Xylosyltransferase Bump-and-hole Engineering to Chemically Manipulate Proteoglycans in Mammalian Cells.

Mammalian cells orchestrate signalling through interaction events on their surfaces. Proteoglycans are an intricate part of these interactions, carrying large glycosaminoglycan polysaccharides that recruit signalling molecules. Despite their importance in development, cancer and neurobiology, a relatively small number of proteoglycans have been identified. In addition to the complexity of glycan extension, biosynthetic redundancy in the first protein glycosylation step by two xylosyltransferase isoenzymes XT1 and XT2 complicates annotation of proteoglycans. Here, we develop a chemical genetic strategy that manipulates the glycan attachment site of cellular proteoglycans. By employing a tactic termed bump- and-hole engineering, we engineer the two isoenzymes XT1 and XT2 to specifically transfer a chemically modified xylose analogue to target proteins. The chemical modification contains a bioorthogonal tag, allowing the ability to visualise and profile target proteins modified by both transferases in mammalian cells. The versatility of our approach allows pinpointing glycosylation sites by tandem mass spectrometry, and exploiting the chemical handle to manufacture proteoglycans with defined GAG chains for cellular applications. Engineered XT enzymes permit a view into proteoglycan biology that is orthogonal to conventional techniques in biochemistry.

Allergic rhinitis and keratoconus: a systematic review and meta-analysis.

BACKGROUND: The relationship between keratoconus and various allergic diseases has been a subject of controversy. OBJECTIVE: In the present study, a systematic review and meta-analysis was conducted to investigate the association between allergic rhinitis (AR) and keratoconus. METHODS: Relevant and eligible studies from PubMed, Web of Science, and Cochrane Library were systematically reviewed to evaluate the association between AR and keratoconus. Observational studies containing the number of patients with and without keratoconus and the number of patients with keratoconus diagnosed with or without AR were included. Two reviewers independently screened for eligible studies and extracted data from the included studies. A bivariate meta-analysis was conducted to compare the odds of keratoconus occurrence in patients with and without AR. The main outcome was the odds ratio of keratoconus occurrence in patients with AR. A sensitivity test was performed using the adjusted odds ratio reported in the included studies to validate the findings. RESULTS: Seven studies involving 775,574 participants were included in this meta-analysis. Among them, 29,082 patients had keratoconus. The pooled odds ratio of keratoconus occurrence in patients with AR was 1.71 (95% confidence interval [CI]: 1.36-2.15; P < 0.001; I2 = 96%), and the pooled adjusted odds ratio was 1.72 (95% CI: 1.23-2.40; P = 0.001; I2 = 97%). CONCLUSION: Patients with AR showed significantly higher odds of keratoconus occurrence than those without AR. Future studies are warranted to investigate the causal relationship and evaluate the cost-effectiveness of early screening using methods such as corneal topography and referral for keratoconus in patients with AR.

Complete genome sequence of Sphingomonas sp. strain R1, a bacterium isolated from tomato (Solanum lycopersicum).

Sphingomonas sp. strain R1 was isolated from the stem of a tomato plant and exhibited antagonism with Agrobacterium. The complete genome sequence of this bacterium consists of one 3,874,532 bp circular chromosome and two plasmids.

Complete genome sequence of Agrobacterium pusense Bbcg2-2, a strain isolated from blueberry crown gall in Taiwan.

Agrobacterium pusense Bbcg2-2 is a strain isolated from a crown gall sample of blueberry (Vaccinium corymbosum) cultivar "Flicker" grown in Taiwan. The complete genome sequence of this bacterium consists of a 2,798,342-bp circular chromosome, a 2,140,031-bp linear chromid, and a 386,016-bp circular plasmid.

Glycoengineered keratinocyte library reveals essential functions of specific glycans for all stages of HSV-1 infection.

