. RESULTS: Approximately 25% of patients in both the COVID-19 (N = 787) and non-COVID-19 cohorts (N = 77,178) experienced interruptions in TIM therapy. In the non-COVID-19 cohort, the likelihood of being hospitalized was 20% less in patients with uninterrupted versus interrupted TIM use (aOR = 0.80, 95% CI 0.71-0.90). Patients with uninterrupted TIM use had a similar likelihood of an ED visit (aOR = 0.99, 95% CI 0.91-1.08) and respiratory outcome (aOR = 0.97, 95% CI 0.71-1.31) versus patients with interrupted TIM use. The likelihood of having an in-person outpatient visit was 87% greater in patients with uninterrupted versus interrupted TIM use (aOR = 1.87, 95% CI 1.81-1.94). Similar findings were observed in the COVID-19 cohort. CONCLUSION: This analysis of real-world claims data showed that uninterrupted TIM use was not associated with an increased likelihood of hospitalizations, ED visits, or negative respiratory outcomes compared to interrupted TIM use among patients with immune-mediated conditions, regardless of COVID-19 diagnosis.

Improvement of quantum efficiency through Gd3+ to Eu3+ energy transfer in YF3 phosphor.

This paper reports the energy transfer from Gd3+ to Eu3+ in YF3 and the consequent downconversion luminescence for the YF3 :Gd3+ , Eu3+ fluoride phosphor. The phosphor was synthesized using a soft chemical route, followed by a reactive atmosphere process. Because of the wide band gap in YF3 and the correct energy site for 8 S7/2 -6 GJ transitions of Gd3+ ions, fluoride YF3 doped with Gd3+ -Eu3+ were studied in their vacuum-ultraviolet (VUV) spectral regions. Powder X-ray diffraction (XRD) analysis showed the structural purity of YF3 . VUV excitation and emission properties were explored using a VUV synchrotron radiation beam line. Downconversion of energy from VUV (157 nm) to visible light with quantum efficiency c. 189% was seen. This YF3 :Gd3+ , Eu3+ phosphor would be an option for mercury-free fluorescence lamps.

Morpho-histochemical adaptations of the digestive tract in Gangetic mud-eel Ophichthys cuchia (Hamilton 1822) support utilization of mud-dwelling prey.

Freshwater mud-eel, Ophichthys cuchia is nocturnal, carnivorous and economically important fish, yet its digestive physiology is unknown. We therefore studied the gastrointestinal (GI) tract of O. cuchia using morphological, osteological, histological and histochemical approach to understand how the structural adequacy of GI tract helps in acquisition of bottom and mud-dwelling prey and supports utilization of uncommon food resources. Morphologically the GI tract showed typical features of carnivorous fishes in the form of sub-terminal mouth, short muscular esophagus, expendable stomach, short intestine and rectum. Osteological investigation clearly showed that the specialized arrangement of teeth in the oral cavity and pharyngeal region helps in digging and manipulation of bottom and mud-dwelling prey. Longitudinal mucosal folds, stratified squamous epithelium with numerous goblet cells of esophagus protect mucosa from mechanical harm and also allow easy transit of prey into the stomach. Large-sized rugae of stomach are complemented with numerous gastric glands which together increase the transit time of carnivorous food stuff and ensure its complete digestion. The pylorus specifically allows only digested and finely ground food stuff into the intestine and thus avoids the intestinal blockage due to entry of undigested food. The enterocytes and goblet cells of intestine are absorptive and lubricative in their functions respectively. A significant increase in the number of goblet cells and thickness of muscularis from the intestine to the rectum was evident which facilitates the easier transit of food, protection for the epithelium from abrasion, and helps in defecation. Histochemistry revealed that the mucins are secreted throughout the GI tract and thus catalyze faster digestion of carnivorous food stuff, providing protection to mucosal membrane from abrasion, acts as a co-factor to support digestion, absorption of proteins, ions, fluids and helps in defecation. The outcome of this study clearly supports the notion that structural adaptations in the digestive tract of fishes can be effectively used as a blueprint to understand why and how particular fish species feed and use unique food. Additionally, the structural and functional adequacy of the digestive tract helps the fishes to acquire and utilize novel habitats and food resources. The results presented in this study will serve as a reference point for future studies, which focus primarily on understanding the evolution of carnivory in Synbranchids.

Assessing disease severity in bio-naïve patients with RA on treatment with csDMARDs: insights from the Corrona Registry.

