Drug Reaction With Eosinophilia and Systemic Symptoms With Pustulosis.

This cohort study examines patients with drug reaction with eosinophilia and systemic symptoms who also have pustules.

ERAP1 and ERAP2 Gene Variants as Potential Clinical Biomarkers of Anti-IL-17A Response in Psoriasis Vulgaris.

BACKGROUND: Interleukin-17A (IL-17A) is a proinflammatory cytokine, playing an essential role in the development of psoriasis. Although treatment with anti-IL-17A monoclonal antibodies has demonstrated high efficacy in psoriasis patients, not all patients respond equally well, highlighting the need for biomarkers to predict treatment response. Specific single nucleotide polymorphisms (SNPs) in the endoplasmatic reticulum aminopeptidase (ERAP) 1 and 2 genes have been associated with psoriasis and other immune-mediated diseases. OBJECTIVES: We aimed to investigate the association between the ERAP1 and ERAP2 genotypes and response to secukinumab treatment in psoriasis patients. METHODS: A total of 75 patients with plaque psoriasis were included. All patients were genotyped for the ERAP1 rs27524, rs27044, rs30187, rs2287987, and rs26653 SNPs, the ERAP2 rs2248374 SNP, and human leukocyte antigen-C*06:02 (HLA-C*06:02) status. RESULTS: Our results demonstrated that individuals with specific ERAP1 and ERAP2 genotypes had a considerably lower response rate to secukinumab treatment. Patients with the ERAP2 rs2248374 G/G genotype had a more than 6-fold increased risk of treatment failure compared with patients with the rs2248374 A/G or -A/A genotypes. Stratifying for HLA-C*06:02 status, the ERAP2 G/G genotype pointed towards an increased risk of treatment failure among HLA-C*06:02-positive patients, although this was not statistically significant. CONCLUSION: Taken together, this unique study breaks new ground by identifying distinct ERAP1 and ERAP2 gene variants that may serve as potential biomarkers for predicting the treatment response to secukinumab in psoriasis patients. Notable, out data extends existing knowledge by linking specific ERAP1 and ERAP2 gene variants to treatment outcome.

"Future patient II" telerehabilitation for patients with heart failure: Protocol for a randomized controlled trial.

Background: Heart failure is a global problem affecting millions of people worldwide. Current care of heart failure patients follows standard protocols and often overlooks the patients' specific needs, which leads to low compliance in the rehabilitation phase. Telerehabilitation, where the patients communicate with health care professionals about their rehabilitation program and monitor their vital signs, aims to increase the degree of compliance as well as enhancing their quality of life. Objective: The aim of this study is to investigate whether application of the Future Patient Telerehabilitation Program II can improve the health-related quality of life for patients with heart failure. Methods: A randomized controlled trial will be conducted. A total of 70 patients will be enrolled, 35 in the intervention group, 35 in the control group. The intervention group will follow an add-on to traditional care, while the control group will follow the conventional Danish cardiac rehabilitation program, which is based on periodic visits to the clinic. The patients will be followed for a period of six months. The intervention group will have access to an online HeartPortal and will use various home-based devices for self-monitoring. The primary outcome to be investigated is health-related quality of life as measured by the EuroQol-5 Dimension. Secondary outcomes are the number of visits to the outpatient clinic, number of readmissions and number of tele-communications contacts (phone and video) with health care professionals. The primary and secondary outcomes will be assessed using questionnaires and through the data generated by digital technologies for self-monitoring. Results: Enrolment began in August 2020. The results will be published in peer-reviewed journals. Results from the Future Patient II Telerehabilitation program are expected to be published in 2024. Discussion: This study is a further development of the Future Patient Telerehabilitation I study, and it is expected to explore the use of video consultation and a weight calculator in relation to telerehabilitation as well as the quality of life for heart failure patients. Conclusion: The expected outcomes are increased quality of life, increased number of phone- and video-consultations with health-care professionals, and the enhanced ability of patients to manage their own disease with the use of a calculator for weight.

Impact of germline DNA repair gene variants on prognosis and treatment of men with advanced prostate cancer.

