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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

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 & 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

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.

Background Interleukin (IL)-23 is a key cytokine in inflammatory bowel disease pathogenesis. Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in patients with moderate-to-severely active ulcerative colitis (UC) during 52 weeks of a Phase 2 randomised clinical trial (AMAC, NCT02589665). The effects of miri on stool frequency (SF) and rectal bleeding (RB) through Week 52 are reported. Methods Patients (Mayo score 6–12 with endoscopic subscore [ES] ≥2) were randomised 1:1:1:1 to receive intravenous (IV) placebo (n = 63), miri 50 mg (n = 63) or 200 mg (n = 62) with possibility of exposure-based (EB) dose increases, or fixed miri 600 mg (n = 61) every 4 weeks (Q4W). Responders to miri at Week 12 (9-point Mayo score decrease ≥2 points and ≥35% change from baseline, with RB=0 or 1 or decrease ≥1) were re-randomised 1:1 into a double-blind maintenance period to receive miri 200 mg subcutaneously (SC) Q4W (n = 47) or every 12 weeks (Q12W; n = 46), and were treated through Week 52. Patients reported UC symptoms, including SF and RB, via a daily diary. Changes from baseline in average Mayo SF and RB subscores at Weeks 2, 4, and 12 were analysed using a mixed model repeated-measures method to account for missingness and baseline characteristics. Results Significant improvement in SF was observed as early as Week 2 in the miri 600 mg Q4W group and as early as Week 4 in the miri 200 mg Q4W group (Figure). Similarly, significant improvement in RB was observed as early as Week 2 in both the miri 200 mg Q4W and 600 mg Q4W groups. Patients who received miri 200 mg Q4W or 600 mg Q4W had a significantly greater reduction in both SF and RB compared with placebo at Week 12 (all p < 0.001) (Figure). Patients who achieved clinical response at Week 12 and were treated with miri 200 mg SC Q4W or SC Q12W maintained a low average SF and RB score at Week 52. Conclusion Significant improvements in SF and RB occurred as early as Week 2 of induction treatment and continued to improve during maintenance treatment with mirikizumab. These data demonstrate the early efficacy and longer-term effects of an IL-23p19 antibody on these patient-reported outcomes.

Tribe Chanteiini Chant and Yoshida-Shaul Chantiinae Chant and Yoshida-Shaul 1986: 2025; Chanteiini, Chant and McMurtry 1994: 237., Published as part of Melo, Elis��ngela A. dos S. F., Gondim, Manoel G. C. Jr, de Moraes, Gilberto J. & Oliveira, An��bal R., 2019, A description of the male of Cocoseius elsalvador Denmark and Andrews (Acari: Phytoseiidae: Typhlodrominae), pp. 129-133 in Acarologia 59 (1) on page 130, DOI: 10.24349/acarologia/20194317, http://zenodo.org/record/4487625, {"references":["Chant D. A., Yoshida-Shaul E. 1986. The subfamily Chantiinae in the family Phytoseiidae (Acari: Gamasina). Can. J. Zool., 64 (9): 2024 - 2034. doi: 10.1139 / z 86 - 306","Chant D. A., McMurtry J. A. 1994. A review of the subfamilies Phytoseiinae and Typhlodrominae. Intern. J. Acarol., 20: 223 - 310. doi: 10.1080 / 01647959408684022"]}

Subfamily Typhlodrominae Wainstein Typhlodromini Wainstein 1962: 26; Typhlodrominae, Chant and McMurtry 1994: 235., Published as part of Melo, Elis��ngela A. dos S. F., Gondim, Manoel G. C. Jr, de Moraes, Gilberto J. & Oliveira, An��bal R., 2019, A description of the male of Cocoseius elsalvador Denmark and Andrews (Acari: Phytoseiidae: Typhlodrominae), pp. 129-133 in Acarologia 59 (1) on page 130, DOI: 10.24349/acarologia/20194317, http://zenodo.org/record/4487625, {"references":["Wainstein B. A. 1962. Revision du genre Typhlodromus Scheuten, 1857 et systematique de la famille des Phytoseiidae (Berlese 1916) (Acarina: Parasitiformes). Acarologia, 4: 5 - 30.","Chant D. A., McMurtry J. A. 1994. A review of the subfamilies Phytoseiinae and Typhlodrominae. Intern. J. Acarol., 20: 223 - 310. doi: 10.1080 / 01647959408684022"]}

