Abstract Liver transplantation is considered to be the most efficient therapeutic option for patients with liver cirrhosis and early stage hepatocellular carcinoma (HCC) in terms of overall survival ...and recurrence rate. The application of restrictive selection criteria based on tumor size and number of nodules is advised to obtain optimal results. Nevertheless, tumor recurrence occurs in 3.5% to 21% of recipients, despite careful pretransplant staging and patient selection. Post transplant recurrence of hepatocarcinoma clearly has a major negative impact on prognosis. Intuitively, an immunosupressed state is undesirable in cancer patients. Inversely, modulation or minimization of immunosuppressive therapy could influence tumor progression and reduce the negative impact of recurrence on posttransplant survival. Experimental evidence shows that mammalian target of rapamycin (mTOR) inhibitors have antiangiogenic and antiproliferative effects. Thus, their application has been proposed as antineoplastic agents for immunosuppressive protocols in liver transplant recipients with HCC and may reduce the rate or the impact of tumor recurrence. Clinical data about efficacy and safety of mTOR-based immunosuppressant protocols in liver transplant recipients with HCC show promising results, namely low recurrence and higher survival rates compared with standard calcineurin inhibitor–based immunosuppressive protocols, even among patients with extended morphological criteria. The safety profile is regarded generally as adequate.
Abstract
Background
Few small studies have assessed the efficacy of topical therapy with tacrolimus in patients with ulcerative colitis (UC). The aim of our study was to evaluate its effectiveness ...and safety in a real-world setting.
Methods
A multicenter observational retrospective study at 25 Spanish GETECCU hospitals was performed. Adult patients with UC who received topical tacrolimus from January 2009 to January 2023 were eligible. Inclusion criteria were proctitis, left-sided, or extensive colitis with persistent distal colonic activity confirmed endoscopically during the previous 3 months. Clinical and biochemical data were collected at baseline, week 4, 8 and 54. Tacrolimus trough levels were evaluated in week 4 and 8. Primary outcome was clinical response at week 8, defined as a ≥3 points or ≥30% decrease of partial Mayo score with ≥1point reduction in the bleeding score. Mean partial mayo scores were compared using the t-test. A p<0.05 was considered statistically significant.
Results
106 patients, 59 (55.6%) males, median age 48.7 years (IQR:39.9-59.7), received rectal tacrolimus during a median of 9.7 weeks (IQR:5-18.7). Sixty-four patients (60.4%) received suppositories, 41 (38.7%) enemas and 1 patient an ointment (0.9%). Thirty (28.3%) were patients with proctitis, 45 (42.4%) with left colitis and 31 (29.2%) with extensive colitis. At baseline, 54 patients (50.9%) received concomitant biological/small molecules therapy, while 14 patients received immunomodulators. Most common dose was 2 mg (84%) Q24H (71.7%).
A significant decrease in mean partial mayo score was observed at week 4 and 8 (figure 1). Clinical response at week 8 was achieved in 63 patients (66.3%) and clinical remission in 42 (44.2%). 32 patients (33.7%) were non-responder at week 8. Clinical response and remission at week 4 were achieved in 56 (57.7%) and 33 (34.4%), respectively. Clinical response at week 8 was similar between the group with concomitant biological therapy and without (64.6.9% vs 68.1%, p=0.8). Clinical response at week 8 was similar among different extensions (proctitis: 55.6%; left colitis: 80%; extensive colitis 57.1%; p=0.052). Clinical outcomes are detailed in table 1.
Median tacrolimus trough levels at week 4 was 3.4 ng/ml (IQR 1.5-6.7) and 2.9 ng/ml (IQR 1.5-6) at week 8.
Adverse events were detected in 21 patients (19.8%), Thirteen were graded as mild and 8 moderate. Treatment was ceased due to adverse events in 11 (10.4%) patients.
Conclusion
Topical tacrolimus is effective in UC achieving clinical response in more than sixty percent at week 8 with even lower doses than reported in clinical trials. Adverse events reported in nearly 20% of patients were mostly mild.
Abstract
Background
Approximately one half of the patients with Crohn’s disease (CD) develop intestinal strictures during their lifetime. The effectiveness of currently approved drugs in ...fibrosis-predominant lesions is very limited. Our aim was to determine the effectiveness of anti-TNF therapy in CD complicated by symptomatic intestinal strictures in a real-world setting.
