Global Response Assessment Research Articles

Coupled metabolic-hydrodynamic modeling enabling rational scale-up of industrial bioprocesses.

Metabolomics aims to address what and how regulatory mechanisms are coordinated to achieve flux optimality, different metabolic objectives as well as appropriate adaptations to dynamic nutrient availability. Recent decades have witnessed that the integration of metabolomics and fluxomics within the goal of synthetic biology has arrived at generating the desired bioproducts with improved bioconversion efficiency. Absolute metabolite quantification by isotope dilution mass spectrometry represents a functional readout of cellular biochemistry and contributes to the establishment of metabolic (structured) models required in systems metabolic engineering. In industrial practices, population heterogeneity arising from fluctuating nutrient availability frequently leads to performance losses, that is reduced commercial metrics (titer, rate, and yield). Hence, the development of more stable producers and more predictable bioprocesses can benefit from a quantitative understanding of spatial and temporal cell-to-cell heterogeneity within industrial bioprocesses. Quantitative metabolomics analysis and metabolic modeling applied in computational fluid dynamics (CFD)-assisted scale-down simulators that mimic industrial heterogeneity such as fluctuations in nutrients, dissolved gases, and other stresses can procure informative clues for coping with issues during bioprocessing scale-up. In previous studies, only limited insights into the hydrodynamic conditions inside the industrial-scale bioreactor have been obtained, which makes case-by-case scale-up far from straightforward. Tracking the flow paths of cells circulating in large-scale bioreactors is a highly valuable tool for evaluating cellular performance in production tanks. The "lifelines" or "trajectories" of cells in industrial-scale bioreactors can be captured using Euler-Lagrange CFD simulation. This novel methodology can be further coupled with metabolic (structured) models to provide not only a statistical analysis of cell lifelines triggered by the environmental fluctuations but also a global assessment of the metabolic response to heterogeneity inside an industrial bioreactor. For the future, the industrial design should be dependent on the computational framework, and this integration work will allow bioprocess scale-up to the industrial scale with an end in mind.

Predictive Factors for a Satisfactory Treatment Outcome with Intravesical Botulinum Toxin A Injection in Patients with Interstitial Cystitis/Bladder Pain Syndrome.

A botulinum toxin A (BoNT-A) intravesical injection can improve the symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS). Patients with IC/BPS have different clinical characteristics, urodynamic features, and cystoscopic findings. This study assessed the treatment outcomes of a BoNT-A intravesical injection and aimed to identify the predictive factors of a satisfactory outcome. This retrospective study included IC/BPS patients treated with 100 U BoNT-A. The treatment outcomes were assessed by global response assessment (GRA) at 6 months. We classified patients according to different clinical, urodynamic, and cystoscopic characteristics and evaluated the treatment outcomes and predictive factors. A total of 238 patients were included. Among these patients, 113 (47.5%) had a satisfactory outcome (GRA ≥ 2) and 125 (52.5%) had an unsatisfactory outcome. Improvements in the IC symptom score, IC problem score, O’Leary–Sant symptom score, and visual analog scale score for pain were significantly greater in patients with a satisfactory outcome than in patients with an unsatisfactory outcome (all p = 0.000). The IC disease duration and maximal bladder capacity (MBC) were significantly different between patients with and without a satisfactory outcome. Multivariate analysis revealed that only the MBC was a predictor for a satisfactory outcome. Patients with a MBC of ≥760 mL and glomerulations of 0/1 (58.7%) or glomerulations of 2/3 (75.0%) frequently had a satisfactory outcome. We found that BoNT-A intravesical injection can effectively improve symptoms among patients with IC/BPS, with a remarkable reduction in bladder pain. A MBC of ≥760 mL is a predictive factor for a satisfactory treatment outcome.

Efficacy and safety of tildrakizumab for plaque psoriasis with continuous dosing, treatment interruption, dose adjustments and switching from etanercept: results from phase III studies

