Golimumab improves health-related quality of life of patients with moderate-to-severe ulcerative colitis: Results of the go-care study.

BACKGROUND: In recent years, improvement of Health-Related Quality of Life (HRQoL) in Ulcerative colitis (UC) has become a relevant measure for treatment efficacy. METHODS: We report results from a multicenter prospective study in Italy investigating HRQoL in adult patients with UC treated with golimumab (GLM). Patients who had shown clinical response after a 6-week induction phase (w0), were followed for an additional 48 weeks (w48) (total 54-week treatment). RESULTS: Of the 159 patients enrolled 90 completed the study. Compared to values at the beginning of treatment (n = 137), significant improvements were observed for mean total Inflammatory Bowel Disease Questionnaire (IBDQ) scores at w0 (168.5) and w48 (181.7). Patients with baseline PMS above the median tended to have greater improvements in IBDQ at w0 (OR 2.037, p = 0.033) and w48 (OR 3.292, p = 0.027). Compared to beginning of GLM treatment, the mean Full Mayo Score (FMS) decreased by 5.9 points at w48, while mean Partial Mayo Score (PMS) decreased by 3.9 points at w0 and by 4.9 points at w48. CONCLUSIONS: GLM improved HRQoL, disease activity and inflammatory biomarkers in UC patients with moderate-to-severely active disease. The greater the burden of disease activity at baseline, the greater the improvement of HRQoL after 24 and 48 weeks of treatment.

Influence of natural seawater variables on the corrosion behaviour of aluminium-magnesium alloy.

Corrosion is an important issue for alloys in natural seawater, where microorganisms can accelerate or mitigate corrosion. Al-Mg alloys are used for marine activities and various associated technologies. Here, the behaviour of AA5083 alloy was investigated in natural seawater with marine exposure lasting up to 50 days and detailing the first 8 days in two experimental series. Experimental work was carried out, including semi-field tests in natural seawater (biotic conditions) compared with abiotic conditions. The open circuit potential (OCP) measurements, during the immersion time, exhibited significantly different behaviours: an OCP downward displacement occurred under abiotic conditions, while, in biotic conditions OCP remained generally stable since the beginning of the immersion, revealing an inhibiting effect of the biological activity on the Al-Mg corrosion. This was accompanied by different surface modifications under biotic conditions: surface and cross-section characterization, performed by scanning electron microscopy with energy dispersive X-ray spectroscopy, showed less corrosion developed on the surface after 8-day immersion and formation of a protective layer during 50-day immersion. The present study shows that marine biological activity positively influences the Al alloy corrosion process, with surface modifications resulting in a protective effect counteracting the aggressiveness of chloride ions.

Patterns and characteristics of TB among key risk groups in Canada, 1993-2018.

BACKGROUND: Canada has a low incidence of TB, although certain groups are disproportionately affected.OBJECTIVE: To describe and compare the epidemiology, trends and characteristics of TB in Quebec, Canada, among all patients reported during 1993-2018.METHODS: Demographics and risk factors were compared for the three groups accounting for most TB diagnoses reported in Quebec (foreign-born, Canadian-born non-Indigenous and Inuit). Average annual incidence and incidence rate ratios (IRRs) were estimated and compared using Poisson regression.RESULTS: Of 6,941 persons with a first episode of TB, 4,077 (59%) were foreign-born, 2,314 (33%) were Canadian-born non-Indigenous and 389 (6%) were Inuit. The average annual incidence for foreign-born, Canadian-born non-Indigenous and Inuit was respectively 17.0, 1.4 and 137.1 per 100,000 population. Compared to Canadian-born non-Indigenous, the IRR for foreign-born and Inuit was respectively 12.3 (95% CI 11.6-12.9) and 98.7 (95% CI 88.6-109.9). There was evidence of community transmission among the Inuit, with more than 80% of patients having a TB contact (2012-2018 data) and 65% (251/389) of diagnoses in those aged <25 years.CONCLUSION: Although TB rates among the Canadian-born non-Indigenous are extremely low, there are persistent and distinct TB epidemics among the foreign-born and Inuit. Tailored approaches to TB prevention and care are needed to address TB among high-risk populations in low TB incidence settings.

