Pirfenidone in unclassifiable interstitial lung disease: a subgroup analysis by concomitant mycophenolate mofetil and/or previous corticosteroid use

Introduction There are currently no approved treatments solely for unclassifiable interstitial lung disease (uILD); however, a recent trial showed this population can benefit from pirfenidone. We report a subgroup analysis of this trial to assess the effects of immunomodulators (concomitant mycophenolate mofetil [MMF] and/or previous corticosteroids) with pirfenidone in patients with uILD. Methods This was a multicenter, international, double-blind, randomized, placebo-controlled phase II trial of patients with progressive fibrosing uILD (NCT03099187). Patients were randomized (1:1) to receive pirfenidone 2403 mg/day or placebo. This analysis assessed forced vital capacity (FVC) change from baseline measured using site spirometry (key secondary endpoint) and safety over 24 weeks by concomitant MMF use at randomization (pre-specified analysis) and/or previous corticosteroid use (post hoc analysis). Results Overall, 253 patients were randomized, including 45 (17.8%) patients (pirfenidone, n = 23; placebo, n = 22) receiving concomitant MMF with/without previous corticosteroids (MMF subgroup); 79 (31.2%) patients (pirfenidone, n = 44; placebo, n = 35) receiving previous corticosteroids without MMF (corticosteroids/no-MMF subgroup); and 129 (51.0%) patients (pirfenidone, n = 60; placebo, n = 69) not receiving concomitant MMF or previous corticosteroids (no-corticosteroids/no-MMF subgroup). At 24 weeks, difference in mean (95% confidence interval) FVC change from baseline between pirfenidone and placebo was − 55.4 mL (− 206.7, 96.0; P = 0.4645) in the MMF subgroup; 128.4 mL (− 6.4, 263.3; P = 0.0617) in the corticosteroids/no-MMF subgroup; and 115.5 mL (35.1, 195.9; P = 0.0052) in the no-corticosteroids/no-MMF subgroup. All subgroups generally exhibited a similar pattern of treatment-emergent adverse events. Conclusion Although limited by design and small sample sizes, this analysis suggests pirfenidone may be less effective in patients with uILD receiving concomitant MMF, whereas a beneficial treatment effect was observed in patients not receiving concomitant MMF regardless of previous corticosteroid use. Pirfenidone was well tolerated regardless of MMF and/or corticosteroid use. Trial Registration Number ClinicalTrials.gov: NCT03099187

Structure and relaxations in liquid and amorphous Selenium

We report a molecular dynamics simulation of selenium, described by a three-body interaction. The temperatures T_g and T_c and the structural properties are in agreement with experiment. The mean nearest neighbor coordination number is 2.1. A small pre-peak at about 1 AA^-1 can be explained in terms of void correlations. In the intermediate self-scattering function, i.e. the density fluctuation correlation, classical behavior, alpha- and beta-regimes, is found. We also observe the plateau in the beta-regime below T_g. In a second step, we investigated the heterogeneous and/or homogeneous behavior of the relaxations. At both short and long times the relaxations are homogeneous (or weakly heterogeneous). In the intermediate time scale, lowering the temperature increases the heterogeneity. We connect these different domains to the vibrational (ballistic), beta- and alpha-regimes. We have also shown that the increase in heterogeneity can be understood in terms of relaxations

A review of the challenges, learnings and future directions of home handheld spirometry in interstitial lung disease