Genus Cocoseius Denmark and Andrews Cocoseius Denmark and Andrews 1981: 155. Type species Cocoseius elsalvador Denmark and Andrews, Published as part of Melo, Elis��ngela A. dos S. F., Gondim, Manoel G. C. Jr, de Moraes, Gilberto J. & Oliveira, An��bal R., 2019, A description of the male of Cocoseius elsalvador Denmark and Andrews (Acari: Phytoseiidae: Typhlodrominae), pp. 129-133 in Acarologia 59 (1) on page 130, DOI: 10.24349/acarologia/20194317, http://zenodo.org/record/4487625, {"references":["Denmark H. A., Andrews K. L. 1981. Plant associated Phytoseiidae of El Salvador, Central America (Acarina: Mesostigmata). Fla. Entomol., 64: 147 - 158. doi: 10.2307 / 3494606"]}

In debatten over de zorg wordt er veel gepraat over de rol van de patiënt. Vaak wordt daarbij gezegd dat de patiënt centraal moet komen te staan. Daar is weinig tegen in te brengen. De vraag is natuurlijk hoe dat in de praktijk moet worden gebracht. Ervaringsverhalen kunnen uitkomst bieden.

Objective: The aim was to translate the findings of the QUASER study into a reflective, dialogic guide to help senior hospital leaders develop an organization wide QI strategy. Design: The QUASER study involved in depth ethnographic research into QI work and practices in two hospitals in each of five European countries. Three translational stakeholder workshops were held to review research findings and advise on the design of the Guide. An extended iterative process involving researchers from each participant country was then used to populate the Guide. Setting: The research was carried out in two hospitals in each of five European countries. Participants: In total, 389 interviews with healthcare practitioners and 803 hours of observations. Intervention: None. Main outcome measure: None. Results: The QUASER Hospital Guide was designed for leadership teams to diagnose their organization’s strengths and weaknesses in the eight QI challenges. The Guide supports organizational dialogue about QI challenges, enables leaders to share perspectives, and helps teams to develop solutions to their situated problems. The Guide includes extensive examples of QI strategies drawn from the data and is published online and on paper. Conclusions: The QUASER Hospital Guide is empirically based, draws on a dialogical approach to Organizational Development and complexity science and can facilitate hospital leadership teams to identify the best solutions for their organization. Key words: Quality improvement, hospital care, patient safety, quality improvement guide, translational research, leadership info:eu-repo/semantics/publishedVersion