The clinical importance of germline variants in DNA repair genes (DRGs) is becoming increasingly recognized, but their impact on advanced prostate cancer prognosis remains unclear. A cohort of 221 newly diagnosed metastatic castration-resistant prostate cancer (mCRPC) patients were screened for pathogenic germline variants in 114 DRGs. The primary endpoint was progression-free survival (PFS) on first-line androgen signaling inhibitor (ARSI) treatment for mCRPC. Secondary endpoints were time to mCRPC progression on initial androgen deprivation therapy (ADT) and overall survival (OS). Twenty-seven patients (12.2%) carried a germline DRG variant. DRG carrier status was independently associated with shorter PFS on first-line ARSI [HR 1.72 (1.06-2.81), P = 0.029]. At initiation of ADT, DRG carrier status was independently associated with shorter progression time to mCRPC [HR 1.56, (1.02-2.39), P = 0.04] and shorter OS [HR 1.99, (1.12-3.52), P = 0.02]. Investigating the contributions of individual germline DRG variants on PFS and OS revealed CHEK2 variants to have little effect. Furthermore, prior taxane treatment was associated with worse PFS on first-line ARSI for DRG carriers excluding CHEK2 (P = 0.0001), but not for noncarriers. In conclusion, germline DRG carrier status holds independent prognostic value for predicting advanced prostate cancer patient outcomes and may potentially inform on optimal treatment sequencing already at the hormone-sensitive stage.

Spatial Profiling of Circular RNAs in Cancer Reveals High Expression in Muscle and Stromal Cells.

Circular RNAs (circRNA) are covalently closed molecules that can play important roles in cancer development and progression. Hundreds of differentially expressed circRNAs between tumors and adjacent normal tissues have been identified in studies using RNA sequencing or microarrays, emphasizing a strong translational potential. Most previous studies have been performed using RNA from bulk tissues and lack information on the spatial expression patterns of circRNAs. Here, we showed that the majority of differentially expressed circRNAs from bulk tissue analyses of colon tumors relative to adjacent normal tissues were surprisingly not differentially expressed when comparing cancer cells directly with normal epithelial cells. Manipulating the proliferation rates of cells grown in culture revealed that these discrepancies were explained by circRNAs accumulating to high levels in quiescent muscle cells due to their high stability; on the contrary, circRNAs were diluted to low levels in the fast-proliferating cancer cells due to their slow biogenesis rates. Thus, different subcompartments of colon tumors and adjacent normal tissues exhibited striking differences in circRNA expression patterns. Likewise, the high circRNA content in muscle cells was also a strong confounding factor in bulk analyses of circRNAs in bladder and prostate cancers. Together, these findings emphasize the limitations of using bulk tissues for studying differential circRNA expression in cancer and highlight a particular need for spatial analysis in this field of research. SIGNIFICANCE: The abundance of circRNAs varies systematically between subcompartments of solid tumors and adjacent tissues, implying that differentially expressed circRNAs discovered in bulk tissue analyses may reflect differences in cell type composition between samples.

Current Knowledge about the New Drug Firibastat in Arterial Hypertension.

Hypertension significantly increases the risk of cardiovascular disease. Currently, effective standard pharmacological treatment is available in the form of diuretics, ACE inhibitors, angiotensin II receptor blockers and calcium channel blockers. These all help to decrease blood pressure in hypertensive patients, each with their own mechanism. Recently, firibastat, a new first-in-class antihypertensive drug has been developed. Firibastat is a prodrug that when crossing the blood-brain barrier, is cleaved into two active EC33 molecules. EC33 is the active molecule that inhibits the enzyme aminopeptidase A. Aminopeptidase A converts angiotensin II to angiotensin III. Angiotensin III usually has three central mechanisms that increase blood pressure, so by inhibiting this enzyme activity, a decrease in blood pressure is seen. Firibastat is an antihypertensive drug that affects the brain renin angiotensin system by inhibiting aminopeptidase A. Clinical trials with firibastat have been performed in animals and humans. No severe adverse effects related to firibastat treatment have been reported. Results from studies show that firibastat is generally well tolerated and safe to use in hypertensive patients. The aim of this review is to investigate the current knowledge about firibastat in the treatment of hypertension.

