Long-term Studies Research Articles

Deciphering Anion Exchange Membrane Water Electrolysis: A Distribution of Relaxation Times Approach

Anion exchange membrane water electrolysis (AEM-WE) is a promising method for hydrogen production, offering advantages over proton exchange membrane water electrolysis (PEM-WE), such as the use of nonprecious metal catalysts and perfluorosulfonic acid free membranes. Despite achieving impressive current densities, challenges in efficiency and stability remain. This study employs electrochemical impedance spectroscopy (EIS), the equivalent circuit model (ECM) and distribution of relaxation times (DRT) analysis to investigate AEM-WE cells. DRT analysis identifies and quantifies five loss mechanisms within the AEM-WE system, including hydrogen and oxygen evolution reactions and ionic transport losses. Long-term experiments reveal catalyst degradation and its impact on performance, providing insights for targeted optimisation. The findings enhance understanding of the electrochemical processes in AEM-WE, offering pathways to improve stability and efficiency.

Comparison of the Novel Ankura Plus Stent and Castor Stent for the Treatment of Stanford Type B Aortic Dissection with an Insufficient Proximal Anchoring Area

To compare the efficacy and safety of the Ankura Plus and Castor stents in Stanford type B aortic dissection (TBAD) with an insufficient proximal anchoring area. Between January 2020 and October 2022, 54 patients with TBAD were enrolled, including 16 patients with Ankura Plus stents and 38 patients with Castor stents. Data from the 2 stents were retrospectively analyzed. The surgical success rate for both stents was 100%, and no endoleaks or deaths occurred during hospitalization. The Ankura Plus stent group had a longer surgery time than the Castor stent group (122.6±5.1 vs. 103.7±10.0, P < 0.001). After an average follow-up of 12months, the patency rates of the main and branch stents were 100% in both groups. The diameter of the true lumen (TL) was significantly increased, the diameter of the false lumen (FL) was reduced, and there was no statistically significant difference in the probability of complete thrombosis of the FL (68.8% vs. 67.6%, P=0.993). There were no significant differences in the incidences of renal failure (6.3% vs. 8.1%, P=0.814), stroke (6.3% vs. 2.7%, P=0.520), or endoleaks (6.3% vs. 10.5%, P=0.621) between the Ankura Plus and Castor stent groups. One patient in the Castor stent group underwent reintervention because of a type I endoleak 3months after surgery. One patient in the Ankura Plus stent group had an additional covered stent placed after 1month due to distal TL stenosis of the main stent. One patient in the Castor stent group died of renal failure 4months after surgery. Both the Ankura Plus and Castor stents are feasible, safe, and effective in the treatment of TBAD with an insufficient proximal anchoring area. Additional long-term studies are required to evaluate the robustness and applicability of Ankura Plus stents.

Rethinking the necessity of long-term toxicity studies for biotherapeutics using weight of evidence assessment

The registration of biotherapeutics for chronic indications requires 6-month toxicity studies. However, extensive experience has shown that the non-clinical safety profiles of biotherapeutics are generally predictable. This suggests that conducting multiple studies, especially a 6-month study may not be necessary. In a meta-analysis of biologics developed for non-oncology indications over last 25 years at Pfizer, we compared organ system findings between short-term (1–3 month) and long-term (6-month) animal studies. Our goal was to determine if there were differences in the safety profiles between the two study durations and their relevance to human risk assessment. Our analysis revealed that most clinically relevant toxicities could be detected in shorter-term studies (87%; 26/30 programs). This suggests either an undifferentiated safety profile between short-and long-term studies, or anticipated toxicities based on the modality, such as immunogenicity or exaggerated pharmacology. However, for 4 out of 30 programs (13%), long-term studies did identify either potential new toxicities or more severe manifestation of exaggerated pharmacology, leading to modifications in clinical trial designs and human risk assessment. Our experience suggests that 3-month toxicity studies may be sufficient to support late-stage clinical development for a majority of standard biotherapeutic programs. This pragmatic and science-based approach aligns with the goal of advancing 3R's initiatives in nonclinical safety assessment.