Quality of endoscopic screening for colorectal cancer in Italy: A national survey.

BACKGROUND: Colorectal cancer (CRC) is a major healthcare problem all over the world and screening is effective in reducing mortality and increasing survival. Since colonoscopy has a central role in faecal immunochemical test (FIT)-based CRC screening and surveillance, consistent quality measures are essential to ensure quality and outcomes. Nevertheless, screening modalities in clinical practice may differ according to the centers experience and the local availability of instrumentation and devices. AIMS: to assess the quality of endoscopic screening for CRC and adherence to international guidelines across Gastroenterology Departments in Italy. METHODS: All members of the Italian Society of Gastroenterology (SIGE) were invited to answer a web-based survey. RESULTS: Data from 64 hospitals from 17 Italian regions were analyzed. 32/64 (50.0%) were from northern, 12/64 (18.75%) from central and 20/64 (31.25%) from southern Italy. Each center is equipped with a median of 5.0 (3.5-7.0) endoscopists involved in CRC screening, 71.4% of which are gastroenterologists. After a positive FIT, most centers (93.8%) schedule a colonoscopy within 3 months. High-definition video endoscopy is routinely performed in 68.8% and chromoendoscopy in 53.1% of centers. Withdrawal time is ≥6 min in 79.9% and cecal intubation rate is ≥90% in 94.4% of departments. Finally, in 92.7% of centers adenoma detection rate (ADR) overcome the minimum standard of 25%. Analyzing the data by regional areas, a significant higher number of median endoscopic examinations/year (6500 vs 4000 and 3000, respectively, p = 0.024) and of endoscopists per center (6.5 vs 5.0 and 3.5, respectively, p < 0.001) has been registered in the northern compared to central-southern centers. CONCLUSIONS: Data from this survey show adequacy and good quality of endoscopic screening for CRC in Italy, highlighting, at the same time, relevant deficiencies and a discrepancy in procedural attitudes between the different centers. These findings call for a urgent action to overcome the shortcomings, refine and homogenize the behaviour of all screening centers in the national territory and improve the outcomes.

Inflammatory markers and BDNF in obstructive sleep apnea (OSA) in Parkinson's disease (PD).

OBJECTIVE: Obstructive sleep apnea (OSA) exacerbates Parkinson's disease (PD) manifestations including cognitive dysfunction. Both OSA and PD have been associated with inflammation. Brain-derived neurotrophic factor (BDNF) has been implicated in cognitive function. We aimed to investigate inflammatory cytokines and BDNF in relation to OSA and PD symptoms. METHODS: In a prospective observational study, patients with PD underwent overnight polysomnography. Morning serum levels of interleukin (IL)-1ß, IL-6, IL-8, TNFα, and BDNF were quantified at baseline (n = 64) and 6 months (n = 38). Outcomes included non-motor and motor standard scores; Montreal Cognitive Assessment (MoCA); and Epworth Sleepiness scale (ESS). Associations were assessed using linear regression, adjusting for age, sex and body mass index. RESULTS: At baseline, IL-6 was associated with the Apnea-Hypopnea Index (ß = 0.013, p = 0.03), and the Oxygen Desaturation Index (ß = 0.028, p = 0.002). No other associations between cytokines and sleep parameters were found. Motor dysfunction was associated with IL-6 (ß = 0.03, p = 0.001). ESS was associated non-significantly with IL-6 (ß = 0.04, p = 0.07) and BDNF (ß = 555, p = 0.06). At follow-up, change in IL-6 was associated with change in non-motor (ß = 0.08, p = 0.007), and motor (ß = 0.03, p = 0.001) symptoms. Change in BDNF was associated with change in ESS (ß = 1450, p = 0.02). INTERPRETATION: We found an association between IL-6 levels and both OSA severity and PD motor dysfunction. At follow-up, increasing IL-6 correlated with deterioration of motor and non-motor PD symptoms. Increasing BDNF correlated with increasing sleepiness. Further work with a larger sample size is needed, but our results support the hypothesis that OSA-related inflammation plays a role in PD manifestations and progression.