Background Patients with interstitial lung disease (ILD) require regular physician visits and referral to specialist ILD clinics. Difficulties or delays in accessing care can limit opportunities to monitor disease trajectory and response to treatment, and the COVID-19 pandemic has added to these challenges. Therefore, home monitoring technologies, such as home handheld spirometry, have gained increased attention as they may help to improve access to care for patients with ILD. However, while several studies have shown that home handheld spirometry in ILD is acceptable for most patients, data from clinical trials are not sufficiently robust to support its use as a primary endpoint. This review discusses the challenges that were encountered with handheld spirometry across three recent ILD studies, which included home spirometry as a primary endpoint, and highlights where further optimisation and research into home handheld spirometry in ILD is required. Abstract body Rate of decline in forced vital capacity (FVC) as measured by daily home handheld spirometry versus site spirometry was of primary interest in three recently completed studies: STARLINER (NCT03261037), STARMAP and a Phase II study of pirfenidone in progressive fibrosing unclassifiable ILD (NCT03099187). Unanticipated practical and technical issues led to problems with estimating FVC decline. In all three studies, cross-sectional correlations for home handheld versus site spirometry were strong/moderate at baseline and later timepoints, but longitudinal correlations were weak. Other issues observed with the home handheld spirometry data included: high within-patient variability in home handheld FVC measurements; implausible longitudinal patterns in the home handheld spirometry data that were not reflected in site spirometry; and extreme estimated rates of FVC change. Conclusions Home handheld spirometry in ILD requires further optimisation and research to ensure accurate and reliable FVC measurements before it can be used as an endpoint in clinical trials. Refresher training, automated alerts of problems and FVC changes, and patient support could help to overcome some practical issues. Despite the challenges, there is value in incorporating home handheld spirometry into clinical practice, and the COVID-19 pandemic has highlighted the potential for home monitoring technologies to help improve access to care for patients with ILD

Prefrontal cortex gyrification index in twins: an MRI study

Cortical development and folding seems to be under environmental as well as genetic control. The aim of our study was to estimate the genetic influence on gyrification and cortical volumes, comparing prefrontal gyrification index (GI) in monozygotic (MZ) and dizygotic (DZ) twin pairs, and unrelated pairs. Twenty-four subjects (6 pairs of MZ and 6 pairs of DZ twins) were included in this study. Prefrontal cortical folding (gyrification) was measured by an automated and manual version of the gyrification index (A-GI, M-GI) according to previously published protocols. MR-imaging was performed and 3 representative slices were selected from coronar MR-imaging scans. The volumes of the total brain, temporal lobes, prefrontal lobes, and cerebellum were analyzed, too. To evaluate similarity in GI, absolute differences in GI, and brain volumes as well as intraclass correlations of twin pairs were compared with regard to twin status. Finally, a control group of unrelated pairs was assembled from the first two study groups and analyzed. Compared to unrelated pairs, twin pairs exhibited more similarity concerning different brain volumes and a trend to more similarity concerning A-GI. MZ twins did not present more similarity concerning GI (automatically and manually measured) and volume measurements compared to DZ twins. Different factors, like intrauterine factors, postnatal development conditions, and especially environmental factors might account for the differences between related and unrelated pairs. The nonexistence of a pronounced similarity in MZ twins compared to DZ twins concerning prefrontal GI raises questions about the extent of genetic influence on GI

Effects of abstinence on brain morphology in alcoholism: A MRI study

Chronic alcohol abuse leads to morphological changes of the brain. We investigated if these volumetric changes are reversible after a period of abstinence. For this reason 41 male and 15 female alcohol patients underwent MRI-scanning after in-patient detoxification (baseline) entering alcoholism treatment programs, and between 6 and 9 months later (follow-up), in a phase of convalescence. Additionally, 29 male and 16 female control subjects were examined. The MRI-scans were delineated and the resulting regions of interest, volumes of lateral ventricles and prefrontal lobes were expressed relatively to total brain volume. Compared to control subjects alcohol patients showed bilaterally decreased prefrontal lobes (11% reduction) and increased lateral ventricles (up to 42% enlargement). The extent of the ventricular increase was depending on patient’s additional psychiatric diagnosis, showing smaller lateral ventricles in patients with additional personality disorder. While at follow-up the size of prefrontal lobes remained unchanged, volumes of the lateral ventricles decreased (5–6% reduction) in alcohol patients with abstinence and improved drinking behavior, especially in patients that underwent only one detoxification. The extent of the ventricular enlargement correlated with the elevation of alcohol related laboratory measures (mean corpuscular volume, gamma-glutamyl transpeptidase). In conclusion this study confirms the hypothesis that alcoholism causes brain damages that are partially reversible. It should be analyzed in further studies with larger sample sizes, if complete brain regeneration is possible maintaining abstinence over a longer period

The Challenge of Regulation in a Minimal Photoautotroph: Non-Coding RNAs in Prochlorococcus

