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- Petroni, M, et al.
(författare)
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SMO-M2 mutation does not support cell-autonomous Hedgehog activity in cerebellar granule cell precursors
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 19623-
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Tidskriftsartikel (refereegranskat)abstract
- Growth and patterning of the cerebellum is compromised if granule cell precursors do not properly expand and migrate. During embryonic and postnatal cerebellar development, the Hedgehog pathway tightly regulates granule cell progenitors to coordinate appropriate foliation and lobule formation. Indeed, granule cells impairment or defects in the Hedgehog signaling are associated with developmental, neurodegenerative and neoplastic disorders. So far, scant and inefficient cellular models have been available to study granule cell progenitors, in vitro. Here, we validated a new culture method to grow postnatal granule cell progenitors as hedgehog-dependent neurospheres with prolonged self-renewal and ability to differentiate into granule cells, under appropriate conditions. Taking advantage of this cellular model, we provide evidence that Ptch1-KO, but not the SMO-M2 mutation, supports constitutive and cell-autonomous activity of the hedgehog pathway.
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- Dahal, Prabin, et al.
(författare)
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Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria : a WorldWide Antimalarial Resistance Network individual participant data meta-analysis
- 2019
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Ingår i: Malaria Journal. - : BMC. - 1475-2875. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.
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- Dahal, Prabin, et al.
(författare)
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Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy : an individual participant data meta-analysis
- 2022
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Ingår i: Malaria Journal. - : Springer Nature. - 1475-2875. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria.Methods: Individual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up.Results: Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged < 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47-74%] of recrudescences in African children and 32% [95% CI 15-45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19-90%] in children under 5 years old treated with > 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0-22%] in those treated with <= 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution.Conclusions: Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.
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- Mineo Bianchi, F, et al.
(författare)
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Posterior muscle-fascial reconstruction and knotless urethro-neo bladder anastomosis during robot-assisted radical cystectomy: Description of the technique and its impact on urinary continence
- 2019
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Ingår i: Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica. - : PAGEPress Publications. - 2282-4197. ; 91:1, s. 5-10
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of our study is to describe the use of posterior muscle-fascial reconstruction during urethro-ileal anastomosis in bladder cancer (BC) patients submitted to robot-assisted radical cystectomy (RC) with orthotopic neobladder (ON) and its role in facilitating day- and night-time continence recovery during a 12-month follow up. Materials and methods: We prospectively collected data from 42 consecutive patients who underwent RARC with totally intracorporeal ON and extended pelvic lymph node dissection (PLND) at our Institution from June 2014 to October 2017. Prior to the urethro-neobladder anastomosis we reconstructed the Denonvilliers Fascia (DF) as previously described for radical prostatectomy using a bidirectional barbed suture. Day and night-time recovery rates were reported at 3, 6 and 12 months after surgery, with continent patients being those using either no urinary pads or 1 safety pads. Results: Median age at surgery was 63 yrs, 41 (97.6%) patients were male. 28 (66.7%) patients presented a clinical T2 disease. Median operative time and median ON reconstruction time were 450 minutes and 180 minutes respectively. 13 (31%) individuals had non-organ confined disease, with 11 (26.2%) patients with positive lymph nodes (median 3 positive lymph nodes) and 2 (4.8%) with non-urothelial cancer at final pathologic examination. Median hospital stay and median catheterization time were 7 (IQR 7-8) and 21 (IQR 19-22). During first 30 post-operative days we recorded 7 (16.7%) low-grade Clavien and 2 (4.8%) IIIa Clavien complications, whereas between 30 and 90 postoperative days we recorded 4 (9.5%) low-grade, 4 (9.5) IIIa and 1 (2.4%) IIIb complications. Day-time and night-time continence rates were 61.9% vs 52.4%, 73.8% vs 64.3% and 90.5% vs 73.8% at three, six and twelve months follow up. Day-time continence was significantly superior in the younger group (97% vs 57%, p 0.01); night-time continence rates were also superior among < 70 yrs patients, despite not reaching statistical significance (77% vs 57%, p 0.3). Conclusions: Posterior muscle-fascial reconstruction aids continence recovery in BC patients undergoing RARC with ON, with younger and fitter patients most benefitting from ON reconstruction.
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