Background Ulcerative colitis (UC) is characterized by the loss of epithelial barrier function and chronic mucosal inflammation. GB004 is an oral, gut-targeted, small molecule stabilizer of hypoxia inducible factor (HIF-1α) that promotes epithelial repair and function. A phase 1b study was conducted in patients with active UC where trends in clinical efficacy favoring GB004 were observed. Here we report the target engagement (TE) and pharmacodynamic (PD) biomarker analysis of colon biopsies and stool samples from the phase 1b study. Methods Subjects with active UC despite 5-ASA treatment were randomized 2:1 to GB004 120 mg solution or placebo (PBO) once daily for 28 days. Colon biopsies (sigmoid and rectum) and stool samples were collected at baseline and Day 28. HIF-1a and myeloperoxidase (MPO) immunohistochemistry was performed on formalin-fixed paraffin-embedded colon biopsies. Gene expression profiling (Affymetrix HTA 2.0) was performed on mRNA extracted from colon biopsies. Fecal calprotectin (FC) and secretory IgA (sIgA) were measured from stool samples. Results presented are overall means for baseline characteristics and differences in mean (HIF-1a, MPO) and median (FC, sIgA) percent change from baseline to Day 28 for GB004 vs PBO. Results Thirty-four subjects (age 45.4 years, Mayo score 7.5, sigmoid colon Mayo endoscopic subscore 2.2, sigmoid colon Robarts Histopathology Index 14.1) were randomized to a GB004 120 mg solution (n=23) or PBO (n=11) group. GB004 demonstrated evidence of TE, with an increase in the percent of HIF-1α positive cells (+11.4%) in sigmoid colon segment sections. Tissue and stool-based PD biomarkers of intestinal inflammation associated with lamina propria neutrophil infiltration and cytotoxicity measured by the MPO+ cell count per mm2 (-7.3%) and FC (-30.4%) levels decreased. Lastly, GB004 resulted in an increase in sIgA levels (+87.16%) and transcriptional changes consistent with enhanced epithelial integrity, such as increases in ITGA6 and TJP1. Conclusion In this phase 1b study, GB004, an oral gut-targeted HIF-1α stabilizer, demonstrated TE in the sigmoid colon and histologic, fecal biomarker, and transcriptional PD effects consistent with a reduction in inflammation and mucosal healing. These observations are consistent with the role of HIF-1α stabilization in improving barrier function in UC patients and support the trends in clinical effects observed, including histologic endpoints. A Phase 2 study of GB004 in patients with mild-to-moderate UC (SHIFT-UC, NCT04556383) is currently ongoing. Sponsored by GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.

This article studies the role of a public regulator in managing the performance of healthcare professionals. It combines a networked governance perspective with responsive regulation theory to show the mechanisms that have added to significant changes in medical cost management in the Netherlands. In a five‐year period, hospital practices transitioned from cosmetic compliance with performance regulation and strategic upcoding to institutionalized compliance more in line with regulatory goals. The article demonstrates how policy changes transformed incentive structures, introduced new forms of accountability, and added actors to the network with technocratic disciplining tasks. The networked character of performance regulation offered opportunities for a responsive, non‐coercive regulatory strategy that engaged various actors in a regulatory conversation about strategic coding. Responsive regulation can reduce strategic responses to performance regulation and manage the gap between administrative and clinical logics. The case study contributes to our understanding of the effectiveness of responsive, non‐punitive regulation in networked settings.

Background and aims Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of Crohn's disease and may serve as a potential biomarker. A phase 2 trial was conducted to examine the efficacy and safety of the anti-MMP9 antibody andecaliximab [GS-5745] in patients with moderately to severely active Crohn's disease. Methods Patients were randomized 1:2:2:2 to receive subcutaneous injections of placebo weekly [QW], andecaliximab 150 mg every 2 weeks [Q2W], andecaliximab 150 mg QW, or andecaliximab 300 mg QW.The co-primary study efficacy endpoints were evaluation of a clinical response, defined as liquid or very soft stool frequency and abdominal pain composite [from Patient-Reported Outcome 2] score ≤ 8 at week 8, and an endoscopic response, defined as a ≥ 50% reduction from baseline in the Simple Endoscopic Score for Crohn's Disease, following 8 weeks of treatment. Results A total of 187 participants were randomized to treatment; 53 participants were randomized to each andecaliximab treatment group and 28 participants were randomized to placebo. Proportions of patients receiving andecaliximab were not different from proportions of patients receiving placebo based on clinical and endoscopic response and Crohn's disease activity index-defined remission at week 8. Rates of adverse events were comparable among the andecaliximab and placebo groups. Conclusions Eight weeks of induction treatment with 150 mg andecaliximab Q2W, 150 mg andecaliximab QW, or 300 mg andecaliximab QW in patients with Crohn's disease did not induce a clinically meaningful symptomatic or endoscopic response. Andecaliximab was well tolerated. Clinical trial registration ClinicalTrials.gov NCT02405442.