Cs diffusion mechanisms in UO2 investigated by SIMS, TEM, and atomistic simulations.

Experimental investigations and atomistic simulations are combined to study the cesium diffusion processes at high temperature in UO2. After 133Cs implantation in UO2 samples, diffusion coefficients are determined using the depth profile evolution after annealing as measured by secondary ion mass spectrometry. An activation energy of 1.8 ± 0.2 eV is subsequently deduced in the 1300-1600 °C temperature range. Experimental results are compared to nudged elastic band simulations performed for different atomic paths including several types of uranium vacancy defects. Activation energies ranging from 0.49 up to 2.34 eV are derived, showing the influence of the defect (both in terms of type and concentration) on the Cs diffusion process. Finally, molecular dynamics simulations are performed, allowing the identification of preferential Cs trajectories that corroborate experimental observations.

Implementing the 4R and 9H regimens for TB preventive treatment in Indonesia.

BACKGROUND: The implementation of tuberculosis preventive treatment (TPT) is challenging especially in resource-limited settings. As part of a Phase 3 trial on TPT, we described our experience with the use of rifampicin for 4 months (4R) and isoniazid for 9 months (9H) in Indonesia.METHODS: In 2011-2017, children and adults with latent TB infection were randomised to either 4R or 9H and followed until 16 months after randomisation for children and 28 months for adults. The primary outcome was the treatment completion rate. Secondary outcomes were Grade 3-5 adverse events (AEs), active TB occurrence, and health costs.RESULTS: A total of 157 children and 860 adults were enrolled. The 4R treatment completion rate was significantly higher than that of 9H (78.7% vs. 65.5%), for a rate difference of 13.2% (95% CI 7.1-19.2). No Grade 3-5 AEs were reported in children; in adults, it was lower in 4R (0.4%) compared to 9H (2.8%). The incidence of active TB was lower with 4R than with 9H (0.09/100 person-year vs. 0.36/100 person-year) (rate difference: -0.36/100 person-year). The total cost per patient was lower for the 4R regimen than for the 9H regimen (USD151.9 vs. USD179.4 in adults and USD152.9 vs. USD206.5 in children)CONCLUSIONS: Completion and efficacy rates for 4R were better than for 9H. Compared to 9H, 4R was cheaper in all age groups, safer in adults and equally safe in children. The Indonesian TB program could benefit from these benefits of the 4R regimen.

TB case fatality and recurrence in a private sector cohort in Mumbai, India.

BACKGROUND: Half of India´s three million TB patients are treated in the largely unregulated private sector, where quality of care is often poor. Private provider interface agencies (PPIAs) seek to improve private sector quality of care, which can be measured in terms of case fatality and recurrence rates.METHODS: We conducted a retrospective cohort survey of 4,000 private sector patients managed by the PATH PPIA between 2014 and 2017. We estimated treatment and post-treatment case-fatality ratios (CFRs) and recurrence rates. We used Cox proportional hazards models to identify predictors of fatality and recurrence. Patient loss to follow-up was adjusted for using selection weighting.RESULTS: The treatment CFR was 7.1% (95% CI 6.0-8.2). At 24 months post-treatment, the CFR was 2.4% (95% CI 1.7-3.0) and the recurrence rate was 1.9% (95% CI 1.3-2.5). Treatment fatality was associated with age (HR 1.02, 95% CI 1.02-1.03), clinical diagnosis (HR 0.61, 95% CI 0.45-0.84), treatment duration (HR 0.09, 95% CI 0.06-0.10) and adherence. Post-treatment fatality was associated with treatment duration (HR 0.87, 95% CI 0.79-0.91) and adherence.CONCLUSIONS: We found a moderate treatment phase CFR among PPIA-managed private sector patient with low rates of post-treatment fatality and recurrence. Routine monitoring of patient outcomes after treatment would strengthen PPIAs and inform future post TB interventions.