INTRODUCTION: This study aimed to characterize disease burden among patients with rheumatoid arthritis (RA) with moderate-to-high disease activity who had received conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) monotherapy for ≥ 6 months but had not advanced to a biologic therapy. METHODS: Patients enrolled in the US Corrona RA Registry between June 1, 2014, and January 30, 2018, with 6 months of continuous csDMARD monotherapy, with moderate-to-high disease activity, who remained biologic naive, and who had ≥ 1 follow-up visit were identified. Disease activity was assessed among patients with a 6-month follow-up visit (± 3 months). Descriptive statistics were used to compare demographics and disease characteristics between patients with or without treatment advancement. RESULTS: The study included 409 patients with a disease activity assessment at 6 months (mean (SD) age 65.9 (12.6) years; mean duration of csDMARD therapy 407 (221) days). Of those patients, more than half (54%, n = 219) remained in moderate-to-high disease activity. Patients remaining in moderate-to-high vs. remission-to-low disease activity had higher baseline swollen (6.1) and tender joint counts (6.8). Over the 6-month period, treatment advancement occurred in 29% of patients. Those who advanced treatment (n = 118) vs. did not advance treatment (n = 291) were younger, had a shorter duration of RA, had higher disease activity, and reported higher levels of pain and fatigue. CONCLUSIONS: The substantial number of patients with persistent moderate-to-high disease on csDMARDs over a 6-month period and who did not advance treatment indicates that there is considerable need for a treat-to-target approach to care for patients with RA.Key Points•For patients with RA and an inadequate response to treatment with initial csDMARD monotherapy, guidelines recommend treatment advancement; however, this may not be occurring in real-world clinical settings.•In the current study, a substantial proportion of patients (54%) on csDMARDs had persistent moderate-to-severe disease activity at the 6-month (± 3 months) follow-up visit; however, only 29% of patients had their medication treatment advanced, indicating that there is considerable need for a treat-to-target approach to care for patients with RA.•Patients with younger age, shorter RA duration, and higher disease activity were more likely to have their medication treatment advanced, which suggests that potentially more aggressive treatment of disease activity is needed across the whole RA population.

Topological Identification Criteria, Stability, and Relevance of Pentagonal Nanochannels in Amorphous Ice.

Considering the potential importance of pentagonal nanochannels (PNCs) in determining the structure of the amorphous ice, we introduce topological criteria to identify the PNCs with an optimal fivefold symmetric environment. The basic building block in our criteria, termed as a bicyclo octamer, is an axisymmetric cluster formed by combination of three 6-membered boat-shaped rings. This bicyclo octamer unit serves as a seamless interface of the PNCs with cubic-hexagonal stacking patterns of the amorphous ice. This interface results in a fivefold symmetric mesostructure of relatively high stability: a central PNC with extended five branches of two-dimensional (2-D) hexagonal (wurtzite) crystalline monolayers stacked with cubic (diamond) layers. We also unearth a hierarchy of symmetric structures in amorphous ice: the PNCs, together with dodecahedron cages, form a network consisting of (nearly) equilateral triangular patterns. At the next hierarchical level of symmetry, such triangular patterns combine to form triangular pyramids with dodecahedron cages as the vertices, PNCs as the edges, and confined 2-D hexagonal crystalline monolayers as the triangular faces of the pyramids. The central core of the pyramids consists of cubic (diamond) regions with a strong local tetrahedral order. The overall structure of the amorphous ice states is found to be profoundly affected by PNCs. Specifically, in states with a relatively large number of PNCs, the cubic-hexagonal stacking is primarily in the form of hexagonal crystalline monolayers stacked from both sides with cubic crystalline layers.

Adult-Onset Isolated Hemichorea Revealing Iatrogenic Hypoparathyroidism and Bilateral Basal Ganglia Calcification.

Isolated hemichorea (HC) in adults has a relatively restricted differential diagnosis including stroke of contralateral basal ganglia nuclei, nonketotic hyperglycemia, and basal ganglia toxoplasmosis in HIV infection. Hypoparathyroidism-related basal ganglia calcification can potentially cause neurological problems, including movement disorders, that are usually bilateral in keeping with bilateral symmetric lesions. We report a patient with video-documented isolated, adult-onset HC due to iatrogenic hypoparathyroidism and bilateral basal ganglia calcification. A 47-year-old woman presented with isolated adult-onset HC of 2 years' duration as the presenting and only neurological feature of hypoparathyroidism and bilateral extensive basal ganglia calcification, 20 years after thyroidectomy-induced hypoparathyroidism. Significant improvement in the unilateral hyperkinesia was noted after correction of hypocalcemia and hypoparathyroidism at 3 months. Isolated HC in adults is a rare presenting feature of hypoparathyroidism with bilateral basal ganglia calcification and is treatable with correction of the underlying metabolic abnormality. In all cases with a movement disorder and brain calcification, hypoparathyroidism should be actively sought as this treatable condition must not be missed.

Design, development and characterization of ketorolac tromethamine polymeric nanosuspension.

Aim: At present, various ophthalmic formulations show low bioavailability. The rationale of present work was to design and develop stable ketorolac tromethamine nanosuspension with sustained effect and greater permeability for ocular drug delivery and increased ocular residence. Materials & methods: Formulations were designed by using central composite design, developed by combined nanoprecipitation and probe sonication method. Results & discussion: Nanosuspensions depicted the size range of the particles in between 199 and 441 nm with slight reduction in crystallinity of drug. In vitro drug release revealed that higher % entrapment efficiency of drug in nanosuspension delays the drug release. Conclusion: Eudragit RL-100-based nanosuspension increases viscosity and avoids problems like drug loss from precorneal surface and rapid drainage through nasolacrimal areas.