SummaryBackgroundChronic psoriasis may require medication adjustments over time.ObjectivesTo evaluate the efficacy/safety of tildrakizumab in subgroups from the reSURFACE studies (N = 1862) that received continuous dosing, higher/lower dosing, treatment interruption/reinitiation and initiation.MethodsResponders [Psoriasis Area and Severity Index (PASI) ≥ 75%] and partial responders (PASI ≥ 50% to < 75%) in Part 3 of the reSURFACE studies (weeks 28–52 or week 64) who received tildrakizumab 200 mg or 100 mg were rerandomized to the same dosage (T100/T100 or T200/T200), a higher/lower dosage (T100/T200 or T200/T100) or placebo (PBO) (T100/PBO or T200/PBO). Patients receiving PBO who relapsed were reinitiated to tildrakizumab. Etanercept (ETN) week‐28 partial responders and nonresponders (PASI < 50%) received tildrakizumab 200 mg (ETN/T200).ResultsAmong T100/T100 and T200/T200 week‐28 partial responders, the proportion of patients who achieved as‐observed PASI 75 responses increased over time. Among T100/T200 week‐28 partial responders, PASI 75 responses increased from week 32 (38·5%) to week 52 (63·2%) and remained consistent in T200/T100 week‐28 responders. Among patients who relapsed in the T100/PBO and T200/PBO groups, 86% and 83% of those who reinitiated tildrakizumab achieved PASI 75 by week 64, respectively. Among ETN/T200 week‐28 partial responders, PASI 75 responses (nonresponder imputation) increased from week 32 (24·1%) to week 52 (74·7%). PASI 90, PASI 100 and Physician's Global Assessment responses were consistent with PASI 75 results. Treatment was well tolerated.ConclusionsPatients generally fared well with tildrakizumab maintenance, reinitiation, dose adjustment or initiation. What's already known about this topic? Tildrakizumab demonstrated significant efficacy vs. placebo with a positive safety profile during the first 28 weeks of treatment in two randomized double‐blind trials. What does this study add? Treatment scenarios with tildrakizumab, such as long‐term continuous dosing (up to 64 weeks), treatment interruption/reinitiation and switching from another biologic, can be part of the management of plaque psoriasis with a reasonable expectation of efficacy and tolerability.

Efficacy and safety of HT080 for lower urinary tract symptoms associated with benign prostatic hyperplasia

Background:Lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) are one of the most common conditions seen in middle-aged and elderly men and threaten their quality of life. Since conventional pharmacotherapy for LUTS/BPH can lead to sexual side effects, herbal therapies are widely used as complementary and alternative treatments worldwide. HT080 is an herbal extract of Cinnamomum cassia and Rosa Laevigata, both of which have been used to treat symptoms typically associated with BPH in traditional Asian medicine. The aims of this trial are to assess whether HT080 can alleviate LUTS/BPH in middle-aged and elderly men, and to investigate the safety of HT080.Methods/design:A double-blind, randomized, placebo-controlled, two-arm parallel group trial will be conducted in men with moderate LUTS/BPH. A total of 100 eligible men aged 40 to 75 years with an International Prostate Symptom Score of 8 to 19 will be randomized in a 1:1 ratio and receive either HT080 (500 mg) or placebo twice a day for 12 weeks. All participants will be evaluated for efficacy and safety at baseline and weeks 6 and 12. The primary endpoint is the change in International Prostate Symptom Score between baseline and week 12. The secondary efficacy variables are uroflowmetry parameters (maximal urinary flow rate and post-void residual volume), serum prostate-specific antigen, testosterone, and dihydrotestosterone levels, the International Index of Erectile Function score, and participant-reported global response assessment scores. The safety assessments include adverse events, laboratory tests results, vital signs, and physical examination.Discussion:This is a first-in human trial designed to investigate the efficacy and safety of HT080 among middle-aged and elderly men with LUTS/BPH. This prospective study with a double-blind randomized design will provide high-quality evidence supporting the use of HT080 for LUTS/BPH.Trial registration:Korean Clinical Research Information Service (KCT0004286) Registered September 6, 2019.

Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream

Atopic dermatitis (AD) is a highly pruritic chronic inflammatory skin disorder. Ruxolitinib, a selective inhibitor of Janus kinase 1 and Janus kinase 2, potently suppresses cytokine signaling involved in AD pathogenesis. We sought to evaluate the efficacy and safety of ruxolitinib (RUX) cream in adults with AD. In this phase 2 study (NCT03011892), 307 adult patients with AD, an Investigator's Global Assessment score of 2 or 3 (mild or moderate), and 3% to 20% affected body surface area were equally randomized for 8 weeks of double-blind treatment to RUX (1.5% twice daily [BID], 1.5% once daily [QD], 0.5% QD, 0.15% QD), vehicle, or triamcinolone cream (0.1% BID for 4 weeks, then vehicle for 4 weeks). Subsequently, patients could apply 1.5% RUX BID for 4 additional weeks of open-label treatment. The primary end point was the comparison between 1.5% RUX cream BID and vehicle in mean percentage change from baseline in Eczema Area and Severity Index at week 4. All RUX regimens demonstrated therapeutic benefit at week 4; 1.5% BID provided the greatest improvement in Eczema Area and Severity Index (71.6% vs 15.5%; P< .0001) and Investigator's Global Assessment responses (38.0% vs 7.7%; P< .001) versus vehicle. Rapid reductions in the itch numerical rating scale score occurred within 36 hours (1.5% BID vs vehicle, ‒1.8 vs ‒0.2; P< .0001) and were sustained through 12 weeks. Patients who transitioned to 1.5% RUX BID improved in all measures. RUX was not associated with clinically significant application-site reactions. RUX cream provided rapid and sustained improvements in AD symptoms and was well tolerated.

170 Forecasting Phase 3 Dose-Response for Abrocitinib, an Oral Janus Kinase 1 Selective Inhibitor, Using Investigator’s Global Assessment and Eczema Area and Severity Index

Abrocitinib is an oral Janus Kinase 1 selective inhibitor under investigation for the treatment of atopic dermatitis (AD). To support a phase 3 study design, dose-response modeling and simulation was used to predict the relationship between abrocitinib dose and clinical AD efficacy measures. Investigator’s Global Assessment (IGA) response (clear [0] or almost clear [1] with ≥2-grade improvement from baseline) at week 12 and Eczema Area and Severity Index (EASI) score over time were measured in a phase 2b, randomized, double-blind, proof-of-concept, dose-ranging trial in patients with moderate-to-severe AD (NCT02780167; N=245 IGA records [nonresponder imputation], N=2220 EASI records from 263 patients). IGA response at week 12 was adequately described by an Emax dose-response model (ie, landmark logistic regression). EASI score, from baseline through week 16, was adequately described across time by a linear dose-response model. The final models were used to simulate IGA response rates (as defined above) and EASI75 response rates (≥75% reduction in EASI score from baseline) in 1000 simulated trials with cohorts of 50 patients/dose. Simulations answered the question: what is the median (90% prediction interval) response rate at week 12 expected in a subsequent AD trial? The predicted rates for IGA response were 6% (0-14%), 26% (14-38%), and 38% (26-54%), and for EASI75 response were 21% (12-30%), 50% (38-62%), and 62% (52-74%) for placebo and abrocitinib doses of 100 mg and 200 mg, respectively. Based on these findings, once-daily abrocitinib doses of 100 mg and 200 mg were forecasted to provide clinically meaningful response relative to placebo in the current randomized, double-blind, placebo-controlled phase 3 trial in patients aged ≥12 years with moderate-to-severe AD.

Therapeutic Effects of Botulinum Toxin A, via Urethral Sphincter Injection on Voiding Dysfunction Due to Different Bladder and Urethral Sphincter Dysfunctions.

Botulinum toxin A (BoNT-A) urethral sphincter injections have been applied in treating voiding dysfunction but the treatment outcome is not consistent. This study analyzed treatment outcomes between patients with different bladder and urethral sphincter dysfunctions. Patients with refractory voiding dysfunction due to neurogenic or non-neurogenic etiology were treated with urethral sphincter 100 U BoNT-A injections. The treatment outcomes were assessed by a global response assessment one month after treatment. The bladder neck opening and urodynamic parameters in preoperative videourodynamic study were compared between successful and failed treatment groups. A total of 80 non-neurogenic and 75 neurogenic patients were included. A successful outcome was noted in 92 (59.4%) patients and a failed outcome in 63 (40.6%). The treatment outcome was not affected by the gender, voiding dysfunction subtype, bladder dysfunction, or sphincter dysfunction subtypes. Except an open bladder neck and higher maximum flow rate, no significant difference was noted in the other variables between groups. Non-neurogenic patients with successful outcomes had a significantly higher detrusor pressure, and patients with neurogenic voiding dysfunction with successful results had higher maximum flow rates and smaller post-void residuals than those who failed the treatment. However, increased urinary incontinence was reported in 12 (13%) patients. BoNT-A urethral sphincter injection is effective in about 60% of either neurogenic or non-neurogenic patients with voiding dysfunction. An open bladder neck during voiding and a higher maximum flow rate indicate a successful treatment outcome.

Intravesical tacrolimus in treatment of intractable interstitial cystitis/bladder pain syndrome - A pilot study.