A public health approach to increase treatment of latent TB among household contacts in Brazil.

SETTING: Two consecutive trials were conducted to evaluate the effectiveness of a public health approach to identify and correct problems in the care cascade for household contacts (HHCs) of TB patients in three Brazilian high TB incidence cities.METHODS: In the first trial, 12 clinics underwent standardised evaluation using questionnaires administered to TB patients, HHCs and healthcare workers, and analysis of the cascade of latent TB care among HHCs. Six clinics were then randomised to receive interventions to strengthen management of latent TB infection (LTBI), including in-service training provided by nurses, work process organisation and additional clinic-specific solutions. In the second trial, a similar but streamlined evaluation was conducted in two clinics, who then received initial and subsequent intensive in-service training provided by a physician.RESULTS: In the evaluation phase of both trials, many HHCs were identified, but few started LTBI treatment. After the intervention, the number of HHCs initiating treatment per 100 active TB patients increased by 10 (95%CI - 11 to 30) in the first trial, and by 44 (95%CI 26 to 61) in the second trial.DISCUSSION: A public health approach with standardised evaluation, local decisions for improvements, followed by intensive initial and in-service training appears promising for improved LTBI management.

Impact of the COVID-19 pandemic on Gastroenterology Divisions in Italy: A national survey.

BACKGROUND: In Italy, the spread of the COVID-19 pandemic has stressed the entire healthcare system and required a huge re-organization of many Divisions, including those of Gastroenterology. AIMS: to assess the impact of COVID-19 pandemic on Gastroenterology Divisions across Italy. METHODS: All members of the Italian Society of Gastroenterology (SIGE) were invited to answer a web-based survey. RESULTS: Data of 121 hospitals from all 20 Italian regions were analyzed. Overall, 10.7% Gastroenterology Divisions have been converted to Covid Units. Outpatients consultations, endoscopic and ultrasound procedures were limited to urgencies and oncology indications in 85.1%, 96.2% and 72.2% of Units, respectively, and 46.7% of them suspended the screening for colorectal cancer. Moreover, 72.2% of the staff received a training for use of personal protective equipment, although 45.5% did not have sufficient devices for adequate replacement. Overall, 132 healthcare workers in 41 Gastroenterology Divisions were found to be infected. CONCLUSION: This is the first study to evaluate, at a country level, the impact of COVID-19 outbreak on Gastroenterology Divisions. Substantial changes of practice and reduction of procedures have been recorded in the entire country. The long-term impact of such modifications is difficult to estimate but potentially very risky for many digestive diseases.

Resource implications of the latent tuberculosis cascade of care: a time and motion study in five countries.

BACKGROUND: The End TB Strategy calls for global scale-up of preventive treatment for latent tuberculosis infection (LTBI), but little information is available about the associated human resource requirements. Our study aimed to quantify the healthcare worker (HCW) time needed to perform the tasks associated with each step along the LTBI cascade of care for household contacts of TB patients. METHODS: We conducted a time and motion (TAM) study between January 2018 and March 2019, in which consenting HCWs were observed throughout a typical workday. The precise time spent was recorded in pre-specified categories of work activities for each step along the cascade. A linear mixed model was fit to estimate the time at each step. RESULTS: A total of 173 HCWs in Benin, Canada, Ghana, Indonesia, and Vietnam participated. The greatest amount of time was spent for the medical evaluation (median: 11 min; IQR: 6-16), while the least time was spent on reading a tuberculin skin test (TST) (median: 4 min; IQR: 2-9). The greatest variability was seen in the time spent for each medical evaluation, while TST placement and reading showed the least variability. The total time required to complete all steps along the LTBI cascade, from identification of household contacts (HHC) through to treatment initiation ranged from 1.8 h per index TB patient in Vietnam to 5.2 h in Ghana. CONCLUSIONS: Our findings suggest that the time requirements are very modest to perform each step in the latent TB cascade of care, but to achieve full identification and management of all household contacts will require additional human resources in many settings.

Association between Bacillus Calmette-Guérin vaccination and lymphoma: a population-based birth cohort study.