Methods
We included adult patients with symptomatic stricturing CD receiving their first-line anti-TNF therapy. Strictures were defined as constant luminal narrowing with pre-stenotic dilatation. We excluded those patients with previous anti-TNF exposure, surgery or endoscopic therapy of the stenosis. The effectiveness of the anti-TNF was defined as a composite outcome combining the persistence of the treatment and without dose or frequency intensification, with no new immunomodulators, surgery or endoscopic therapy during follow-up. A multivariate Cox regression was performed and the final multivariate model was determined using a backward procedure.
Results
A total of 262 patients from 32 sites were included (141 received infliximab and 121 adalimumab). The median number of stenosis per patient was 1 (range 1–9). The treatment was effective in 81% and 59% of patients after 6 and 12 months, respectively, while this outcome was fulfilled by 21% after a median of 40 months (IQR, 19–85). During follow-up, anti-TNF therapy required a dose or frequency adjustment in 39% of patients, 12% required a new immunomodulator or endoscopic therapy in 4%. The proportion of subjects requiring surgery was 15% and 21% after 1 and 2 years, respectively, with an overall rate of surgery of 32%. Infliximab was associated with a higher rate of surgery as compared with adalimumab (OR 1.78; 95% CI, 1,025-3,09). A shorter time since the diagnosis of CD or the stricture and the initiation of anti-TNF therapy was associated with a greater effectiveness at 6 and 12 months (HR 0.99 95% CI 0.99–1, p = 0.045; HR 0.99 95% CI 0.99–0.99, p = 0.015; HR 0.98 95% CI 0.96–0.99, p = 0.024; HR 0.99 95% CI 0.98–1.0, p = 0.046; respectively). In the survival analysis, younger age, lower albumin levels at baseline, strictures being located in the descending colon, concomitant use of mesalamine and the presence of ulcers or lymphadenopathy at the stricture were associated with lower effectiveness. The anti-TNF agent was discontinued in 131 patients (50%), and 88 subjects (34%) required a switch to a new biologic.
Conclusion
Anti-TNF agents are effective in approximately 20% of patients with CD complicated with symptomatic strictures. Early introduction of anti-TNF therapy improves the effectiveness in the short term in these patients. Some clinical and radiological predictors can identify patients with a lower probability of response.
Policosanol is a natural mixture of higher aliphatic primary alcohols isolated from sugar cane wax (Saccharum officinarum, L) with cholesterol-lowering effects demonstrated in experimental models and ...in patients with type II hyperlipoproteinemia. The purpose of this study is to determine the effect of policosanol on arterial blood pressure and its interaction with propranolol and nifedipine.
Single doses of policosanol (25, 50 and 200 mg/kg) orally administered to spontaneously hypertensive rats (SHR) did not significantly change arterial pressure.
The study on pharmacological interactions between policosanol (200 mg/kg) and both antihypertensive agents revealed that pretreatment with high doses of policosanol significantly increased propranolol-induced hypotensive effects, while the effects of nifedipine remained unchanged.
Our results show that policosanol does not antagonize the hypotensive effect of beta-blockers but it can increase the hypotensive effect of beta-blockers without modifying cardiac frequency.
We introduce the Automatic Learning for the Rapid Classification of Events (ALeRCE) broker, an astronomical alert broker designed to provide a rapid and self--consistent classification of large ...etendue telescope alert streams, such as that provided by the Zwicky Transient Facility (ZTF) and, in the future, the Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST). ALeRCE is a Chilean--led broker run by an interdisciplinary team of astronomers and engineers, working to become intermediaries between survey and follow--up facilities. ALeRCE uses a pipeline which includes the real--time ingestion, aggregation, cross--matching, machine learning (ML) classification, and visualization of the ZTF alert stream. We use two classifiers: a stamp--based classifier, designed for rapid classification, and a light--curve--based classifier, which uses the multi--band flux evolution to achieve a more refined classification. We describe in detail our pipeline, data products, tools and services, which are made public for the community (see \url{https://alerce.science}). Since we began operating our real--time ML classification of the ZTF alert stream in early 2019, we have grown a large community of active users around the globe. We describe our results to date, including the real--time processing of \(9.7\times10^7\) alerts, the stamp classification of \(1.9\times10^7\) objects, the light curve classification of \(8.5\times10^5\) objects, the report of 3088 supernova candidates, and different experiments using LSST-like alert streams. Finally, we discuss the challenges ahead to go from a single-stream of alerts such as ZTF to a multi--stream ecosystem dominated by LSST.
