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Dry evergreen montane forests in Ethiopia are severely threatened. The status of species composition and structure of forest vegetation are important indicators to understand the trends of threats on local plant communities. In the present study, we examined the floristic composition and structure of the Kibate Forest, Wonchi Highland, Ethiopia along environmental gradients. Sixty-six (30 m × 30 m) plots were established every 100 m interval along altitudinal gradients (2811‒3073 m a.s.l.) in five transect lines for vegetation and environmental data collection. In total, 125 vascular plant species belonging to 104 genera and 52 families were identified. Eighteen species (14%) were endemic to Ethiopia and Eritrea. The two most dominant families, Asteraceae (29 species) and Lamiaceae (eight species) accounted for 30% of the total number of species. The highest number of species (54%) was herbs. Four major community types (viz., Olinia rochetiana-Myrsine melanophloeos, Ilex mitis-Galiniera saxifraga, Erica arborea-Protea gaguedi, and Hagenia abyssinica-Juniperus procera) were identified. The highest species richness, evenness, diversity, and importance value index were in community types 2 and 4. About 82% of the species and all endemic taxa except five were recorded in these two community types. The most dominant woody species were O. rochetiana, E. arborea, Olea europaea subsp. cuspidata, Myrica salicifolia, I. mitis var. mitis, and H. abyssinica with different patterns of population structure. The results show that there was a weak correlation between species richness and altitude. Our findings confirm that environmental variables both with interactions (such as altitude) and without interactions (such as livestock grazing) significantly (p

Osmanl�� Devleti���nin son d��nemlerinde Kosova Valili��i ve Selanik���teki 3. Ordu Komutanl������ g��revlerini y��r��ten Mahmut ��evket Pa��a, 31 Mart Vakas��ndan sonra t��m ��lkenin tan��d������, siyaset ve devlet tarihi i��inde etkili bir konuma ula��m���� bir devlet adam��d��r. 12 Ocak 1910 tarihinden itibaren Harbiye Naz��r�� olarak kabineye girmi��, 1912���de Arnavutluk���ta ya��anan isyanda ald������ kararlar nedeniyle a����r ele��tirilere u��ray��nca 9 Temmuz 1912���de Harbiye Naz��rl������ndan istifa etmi��tir. Balkan Sava����n��n ba��lamas��yla ��lke i��inde huzursuzluk ve karga��a artm����, ��ttihat ve Terakki ileri gelenlerinin d��zenledi��i Bab����li bask��n��yla h��k��met devrilmi��, Mahmut ��evket Pa��a, Harbiye Naz��rl������ da uhdesinde kalarak Sadrazaml����a getirilmi��tir. ��lkenin s��k��nt��l�� g��nler ya��ad������ bir d��nmede, 11 Haziran 1913 g��n�� u��rad������ silahl�� sald��r�� sonucu hayat��n�� kaybetmi��tir. Gerek Harbiye Naz��rl������ gerekse Sadrazaml��k makamlar��nda bulundu��u s��rece asker�� alanda reform ��al����malar��na b��y��k ��nem vermi��, t��m olumsuz ko��ullara ra��men yeni projelerin ve at��l��mlar��n hayata ge��irilmesine ��nc��l��k etmi��tir. Etkileri g��n��m��zde dahi hissedilen bu ��al����malar��ndan biri 1911���de S��vari Binicilik ve Tatbikat Okulunun a����lmas��d��r. Sadece asker�� binicilikle s��n��rl�� kalmay��p T��rk spor tarihi i��in ��nemli bir ad��m olan bu a����l����, binicilik sporunun ��a��da��la��mas�� ve T��rk binicilerinin uluslararas�� yar����malarda yer almas��n�� sa��layacak temellerin at��lmas��na ��nc��l��k etmi��tir.