BACKGROUND: Most risk factors for lymphoma identified so far relate to immunosuppression, but its aetiology remains unclear. OBJECTIVES: We investigated whether Bacillus Calmette-Guérin (BCG) vaccination is associated with lymphoma, overall and separately for Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). METHODS: A cohort of 400 611 subjects born in the province of Québec, Canada, between 1970 and 1974 was used. Information on BCG vaccination was extracted from the Quebec BCG Vaccination Registry. Lymphomas cases were individuals who had ≥2 health encounters, medical visits or hospitalizations, for lymphoma within 2 months or who were identified through the Quebec Tumor Registry. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence interval (CI), adjusting for potential confounders. RESULTS: A total of 178 335 (46.0%) subjects were BCG-vaccinated, and 1478 (0.38%) cases of lymphomas were ascertained. Amongst them, 922 were identified as NHL and 421 as HL. After adjustment, no association was observed between BCG vaccination and either lymphoma (any type) (HR = 1.03, 95% CI: 0.96-1.11) or NHL (HR = 0.99, 95% CI: 0.86-1.13). For HL, nonproportional hazards were observed. Before the age of 18, the risk of HL was elevated amongst vaccinated individuals (HR = 2.26, 95% CI: 1.39-3.69). However after 18 years of age, no association was found (HR = 0.93, 95% CI: 0.75-1.15). CONCLUSION: Bacillus Calmette-Guérin vaccination may increase the risk of HL before 18 years of age, but residual confounding cannot entirely be excluded. Given the benefits of BCG vaccination, these results need to be reproduced in other populations before firm conclusions can be drawn.

Exploring the interior of cuticles and compressions of fossil plants by FIB-SEM milling and image microscopy.

We present the first study of cuticles and compressions of fossil leaves by Focused Ion Beam Scanning Electron Microscopy (FIB-SEM). Cavities preserved inside fossil leaf compressions corresponding to substomatal chambers have been observed for the first time and several new features were identified in the cross-section cuts. These results open a new way in the investigation of the three-dimensional structures of both micro- and nanostructural features of fossil plants. Moreover, the application of the FIB-SEM technique to both fossils and extant plant remains represent a new source of taxonomical, palaeoenvironmental and palaeoclimatic information.

Spinal accessory nerve preservation in modified neck dissections: surgical and functional outcomes.

The spinal accessory nerve (SAN) or XI cranial nerve is frequently encountered during neck surgery, and as such is at risk of iatrogenic injury, resulting in "shoulder syndrome". Modified neck dissection (MND) with preservation of the SAN is based on desire to minimise the functional deformity associated with section of the eleventh nerve. The aim of this study was to analyse the intra-operative variations of the spinal accessory nerve pathway and to evaluate shoulder dysfunction postoperatively. The cross-sectional demonstration analysis was created through the medical records retrospectively of 165 consecutive patients who underwent neck dissections at our institution in the past 5 years with attention to ultrasound and MRI preoperative findings, type of neck dissection, type of identification and dissection of SAN, postoperative morbidity and survival rate. The safest identification of SAN is in the posterior neck triangle where it may be recognised exiting from the posterior border of the sternocleidomastoid muscle (SCM) at Erb's point. For exact preoperative planning, ultrasound and MRI are superior to determine the position of the eleventh nerve. The mean distance between the greater auricular point and the SAN was 0.90 cm. Average length of the trunk from Erb's point until the penetration in the trapezius muscle was around 5.1 cm, ranging from 4.8 to 5.4 cm. The diversity in the course from the posterior border of the SCM and posterior neck triangle was confirmed in 9 cases (15%), predominantly at the level of entering the posterior neck triangle. The frequency of postoperative morbidity of SAN was 46.7% for radical neck dissections, 42.5% for selective neck dissections and 25% for MND. For each separate type of dissection, different subtypes were included. Identification of the SAN over established landmarks is unconditionally reliant on the exact preoperative mapping of the nerve with imaging diagnostics. MND has similar regional control rates to more comprehensive operations in appropriately selected patients and significantly reduces the risk of functional disability.