Interstitial cystitis/Bladder pain syndrome (IC/BPS) is a chronic condition with limited effectiveness of current treatments without any cure. Cyclosporine A is effective in intractable cases of BPS/IC. Tacrolimus has same mechanism of action. The purpose of this pilot study was to find if tacrolimus instilled in bladder is effective in treating BPS/IC without side effects. From February 2013 till Dec. 2017 tacrolimus dissolved in DMSO/sterile water was instilled in bladder of 24 patients of intractable BPS/IC. Patients received one to six cycles of therapy at interval of 14days. Base line complete blood count, blood glucose, renal and liver function test were done and repeated after every three instillations. Serum tacrolimus level was also measured in 10 patients. Primary study endpoint was Global Response Assessment (GRA) score. 13 out of 24 patients showed improvement in a follow up extending from 6 to 63month. Except for post- instillation flare in symptoms no side effects were observed in the patients during follow-up. Blood levels of tacrolimus reach same safe level irrespective of using either DMSO or water for preparing the solution. Intravesical tacrolimus dissolved in DMSO/water has been found effective in 54% patients of intractable BPS/IC without significant side effects in this pilot study. For the first time we have discovered that though tacrolimus is believed to be insoluble in water it gets absorbed by bladder urothelium when a solution of tacrolimus in water is instilled in urinary bladder. It should be offered to the patients before offering surgery.

Efficacy and safety of tofacitinib for the treatment of chronic plaque psoriasis: a systematic review and meta-analysis.

BackgroundTofacitinib is an oral Janus kinase (JAK) inhibitor that targets JAK1 and JAK3, and thus regulates immune response. Therefore, tofacitinib is used to treat immune-mediated inflammatory diseases such as chronic plaque psoriasis. The objective of this study was to systematically assess the efficacy and safety of tofacitinib in treating chronic plaque psoriasis.ObjectiveTo systematically review the efficacy and safety of tofacitinib in the treatment of chronic plaque psoriasis, we performed a meta-analysis to evaluate the efficacy and safety of tofacitinib in patients with chronic plaque psoriasis.MethodsDatabases including PubMed, Embase, and The Cochrane Library were searched for randomized controlled trials about the efficacy and safety of tofacitinib in treating chronic plaque psoriasis from inception to August 2017 (PROSPERO Code No: CRD42017076587).ResultsSix articles (seven randomized controlled trial studies) involving 3743 patients were included. The meta-analysis results showed that for efficacy, tofacitinib (5 mg or 10 mg) compared with placebo can significantly improve the Physician’s Global Assessment response, PASI75, and PASI90 after treatment. For safety, the incidence of adverse reactions was statistically significantly higher for tofacitinib compared with placebo.ConclusionTreatment of chronic plaque psoriasis with tofacitinib is effective, but there may be more adverse reactions.

Anxiety severity does not influence treatment outcomes in patients with interstitial cystitis/bladder pain syndrome.

Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) typically experience anxiety mood status, which is closely connected with physical and psychological status and treatment outcome. This study aimed to evaluate the impact of anxiety severity on therapeutic results in IC/BPS patients. We prospectively enrolled IC/BPS patients who had previously undergone any kind of treatment for their disease. The primary endpoint was a change in Beck Anxiety Inventory (BAI) scores at 3 months after treatment. Secondary endpoints included changes in the Global Response Assessment (GRA), O'Leary-Sant symptom score (OSS), and Numerical Rating Scale (NRS) at 3 months after treatment. Urodynamic studies were also compared with the clinical symptom scores. Overall, 85 IC/BPS patients (mean age, 53.1 ± 12.4 years) were included in the study. At 3 months, changes in the GRA were not significantly different among the different anxiety severity groups. At baseline, 55 (64.7%) patients had moderate or severe anxiety. We observed a significant positive correlation between the change in BAI and the change in OSS after treatment and a significantly negative correlation with GRA at 3 months. Moreover, improvements in OSS and NRS were associated with the change in GRA. Changes in IC symptoms, but not physiological outcomes, were associated with improved anxiety status after treatment. In addition, the change in BAI was significantly associated with age, baseline BAI, and changes in OSS and GRA after treatment. Baseline anxiety severity does not influence treatment outcomes of IC/BPS. Patients should receive active treatment regardless of their baseline anxiety status.