Performance and Safety of the Extravascular Implantable Cardioverter-Defibrillator Through Long-Term Follow-Up: Final Results From the Pivotal Study.

Substernal lead placement of the extravascular implantable cardioverter-defibrillator (EV ICD) permits both defibrillation at thresholds similar to those seen with transvenous ICDs and effective antitachycardia pacing (ATP), while avoiding the vasculature and associated complications. The global Pivotal study has shown the EV ICD system to be safe and effective through 6 months, but long-term experience has yet to be published. We aim to report the performance and safety of the EV ICD system throughout the study. The EV ICD Pivotal study was a prospective, global, single-arm, pre-market clinical study. Individuals with a class I or IIa indication for a single-chamber ICD per guidelines were enrolled. Freedom from major system- or procedure-related complications, as well as appropriate and inappropriate therapy rates, were assessed through 3 years using the Kaplan-Meier method. Anti-tachycardia pacing success was calculated using simple proportions. An implant was attempted in 316 patients [25.3% female, 53.8±13.1 years old, 81.6% primary prevention, LVEF 38.9%±15.4%]. Of 299 patients with a successful implant, 24 experienced 82 spontaneous arrhythmic episodes that were appropriately treated with either ATP only (38, 46.3%), shock only (34, 41.5%), or both (10, 12.2%) for a Kaplan-Meier-estimated rate of first any appropriate therapy of 9.2% at 3 years. Antitachycardia pacing was successful in 77.1% (37/48) of episodes, and ATP usage significantly increased from discharge to last follow-up visit (P<0.0001). Shock therapy was successful in 100% (27/27) of discrete, spontaneous ventricular arrhythmias. The inappropriate shock rates at 1 and 3 years were 9.8% and 17.5%, respectively, with P-wave oversensing the predominant cause. No major intraprocedural complications were reported and the estimated freedom from system- or procedure-related major complications was 91.9% at 1 year and 89.0% at 3 years. The most common major complications were lead dislodgement (10 events; n=9 patients, 2.8%), postoperative wound or device pocket infection (n=8, 2.5%), and device inappropriate shock delivery (n=4, 1.3%). Twenty-four system revisions were performed as a result of major complications related to the EV ICD system or procedure. From implant to study completion, the EV ICD Pivotal study demonstrated that a single integrated system with an extravascular lead placed in the substernal space maintains high ATP success, effective defibrillation, and a consistent safety profile.

Commentary on: Long-term experience with AMS-700 CXR inflatable penile prosthesis in high-risk patients with corporal fibrosis.

Commentary on: Long-term experience with AMS-700 CXR inflatable penile prosthesis in high-risk patients with corporal fibrosis.

Grazing intensity by sheep affects spatial diversity in botanical composition of Inner Mongolian grassland

Overgrazing by sheep causes degradation of grasslands in the Inner Mongolian steppe, yet our understanding of its impact on grassland plant communities is limited by lack of observations at high spatial resolution. Employing a nested experimental design in a long-term grazing experiment provides insights into effects of increasing sheep grazing intensity on community composition, diversity, and spatial patterns in the grassland vegetation. Effects of observed changes in the plant community are discussed based on monthly weight gain of sheep during grazing. The design of the long-term experiment included four triplicated grazing intensities applied during an 8-year period. At the end of that period, we evaluated vegetation coverage, categorized plant species by functional groups, and analyzed the data using a mixed linear model. Moreover, spatial autocorrelation methods were employed to investigate spatial patterns, visualized via a kriging model. We found that the plant community composition differed among grazing treatments, with high grazing intensity showing higher plant species richness and stronger clustering of plants at our fine scale of observation. These fine-grained spatial scale observations are usually not recorded in larger spatial scale analyses of grassland responses to overgrazing. While the grazing intensities used in our study did not influence individual sheep weight gain, total sheep weight gain per hectare increased with an increase in grazing intensity. Our study shows that in a sheep grazing intensity experiment in Inner Mongolia grasslands total sheep weight gain may increase at the expense of fine-scale species composition and spatial dynamics of the grassland vegetation. These insights may be used for determining trade-offs of sheep meat production with original composition and structure of grassland plant communities. Effects on other ecosystem properties and functions, such as on belowground biodiversity, remain to be assessed.