Viral and host glycans represent an understudied aspect of host-pathogen interactions, despite potential implications for treatment of viral infections. This is due to lack of easily accessible tools for analyzing glycan function in a meaningful context. Here we generate a glycoengineered keratinocyte library delineating human glycosylation pathways to uncover roles of specific glycans at different stages of herpes simplex virus type 1 (HSV-1) infectious cycle. We show the importance of cellular glycosaminoglycans and glycosphingolipids for HSV-1 attachment, N-glycans for entry and spread, and O-glycans for propagation. While altered virion surface structures have minimal effects on the early interactions with wild type cells, mutation of specific O-glycosylation sites affects glycoprotein surface expression and function. In conclusion, the data demonstrates the importance of specific glycans in a clinically relevant human model of HSV-1 infection and highlights the utility of genetic engineering to elucidate the roles of specific viral and cellular carbohydrate structures.

Complete genome sequence of Vibrio parahaemolyticus strain PH1273, isolated from aquacultured shrimp in the Philippines.

We announce the complete genome sequence of Vibrio parahaemolyticus strain PH1273. This strain was collected from a Penaeus vannamei pond in the Philippines in 2015. Genome analysis revealed that it lacks the gene pirAB responsible for causing acute hepatopancreatic necrosis disease but encode multiple secretion systems and the associated effectors.

Systematic Review and Critical Appraisal of Urticaria Clinical Practice Guidelines: A Global Guidelines in Dermatology Mapping Project (GUIDEMAP).

BACKGROUND: Management of urticaria can be optimized with clinical practice guidelines (CPGs). However, the quality of recent urticaria CPGs remains unclear. OBJECTIVE: To identify and appraise urticaria CPGs worldwide published in the last 5 years. METHODS: A search for relevant urticaria CPGs was conducted between January 1, 2017, and May 31, 2022, using the following databases: MEDLINE, Embase, National Institute for Health and Care Excellence (NICE) Evidence Search, Guidelines International Network, ECRI Guidelines Trust, Australian Clinical Practice Guidelines, Trip Medical Database, and DynaMed. The included CPGs were critically appraised using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, Lenzer et al's red flags, and the Institute of Medicine (IOM) criteria of trustworthiness. RESULTS: We included 21 urticaria CPGs. Most guidelines reviewed treatment recommendations of chronic spontaneous urticaria. The majority of guidelines were from European and Asian countries with high and high-middle sociodemographic index, written in English, and openly accessible. Seventeen guidelines (81%) had at least 1 AGREE II domain rated poor quality. Applicability, rigor of development, and stakeholder involvement were the 3 AGREE II domains that scored the lowest across guidelines. Appraisal with Lenzer et al's red flags showed that 18 guidelines (86%) raised at least 1 red flag indicating potential bias. The top 3 domains raising red flags were: no inclusion of nonphysician experts/patient representative/community stakeholders, no or limited involvement of a methodologist in the evaluation of evidence, and lack of external review. Based on IOM's criteria of trustworthiness, 20 guidelines (95%) had 1 or more criteria that did not meet best practice standards. The 3 domains with the highest number of best practice standards not met were updating procedures, rating strength of recommendations, and external review. Guidelines scored highest for the AGREE II domains of defining scope and purpose and clarity of presentation, and had the most fully met IOM's best practice standard for articulation of recommendations. However, only 1 urticaria CPG by NICE was identified as rigorously developed across all 3 appraisal tools. CONCLUSIONS: The quality of urticaria CPGs in the last 5 years varied widely. Only the NICE urticaria guideline consistently demonstrated excellent quality, high trustworthiness, and low risk of bias. Use of a rigorous framework to rate certainty of evidence and grade strength of recommendation, involvement of methodologists, stakeholder engagement with external review, and clear guidance for updating can help improve the quality of future CPGs.

Synthesis and Physical Characteristics of Undoped and Potassium-Doped Cubic Tungsten Trioxide Nanowires through Thermal Evaporation.