Hyaluronic acid improves pain symptoms more than bladder storage symptoms in women with interstitial cystitis

ObjectiveIntravesical hyaluronic acid (HA) therapy is one of acceptable methods to treat bladder pain and storage symptoms (i.e., urgency, frequency and nocturia) of interstitial cystitis/bladder pain syndrome (IC/BPS). We aim to assess the impacts of intravesical HA on bladder pain and storage symptoms, respectively, and to investigate their associated factors in patients with IC/BPS. Materials and methodsIn this prospective, multicenter study, 103 women with refractory IC/BPS undergoing a standard protocol of intravesical HA therapy were enrolled. A pain Visual Analog Scale (VAS) and the Interstitial Cystitis Symptom and Problem Index (ICSI & ICPI) were used to assess symptoms and bother associated with IC/BPS. The Scaled Global Response Assessment (GRA) was used to evaluate patients' perception of overall changes in bladder pain and storage symptoms, respectively, after treatment. ResultsMean age of participants was 43.6 ± 11.8 years. The average duration of symptoms was 5.1 ± 5.0 years. Significant improvements in pain VAS, ICSI and ICPI scores were observed after treatment. However, patients reported significantly different rates of moderate/marked improvement in bladder pain and storage symptoms (73.8% vs. 47.6%; P < 0.001) on the GRA, respectively. “Lower pain VAS score” and “reduced functional bladder capacity” were found to be the factors that adversely affected the treatment responses of bladder pain and storage symptoms, respectively, after repeated statistical analyses. ConclusionBladder instillation of HA seemed more efficient in improving bladder pain than storage symptoms associated with IC/BPS. The persistence of bladder storage symptoms after treatment might result from a reduced functional bladder capacity.

Clinical pharmacology, efficacy and safety study of a triple‐secured fibrinogen concentrate in adults and adolescent patients with congenital fibrinogen deficiency

Essentials A novel fibrinogen concentrate was evaluated in patients with congenital fibrinogen deficiency. An open-label, phase 2-3 trial studied pharmacology, efficacy, and safety in patients >6years. The product offers safe and effective therapy in the treatment and prophylaxis of bleeding. Data in recovery show the need of adjusted treatment and further investigation in children. SUMMARY: Background Single-factor replacement therapy is considered the most suitable treatment option for hereditary fibrinogen deficiency. A triple-secured plasma-derived human fibrinogen product was developed to increase the safety of the former fibrinogen concentrate. Objectives This non-randomized, open-label, prospective study investigated pharmacokinetics, efficacy, and safety of a novel fibrinogen concentrate (FibCLOT® /CLOTTAFACT® LFB, France) in inherited deficiency. Patients/Methods Fourteen patients ≥40 kg received fibrinogen concentrate for pharmacology and 16 ≥ 23kg received treatment for bleeding or surgery. Each treatment was followed by a 3-week safety observation period. Key outcomes included number of infusions, dose, bleeding control, daily assessment, hemoglobin, blood loss, transfusions, and physicians' global assessment of response. Results Incremental recovery was 2.35mg mL-1 permgkg-1 and maximal concentration 1.41gL-1 (geometric mean) after 0.060gkg-1 infusion in 14afibrinogenemic patients. Terminal half-life was 69.3h (non-compartmental analysis). The maximum clot firmness was increased by a mean of 10.3mm from baseline to maximal effect. Sixteen patients participated to the efficacy phase: 32 bleeding episodes were treated in 9 patients, and 15 patients underwent 38 surgical/invasive procedures. All patients achieved appropriate hemostasis: response to treatment was successful in all bleeds (95% CI, 0.89-1.00) and procedures (95% CI, 0.91-1.00). Most (94%) bleeds were controlled with a single infusion (median 0.050g kg-1 ). Two patients experienced asymptomatic distal venous thromboses identified by systematic ultrasound. Conclusion FibCLOT® /CLOTTAFACT® showed a pharmacokinetic profile comparable to that of other fibrinogen concentrates and provides safe and clinically effective substitution therapy for fibrinogen-deficient patients.

RNA-Seq analysis of the T3SA regulon in Shigella flexneri reveals two new chromosomal genes upregulated in the on-state.

