Effective new therapies are needed for rheumatoid arthritis. Current therapies target the products of activated macrophages; however, T cells also have an important role in rheumatoid arthritis. A ...fusion protein--cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis. CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells, blocking the engagement of CD28 on T cells and preventing T-cell activation. A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis.
We randomly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig per kilogram of body weight (105 patients), 10 mg of CTLA4Ig per kilogram (115 patients), or placebo (119 patients) for six months. All patients also received methotrexate therapy during the study. The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology (ACR), which define the response according to its extent: 20 percent (ACR 20), 50 percent (ACR 50), or 70 percent (ACR 70). Additional end points included measures of the health-related quality of life.
Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo (60 percent vs. 35 percent, P<0.001). Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group. The group given 10 mg of CTLA4Ig per kilogram had clinically meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey. CTLA4Ig was well tolerated, with an overall safety profile similar to that of placebo.
In patients with active rheumatoid arthritis who were receiving methotrexate, treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life. CTLA4Ig is a promising new therapy for rheumatoid arthritis.
Purpose: To assess the "real world" utility of repeated injection with the dexamethasone intravitreal implant (DEX) in routine practice. Methods: This was a retrospective, single-center analysis of ...consecutive patients with diabetic macular edema, or macular edema following retinal vein occlusion, treated with DEX. None had received prior intravitreal steroid treatment. DEX was implanted as per the manufacturer's instructions. Results: Seventy-eight individuals (95 eyes) were included (50.0% female; mean age: 68.1 + or - 12.4 years; mean duration of macular edema: 13.2 + or - 12.9 months). Thirty-three eyes (34.7%) had received previous treatment with an anti-vascular endothelial growth factor (anti-VEGF) and/or laser. Thirty eyes (31.6%) underwent one round of DEX implantation; the remainder received 2-5 cycles (total: 225 cycles). Initial DEX treatment led to significant increases in visual acuity (VA) at 6 weeks (mean change: 4.6 letters; P=0.004). Greater VA improvements during the first treatment cycle were associated with inferior baseline VA (P=0.02), borderline associated with baseline central macular thickness (CMT; P=0.06), and independent of prior anti-VEGF treatment (P=0.39). In an analysis of all DEX injections, VA improvements were robust across cycles 1 and 2 but reduced in cycle 3 (P=0.03). CMT improvements did not differ based on injection number (P=0.20). Increases in intraocular pressure (IOP) were largest over the first 6 weeks (but rebounded towards baseline more rapidly) in cycle 1 versus cycles 2 and 3 (P<0.001). IOP rises were typically manageable with topical medications. Conclusion: This analysis confirms the broad utility of DEX and may inform decision-making in routine practice. Keywords: corticosteroid, dexamethasone intravitreal implant, diabetic macular edema, intraocular pressure, retinal vein occlusion, visual acuity
Background
Operating room (OR) practice during the COVID‐19 pandemic is driven by basic principles, shared experience and nascent literature. This study aimed to identify the knowledge needs of the ...global OR workforce, and characterize supportive evidence to establish consensus.
Methods
A rapid, modified Delphi exercise was performed, open to all stakeholders, informed via an online international collaborative evaluation.
Results
The consensus exercise was completed by 339 individuals from 41 countries (64·3 per cent UK). Consensus was reached on 71 of 100 statements, predominantly standardization of OR pathways, OR staffing and preoperative screening or diagnosis. The highest levels of consensus were observed in statements relating to appropriate personal protective equipment (PPE) and risk distribution (96–99 per cent), clear consent processes (96 per cent), multidisciplinary decision‐making and working (97 per cent). Statements yielding equivocal responses predominantly related to technical and procedure choices, including: decontamination (40–68 per cent), laminar flow systems (13–61 per cent), PPE reuse (58 per cent), risk stratification of patients (21–48 per cent), open versus laparoscopic surgery (63 per cent), preferential cholecystostomy in biliary disease (48 per cent), and definition of aerosol‐generating procedures (19 per cent).
Conclusion
High levels of consensus existed for many statements within each domain, supporting much of the initial guidance issued by professional bodies. However, there were several contentious areas, which represent urgent targets for investigation to delineate safe COVID‐19‐related OR practice.
Antecedentes
La práctica en el quirófano (operating room, OR) durante la pandemia por la COVID‐ 19 se basa en principios básicos, experiencias compartidas y literatura reciente. Este estudio tuvo como objetivo identificar las necesidades de conocimiento global del personal de quirófano y caracterizar la evidencia existente para establecer un consenso.
Métodos
Se realizó un estudio basado en una metodología Delphi modificada y rápida, abierta a todos los interesados y a través de una evaluación colaborativa internacional online.