We report an efficient method to synthesize undoped and K-doped rare cubic tungsten trioxide nanowires through the thermal evaporation of WO3 powder without a catalyst. The WO3 nanowires are reproducible and stable with a low-cost growth process. The thermal evaporation processing was conducted in a three-zone horizontal tube furnace over a temperature range of 550-850 °C, where multiple substrates were placed at different temperature zones. The processing parameters, including pressure, temperature, type of gas, and flow rate, were varied and studied in terms of their influence on the morphology, aspect ratio and density of the nanowires. The morphologies of the products were observed with scanning electron microscopy. High resolution transmission electron microscopy, X-ray photoelectron spectroscopy, and X-ray diffraction studies were conducted to further identify the chemical composition, crystal structure and growth direction of the nanostructures. Additionally, the growth mechanism has been proposed. Furthermore, we investigated the potassium doping effect on the physical properties of the nanostructures. Photoluminescence measurements show that there were shorter emission bands at 360 nm and 410 nm. Field emission measurements show that the doping effect significantly reduced the turn-on electric field and increased the enhancement factor. Furthermore, as compared with related previous research, the K-doped WO3 nanowires synthesized in this study exhibited excellent field emission properties, including a superior field enhancement factor and turn-on electric field. The study reveals the potential of WO3 nanowires in promising applications for sensors, field emitters and light-emitting diodes.

A universal GlycoDesign for lysosomal replacement enzymes to improve circulation time and biodistribution.

Currently available enzyme replacement therapies for lysosomal storage diseases are limited in their effectiveness due in part to short circulation times and suboptimal biodistribution of the therapeutic enzymes. We previously engineered Chinese hamster ovary (CHO) cells to produce α-galactosidase A (GLA) with various N-glycan structures and demonstrated that elimination of mannose-6-phosphate (M6P) and conversion to homogeneous sialylated N-glycans prolonged circulation time and improved biodistribution of the enzyme following a single-dose infusion into Fabry mice. Here, we confirmed these findings using repeated infusions of the glycoengineered GLA into Fabry mice and further tested whether this glycoengineering approach, Long-Acting-GlycoDesign (LAGD), could be implemented on other lysosomal enzymes. LAGD-engineered CHO cells stably expressing a panel of lysosomal enzymes [aspartylglucosamine (AGA), beta-glucuronidase (GUSB), cathepsin D (CTSD), tripeptidyl peptidase (TPP1), alpha-glucosidase (GAA) or iduronate 2-sulfatase (IDS)] successfully converted all M6P-containing N-glycans to complex sialylated N-glycans. The resulting homogenous glycodesigns enabled glycoprotein profiling by native mass spectrometry. Notably, LAGD extended the plasma half-life of all three enzymes tested (GLA, GUSB, AGA) in wildtype mice. LAGD may be widely applicable to lysosomal replacement enzymes to improve their circulatory stability and therapeutic efficacy.

In vivo interrogation of regulatory genomes reveals extensive quasi-insufficiency in cancer evolution.

In contrast to mono- or biallelic loss of tumor-suppressor function, effects of discrete gene dysregulations, as caused by non-coding (epi)genome alterations, are poorly understood. Here, by perturbing the regulatory genome in mice, we uncover pervasive roles of subtle gene expression variation in cancer evolution. Genome-wide screens characterizing 1,450 tumors revealed that such quasi-insufficiency is extensive across entities and displays diverse context dependencies, such as distinct cell-of-origin associations in T-ALL subtypes. We compile catalogs of non-coding regions linked to quasi-insufficiency, show their enrichment with human cancer risk variants, and provide functional insights by engineering regulatory alterations in mice. As such, kilo-/megabase deletions in a Bcl11b-linked non-coding region triggered aggressive malignancies, with allele-specific tumor spectra reflecting gradual gene dysregulations through modular and cell-type-specific enhancer activities. Our study constitutes a first survey toward a systems-level understanding of quasi-insufficiency in cancer and gives multifaceted insights into tumor evolution and the tissue-specific effects of non-coding mutations.

The Regulatory Role of Nuclear Respiratory Factor 1 in Bladder Cancer Cells.