Co-inoculum of Beauveria brongniartii and B. bassiana shows in vitro different metabolic behaviour in comparison to single inoculums.

The use of entomopathogenic fungi for biocontrol of plant pests is recently receiving an increased interest due to the need of reducing the impact of agricultural practices on the environment. Biocontrol efficacy could be improved by co-inoculation of different microorganisms. However, interactions between the fungal species can trigger or depress the biocontrol activity. Co-inoculation of two entomopathogenic fungi (Beauveria bassiana and B. brongniartii) was performed in vitro to evaluate the effects of their joint behaviour on a range of different carbon sources in comparison to single inoculation. The two species showed a very different metabolic profile by Phenotype MicroArrayTM. B. bassiana showed a broader metabolism than B. brongniartii on a range of substrates. B. brongniartii showed a greater specificity in substrate utilization. Several carbon sources (L-Asparagine, L-Aspartic Acid, L- Glutamic Acid, m- Erythritol, D-Melezitose, D-Sorbitol) triggered the fungal metabolism in the co-inoculum. SSR markers and Real Time qPCR analysis showed that different substrates promoted either the growth of one or the other species, suggesting a form of interaction between the two fungi, related to their different ecological niches. The methodological approach that combines Phenotype MicroArrayTM and SSR genotyping appeared useful to assess the performance and potential competition of co-inoculated entomopathogenic fungi.

Tuning the upconversion light emission by bandgap engineering in bismuth oxide-based upconverting nanoparticles.

In the field of novel applications involving upconverting processes, the determination of new strategies for realizing emission-tunable nanomaterials is a challenge. In this work the design of Y3+ and Er3+ codoped bismuth oxide-based upconverting nanoparticles is presented, evidencing that the active role of the matrix allows for the emission selectivity with chromaticity control. The bandgap of the bismuth oxide-based host can be manipulated in the range of 0.65 eV, consequently leading to upconversion emission color tunability from red to yellow-greenish. The resulting fine control of the nanoparticle chromaticity through accurate host bandgap engineering reveals a novel concept for the development of a new generation of upconverting nanophosphors.

Validated methods for identifying tuberculosis patients in health administrative databases: systematic review.

BACKGROUND: An increasing number of studies are using health administrative databases for tuberculosis (TB) research. However, there are limitations to using such databases for identifying patients with TB. OBJECTIVE: To summarise validated methods for identifying TB in health administrative databases. METHODS: We conducted a systematic literature search in two databases (Ovid Medline and Embase, January 1980-January 2016). We limited the search to diagnostic accuracy studies assessing algorithms derived from drug prescription, International Classification of Diseases (ICD) diagnostic code and/or laboratory data for identifying patients with TB in health administrative databases. RESULTS: The search identified 2413 unique citations. Of the 40 full-text articles reviewed, we included 14 in our review. Algorithms and diagnostic accuracy outcomes to identify TB varied widely across studies, with positive predictive value ranging from 1.3% to 100% and sensitivity ranging from 20% to 100%. CONCLUSIONS: Diagnostic accuracy measures of algorithms using out-patient, in-patient and/or laboratory data to identify patients with TB in health administrative databases vary widely across studies. Use solely of ICD diagnostic codes to identify TB, particularly when using out-patient records, is likely to lead to incorrect estimates of case numbers, given the current limitations of ICD systems in coding TB.

Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy.

