Background: Blue-yellow axis dyschromatopsia is well-known in Autosomal Dominant Optic Atrophy (ADOA) patients, but there were no data on the correlation between retinal structure and short-wavelength automated perimetry (SWAP) values in this pathology. Methods: In this cross-sectional case-control study, we assessed the correlation between best corrected visual acuity (BCVA), standard automated perimetry (SAP), SWAP, and optical coherence tomography (OCT) parameters of 9 ADOA patients compared with healthy controls. Correlation analysis was performed between BCVA, mean deviation, pattern standard deviation (PSD), and fovea sensitivity (FS) values and the OCT thickness of each retinal layer and the peripapillary retinal nerve fiber layer (pRNFL). Results: The following significant and strong correlations were found: between BCVA and ganglion cell layer (GCL) and the global (G) pRNFL thicknesses; between SAP FS and GCL and the G-pRNFL thicknesses; between SWAP PSD and total retina, GCL, inner plexiform layer, inner nuclear layer, inner retinal layer and the temporal pRNFL thicknesses. We found a constant shorter duration of the SITA-SWAP compared with the SITA-STANDARD strategy. Conclusions: SWAP, SAP, and BCVA values provided relevant clinical information about retinal involvement in our ADOA patients. The perimetric functional parameters that seemed to correlate better with structure involvement were FS on SAP and PSD on SWAP.

Intestinal schistosomiasis is a chronic and debilitating disease that affects public health systems worldwide. Control interventions to reduce morbidity primarily involve the diagnosis and treatment of infected individuals. However, the recommended Kato-Katz (KK) parasitological method shows low sensitivity in individuals with low parasite loads and is not useful for monitoring elimination of parasite transmission at later stages. In the current study, we evaluated the accuracy of serum reactivity levels of different immunoglobulin isotypes in an enzyme-linked immunosorbent assay (ELISA), utilizing Schistosoma mansoni crude extracts, with the aim to improve the diagnosis of infected individuals with low parasite loads. The serum reactivity of IgM and IgG subclass antibodies (IgG1, IgG3, and IgG4) against soluble adult worm and egg antigen preparations was evaluated in residents from a schistosomiasis-endemic area in northern Minas Gerais, Brazil. The parasitological status of the study population was determined through fecal examination with multiple parasitological tests to create a consolidated reference standard (CRS) plus a fecal DNA detection test (q-PCR). Twelve months after praziquantel treatment, a second serum sample was obtained from the population for reexamination. A two-graph receiver operating characteristic curve (TG-ROC) analysis was performed using the serum reactivity of non-infected endemic controls and egg-positive individuals, and the cut-off value was established based on the intersection point of the sensibility and specificity curves in TG-ROC analyses. The diagnostic accuracy of each serological test was evaluated in relation to the parasitological CRS and to the combination of CRS plus qPCR results. The data revealed that serum reactivity of IgM and IgG3 against S. mansoni antigens did not allow identification of infected individuals from the endemic area. In contrast, serum IgG1 and IgG4-reactivity against schistosome antigens could distinguish between infected and non-infected individuals, with AUC values ranging between 0.728-0.925. The reactivity of IgG4 anti-soluble egg antigen - SEA (sensitivity 79 %, specificity 69 %, kappa = 0.49) had the best diagnostic accuracy, showing positive reactivity in more than 75 % of the infected individuals who eliminated less than 12 eggs per gram of feces. Moreover, serum IgG4 reactivity against SEA and against soluble worm antigen preparation (SWAP) was significantly reduced in the serum of infected individuals after 12 months of confirmed parasitological cure and in the absence of re-infection. These results reinforce that the described IgG4 anti-SEA ELISA assay is a sensitive alternative for the diagnosis of active intestinal schistosomiasis in individuals from endemic areas, including in those with a very low parasite load.

WNTs are essential factors for stem cell biology, embryonic development, and for maintaining homeostasis and tissue repair in adults. Difficulties in purifying WNTs and their lack of receptor selectivity have hampered research and regenerative medicine development. While breakthroughs in WNT mimetic development have overcome some of these difficulties, the tools developed so far are incomplete and mimetics alone are often not sufficient. Here, we developed a complete set of WNT mimetic molecules that cover all WNT/β-catenin-activating Frizzleds (FZDs). We show that FZD1,2,7 stimulate salivary gland expansion in vivo and salivary gland organoid expansion. We further describe the discovery of a novel WNT-modulating platform that combines WNT and RSPO mimetics\' effects into one molecule. This set of molecules supports better organoid expansion in various tissues. These WNT-activating platforms can be broadly applied to organoids, pluripotent stem cells, and in vivo research, and serve as bases for future therapeutic development.