BACKGROUND/AIM: Nuclear respiratory factor 1 (NRF1) is a key mediator of genes involved in mitochondrial biogenesis and the respiratory chain; however, its role in bladder cancer remains unknown. Transitional cell carcinoma, also known as urothelial cell carcinoma, is the most common type of bladder cancer resistant to chemotherapy. An established high-grade and invasive transitional cell carcinoma line from patients with urinary bladder cancer, known as T24, has been extensively used in cancer research. In this study, we aimed to investigate the mechanisms through which NRF1 regulates proliferation and cell migration of bladder cancer cells using the T24 cell line. MATERIALS AND METHODS: Cells were transfected with plasmid cloning DNA for NRF1 to evaluate the effect of NRF1 overexpression on bladder cancer cells. Western blot was used to examine epithelial and mesenchymal markers (E-cadherin and α-smooth muscle actin), transcriptional regulators for epithelial-mesenchymal transition (snail family transcriptional repressors), components of transforming growth factor-ß1/SMADs signaling, high-mobility group box 1 (HMGB1), and receptor for advanced glycation end-products (RAGE). The in situ expression of E-cadherin, α-smooth muscle actin and SMAD7 was determined using immunofluorescence staining. Cell migration capacity was assessed by wound-healing assay. RESULTS: Transfection with NRF1 expression vector repressed the migration capacity of bladder cancer cells, diminishing HMGB1/RAGE expression and reducing transforming growth factor ß-associated epithelial-mesenchymal transition in T24 cells. CONCLUSION: Therapeutic avenues that increase NRF1 expression may serve as an adjunct to conventional treatments for bladder cancer.

Evaluation of the Efficacy of a Combined Treatment Using the mTOR-Inhibitor Everolimus and [177Lu]Lu-DOTA-TATE in Nude CD1 Mice with SSTR-Expressing Pancreatic AR42J Xenograft Tumors.

Therapy options for advanced pancreatic neuroendocrine tumors (pNETs) include the mTOR inhibitor everolimus and peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE, however further optimization in the therapeutic landscape is required as response rates are still low. In this study, we investigated the synergistic and potentially enhanced efficacy of a combined treatment with everolimus and [177Lu]Lu-DOTA-TATE in a mouse model. Baseline [68Ga]Ga-DOTA-TATE PET scans were obtained five days after athymic CD1 mice were inoculated with AR42J tumor cells, before separating the animals into four groups. Group 1 received a placebo, group 2 everolimus, group 3 a placebo and PRRT, and group 4 everolimus and PRRT. The treatment response was monitored by manually measuring the tumor volumes (manual tumor volume, MTV) and conducting sequential [68Ga]Ga-DOTA-TATE PET scans at one, two, and four weeks after treatment induction. The biological tumor volume (BTV) was derived from PET scans using threshold-based volume of interest (VOI) measurements. Tracer uptake was measured semi-quantitatively as a tumor to background ratio (TBR). Mice were euthanized due to excessive tumor growth according to the ethics protocol; blood samples were drawn for the preparation of full blood counts and kidneys were obtained for histological analysis. For the histological assessment, a standardized score (renal damage score, RDS) was used. Full blood counts showed significantly increased numbers of neutrophils and lymphocytes in the groups receiving PRRT. All other parameters did not differ relevantly. In the histological analysis, groups receiving PRRT had a significantly higher RDS, whereas everolimus only tended to cause an increase in the RDS. Mice in groups 1 and 2 had to be euthanized due to excessive tumor growth two weeks after the start of the therapy, whereas follow-up in groups 3 and 4 comprised four weeks. PRRT significantly inhibited tumor growth; the administration of everolimus did not induce an additional effect. A good correlation existed between MTV and BTV. PRRT significantly reduced the TBR. [68Ga]Ga-DOTA-TATE PET is suitable for monitoring tumor growth in the applied model. The high efficacy of [177Lu]Lu-DOTA-TATE is not enhanced by the combination with everolimus.

