Janus kinase inhibitors: between prescription authorization and reimbursability.

Following the restrictions on the reimbursability of Janus kinase inhibitors introduced by the Italian Medicines Agency, the Italian Society of Rheumatology has drafted this document to shed light on the clinical conditions and reimbursability criteria set out in the prescription forms.

Anti-tumor necrosis factor α: originators versus biosimilars, comparison in clinical response assessment in a multicenter cohort of patients with inflammatory arthropathies.

OBJECTIVE: To compare etanercept and adalimumab biosimilars (SB4 and ABP501) and respective bioriginators in terms of safety and efficacy in a real-life contest. METHODS: We consequently enrolled patients affected by rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with SB4, and ABP501, or with corresponding originators, belonging to the main biological prescribing centers in the Lazio region (Italy), from 2017 to 2020. Data were collected at recruitment and after 4, 8, 12, and 24 months of therapy. RESULTS: The multicenter cohort was composed by 455 patients treated with biosimilars [SB4/ABP501 276/179; female/male 307/146; biologic disease-modifying anti-rheumatic drug (b-DMARD) naïve 56%, median age/ interquartile range 55/46-65 years] and 436 treated with originators (etanercept/adalimumab 186/259, female/ male 279/157, b-DMARD naïve 67,2%, median age/interquartile range 53/43-62 years). No differences were found about safety, but the biosimilar group presented more discontinuations due to inefficacy (p<0.001). Female gender, being a smoker, and being b-DMARD naïve were predictive factors of reduced drug survival (p=0.05, p=0.046, p=0.001 respectively). The retention rate at 24 months was 81.1% for bioriginators and 76.5% for biosimilars (median retention time of 20.7 and 18.9 months, respectively) (p=0.002). Patients with remission/low disease activity achievement at 4 months showed a cumulative survival of 90% to biosimilar therapy until 24 months (p=0.001); early adverse reactions instead represented a cause of subsequent drug discontinuation (p=0.001). CONCLUSIONS: Real-life data demonstrated a similar safety profile between biosimilars and originators, but a reduced biosimilar retention rate at 24 months. Biosimilars could be considered a valid, safe, and less expensive alternative to originators, allowing access to treatments for a wider patient population.

Factors Associated With Genotypic Resistance and Outcome Among Solid Organ Transplant Recipients With Refractory Cytomegalovirus Infection.

Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV genotypic resistance in refractory infections and disease in the SOTR (Solid Organ Transplant Recipients) population, and the factors associated with outcomes. We included all SOTRs who were tested for CMV genotypic resistance for CMV refractory infection/disease over ten years in two centers. Eighty-one refractory patients were included, 26 with genotypically resistant infections (32%). Twenty-four of these genotypic profiles conferred resistance to ganciclovir (GCV) and 2 to GCV and cidofovir. Twenty-three patients presented a high level of GCV resistance. We found no resistance mutation to letermovir. Age (OR = 0.94 per year, IC95 [0.089-0.99]), a history of valganciclovir (VGCV) underdosing or of low plasma concentration (OR= 5.6, IC95 [1.69-20.7]), being on VGCV at infection onset (OR = 3.11, IC95 [1.18-5.32]) and the recipients' CMV negative serostatus (OR = 3.40, IC95 [0.97-12.8]) were independently associated with CMV genotypic resistance. One year mortality was higher in the resistant CMV group (19.2 % versus 3.6 %, p = 0.02). Antiviral drugs severe adverse effects were also independently associated with CMV genotypic resistance. CMV genotypic resistance to antivirals was independently associated with a younger age, exposure to low levels of GCV, the recipients' negative serostatus, and presenting the infection on VGCV prophylaxis. This data is of importance, given that we also found a poorer outcome in the patients of the resistant group.

Transplantation to save the life, TSH screening to save the brain: A report and brief literature review of autoimmune thyroid disease after HSCT for severe combined immunodeficiency.

Autoimmune thyroid disease has been described as a complication of HSCT for different indications and as a manifestation of inborn errors of immunity, like SCID. A 1-month female was diagnosed with RAG1-mutated SCID and received allogenic HSCT. She developed autoimmune hypothyroidism 5 months after transplantation and was treated with levo-thyroxine with a good response. Autoimmune thyroid disease can develop after HSCT during the immune reconstitution phase, leading to potentially severe neurological and growth impairment, particularly in SCID patients, often transplanted during the first year of life. Recommendations regarding early and frequent vigilance for thyroid function are needed in these patients.

Patients with systemic lupus erythematosus and their experience with vaccination against COVID-19: a descriptive and explanatory study.

Not available.

Material effects on dynamics in triple-nozzle gas-puff Z pinches.