Shigella spp. are enterobacteria that invade human colonic mucosal cells using their Type Three Secretion Apparatus (T3SA). Shigella spp. possess a large plasmid that encodes most of its virulence factors and has been the focus of seminal work that defined the T3SA regulon. Thus, a global assessment of the transcriptional response regulated by the T3SA has been lacking. Herein we used RNA-Seq to identify genes that are differentially expressed when the T3SA is active (on-state) versus inactive (off-state). The quality of the RNA-Seq dataset was validated by its correlation with a prior microarray study. Using novel insights about the expression of non-coding regions, bioinformatic tools and experimentations, we demonstrated the existence of six operons and evidence that ipaH2.5 is a pseudogene. In addition, 86 chromosomal genes were downregulated in the on-state including several non-coding transcripts corresponding to short antisense RNA embedded in the 16S and 23S RNA genes, and 40 coding transcripts, whose cognate proteins were highly connected at the genetic and biochemical levels. Finally, we identified two novel chromosomal genes dubbed gem1 and gem3, which were upregulated in the on-state similarly to genes belonging to the T3SA regulon. The latter findings were validated on biological triplicates by droplet digital PCR. To our knowledge gem1 and gem3 are the first chromosomal members of the T3SA regulon that have no homologs on the plasmid. Our approach provides a path to optimizing RNA-Seq studies in case of bacterial models that had previously been the subject of medium to large scale studies.

Occurrence, sources and effects of polycyclic aromatic hydrocarbons in the Tunis lagoon, Tunisia: an integrated approach using multi-level biological responses in Ruditapes decussatus.

Coastal lagoons are critical ecosystems presenting a strategic economic importance, but they are subjected to potential anthropogenic impact. As part of the Tunis lagoon (Tunisia) biomonitoring study, levels, composition pattern and sources of polycyclic aromatic hydrocarbons (PAHs) in surface sediments along with their bioavailability in clam Ruditapes decussatus were investigated in polluted (S2-S4) and reference (S1) sites. In order to investigate the contamination effects at different biological levels in clams, a wide set of biomarkers, including gene expression changes, enzymatic activities disruption and histopathological alterations, was analysed. Biomarkers were integrated in a biomarker index (IBR index) to allow a global assessment of the biological response. Principal component analysis (PCA) was used for chemical and biological data integration to rank the sampling sites according to their global environmental quality. Sediment PAHs levels ranged between 144.5 and 3887.0 ng g-1 dw in the Tunis lagoon sites versus 92.6 ng g-1 dw in the reference site. The high PAH concentrations are due to anthropogenic activities around the lagoon. PAH composition profiles and diagnostic isomer ratios analysis indicated that PAHs were of both pyrolitic and petrogenic origins. Clams sampled from S2 and S3 exhibited the highest PAH contents with 2192.6 ng g-1 dw and 2371.4 ng g-1 dw, respectively. Elevated levels of tissue PAHs were associated to an increase in biotransformation and antioxidant activities, and lipid peroxidation levels along with an overexpression of different genes encoding for general stress response, mitochondrial metabolism and antioxidant defence, in addition to the emergence of severe and diverse histopathological alterations in the clams' digestive glands. IBR index was suitable for sampling sites ranking (S1 = 0 < S4 = 0.4 < S3 = 1.15 < S2 = 1.27) based on the level of PAH-induced stress in clams. PCA approach produced two components (PC1, 83.8% and PC2, 12.2%) that describe 96% of the variance in the data and thus highlighted the importance of integrating contaminants in sediments, their bioaccumulation and a battery of biomarkers of different dimensions for the assessment of global health status of coastal and lagoon areas.

Collapse performance of composite steel frames under fire

Collapse of steel structures under extreme hazards has been placed at the forefront of research in recent decades. While significant number of studies has been conducted in the past on steel members and subassemblies under fire, the response of steel buildings exposed to fire loadings has not received a similar level of attention. In addition, only handful of previous studies, mainly 2D with only one study pertaining to 3D frames, encompassed the full response of the system up to and including collapse. In this study, a 3D numerical finite element model is developed for a six-story steel-frame building with moment frames, gravity frames, and center concentrically braced frame to evaluate the collapse behavior of the structure under fire loading. A standard and a parametric fire curve are selected to simulate the fire loadings and are applied independently to the building model under two different contained fire scenarios. The two scenarios include first floor corner compartment fire and whole first floor fire. This allowed for the assessment of different global system response where collapse is triggered by twist of the entire structure accompanied by lateral deformation in the case of a corner compartment fire and progressive vertical displacement of the entire system in the case of the whole first floor fire. The simulation results show that structural response of steel buildings including collapse mechanism and behavior of structural members and connections during fire events can be predicted with reasonable accuracy using advanced numerical finite element analysis.