Visual working memory is highly limited, and its capacity is tied to many indices of cognitive function. For this reason, there is much interest in understanding its architecture and the sources of its limited capacity. As part of this research effort, researchers often attempt to decompose visual working memory errors into different kinds of errors, with different origins. One of the most common kinds of memory error is referred to as a \"swap,\" where people report a value that closely resembles an item that was not probed (e.g., an incorrect, non-target item). This is typically assumed to reflect confusions, like location binding errors, which result in the wrong item being reported. Capturing swap rates reliably and validly is of great importance because it permits researchers to accurately decompose different sources of memory errors and elucidate the processes that give rise to them. Here, we ask whether different visual working memory models yield robust and consistent estimates of swap rates. This is a major gap in the literature because in both empirical and modeling work, researchers measure swaps without motivating their choice of swap model. Therefore, we use extensive parameter recovery simulations with three mainstream swap models to demonstrate how the choice of measurement model can result in very large differences in estimated swap rates. We find that these choices can have major implications for how swap rates are estimated to change across conditions. In particular, each of the three models we consider can lead to differential quantitative and qualitative interpretations of the data. Our work serves as a cautionary note to researchers as well as a guide for model-based measurement of visual working memory processes.

SURP domains are exclusively found in splicing-related proteins in all eukaryotes. SF3A1, a component of the U2 snRNP, has two tandem SURP domains, SURP1, and SURP2. SURP2 is permanently associated with a specific short region of SF3A3 within the SF3A protein complex whereas, SURP1 binds to the splicing factor SF1 for recruitment of U2 snRNP to the early spliceosomal complex, from which SF1 is dissociated during complex conversion. Here, we determined the solution structure of the complex of SURP1 and the human SF1 fragment using nuclear magnetic resonance (NMR) methods. SURP1 adopts the canonical topology of α1-α2-310 -α3, in which α1 and α2 are connected by a single glycine residue in a particular backbone conformation, allowing the two α-helices to be fixed at an acute angle. A hydrophobic patch, which is part of the characteristic surface formed by α1 and α2, specifically contacts a hydrophobic cluster on a 16-residue α-helix of the SF1 fragment. Furthermore, whereas only hydrophobic interactions occurred between SURP2 and the SF3A3 fragment, several salt bridges and hydrogen bonds were found between the residues of SURP1 and the SF1 fragment. This finding was confirmed through mutational studies using bio-layer interferometry. The study also revealed that the dissociation constant between SURP1 and the SF1 fragment peptide was approximately 20 μM, indicating a weak or transient interaction. Collectively, these results indicate that the interplay between U2 snRNP and SF1 involves a transient interaction of SURP1, and this transient interaction appears to be common to most SURP domains, except for SURP2.

Prior research supports the learnability of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition Alternative Model of Personality Disorders (AMPD). However, researchers have yet to compare novice ratings on the AMPD\'s Level of Personality Functioning Scale and the 25 pathological personality traits with expert ratings. Furthermore, the AMPD has yet to be examined with the idiographic Shedler-Westen Assessment Procedure (SWAP). We compared the aggregated AMPD clinical profile of a group of psychology doctoral students who learned the AMPD to high levels of reliability to that of an expert rater using the crucible of the classical case of \"Madeline G.\" Examination of AMPD and SWAP ratings of \"Madeline G.\" revealed excellent overall concordance but suggests that novice raters tend to perceive lower levels of personality impairment.