Functional biomarkers derived from computed tomography and magnetic resonance imaging differentiate PDAC subgroups and reveal gemcitabine-induced hypo-vascularization.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a molecularly heterogeneous tumor entity with no clinically established imaging biomarkers. We hypothesize that tumor morphology and physiology, including vascularity and perfusion, show variations that can be detected by differences in contrast agent (CA) accumulation measured non-invasively. This work seeks to establish imaging biomarkers for tumor stratification and therapy response monitoring in PDAC, based on this hypothesis. METHODS AND MATERIALS: Regional CA accumulation in PDAC was correlated with tumor vascularization, stroma content, and tumor cellularity in murine and human subjects. Changes in CA distribution in response to gemcitabine (GEM) were monitored longitudinally with computed tomography (CT) Hounsfield Units ratio (HUr) of tumor to the aorta or with magnetic resonance imaging (MRI) ΔR1 area under the curve at 60 s tumor-to-muscle ratio (AUC60r). Tissue analyses were performed on co-registered samples, including endothelial cell proliferation and cisplatin tissue deposition as a surrogate of chemotherapy delivery. RESULTS: Tumor cell poor, stroma-rich regions exhibited high CA accumulation both in human (meanHUr 0.64 vs. 0.34, p < 0.001) and mouse PDAC (meanAUC60r 2.0 vs. 1.1, p < 0.001). Compared to the baseline, in vivo CA accumulation decreased specifically in response to GEM treatment in a subset of human (HUr -18%) and mouse (AUC60r -36%) tumors. Ex vivo analyses of mPDAC showed reduced cisplatin delivery (GEM: 0.92 ± 0.5 mg/g, vs. vehicle: 3.1 ± 1.5 mg/g, p = 0.004) and diminished endothelial cell proliferation (GEM: 22.3% vs. vehicle: 30.9%, p = 0.002) upon GEM administration. CONCLUSION: In PDAC, CA accumulation, which is related to tumor vascularization and perfusion, inversely correlates with tumor cellularity. The standard of care GEM treatment results in decreased CA accumulation, which impedes drug delivery. Further investigation is warranted into potentially detrimental effects of GEM in combinatorial therapy regimens.

Nuclear Respiratory Factor 1 Overexpression Inhibits Proliferation and Migration of PC3 Prostate Cancer Cells.

BACKGROUND/AIM: The role of nuclear respiratory factor 1 (NRF1) on the prostate cancer progression is controversial. We aimed to investigate the effect of NRF1 overexpression on the metastasis potential of PC3 prostate cancer cells and the associated molecular mechanisms. MATERIALS AND METHODS: Cell survival, migration capacity, mitochondrial biogenesis, the expression of TGF-ß signaling and EMT markers were examined after overexpression and silencing of NRF1 in PC3 cells. RESULTS: We found that NRF1-overexpressing cells exhibited a decreased cell viability and proliferation ability as well as a reduced migration capacity compared to control cells. Moreover, ectopic expression of NRF1 increased the mitochondrial biogenesis and inhibited the EMT characteristics, including a decrease in the mesenchymal marker, α-SMA and an increase in the epithelial cell marker, E-cadherin. We also demonstrated that overexpression of NRF1 suppressed the expression of TGF-ß signaling in PC3 cells. As expected, silencing of NRF1 reversed the abovementioned effects. CONCLUSION: This study demonstrated that upregulation of NRF1 holds the potential to inhibit the metastasis of prostate cancer, possibly through an elevation of mitochondrial biogenesis and the subsequent repression of TGF-ß-associated EMT. Therapeutic avenues that increase NRF1 expression may serve as an adjunct to conventional treatments of prostate cancer.

Risk Factors and Incidence Rates of Self-Reported Short-Term Adverse Events of COVID-19 Vaccine Booster Dose.