Supervised walking improves cardiorespiratory fitness, exercise tolerance, and fatigue in women with primary Sjögren's syndrome: a randomized-controlled trial.

The aim of this study was to evaluate the safety and effectiveness of a supervised walking program in women with primary Sjögren's syndrome (pSS). Forty-five sedentary women fulfilling the American European Consensus Criteria for pSS were randomized to a training group (TG, n = 23) or control group (CG, n = 22). Patients in the TG were submitted to supervise walking three times a week for 16weeks. The patients of the CG were instructed to not perform any kind of regular physical exercise. Physical fitness [maximum oxygen uptake (VO2max) and distance], EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), hematological tests, and Medical Outcomes Study 36 (SF-36) were assessed at baseline and week16. In addition, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), Functional Assessment of Chronic Illness Therapy Fatigue Subscale (FACIT-fatigue), and Beck Depression Inventory (BDI) were measured prior to intervention, after 8 and 16weeks. Patient global assessment of response to therapy was completed at the final assessment. An intent-to-treat analysis was performed. After 16weeks, the mean change of VO2max (ml/kg/min), distance, and FACIT-fatigue were higher in the TG than in the CG (p = 0.016, p = 0.043 and p = 0.030, respectively). Improved cardiorespiratory fitness was associated with improvements in fatigue scores and physical components of quality of life (SF-36). Furthermore, improved fatigue scores were associated with reduced depression and improvements in the physical and mental components of SF-36. Overall, 95.4% of patients in the TG rated themselves as clinically improved versus 62% of the patients in the CG (p = 0.049). There was no flare in disease activity and no serious adverse events with exercise. This supervised walking program was demonstrated to be feasible and safe with improvements in cardiorespiratory fitness, exercise tolerance, fatigue, and patient perception of improvement in pSS patients. Clinical Trials.gov ID, number NCT02370225.

Therapeutic Efficacy and Quality of Life Improvement in Women with Detrusor Underactivity Following Transurethral Incision of the Bladder Neck

Aims: To investigate the effects of transurethral incision of the bladder neck (TUI-BN) on long-term outcomes and quality of life (QoL) improvements in women with detrusor underactivity (DU) refractory to standard medical treatment. Materials and Methods: Data were retrieved for female patients with treatment-refractory DU who underwent TUI-BN between 2007 and 2018. Urodynamic parameters were measured at baseline and follow-up and were analyzed for surgical outcome. Patients who were capable of spontaneously voiding with a voiding efficiency (VE) of ≥50% with or without the aid of abdominal pressure were considered to have achieved satisfactory outcomes. Changes in self-reported QoL were measured based on the International Prostate Symptom Score QoL (IPSS-QoL), and treatment improvements were measured based on the global response assessment (GRA) index. Moreover, the voiding statuses of patients before and after TUI-BN were compared. Results: Overall, 82 women, with a mean age of 60.8 ± 17.9 years (range 12–102), were included. Most patients experienced chronic urinary retention or large postvoid residual (PVR) urine. Median follow-up period was 5 years (range 1–12). Following TUI-BN, 40 (48.8%) patients achieved satisfactory outcomes, with a mean GRA of 1.4 ± 0.93. Mean maximum flow rate, voided volume, PVR volume, VE, and IPSS-QoL were all significantly improved. Among all patients, 50 (61%) were subsequently able to spontaneously void with or without the aid of abdominal pressure without the need for catheterization. Indwelling catheters were required in 19 (23.2%) patients at baseline and in 5 (6.1%) following TUI-BN (P &lt; 0.01). Moreover, 5 (6.1%) patients developed stress urinary incontinence and 2 (2.4%) experienced vesicovaginal fistulae following TUI-BN procedures, all of whom recovered satisfactorily after treatment. Conclusions: TUI-BN is an effective procedure for reducing the bladder outlet resistance and improving VE and QoL. Moreover, the procedure is durable with an acceptable incidence of complications.

Efficacy and safety of anakinra for undifferentiated autoinflammatory diseases in children: a retrospective case review.