Nutritional evaluation of an aqueous-processed canola protein concentrate in diets of Atlantic Salmon Salmo salar at different life stages

A novel aqueous processing method was applied on canola defatted meal to produce a protein concentrate (>76 % crude protein, dry matter basis). This aqueous-processed canola protein concentrate (ACPC) was evaluated in three experiments with Atlantic salmon. The objectives were to (1) estimate the nutrient digestibility of ACPC in juvenile fish, (2) appraise its nutrient digestibility in post-smolt salmon, and (3) evaluate the long-term effect of ACPC on growth, survival, nutrient utilization, body composition, fillet pigmentation and gut histology of post-smolt salmon. In the first study, one Reference and one test diet, which was a blend of 70 % Reference and 30 % ACPC (70:30 ratio), were fed to juvenile salmon (57 ± 7 g) and feces were collected using settling columns. In the second study, post-smolt salmon (228 ± 4 g) were fed one Reference and three test diets, which consisted of three Reference to ACPC ratios: 90:10, 80:20 and 70:30. Feces were collected by manual stripping. The long-term study (168 days) was designed as a 2 × 4 full factorial analysis with two types of formula (Americas, with processed animal proteins (PAPs), and Europe, without PAPs) and four inclusion levels of ACPC (0, 10, 15, 20 %) fed to post-smolt Atlantic salmon (228 ± 5 g). Fish were bulk weighed every 28 or 56 days. Distal intestine and fillet were sampled (10 fish/tank) at the end for histological examination and color measurement, respectively. All diets (43–49 % crude protein, 18–25 % crude lipid depending on studies) were extruded and fed to apparent satiation. The apparent digestibility coefficients (ADCs) of ACPC protein in juvenile and post-smolt salmon were 89 % and ≥ 94 %, respectively. The essential amino acids ADCs in juvenile and post-smolt salmon were 83–99 % and 91–99 %, respectively. ACPC protein digestibility was not significantly affected by its inclusion level (P = 0.470). In the third experiment, growth (TGC: 0.143–0.160) and feed intake (668–780 g/fish) were not significantly affected by ACPC inclusion (P ≥ 0.10). Feed conversion ratios varied between 1.04 and 1.08. An unexpected occurrence of disease caused 1.6 % mortality over three weeks during the 24-week long-term study and survival was significantly higher in salmon fed ACPC-containing diets (P < 0.001). ACPC inclusion significantly increased fillet redness (P < 0.001) and increased villus length of distal intestine (P < 0.001). In conclusion, ACPC was a safe and nutritive protein alternative in salmon diets, regardless of inclusion level.

Long-Term Three-Dimensional Morphometric Outcome Study of Nasal Bone in Cleft Patients.

Cleft lip nose deformities are characterized by underlying features in the bony skeleton as well as the soft tissues; however, no previous study has focused on the evaluation of the nasal bone. The aim of this study was to compare nasal bone features among adult patients with unilateral cleft lip with or without cleft palate, those with bilateral cleft lip and palate, and controls. Included in this retrospective study were patients aged ≥16 years with nonsyndromic cleft who underwent long-term orthodontic treatment and controls aged 18-45 years who underwent surgery for jaw deformities at Keio University Hospital. Piriform width, nasal width, and nasomaxillary angle values measured on CT were compared among the groups using the Wilcoxon rank sum test. Nine patients had unilateral cleft lip and alveolar cleft, 19 had unilateral cleft lip and cleft palate, and 14 had bilateral cleft lip and palate (BCLCP). There were 18 controls. Mean piriform width and mean nasomaxillary angle were significantly greater in the BCLCP group than the control group (20.1±2.54mm versus 18.8±1.35mm, P<0.05; and 105.8±8.13 degrees versus 100.4±7.95 degrees, P<0.05, respectively). There was no significant difference in mean nasal width among the groups. Nasal bone morphology was not affected by initial cleft lip alone or by the presence or absence of cleft palate. Patients with bilateral cleft lip and palate have a wider and lower nose than those without cleft deformity and might benefit more from reduction of the bony nasal width than from treatment of the soft tissues.