Inflammation plays a considerable role in the progression of Duchenne Muscular Dystrophy (DMD), a severe muscle disease caused by a mutation in the dystrophin gene. We previously showed that genetic ablation of Protein Kinase C θ (PKCθ) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease. RESEARCH IN CONTEXT: Duchenne muscular dystrophy (DMD) is a severe muscle disease affecting 1:3500 male births. DMD is caused by a mutation in dystrophin gene, coding for a protein required for skeletal and cardiac muscle integrity. Lack of a functional dystrophin is primarily responsible for the muscle eccentric contraction-induced muscle damage, observed in dystrophic muscle. However, inflammation plays a considerable role in the progression of DMD. Glucocorticoids, which have anti-inflammatory properties, are being used to treat DMD with some success; however, long term treatment with these drugs induces muscle atrophy and wasting, outweighing their benefit. The identification of specific targets for anti-inflammatory therapies is one of the ongoing therapeutic options. Although blunting inflammation would not be a "cure" for the disease, the emerging clue is that multiple strategies, addressing different aspects of the pathology, which may eventually converge, may be successful. In this context, we previously showed that genetic ablation of Protein Kinase C θ (PKCθ), an enzyme known to be involved in immune response, in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease.

Phenotyping of difficult asthma using longitudinal physiological and biomarker measurements reveals significant differences in stability between clusters.

BACKGROUND: Although the heterogeneous nature of asthma has prompted asthma phenotyping with physiological or biomarker data, these studies have been mostly cross-sectional. Longitudinal studies that assess the stability of phenotypes based on a combination of physiological, clinical and biomarker data are currently lacking. Our objective was to assess the longitudinal stability of clusters derived from repeated measures of airway and physiological data over a 1-year period in moderate and severe asthmatics. METHODS: A total of 125 subjects, 48 with moderate asthma (MA) and 77 with severe asthma (SA) were evaluated every 3 months and monthly, respectively, over a 1-year period. At each 3-month time point, subjects were grouped into 4 asthma clusters (A, B, C, D) based on a combination of clinical (duration of asthma), physiological (FEV1 and BMI) and biomarker (sputum eosinophil count) variables, using k-means clustering. RESULTS: Majority of subjects in clusters A and C had severe asthma (93 % of subjects in cluster A and 79.5 % of subjects in cluster C at baseline). Overall, a total of 59 subjects (47 %) had stable cluster membership, remaining in clusters with the same subjects at each evaluation time. Cluster A was the least stable (21 % stability) and cluster B was the most stable cluster (71 % stability). Cluster stability was not influenced by changes in the dosage of inhaled corticosteroids. CONCLUSION: Asthma phenotyping based on clinical, physiologic and biomarker data identified clusters with significant differences in longitudinal stability over a 1-year period. This finding indicates that the majority of patients within stable clusters can be phenotyped with reasonable accuracy after a single measurement of lung function and sputum eosinophilia, while patients in unstable clusters will require more frequent evaluation of these variables to be properly characterized.

Exacerbation risk in severe asthma is stratified by inflammatory phenotype using longitudinal measures of sputum eosinophils.

BACKGROUND: Airway inflammatory phenotyping is increasingly applied to subjects with asthma. However, its relationship to clinical outcomes in difficult asthma is incompletely elucidated. OBJECTIVE: The goal of our study was to determine the relationship between exacerbation rates and phenotypes of difficult asthma based on the longitudinal measures of sputum eosinophils and neutrophils. METHODS: Subjects in the longitudinal observational study from two tertiary care centres that completed 1 year of observation and provided at least three sputum samples were classified by inflammatory phenotypes using previously established thresholds. Kaplan-Meier curves and univariable and multivariable Cox proportional hazard models were used to determine the association between inflammatory phenotypes and exacerbation rate. RESULTS: During the study, 115 exacerbations occurred in 73 severe asthmatic subjects. Subjects with the persistently eosinophilic phenotype had a significantly shorter time to first exacerbation and greater risk of exacerbation over a 1-year period than those with the non-eosinophilic phenotype based on the univariable and multivariable Cox proportional hazard model (hazard ratio [HR], 3.24; 95% confidence interval [CI], 1.35-7.72; adjusted HR, 3.90; 95% CI, 1.34-11.36). No significant differences in time to first exacerbation or exacerbation risk over a 1-year period were observed among the neutrophilic phenotypes. CONCLUSIONS: The persistent eosinophilic phenotype is associated with increased exacerbation risk compared with the non-eosinophilic phenotype in severe asthma. No differences in time to first exacerbation or exacerbation risk over a 1-year period were detected among neutrophilic phenotypes.