•Parkinsonian disorders are associated with atrophy in striatal regions.•Thalamic and putaminal atrophy is greatest in PSP patients relative to controls.•Caudal & putamen atrophy correlates with NPI ...scores when controlling for diagnosis.•Striatal regions have greater morphological changes in PSP over PD, MSA, and HCs.
Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) present similarly with bradykinesia, tremor, rigidity, and cognitive impairments. Neuroimaging studies have found differential changes in the nigrostriatal pathway in these disorders, however whether the volume and shape of specific regions within this pathway can distinguish between atypical Parkinsonian disorders remains to be determined. This paper investigates striatal and thalamic volume and morphology as distinguishing biomarkers, and their relationship to neuropsychiatric symptoms. Automatic segmentation to calculate volume and shape analysis of the caudate nucleus, putamen, and thalamus were performed in 18 PD patients, 12 MSA, 15 PSP, and 20 healthy controls, then correlated with clinical measures. PSP bilateral thalami and right putamen were significantly smaller than controls, but not MSA or PD. The left caudate and putamen significantly correlated with the Neuropsychiatric Inventory total score. Bilateral thalamus, caudate, and left putamen had significantly different morphology between groups, driven by differences between PSP and healthy controls. This study demonstrated that PSP patient striatal and thalamic volume and shape are significantly different when compared with controls. Parkinsonian disorders could not be differentiated on volumetry or morphology, however there are trends for volumetric and morphological changes associated with PD, MSA, and PSP.
Hidradenitis suppurativa (HS) is a chronic skin condition causing lesions in which high levels of interleukin (IL)-23 and T-helper 17 cells are found. Adalimumab remains the only approved treatment. ...Guselkumab, an antibody targeting the p19 protein subunit of extracellular IL-23, is approved for the treatment of moderate–severe psoriasis, but evidence on its efficacy in treating HS is limited.
To assess the effectiveness and safety of guselkumab in treating moderate–severe HS under clinical practice conditions.
A multicentre retrospective observational study was carried out in 13 Spanish Hospitals including adult HS patients treated with guselkumab within a compassionate use programme (March 2020–March 2022). Data referred to patient demographic and clinical characteristics at treatment initiation (baseline), patient-reported outcomes (Numerical Pain Rating Scale NPRS and Dermatology Life Quality Index DLQI), physician scores (International Hidradenitis Suppurativa Severity Score System IHS4, HS Physical Global Score HS-PGA and Hidradenitis Suppurativa Clinical Response HiSCR) were recorded at baseline and at 16, 24, and 48 weeks of treatment.
A total of 69 patients were included. Most (84.10%) had severe HS (Hurley III) and had been diagnosed for over ten years (58.80%). The patients had been subjected to multiple non-biological (mean 3.56) or biological (mean 1.78) therapies, and almost 90% of those treated with biologics had received adalimumab. A significant decrease in IHS4, HS-PGA, NPRS, and DLQI scores was observed from baseline to 48 weeks of guselkumab treatment (all p<0.01). HiSCR was achieved in 58.33% and 56.52% of the patients at 16 and 24 weeks, respectively. Overall, 16 patients discontinued treatment, mostly due to inefficacy (n=7) or loss of efficacy (n=3). No serious adverse events were observed.
Our results indicate that guselkumab may be a safe and effective therapeutic alternative for patients with severe HS that fail to respond to other biologics.
La hidradenitis supurativa (HS) es una situación cutánea crónica que causa lesiones en las que se encuentran altos niveles de interleucina (IL)-23 y células TH-17 colaboradoras, siendo adalimumab el único tratamiento aprobado. Guselkumab, un anticuerpo que focaliza la subunidad de la proteína p19 de IL-23 extracelular, ha sido aprobado para tratar la psoriasis de moderada a severa, siendo limitada la evidencia sobre su eficacia en el tratamiento de la HS.
Evaluar la efectividad y seguridad de guselkumab para el tratamiento de la HS de moderada a severa, en condiciones de práctica clínica.