Living Shorelines Equal or Outperform Natural Shorelines as Fish Habitat Over Time: Updated Results from a Long-Term BACI Study at Multiple Sites

Living Shorelines Equal or Outperform Natural Shorelines as Fish Habitat Over Time: Updated Results from a Long-Term BACI Study at Multiple Sites

European croplands under climate change: Carbon input changes required to increase projected soil organic carbon stocks

Increasing soil organic carbon (SOC) stocks in agricultural systems is a pivotal strategy for promoting soil health and mitigating climate change. Global initiatives have set ambitious targets, aspiring to achieve an annual SOC stock increase of 4 ‰. In the European Union, the recently approved Nature Restoration Law aims to increase SOC stock trends in the top 30 cm of cropland mineral soils. However, current monitoring and reporting practices in some countries rely on simplistic SOC models with default parameters, which may not provide reliable predictions.In this paper, we study the feasibility of a 4 ‰ target in European croplands (i.e., an aspirational target proposed by The international “4 per 1000” Initiative), through estimations of required C input changes. To ensure robust predictions, we propose a novel calibration approach that links model parameters to pedo-climatic variables via statistical relationships from 16 long-term experiments. The effectiveness of the method is evaluated for three SOC models across 4281 sites from the European LUCAS soil survey.Our findings demonstrate that the statistical calibration of the multi-model ensemble improves the accuracy of 2015 and 2018 SOC stock predictions, compared to default parameterization. This improvement was however mainly due to the substantial enhancement of one of the models. According to the weighted multi-model mean, median C input changes to reach a 4 ‰ target for Northern, Central, and Southern Europe stand at 1.85, 1.20, and 0.13 Mg C ha−1 yr−1 under RCP 2.6, and 2.21, 1.26, and −0.10 Mg C ha−1 yr−1 under RCP 6.0, respectively.To achieve the aspirational 4 ‰ target, estimated C input change requirements exceed the predicted changes in net primary productivity under RCP 2.6 and RCP 6.0. This emphasizes the importance of strategic land-use and land-management interventions to enhance SOC stocks.

Long-term study of the combined effects of ocean acidification and warming on the mottled brittle star Ophionereis fasciata.

The global ocean is rapidly changing, posing a substantial threat to the viability of marine populations due to the co-occurrence of multiple drivers, such as ocean warming (OW) and ocean acidification (OA). To persist, marine species must undergo some combination of acclimation and adaptation in response to these changes. Understanding such responses is essential to measure and project the magnitude and direction of current and future vulnerabilities in marine ecosystems. Echinoderms have been recognised as a model in studying of OW-OA effects on marine biota. However, despite their global diversity, vulnerability, and ecological importance in most marine habitats, brittle stars (ophiuroids) are poorly studied. A long-term mesocosm experiment was conducted on adult mottled brittle star (Ophionereis fasciata) as a case study to investigate the physiological response and trade-offs of marine organisms to ocean acidification, ocean warming and the combined effect of both drivers. Long-term exposure of O. fasciata to high temperature and low pH affected survival, respiration and regeneration rates, growth rate, calcification/dissolution, and righting response. Higher temperatures increased stress and respiration and decreased regeneration and growth rates as well as survival. Conversely, changes in pH had more subtle or no effect affecting only respiration and calcification. Our results indicate that exposure to a combination of high temperature and low pH produces complex responses for respiration, righting response and calcification. We address the knowledge gap of the impact of a changing ocean on ophiuroids in the context of echinoderm studies, proposing this class as an ideal alternative echinoderm for future research.

Integration of livelihood support with MHPSS in rehabilitation of torture survivors in LMICs: Addressing poverty and mental health dynamics.