With the spread of the new SARS-CoV-2 variants, many countries have begun COVID-19 vaccine booster programs with the mix-and-match strategy. However, research on the adverse events (AE) of booster doses is still scarce. The aim of our study was to analyze the reported incidence rate (IR), and factors associated with AE, including short-term serious adverse events (SAE) and short-term non-serious adverse events (NSAE), among different vaccine products through the hospital-based Vaccine Adverse Event Reporting System (VAERS). A total of 7432 records were collected during the three-month study period. While more than half of the responses (52.2%) reported the presence of AE after receiving a booster dose, only a few AE were considered SAE (2.4%). AE were significantly higher among women and people of younger age, and the brand of vaccines is the strongest factor associated with post-booster dose AE. The incidence of AE in mRNA1273 is higher than in BNT162b2 and MVC-COV1901 (IRR mRNA1273 vs. BNT162b2: 1.22, 95% CI: 1.11-1.34; BNT162b2 vs. MVC-COV1901: 2.77, 95% CI: 2.27-3.39). The IR of different groups were calculated to support the decision making of the booster vaccine. Although AE were not uncommon for booster vaccines, almost all AE were not serious and predictable using estimated IR. This result can be used to optimize booster vaccine decision making.

Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction.

Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.

Synthesis and Characterization of Indium Tin Oxide Nanowires with Surface Modification of Silver Nanoparticles by Electrochemical Method.

In this study, indium tin oxide nanowires (ITO NWs) with high density and crystallinity were synthesized by chemical vapor deposition (CVD) via a vapor-liquid-solid (VLS) route; the NWs were decorated with 1 at% and 3 at% silver nanoparticles on the surface by a unique electrochemical method. The ITO NWs possessed great morphologies with lengths of 5~10 µm and an average diameter of 58.1 nm. Characterization was conducted through transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD) and X-ray photoelectron spectroscope (XPS) to identify the structure and composition of the ITO NWs. The room temperature photoluminescence (PL) studies show that the ITO NWs were of visible light-emitting properties, and there were a large number of oxygen vacancies on the surface. The successful modification of Ag was confirmed by TEM, XRD and XPS. PL analysis reveals that there was an extra Ag signal at around 1.895 eV, indicating the potential application of Ag-ITO NWs as nanoscale optical materials. Electrical measurements show that more Ag nanoparticles on the surface of ITO NWs contributed to higher resistivity, demonstrating the change in the electron transmission channel of the Ag-ITO NWs. ITO NWs and Ag-ITO NWs are expected to enhance the performance of electronic and optoelectronic devices.

Systematic review and critical appraisal of psoriasis clinical practice guidelines: a Global Guidelines in Dermatology Mapping Project (GUIDEMAP).

BACKGROUND: Clinical practice guidelines (CPGs) developed with rigorous methods can help optimize clinical care for patients with psoriasis. OBJECTIVES: To conduct an updated systematic review and comprehensive critical appraisal of global psoriasis CPGs. METHODS: A search of MEDLINE and Embase for psoriasis CPGs published between 1 January 2015 and 31 March 2021 was performed. Other guideline repositories were also searched for relevant CPGs. Descriptive analysis was conducted to summarize included guidelines. Three critical appraisal tools were used to assess the quality of included CPGs: the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, Lenzer et al.'s red flags, and the US Institute of Medicine's (IOM) criteria of trustworthiness. RESULTS: We included 33 psoriasis CPGs, with 25 openly accessible. Most CPGs were from high sociodemographic index countries in North America and Europe. Five CPGs received 'excellent quality' appraisals across all six AGREE II domains. Stakeholder involvement, rigour of development and applicability were the three domains with the lowest appraisal scores for AGREE II. Twenty-two CPGs raised at least one red flag indicative of potential bias. By the IOM's standards, external review of the guideline draft prior to publication and clear updating procedures were most often not addressed by guidelines, and only three CPGs were assessed as having higher overall trustworthiness. CONCLUSIONS: Most psoriasis guidelines were unable to consistently demonstrate high quality across multiple appraisal tools. The EuroGuiDerm guideline on the systemic treatment of psoriasis vulgaris was the only CPG to receive 'excellent quality' across all six AGREE II domains, to raise no Lenzer's red flags, and to have higher trustworthiness by IOM criteria.