Besides excellent guidelines and newly developed highly effective drugs, evidence-based strategic use of these new drugs has especially contributed to enormous advances in rheumatoid arthritis treatment, apparent especially since 2000. Currently, the treat-to-target (T2T) strategy has proven to be the most successful in several studies and systematic reviews. The target is to achieve remission, which should be reached and sustained for an optimal outcome (i.e. stable over a long time period). If the initial disease-modifying antirheumatic drug (DMARD) treatment fails, the best strategy for continuing treatment is controversial, with swap or switch being open to debate (change within a class of drugs or change in the mechanism of action). Recent studies seem to indicate that switching to another mechanism of action is the most successful approach. A hotly discussed topic is the question whether DMARD treatment can or should be tapered when sustained remission has been achieved? Many patients wish for a reduction of drugs in cases of stable remission; however, the stable disease control might become destabilized by tapering. The main priority is the reduction or tapering of glucocorticoid treatment. When the decision for reduction of DMARD treatment is made together with the patient, a complete cessation bears a high risk of a flare, therefore, a careful step by step reduction of DMARD treatment should be preferred. In the case of a running combination, the question whether the conventional DMARD (mostly methotrexate), the biological (b)DMARD or targeted synthetic (ts)DMARD should be reduced first, must be decided on an individual basis. Most patients prefer to first reduce methotrexate and transfer to a monotherapy.
UNASSIGNED: Neben guten Leitlinien und neu entwickelten hochwirksamen Medikamenten trägt die evidenzbasierte strategische Nutzung dieser Medikamente zu den enormen in den letzten 20 Jahren feststellbaren Fortschritten bei der Behandlung der rheumatoiden Arthritis (RA) bei. Gegenwärtig gilt das Vorgehen nach dem Treat-to-target(T2T)-Prinzip als bestmögliche Strategie. Das Ziel ist dabei das Erreichen einer Remission, diese sollte für ein optimales Outcome nach neuer Erkenntnis anhaltend (d. h. stabil über einen längeren Zeitraum) erreicht werden. Strittig ist bei Versagen der b(„biological“)DMARD(„disease-modifying antirheumatic drug“)-Starttherapie der strategische Umgang mit dem Therapiewechsel, zur Debatte stehen Swap oder Switch (Wechsel innerhalb der Wirkstoffklasse bzw. Wechsel des Wirkprinzips). Neuere Daten sprechen zunehmend dafür, dass ein Wechsel des Wirkprinzips dann der erfolgreichere Weg ist. Ein viel diskutiertes Thema ist die Frage, ob im Status der stabil anhaltenden Remission die DMARD-Therapie reduziert werden kann bzw. sollte. Einerseits besteht dabei die Gefahr, die gute Einstellung zu verlieren, andererseits ist die Reduzierung ein Wunsch vieler Patienten. Der Abbau bzw. das Ausschleichen der Kortikoidtherapie steht dabei an erster Stelle. Wenn man sich (gemeinsam mit dem Patienten) danach für die Reduzierung der DMARD-Therapie entscheidet, so birgt ein komplettes Absetzen ein sehr hohes Risiko eines baldigen Flare, der vorsichtigen schrittweisen Reduzierung ist deshalb der Vorzug zu geben. Ob bei laufender Kombi zuerst das konventionelle DMARD (meist Methotrexat [Mtx]) oder das bDMARD bzw. ts(„targeted synthetic“)DMARD reduziert werden soll, muss dabei individuell entschieden werden – die Mehrheit der Patienten wünscht vorrangig den Mtx-Abbau und Übergang zur Monotherapie.

OBJECTIVE: To compare the results of short-wavelength automated perimetry (SWAP) in diabetic patients without retinopathy and healthy subjects and show if it is possible to detect an abnormal function of the retina in diabetic patients before vascular changes on the retina develop. Further, the effect of diabetes duration and long-term glycaemic control on the visual field was examined.
METHODS: The study group included 22 patients with diabetes type 1 or 2, without any signs of retinopathy. The control group consisted of 21 healthy subjects. Short-wavelength automated perimetry was performed on the Humphrey Field Analyzer (HFA 860, Carl Zeiss Meditec), SITA SWAP, 24-2 test. In diabetic patients, the duration of diabetes and the level of glycohemoglobin (HbA1c) was registered. The visual field indices MD (mean deviation) and PSD (pattern standard deviation) were compared between both groups by the Mann-Whitney test. The correlation between the visual field indices, HbA1c and duration of diabetes was assessed by the Spearman correlation coefficient.
RESULTS: The mean value of MD in the study and control group was -3.64±3.66 dB and -1.48±2.12 dB respectively, the values in the study group were significantly lower (p < 0.05). Mean PSD in the study group was 2.92±1.04 dB and 2.23±0.33 dB in the control group, again the difference was statistically significant (p < 0.05). Patients in the study group suffered from diabetes for 17±9.4 years in average. The mean value of HbA1c in the study group was 60.64±16.63 mmol/mol. A significant correlation was found only for PSD and HbA1c (p > 0.05). The duration of diabetes had no effect on either of the visual field indices.
CONCLUSIONS: Short-wavelength sensitivity of retina seems to be affected in diabetic patients without clinically significant retinopathy suggesting a neuroretinal impairment at early stages of the retinopathy. We found no association between the visual field and the control or duration of diabetes.

BACKGROUND: In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma-either ADA dose optimization or switching to vedolizumab or ustekinumab.
METHODS: Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics.
RESULTS: Adalimumab was optimized (n = 61 patients, 42 Crohn\'s disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn\'s disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P < 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (>24 months) than in the optimization group (13.3 months, P < 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 μg/g (HR, 3.53; 95% CI, 1.16-10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13-0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation.
CONCLUSIONS: In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

Inflammatory bowel disease (IBD) management has changed dramatically over the past 20 years, after the introduction of targeted biological therapies. However, the impact of these new drugs in changing the natural history of disease is still under debate. Recent evidence seems to suggest that the extent of their efficacy might be, at least partially, dependent on the timing of their introduction and on the subsequent management strategy. In this complex landscape, the potential role for a more dynamic approach with treatments based on sequencing and combining targeted therapies has been explored only minimally so far. In this review, we aim to explore the potential biological rationale behind the use of sequential and combination therapies in IBD, to summarise the current knowledge on this topic and to propose a management algorithm that combines these notions.