Prochlorococcus, an extremely small cyanobacterium that is very abundant in the world's oceans, has a very streamlined genome. On average, these cells have about 2,000 genes and very few regulatory proteins. The limited capability of regulation is thought to be a result of selection imposed by a relatively stable environment in combination with a very small genome. Furthermore, only ten non-coding RNAs (ncRNAs), which play crucial regulatory roles in all forms of life, have been described in Prochlorococcus. Most strains also lack the RNA chaperone Hfq, raising the question of how important this mode of regulation is for these cells. To explore this question, we examined the transcription of intergenic regions of Prochlorococcus MED4 cells subjected to a number of different stress conditions: changes in light qualities and quantities, phage infection, or phosphorus starvation. Analysis of Affymetrix microarray expression data from intergenic regions revealed 276 novel transcriptional units. Among these were 12 new ncRNAs, 24 antisense RNAs (asRNAs), as well as 113 short mRNAs. Two additional ncRNAs were identified by homology, and all 14 new ncRNAs were independently verified by Northern hybridization and 5′RACE. Unlike its reduced suite of regulatory proteins, the number of ncRNAs relative to genome size in Prochlorococcus is comparable to that found in other bacteria, suggesting that RNA regulators likely play a major role in regulation in this group. Moreover, the ncRNAs are concentrated in previously identified genomic islands, which carry genes of significance to the ecology of this organism, many of which are not of cyanobacterial origin. Expression profiles of some of these ncRNAs suggest involvement in light stress adaptation and/or the response to phage infection consistent with their location in the hypervariable genomic islands

Increased d-amino acid oxidase expression in the bilateral hippocampal CA4 of schizophrenic patients: a post-mortem study

An important risk gene in schizophrenia is d-amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1–3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local d-serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples

Association of early life stress and cognitive performance in patients with schizophrenia and healthy controls

As core symptoms of schizophrenia, cognitive deficits contribute substantially to poor outcomes. Early life stress (ELS) can negatively affect cognition in patients with schizophrenia and healthy controls, but the exact nature of the mediating factors is unclear. Therefore, we investigated how ELS, education, and symptom burden are related to cognitive performance. The sample comprised 215 patients with schizophrenia (age, 42.9 ± 12.0 years; 66.0 % male) and 197 healthy controls (age, 38.5 ± 16.4 years; 39.3 % male) from the PsyCourse Study. ELS was assessed with the Childhood Trauma Screener (CTS). We used analyses of covariance and correlation analyses to investigate the association of total ELS load and ELS subtypes with cognitive performance. ELS was reported by 52.1 % of patients and 24.9 % of controls. Independent of ELS, cognitive performance on neuropsychological tests was lower in patients than controls (p < 0.001). ELS load was more closely associated with neurocognitive deficits (cognitive composite score) in controls (r = −0.305, p < 0.001) than in patients (r = −0.163, p = 0.033). Moreover, the higher the ELS load, the more cognitive deficits were found in controls (r = −0.200, p = 0.006), while in patients, this correlation was not significant after adjusting for PANSS. ELS load was more strongly associated with cognitive deficits in healthy controls than in patients. In patients, disease-related positive and negative symptoms may mask the effects of ELS-related cognitive deficits. ELS subtypes were associated with impairments in various cognitive domains. Cognitive deficits appear to be mediated through higher symptom burden and lower educational level

Reduced prefrontal gyrification in obsessive–compulsive disorder

Structural magnetic resonance imaging (MRI) studies reveal evidence for brain abnormalities in obsessive–compulsive disorder (OCD), for instance, reduction of gray matter volume in the prefrontal cortex. Disturbances of gyrification in the prefrontal cortex have been described several times in schizophrenia pointing to a neurodevelopmental etiology, while gyrification has not been studied so far in OCD patients. In 26 OCD patients and 38 healthy control subjects MR-imaging was performed. Prefrontal cortical folding (gyrification) was measured bilaterally by an automated version of the automated-gyrification index (A-GI), a ratio reflecting the extent of folding, from the slice containing the inner genu of the corpus callosum up to the frontal pole. Analysis of covariance (ANCOVA, independent factor diagnosis, covariates age, duration of education) demonstrated that compared with control subjects, patients with OCD displayed a significantly reduced A-GI in the left hemisphere (p = 0.021) and a trend for a decreased A-GI in the right hemisphere (p = 0.076). Significant correlations between prefrontal lobe volume and A-GI were only observed in controls, but not in OCD patients. In conclusion, prefrontal hypogyrification in OCD patients may be a structural correlate of the impairment in executive function of this patient group and may point to a neurodevelopmental origin of this disease