The integration of livelihood support with mental health and psycho-social support (MHPSS) seems crucial for the rehabilitation of torture survivors in low- and middle-income countries (LMICs). This study aimed to explore the intersec-tionality of poverty and mental health, and the integration of livelihood support with-in MHPSS frameworks related to the rehabilitation of torture survivors in LMICs. A cross-sectional study was conducted using a semi-structured questionnaire distributed to members of the International Rehabilitation Council for Torture Victims (IRCT) in LMICs (n=25). The questionnaire explored the perception of IRCT centres in LMIC countries regard-ing the extent to which poverty contributes to poor mental health outcomes among torture sur-vivors and the effectiveness of integrating livelihood support into MHPSS interventions. The study highlighted the significant economic challenges faced by torture survivors, indicating a high prevalence of extreme poverty among this group. The study found that 92% of respondents believed that poverty and mental health outcomes of torture survivors are strongly linked. Eco-nomic and social inequalities were identified as key determinants of mental health, emphasizing the need to address these inequalities in rehabilitation programs for torture survivors. The study underscores the critical connection between poverty, mental health, and the experience of torture. In the view of most IRCT centres, the integration of livelihood support with MHPSS is essential for addressing economic disparities and promoting long-term resilience among survivors. The results highlight the need to conduct long-term longitudinal studies that provide support to this perception. The study recommends enhancing coordination among stakeholders, addressing cultural and social barriers, securing sustainable funding, and developing strategies to integrate livelihood support with MHPSS for torture survivors. According to participants, rehabilitation programmes should include economic empowerment, mental health support, and social integration, to contribute to a holistic recovery, long-term resilience, and overall well-being.

Assessment of prolonged safety and tolerability of erenumab in migraine patients in a long-term open-label study (APOLLON)

BackgroundEfficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab’s tolerability and safety profile in individuals experiencing episodic and chronic migraines.MethodsThe study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption (‘drug holiday’) of up to 24 weeks.Results701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed.ConclusionsAPOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment.Trial registrationClinicalTrials.gov ID: NCT04084314 (https://clinicaltrials.gov/study/NCT04084314), First submitted: 2019-09-06.

Acceleration of propagation of source material for Sorbus Sensu Lato Breeding

Aim. The permanent growth of interest in rowan and other currently underestimated Sorbus sensu lato crops has prompted the search to improve the accelerated propagation technique of its most valuable genotypes for breeding. Methods. The experiments involved 3–7-year-old Sorbus sensu lato plants from the National Dendrological Park "Sofiyivka" of the National Academy of Sciences of Ukraine collection. Statistical analysis of the experimental data was performed according to Ronald Fisher. Results. It was found that the germination rate of the studied sorboid plants depended on the method of seed preparation. In contrast, the grafting efficiency depended more on the grafting method than on the graft genotype. The use of our modified MS media allowed us to obtain clone formation coefficients (6.6–7.9) sufficient for effective micropropagation and to induce morphogenesis with 59.9–88.8 % of rooted microclones, as well as to achieve stable results of adaptation of the studied Sorbus sensu lato to non-sterile ex vitro conditions both in peat disks (69.1–90.3 %) and in containers with soil substrates (70.4–93.0 %). Conclusions. The results of comparing the methods of accelerated propagation of source material for breeding sorboid crops obtained in long-term experiments showed the advantages of micropropagation and the prospects for introducing the micropropagation link into breeding practice and nursery of the most valuable for horticulture Sorbus sensu lato.

Picturing the Multiple Sclerosis Patient Journey: A Symptomatic Overview.

Background: Multiple sclerosis (MS) presents a wide range of clinical symptoms, historically understood through long-term studies of earlier patient cohorts. However, due to improved diagnostic criteria, modern patients are diagnosed earlier and benefit from effective treatments, altering the disease's natural history. This study aimed to assess the clinical symptoms of MS patients in a modern population at various stages: before diagnosis, at diagnosis, during the disease course, and at the time of the survey. Methods: This was an observational study with retrospective and cross-sectional components; patients that fulfilled the 2017 revised McDonald criteria for MS completed a survey evaluating demographic and clinical data. Results: We included 163 patients, 69.9% female, with a mean age of 48.21 years; 87.1% had relapsing-remitting MS (RRMS), with a median EDSS of 2.0. Before diagnosis, 74.2% of patients experienced symptoms, mainly sensory issues (39.3%), fatigue (29.4%), and imbalance (27%). Motor and coordination symptoms were more common in progressive forms. At diagnosis, sensory (46.6%) and motor complaints (36.8%) were most prevalent. In RRMS and secondary progressive MS (SPMS), sensory and motor complaints predominated alongside imbalance, while primary progressive MS (PPMS) was characterized by motor, imbalance, and genitourinary symptoms. Throughout the disease, sensory symptoms were most common (76.1%), with fatigue (73%) and motor issues (62.6%) more prevalent in progressive forms. At the time of the survey, 50.7% of RRMS patients were asymptomatic, while progressive patients continued to experience motor symptoms, imbalance, and fatigue. Conclusions: The study reflects the modern spectrum of MS symptoms, consistent with previous research.