Resultados
El procedimiento de consenso fue completado por 339 personas de 41 países (64% Reino Unido). Se llegó a un consenso en 71/100 ítems, predominantemente en relación a la estandarización de los circuitos en OR, la dotación de personal y el cribaje preoperatorio o el diagnóstico. Los niveles más altos de consenso se observaron en los ítems relacionadas con el equipo personal y de protección (personal protective equipment, PPE) apropiado y la distribución de riesgos (96‐99%), claridad en los procesos de consentimiento (96%), toma de decisiones multidisciplinarias y trabajo (97%). Los ítems que generaron respuestas equívocas estaban relacionadas principalmente con opciones técnicas y de procedimiento, incluyendo: descontaminación (40‐68%), sistemas de flujo laminar (13‐61%), reutilización de PPE (58%), estratificación de los pacientes por riesgo (21‐48%), cirugía abierta versus laparoscópica (63%), colecistostomía preferente en patología biliar (48%) y definición de procedimientos generadores de aerosol (19%).
Conclusión
Existieron altos niveles de consenso para muchos ítems dentro de cada ámbito, apoyando gran parte de la orientación inicial emitida por los organismos profesionales. Sin embargo, surgieron varias áreas polémicas, que representan objetivos urgentes para la investigación para poder definir la práctica segura en OR relacionada con la COVID‐19.
This study has revealed global expert consensus on operating room practice during the COVID‐19 pandemic. Across 41 countries, 339 worldwide experts demonstrated consensus regarding 71 of 100 statements, supporting much of the initial guidance issued by a number of professional organizations. Non‐consensus items represent research targets.
Precaution and prevention
Cordyceps militaris has been previously shown to invert the chirality of (
r
)-2-phenylpropionic acid to its antipode in the absence of any other biotransformation. To investigate the mechanism of ...this unusual biotransformation. (
r,
s
)-2-
2H
1-2-phenylpropionic acid, (
r,
s
)-2-
2H,3,3,3-
2H
3-2-phenylpropionic acid, and (
r,
s
)-3,3,3-
2H
3-2-phenylpropionic acid were synthesized and incubated with
C. militaris. NMR spectroscopy showed that deuterium exchange of the α-methine proton occurred during the inversion process but there was no exchange of the β-methyl protons. There were no significant differences in the rates of chiral inversion of the three deuterated derivatives and the undeuterated compound, and with all the compounds attaining 84% enantiomeric excess of the (
s
)-enantiomer after 48 h incubation. The deuterium exchange is not therefore the rate limiting process in this biotransformation. The recovery profiles demonstrated that there was rapid metabolism of the β-methyl deuterated derivatives which did not occur for the undeuterated 2-phenylpropionic acid or the derivative which was only deuterated at the α-carbon. These studies clearly illustrate that
C. militaris is a useful
in vitro model of the chiral inversion of 2-arylpropionic acid derivatives in mammalian systems.
Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the ...CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
A series of
in vitro assays for determining the biocompatibility of ocular biomaterials have been developed and used to assess the differences in performance of omafilcon A, etafilcon A and nelfilcon ...A contact lens materials. The assays assessed bacterial attachment, macrophage adhesion, granulocyte adhesion and activation, epithelial cell adhesion and corneal cell contact damage. Overall, omafilcon A was found to be more biocompatible than the other materials although there was no significant difference between the epithelial cell adhesion and granulocyte adhesion and activation on any of the hydrogels. Etailcon A performed less well compared to nelfilcon A and omafilcon A with respect macrophage adhesion and bacterial adhesion. The results indicate that these biological assays can be successfully applied for the testing of contact lens materials and may be particularly useful in the
in vitro screening of new extended wear contact lens materials where cell adhesion and activation may have a greater influence on clinical performance.
Hans‐Ulrich Treichel's Frankfurt Poetikvorlesungen offer fascinating insight into the literary strategies which he employs in his creative writing. The lectures supply a literary topography which ...consists of three points of psychological, rather than political, orientation: Ostwestfalen, Berlin and Italy. This article seeks to introduce readers to Treichel's prose and poetry by reference to these fixed points. What emerges is that Treichel's landscape is very much that of a generation of young West Germans; that it is rooted in a specifically Western experience, and that the GDR, where it appears at all in Treichel's fiction, is viewed very much from an outsider's perspective. The article traces his development from his earliest poetic experiments, by way of short prose sketches, to the acclaimed story Der Verlorene (1998) and the latest novel Tristanakkord (2000). Drawing both on Treichel's published work and on unpublished earlier versions of the Poetikvorlesungen, the article concludes that Treichel's fiction is characterised by a masterly portrayal of embarrassment, vulnerability, even trauma. His apparent retreat into the personal and private does not betoken a refusal to ask fundamental social and political questions, so much as an indirect method of addressing precisely those questions.
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