Se llevó a cabo un estudio observacional retrospectivo y multicéntrico en 13 hospitales españoles, que incluyó pacientes adultos de HS tratados con guselkumab, dentro de un programa de uso compasivo (de marzo de 2020 a marzo de 2022). Se registraron al inicio y a las 16, 24 y 48 semanas de tratamiento los datos referentes a las características demográficas y clínicas de los pacientes, los resultados reportados por el paciente (Numerical Pain Rating Scale NPRS y Dermatology Life Quality Index DLQI), puntuaciones del facultativo (International Hidradenitis Suppurativa Severity Score System IHS4, HS Physical Global Score HS-PGA e Hidradenitis Suppurativa Clinical Response HiSCR).
Se incluyó un total de 69 pacientes, de los cuales la mayoría (84,10%) tenían HS severa (Hurley III) y habían sido diagnosticados hacía más de 10 años (58,80%). Dichos pacientes habían sido sometidos a múltiples terapias no biológicas (media 3,56) o biológicas (media 1,78), y casi el 90% de los tratados con biológicos habían recibido adalimumab. Se observó una reducción significativa de las puntuaciones IHS4, HS-PGA, NPRS y DLQI desde el inicio hasta las 48 semanas del tratamiento con guselkumab (total p<0,01). Se logró HiSCR en el 58,33% y el 56,52% de los pacientes, a las 16 y 24 semanas, respectivamente. A nivel global, 16 pacientes discontinuaron el tratamiento, en su mayoría debido a ineficacia (n=7) o pérdida de eficacia (n=3), no observándose episodios adversos graves.
Nuestros resultados indican que guselkumab puede ser una alternativa terapéutica segura y efectiva para los pacientes con HS severa que no responden a otros biológicos.
Coherent elastic neutrino–nucleus scattering (CEνNS) offers a unique way to study neutrino properties and to search for new physics beyond the Standard Model. Nuclear reactors are promising sources ...to explore this process at low energies since they deliver large fluxes of anti-neutrinos with typical energies of a few MeV. In this paper, a new-generation experiment to study CEνNS is described. The NUCLEUS experiment will use cryogenic detectors which feature an unprecedentedly low-energy threshold and a time response fast enough to be operated under above-ground conditions. Both sensitivity to low-energy nuclear recoils and a high event rate tolerance are stringent requirements to measuring CEνNS of reactor anti-neutrinos. A new experimental site, the Very-Near-Site (VNS), at the Chooz nuclear power plant in France is described. The VNS is located between the two 4.25 GWth reactor cores and matches the requirements of NUCLEUS. First results of on-site measurements of neutron and muon backgrounds, the expected dominant background contributions, are given. In this paper a preliminary experimental set-up with dedicated active and passive background reduction techniques and first background estimations are presented. Furthermore, the feasibility to operate the detectors in coincidence with an active muon veto at shallow overburden is studied. The paper concludes with a sensitivity study pointing out the physics potential of NUCLEUS at the Chooz nuclear power plant.
The NUCLEUS experiment aims for the detection of coherent elastic neutrino-nucleus scattering at a nuclear power reactor with gram-scale, ultra-low-threshold cryogenic detectors. This technology ...leads to a miniaturization of neutrino detectors and allows to probe physics beyond the Standard Model of particle physics. A 0.5 g NUCLEUS prototype detector, operated above ground in 2017, reached an energy threshold for nuclear recoils of below 20 eV. This sensitivity is achieved with tungsten transition edge sensors which are operating at temperatures of 15 mK and are mainly sensitive to non-thermal phonons. These small recoil energies become accessible for the first time with this technology, which allows collecting large-statistics neutrino event samples with a moderate detector mass. A first-phase cryogenic detector array with a total mass of 10 g enables a 5-sigma observation of coherent scattering within several weeks. We identified a suitable experimental site at the Chooz Nuclear Power Plant and performed muon and neutron background measurements there. The operation of a NUCLEUS cryogenic detector array at such a site requires highly efficient background suppression. NUCLEUS plans to use an innovative technique consisting of separate cryogenic anticoincidence detectors against surface backgrounds and penetrating (gamma, neutron) radiation. We present first results from prototypes of these veto detectors and their operation in coincidence with a NUCLEUS target detector.
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