Striped Field Mouse Invading Human-Modified Environments of Lithuania during Last Five Decades

The striped field mouse (Apodemus agrarius) is expanding in several European countries, but the details of this process are not always documented due to a lack of long-term studies. We conducted an analysis of changes in relative abundances and proportions of A. agrarius in small mammal communities in nine different habitat groups in Lithuania during 1975–2023. We found an increase in the abundance and proportion of A. agrarius, increasing synanthropization of the species, and tolerance to anthropogenization of habitats. Temporal variations in the relative abundance and proportion of species were observed, with lower values in February–July and higher values in September–January. The main finding is a remarkable increase in species presence in the country after the 1990s, with a peak observed in the 2010s–2020s, confirmed by eight local studies. During these decades, it was the third most abundant species, representing 19.8–20.0% of the individuals caught. It is also important to note that A. agrarius has recently been most abundant in commensal habitats (0.029 ± 0.006 individuals/trap day), with the highest species proportion in agricultural areas (24.8 ± 1.8%). There are many indications that the expansion of A. agrarius in Lithuania is becoming invasive.

Long-term experience with octreotide and lanreotide for the treatment of gastroenteropancreatic neuroendocrine tumors.

The somatostatin analogs (SSA) octreotide and lanreotide are a mainstay in the treatment of neuroendocrine tumors (NET). The two pivotal trials differed considerably in terms of patient characteristics and are not directly comparable. Further comparative data are lacking. This retrospective chart review study included patients with gastroenteropancreatic NET grade 1 or 2 who were treated with octreotide LAR or lanreotide autogel. The main aim was to compare the two SSA based on progression-free survival (PFS) and overall survival (OS) from treatment start. In total, 129 patients were analyzed, 60% (n = 77) had a small intestinal NET and 31% (n = 40) a pancreatic NET. Histologically, 34% (n = 44) had NET G1, 55% (n = 71) a NET G2, and 11% (n = 14) a NET G1/G2 unclassified. Lanreotide was used in 90 patients (70%) and octreotide in 39 patients (30%). Overall, the median PFS was 32.2months (95%CI 23.0-42.9months). No PFS difference (p = 0.8) was observed between lanreotide (29.8months, 95%CI 18.7-48.5months) and octreotide (36.0months, 95%CI 23.2-68.2months). Median OS from treatment start was calculated at 93.5months (95%CI 71.1-132.9months). Again, the median OS following lanreotide (113.4months, 95%CI 62.3-NA months) or after octreotide (90.3months, 95%CI 71.1-NA months) did not differ significantly (p > 0.9). Our long-term experience with octreotide and lanreotide in NET did not reveal differences in antitumor effectiveness. This is consistent with previous reports and might suggest that both SSA can be used interchangeably if needed.

Ciclesonide exhibits lung-protective effects in neonatal rats exposed to intra-amniotic enterotoxin.