BACKGROUND & AIMS: Mirikizumab is an antibody against the p19 subunit of interleukin 23 that has demonstrated clinical efficacy and was well tolerated following 12 weeks of induction treatment in a phase 2 trial of patients with moderate to severe ulcerative colitis. We present results of the open-label extended induction period in patients who did not initially respond to treatment with mirikizumab. METHODS: This study was a continuation of I6T-MC-AMAC, a double-blind trial, performed at 75 sites in 14 countries, in which patients with moderate to severe ulcerative colitis were randomly assigned to 12 weeks induction therapy with 50 mg, 200 mg, or 600 mg mirikizumab or placebo. Patients without a clinical response (a 9-point decrease in Mayo subscore of ≥2 points and ≥35% from baseline and either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 were offered the opportunity to participate in an open-label, extended induction study for another 12 weeks, in which they received either 600 mg intravenous mirikizumab (n = 20) or, following a protocol amendment, 1000 mg intravenous mirikizumab (n = 64) every 4 weeks. At week 24, patients with a clinical response continued the extension maintenance period and received 200 mg subcutaneous mirikizumab. Endpoints included clinical remission (Mayo subscores of 0 for rectal bleeding, 0 or 1 with a 1-point decrease from baseline), clinical response, endoscopic remission (Mayo endoscopic subscore of 0), or endoscopic improvement (endoscopic subscore of 0 or 1), at study weeks 24 and 52. Data were analysed for patients who received mirikizumab or placebo during the induction phase of the study. RESULTS: Among participants who did not respond to induction mirikizumab, 50.0% of those who received the 12-week extension of 600 mg mirikizumab and 43.8% who received the extension of 1000 mg mirikizumab achieved a clinical response; 15.0% and 9.4% achieved clinical remission, respectively. Endoscopic improvement was achieved by 20.0% of subjects in the 600 mg mirikizumab group and 15.6% subjects in the 1000 mg mirikizumab group. Among initial nonresponders to mirikizumab who had clinical response at study week 24 and continued into maintenance therapy, 65.8% maintained the clinical response, 26.3% achieved clinical remission, and 34.2% had endoscopic improvement at week 52. No new safety concerns were identified. CONCLUSIONS: Extended doses of mirikizumab (600 mg and 1000 mg) for an additional 12 weeks produce a clinical response in up to 50% of patients who did not have a clinical response to 12 weeks of induction doses (50 mg, 200 mg, or 600 mg). Most of the responders to the extended doses maintained clinical response for up to 52 weeks. Clinicaltrials.gov no: NCT02589665. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:20 issue:1 pages:105-+ ispartof: location:United States status: published

Contains fulltext : 227827.pdf (Author’s version postprint ) (Open Access) 01 januari 2021

The values of patient autonomy and community participation have become central in health care. However, care practices involve a plurality of possibly conflicting values. These values often transgress the borders of the individual professional–client relationship as they involve family members, other professionals and community organisations. Good care should acknowledge this relational complexity, which requires a collective handling of the tensions between values. To better understand this process, we draw on [Mol, A. 2008. The Logic of Care: Health and the Problem of Patient Choice. Routledge; Mol, A., I. Moser, and J. Pols. 2010a. Care in Practice: On Tinkering in Clinics, Homes and Farms. Transcript Verlag.) by developing the notion of collective tinkering. An ethnographic study was conducted in two teams in community housing services for people with Intellectual Disabilities and Severe Mental Illness. Collective tinkering is analysed (1) within teams; (2) between professionals, family members and professionals from different organisations providing care for the same client; and (3) in organising practices for a collective of clients. Collective tinkering involves assembling goods into a care practice, attentively experimenting with these care practices, and adjusting care accordingly within a collective of those involved in care for a particular client (group). When collective tinkering does not occur, the stakeholders excluded (e.g. clients or family members) may experience poor quality of care.