The transcriptional landscape and biomarker potential of circular RNAs in prostate cancer.

BACKGROUND: Circular RNAs (circRNAs) constitute a largely unexplored source for biomarker discovery in prostate cancer (PC). Here, we characterize the biomarker potential of circRNAs in PC, where the need for novel diagnostic and prognostic tools to facilitate more personalized management is pressing. METHODS: We profiled the transcriptomic landscape of circRNAs in PC by total RNA sequencing of 31 adjacent-normal and 143 tumor samples from localized (radical prostatectomy (RP)) and metastatic PC patients (cohort 1, training). Diagnostic and prognostic potential was evaluated in cohort 1, and 39 top circRNA candidates were selected for validation in two additional PC cohorts (cohort 2, n = 111; RP cohort 3, n = 191) by NanoString-based expression analysis. Biochemical recurrence (BCR)-free survival was assessed using Kaplan-Meier, univariate, and multivariate Cox regression analyses. The circRNA candidates were further detected in extracellular vesicle (EV)-enriched plasma samples from PC patients and controls (cohort 4, n = 54). RESULTS: Expression of circABCC4, circFAT3, circATRNL1, and circITGA7 was highly cancer-specific (area under the curve 0.71-0.86), while low circITGA7 expression was significantly (P < 0.05) associated with BCR in univariate analysis in two RP cohorts. Moreover, we successfully trained and validated a novel 5-circRNA prognostic signature (circKMD1A/circTULP4/circZNF532/circSUMF1/circMKLN1) significantly associated with BCR beyond routine clinicopathological variables (RP cohort 1: P = 0.02, hazard ratio = 2.1; RP cohort 3: P < 0.001, hazard ratio = 2.1). Lastly, we provide proof-of-principle for detection of candidate circRNAs in EV-enriched plasma samples from PC patients. CONCLUSIONS: circRNAs hold great biomarker potential in PC and display both high cancer specificity and association to disease progression.

Does central nervous system dysfunction underlie patellofemoral pain in young females? Examining brain functional connectivity in association with patient-reported outcomes.

Patellofemoral pain (PFP) is defined as retro- or peri-patellar knee pain without a clear structural abnormality. Unfortunately, many current treatment approaches fail to provide long-term pain relief, potentially due to an incomplete understanding of pain-disrupted sensorimotor dysfunction within the central nervous system. The purposes of this study were to evaluate brain functional connectivity in participants with and without PFP, and to determine the relationship between altered brain functional connectivity in association with patient-reported outcomes. Young female patients with PFP (n = 15; 14.3 ± 3.2 years) completed resting-state functional magnetic resonance imaging (rs-fMRI) and patient-reported outcome measures. Each patient with PFP was matched with two controls (n = 30, 15.5 ± 1.4 years) who also completed identical rs-fMRI testing. Six bilateral seeds important for pain and sensorimotor control were created, and seed-to-voxel analyses were conducted to compare functional connectivity between the two groups, as well as to determine the relationship between connectivity alterations and patient-reported outcomes. Relative to controls, patients with PFP exhibited altered functional connectivity between regions important for pain, psychological functioning, and sensorimotor control, and the connectivity alterations were related to perceived disability, dysfunction, and kinesiophobia. The present results support emergent evidence that PFP is not localized to structural knee dysfunction, but may actually be resultant to altered central neural processes. Clinical significance: These data provide potential neuro-therapeutic targets for novel therapies aimed to reorganize neural processes, improve neuromuscular function, and restore an active pain-free lifestyle in young females with PFP.

Framboidal Nanoparticles Containing a Curcumin-Phenylboronic Acid Complex with Antiangiogenic and Anticancer Activities.