Despite the advances in perinatal care, bronchopulmonary dysplasia (BPD) continues to be a highly prevalent chronic lung disease that affects newborns, especially affecting premature newborns. There is no specific cure for BPD, and treatments aimed at reducing the risk of developing BPD focus mainly on lung-protective ventilation strategies, surfactant therapy, and/or corticosteroid administration. Our objective was to evaluate whether systemic postnatal administration of a new glucocorticoid, ciclesonide, can attenuate the alteration of lung structure and pulmonary hypertension in a rat model of chorioamnionitis-induced BPD, with minimal adverse effects on the developing brain. Endotoxin (ETX) or saline was administered to pregnant rats by intra-amniotic (i.a.) injection on day 20 of pregnancy, and pups were delivered by cesarean section on day 22. Ciclesonide (0.5 mg/kg) was administered postnatally for five consecutive days to pups previously exposed to i.a. ETX. On postnatal day 14, we assessed lung function (compliance), lung structure (radial alveolar count, mean linear intercept, pulmonary vessel density), pulmonary hypertension, and brain histology (edema, inflammation, apoptosis, hemorrhage, and infarction). On postnatal day 14, the effects of i.a. ETX administration were evident in neonatal rats not receiving treatment; these animals showed impaired lung compliance, disrupted lung structure, and developing pulmonary hypertension compared to those receiving i.a. saline. Postnatal administration of ciclesonide for 5 days was associated with significantly better outcomes in terms of lung compliance, alveolarization, lung vascular growth, and pulmonary hypertension, without affecting the brain histological parameters evaluated. Postnatal ciclesonide administration preserved lung function and structure and prevented pulmonary hypertension in a BPD model induced by antenatal i.a. ETX administration, without causing any adverse effects on brain development. These findings suggest that the new glucocorticoid, ciclesonide, may provide a novel strategy for the prevention of BPD; however, more long-term studies are required.

Effects of Thinning on the Diversity, Composition, and Spatial Structure in a Mixed Temperate Forest

structure in a temperate mixed forest. Design/methodology/approach: Data were collected in a 1 ha research plot. Five scenarios were evaluated through computer simulations: no thinning (T1), thinning with removal of 25% of basal area (Gha-1), (T2), thinning with removal of 25% of Gha-1 (T3), thinning with removal of 45% of Gha-1 (T4), and thinning with removal of 70% of Gha-1 (T5). The importance value index, alpha diversity, Pretzsch's A index and structural complexity index were estimated. A spatial distribution analysis was performed using the pair-correlation function g(r). Results: Pinus douglasiana and Quercus resinosa were the species of highest ecological value. Due to the removal effect, no significant changes in tree diversity were observed in the applied thinning scenarios. However, as thinning became more intense, at least one species (Quercus candicans) was lost. Thinning from below affected the oaks and thinning from above affected the pine species, which is also reflected in the spatial distribution of the remaining trees. Limitations on study/implications: The analysis is static; therefore, it is recommended that a long-term study be conducted under varying ecological conditions. Findings/conclusions: The effect of thinning on forest diversity, composition and structure depends on the type of thinning, condition of the structure, initial composition and intensity of removal. Thinning of less than 25% of the basal area, in the immediacy, allows timber harvesting without generating changes in the diversity, structure and composition of the temperate mixed forest under study.

Safety and Efficacy of Upadacitinib in Crohn's Disease: An Updated Systematic Review.

Crohn's disease (CD) is a chronic inflammatory bowel disease that significantly impacts patient quality of life. This systematic review evaluates the safety and efficacy of upadacitinib, a selective Janus kinase (JAK) inhibitor, in the treatment of CD. A comprehensive literature search was conducted across multiple databases, yielding seven studies published between 2020 and 2024, encompassing 1,481 patients. The review includes randomized controlled trials, post hoc analyses of phase 3 trials, and observational studies. Findings consistently demonstrate upadacitinib's superiority over placebo in inducing and maintaining clinical remission, achieving endoscopic response, and normalizing inflammatory markers. Notably, upadacitinib showed rapid symptom relief, with clinical remission observed as early as five to six days after treatment initiation. Efficacy was observed across various patient populations, including those with prior biologic failure. Long-term studies indicated sustained clinical and endoscopic improvements, with remission rates maintained for up to 30 months. Upadacitinib also demonstrated effectiveness in real-world, treatment-refractory cohorts. Safety profiles were generally consistent with those of other JAK inhibitors. Common adverse events included infections, particularly herpes zoster, and laboratory abnormalities such as neutropenia and elevated creatine kinase. Serious adverse events were infrequent, although careful monitoring is warranted. This review suggests that upadacitinib is a promising treatment option for moderate to severe CD, offering rapid and sustained efficacy with an acceptable safety profile.