ObjectiveThe aim was to carry out a retrospective review of the efficacy and safety of anakinra in paediatric patients with undifferentiated autoinflammatory disease (uAID).MethodsWe carried out a retrospective study of children with uAID at a single quaternary centre. The clinical efficacy of anakinra was evaluated using physician global assessment (PGA) and serological response assessed by levels of serum amyloid A and CRP. Safety was assessed by exploring adverse events, including infection and drug reactions.ResultsThis study included 22 patients, 64% females and 36% males of median age 7.1 years (range 0.13–14.11 years), with uAID. The median starting dose of anakinra was 2 mg/kg (range 2–6 mg/kg) and the median duration of treatment 19.6 months (range 0.8–100 months). Before anakinra treatment, the median PGA, on a three-point Likert scale, was 2 (range 1–2), which fell to 1 (range 0–2) within 3 months of treatment. Eight of 22 (36%) patients achieved complete clinical and serological remission; 8/22 (36%) achieved a partial response; and 6/22 (28%) had no response to anakinra. Adverse events included death (3/22, 14%) and allogeneic haematopoietic stem cell transplantation (1/22, 5%). There were no new safety signals, and anakinra was well tolerated overall.ConclusionRetrospectively, 72% of children with uAID responded well to anakinra, with 36% achieving full clinical and serological remission within 3 months. This suggests that empirical trials of IL-1 blockade might be warranted in children with uAID. Clear stopping criteria based on predefined parameters should be considered, because non-responders required alternative therapies, facilitated by a definitive molecular diagnosis where possible.

Intravesical injections of platelet-rich plasma is effective and safe in treatment of interstitial cystitis refractory to conventional treatment-A prospective clinical trial.

Current treatments for interstitial cystitis/bladder pain syndrome (IC/BPS) are usually unsuccessful in achieving long-term bladder pain relief and irritable symptom improvement. This study investigated the clinical efficacy of platelet-rich plasma (PRP) intravesical injections on IC/BPS patients refractory to conventional therapies. Forty patients received four monthly intravesical injections of 10 mL PRP extracted from 50 mL of whole blood. The primary end-point was Global Response Assessment (GRA) at 3 months after the 4th PRP injection. Secondary endpoints included changes in O'Leary-Sant symptom score (OSS), visual analog scale (VAS) of pain, daily frequency, nocturia, functional bladder capacity (FBC), maximum flow rate, voided volume, post-void residual volume (PVR) from baseline to 3 months after the 4th PRP injection. All 40 patients (37 women and 3 men, aged 55.5 ± 11.1 years) completed the four injections and follow-up visits. GRA improved after the 1st PRP injection and the satisfaction persists till the primary end-point. The success rate was 45%, 52%, 70%, 70%, and 67.5% after the 1st, 2nd, 3rd, 4th, and 3 months after the 4th PRP injection, respectively. OSS and VAS also significantly decreased. The PVR did not change after repeated PRP injections, FBC increased, frequency, and nocturia were decreased after PRP injections. All patients were free of urinary tract infection or difficulty urinating. The study demonstrated that repeated intravesical injections of autologous PRP can increase bladder capacity and provide IC symptom improvement in patients with IC/BPS refractory to conventional therapy. Autologous PRP injection is safe and effective in selected patients.

Higher urge severity score predicts resumption of overactive bladder (OAB) medication following discontinuation of mirabegron treatment in patients with OAB.

This study investigated factors predicting the resumption of mirabegron following its discontinuation with successful treatment of overactive bladder (OAB). In all, 374 OAB patients reporting an improvement in subjective symptoms after a minimum of 3 months treatment with mirabegron 25 mg, q.d., were screened. Those wanting to continue with the medication (n = 109) were excluded from the study. The remaining 265 patients discontinued mirabegron and their outcomes were evaluated at baseline (discontinuation) and 1, 3, 6, 9, and 12 months using the International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), Urgency Severity Scale (USS), Patient's Perception of Bladder Condition (PPBC), and Global Response Assessment (GRA), as well as uroflowmetry and post-void residual (PVR). After mirabegron discontinuation, 203 patients completed follow-up. The mean (±SD) duration from discontinuing medication to resumption of mirabegron was 2.25 ± 1.17 months (range 1-12 months). Compared with the 111 (54.7%) patients who did not resume mirabegron, the 92 (45.3%) patients who resumed mirabegron had a higher USS at time of discontinuation (1.18 ± 1.76 vs. 0.65 ± 1.33; P = 0.017). The USS was a strong predictor of mirabegron resumption (P = 0.02; odds ratio 1.315; 95% confidence interval 1.051-1.646). Among OAB patients who were successfully treated with mirabegron for ≥3 months, nearly half requested resumption of mirabegron after discontinuation. A higher USS was found to predict retreatment after discontinuation of mirabegron in OAB patients.