Curcumin (Cur) has a wide range of bioactivities that show potential for the treatment of cancer as well as chronic diseases associated with inflammation and aging. However, the therapeutic efficacy of Cur has been hampered by its rapid degradation under physiological conditions and low aqueous solubility. To address these problems, we prepared Cur-loaded polymeric nanoparticles (CNPs), in which Cur was complexed with phenylboronic acid-containing framboidal nanoparticles (NPs), by simple mixing of Cur and NPs in an aqueous solution. CNPs showed improved chemical stability of Cur and released it in a sustained manner under physiological conditions. Furthermore, CNPs significantly enhanced the antiangiogenic and anticancer activities of Cur in chicken chorioallantoic membrane models.

Validation of data submitted by the treating surgeon in the Victorian Audit of Surgical Mortality.

BACKGROUND: The Victorian Audit of Surgical Mortality (VASM) seeks to peer review all deaths associated with surgical care in Victoria, Australia. The effectiveness of the VASM as an educational and quality improvement tool is dependent on the accuracy of source data it receives. We aimed to examine the accuracy and quality of source data provided by the treating surgeon for peer review, and the inter-rater concordance level between the external validator findings and the treating surgeon. METHODS: Of the 629 cases that completed the VASM audit second-line peer review process over a 4-year period (from 1 July 2012 to 30 June 2016), a total of 32 (5%) were randomly selected for the external validation process. The blinded external validator was impartial to the VASM audit, and was provided only de-identified patient medical records. The analysis for the checked and validated data points and their concordance was determined using Gwet's agreement coefficient, which provides a stable inter-rater reliability coefficient not affected by prevalence and marginal probability. RESULTS: The inter-rater concordance analysis suggested that there is a high level of agreement (82.9% overall) between the treating surgeon and external validator. The use of thromboembolism deterrent stockings was the only variable where agreement was poor (52.4%) with a Gwet score of 0.10 (-0.40 to 0.60). CONCLUSION: The inter-rater concordance analysis results support the validity of the VASM process, which is dependent on the accuracy of data submitted by the treating surgeon.

Towards a pragmatic human migraine model for drug testing: 2. Isosorbide-5-mononitrate in healthy individuals.

Background A model for the testing of novel anti-migraine drugs should preferably use healthy volunteers for ease of recruiting. Isosorbide-5-mononitrate (5-ISMN) provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation of any model. The hypothesis of the present study was that sumatriptan is effective in 5-ISMN-induced headache in healthy individuals. Methods In a double-blind, randomised, crossover design, 30 healthy volunteers of both sexes received 5-ISMN 60 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves. Results 5-ISMN induced a reproducible headache in all 30 participants. The headache had several migraine-like features in all participants and 20 individuals developed a migraine-like attack. Median peak headache score was 5 on both experimental days ( p = 1.00). There was no reduction, but instead an increase in headache intensity 2 hours after sumatriptan ( p = 0.003). Difference in area under the headache score curve (AUC) 0-4 hours between sumatriptan and placebo was not significant ( p = 0.30). Conclusion 5-ISMN is a very powerful inducer of migraine-like headache in healthy individuals but the headache does not respond to sumatriptan. The model is not useful for future drug testing.

Toward a pragmatic migraine model for drug testing: I. Cilostazol in healthy volunteers.

BACKGROUND: A model for the testing of novel antimigraine drugs should ideally use healthy volunteers for ease of recruiting. Cilostazol provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation. The hypothesis of the present study was that sumatriptan but not placebo is effective in cilostazol-induced headache in healthy individuals. METHODS: In a double-blind, randomized, cross-over design, 30 healthy volunteers of both sexes received cilostazol 200 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves. RESULTS: Cilostazol induced a reproducible headache in 90% of the participants. The headache had several migraine-like features in most individuals. Median peak headache score was 2 on the sumatriptan day and 3 on the placebo day (p = 0.17). There was no reduction in headache intensity two hours after sumatriptan (p = 0.97) and difference in AUC 0 to four hours between two experimental days was not significant (p = 0.18). On the placebo day eight participants took rescue medication compared to 3 on the sumatriptan day (p = 0.13). CONCLUSION: Despite similarities with migraine headache, cilostazol-induced headache in healthy volunteers does not respond to sumatriptan.