Contains fulltext : 228779.pdf (Publisher’s version ) (Open Access) 19 januari 2021

Background Gene expression profile analysis on mammalian cell lines and animal models after exposure to botulinum neurotoxin (BoNT) has been investigated in several studies in recent years. Microarray analysis provides a powerful tool for identifying critical signaling pathways involved in the biological and inflammatory responses to BoNT and helps determine the mechanism of the function of botulinum toxins. One of the pivotal clinical characteristics of BoNT is its prolonged on-site effects. The role of BoNT on the blockage of neurotransmitter acetylcholine release in the neuromuscular junction has been well established. However, the effects of the treatment time of BoNT on the human cellular model and its potential mechanism remain to be defined. Methods This study aimed to use gene microarray technology to compare the two physiological critical time points of BoNT type A (BoNT/A) treatment of human neuroblastoma cells and to advance our understanding of the profound biological influences that toxin molecules play in the neuronal cellular system. SH-SY5Y neuroblastoma cells were treated with BoNT/A for 4 and 48 h, which represent the time needed for the entrance of toxin into the cells and the time necessary for the initial appearance of the on-site effects after BoNT application, respectively. Results A comparison of the two time points identified 122 functional groups that are significantly changed. The top five groups are alternative splicing, phosphoprotein, nucleus, cytoplasm, and acetylation. Furthermore, after 48 h, there were 744 genes significantly up-regulated, and 624 genes significantly down-regulated (p‹ 0.01). These genes fell into the following neurological and biological annotation groups: Nervous system development, proteinaceous extracellular matrix, signaling pathways regulating pluripotency of stem cells, cellular function and signal transduction, and apoptosis. We have also noticed that the up-regulated groups contained neuronal cell development, nervous system development, and metabolic processes. In contrast, the down-regulated groups contained many chromosomes and cell cycle categories. Conclusions The effects of BoNT/A on neuronal cells extend beyond blocking the neurotransmitter release, and that BoNT/A is a multifunctional molecule that can evoke profound cellular responses which warrant a more in-depth understanding of the mechanism of the toxin’s effects after administration.

Background and aims Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease. Approach and results In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients. Conclusions In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.

Background & Aims Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. Methods This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. Results There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59–1.77; p = 0.94) and 1.28 (95% CI 0.75–2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. Conclusions Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. Lay summary Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. ClinicalTrials.gov Identifier NCT03205345 .

BACKGROUND & AIMS: Interleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC. METHODS: We performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (N = 63), mirikizumab 50 mg (N = 63) or 200 mg (N = 62) with exposure-based dosing, or mirikizumab 600 mg with fixed dosing (N = 61) at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including ≥2 points and ≥35% from baseline with either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (N = 47) or every 12 weeks (N = 46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding, with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any nonsignificant comparison result ended the formal statistical testing procedure. RESULTS: At week 12, 15.9% (P = .066), 22.6% (P = .004), and 11.5% (P = .142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg, P > .05). Clinical responses occurred in 41.3% (P = .014), 59.7% (P < .001), and 49.2% (P = .001) of patients in the 50-mg, 200-mg, and 600-mg groups, respectively, compared with 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission. CONCLUSIONS: In a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab showed durable efficacy throughout the maintenance period. Clinicaltrials.gov, Number NCT02589665. ispartof: GASTROENTEROLOGY vol:158 issue:3 pages:537-+ ispartof: location:United States status: published

In order to address urban challenges Urban Living Labs (ULL’s) are set up as new forms of partnership between state, (market) and civil society. The primary governance challenge of ULL’s is to effectively use their liminal in-between position to create livable cities. However, liminal space at the same time is claimed to generate certain risks in terms of legitimate decision-making and accountability. By zooming in on the empirical case of ULL’s in a large Dutch city in the Randstad area the authors ask: Which key value trade-offs are made in the liminal space of ULL’s and which new institutional rules emerge in order to deal with these trade-offs? In this chapter the authors identify the following trade-offs: institutional collaboration versus autonomous activism, professional versus lay participation and values, the social versus the material, place bound experimentation versus placeless learning and accountability and capital value versus societal value. Calls for new institutional rules for city making to deal with these trade-offs can potentially address the lack of legitimacy in decision-making, yet may also hamper the open-ended nature of experimentation by introducing bureaucratic procedures and co-opting labs into implementing formal policy.

Additional file 1: Table S1. BoNT/A effects on the neurological system related functional groups with gene list and fold changes from the DAVID Analysis. Table S2. BoNT related cellular biological functions. Table S3. Cell structure related functional groups and gene fold changes. Table S4. Cell fate determination functional groups and gene fold changes.