The gas-puff Z pinch has a long history with myriad applications as an efficient neutron or x-ray source. Its simplicity as a load configuration makes it suitable for studying fundamental plasma physics phenomena such as instabilities and energy transport. For example, the implosion of cylindrical shells onto a fusion fuel are inherently susceptible to instability growth on their external surfaces; if such instabilities are unmitigated, then the consequences in terms of degraded performance can be substantial. Similarly, mitigating heat transport from a hot fuel to its colder surrounding container can make fusion conditions more easily achievable. Here we have conducted a systematic study of triple-nozzle (outer liner, inner liner, fuel) gas puffs using two-dimensional (2D) magnetohydrodynamic simulations to investigate the effect of load material on the relevant dynamics. Analogous to past studies on spherical blast waves and converging shock waves, a trend emerges linking increased radiative cooling, lower adiabatic index, and increased magneto-Rayleigh-Taylor instability growth. Notably, our results suggest that, for the present configuration, Ar radiates less than both Ne and Kr during the early stages of the implosion while mass is being swept up and perturbations begin to seed instability growth. Consequently, pinches with Ar on the outer surface exhibit more stable 2D behavior. Here we also present a parameter scan of thermonuclear neutron yield, Y, as a function of peak current, I_{pk} and dopant concentration with Ne or Ar, depending on the inner liner material. Above 6 MA, our results suggest Y∝I_{pk}^{5} and even substantial mixing (10% by volume) of Ne into the fuel does not drastically reduce yield, suggesting an Ar/Ne/fuel configuration may reliably achieve DD thermonuclear yields of 10^{13}-10^{14}/cm in the 10-20 MA range.

Tofacitinib Decreases Autophagy of Fibroblast-Like Synoviocytes From Rheumatoid Arthritis Patients.

The pathway of Janus tyrosine kinases (JAKs) has a central role in the pathogenesis of Rheumatoid Arthritis (RA) by regulating multiple immune functions and cytokine production. The JAK inhibitor tofacitinib is effective in RA patients not responding to methotrexate or TNF-inhibitors. Since hyperactive autophagy has been associated with impaired apoptosis of RA fibroblast-like synoviocytes (FLS), we aimed to investigate the role of tofacitinib in modulating autophagy and apoptosis in these cells. FLS isolated from RA biopsies were cultured with tofacitinib in presence of autophagy inducer rapamycin and in serum deprivation condition. Levels of autophagy, apoptosis, and citrullinated proteins were analyzed by western blot, flow cytometry, immunocytofluorescence, and Real-Time PCR. Rapamycin induced an increase in RA-FLS autophagy while the levels of autophagy marker LC3-II were reduced after in vitro treatment with tofacitinib. The analysis of autophagic flux by specific fluorescence dye confirmed the reduction of autophagy in RA FLS. The treatment with tofacitinib did not influence apoptosis of RA FLS. Modulation of the autophagic process by tofacitinib did not significantly change citrullination. The results of this study demonstrate that tofacitinib is able to modulate autophagy of FLS contributing to its effectiveness in RA patients.

Mitigation of magneto-Rayleigh-Taylor instability growth in a triple-nozzle, neutron-producing gas-puff Z pinch.

The gas-puff Z-pinch is a well-known source of x-rays and/or neutrons, but it is highly susceptible to the magneto-Rayleigh-Taylor instability (MRTI). Approaches to MRTI mitigation include density profile tailoring, in which nozzles are added or modified to alter the acceleration trajectory, and axial pre-magnetization, in which perturbations are smoothed out via magnetic field line tension. Here, we present two-dimensional magnetohydrodynamic simulations of loads driven by an 850 kA, 160 ns driver that suggest these mitigation strategies can be additive. The initial axial magnetic field, B_{z0}, to stabilize a 2.5-cm-radius Ne gas liner imploding onto an on-axis deuterium target can be reduced from 0.7 T to 0.3 T by adding a second liner with a radius of 1.25 cm. Because MRTI mitigation tends to increasingly lower yield with higher B_{z0}, the use of a lower field is advantageous. Here, we predict a reduction in yield penalty from >100× with the single liner to <10× with a double liner. A premagnetized, triple nozzle gas puff could therefore be an attractive source for intense neutrons or other fusion applications.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

Azimuthal magnetic field distribution in gas-puff Z-pinch implosions with and without external magnetic stabilization.

An experimental study of the magnetic field distribution in gas-puff Z pinches with and without a preembedded axial magnetic field (B_{z0}) is presented. Spatially resolved, time-gated spectroscopic measurements were made at the Weizmann Institute of Science on a 300 kA, 1.6 µs rise time pulsed-power driver. The radial distribution of the azimuthal magnetic field, B_{θ}, during the implosion, with and without a preembedded axial magnetic field of B_{z0}=0.26T, was measured using Zeeman polarization spectroscopy. The spectroscopic measurements of B_{θ} were consistent with the corresponding values of B_{θ} inferred from current measurements made with a B-dot probe. One-dimensional magnetohydrodynamic simulations, performed with the code trac-ii, showed agreement with the experimentally measured implosion trajectory, and qualitatively reproduced the experimentally measured radial B_{θ} profiles during the implosion when B_{z0}=0.26T was applied. Simulation results of the radial profile of B_{θ} without a preembedded axial magnetic field did not qualitatively match experimental results due to magneto-Rayleigh-Taylor (MRT) instabilities. Our analysis emphasizes the importance of MRT instability mitigation when studying the magnetic field and current distributions in Z pinches. Discrepancies of the simulation results with experiment are discussed.

A method to assess heart rate variability in neonate rats: validation in normotensive and hypertensive animals.

Several studies have focused on the heart rate variability (HRV) of murine species, while studies discussing HRV in murine neonates and infants remain scarce, since recording hemodynamic signals through invasive methods in small animals has been found to be quite challenging. Thus, this study aimed at describing and validating a novel method to assess HRV in newborn rats. An electrocardiogram (ECG) system was used to determine RR intervals in awake newborns and evaluate HRV in normotensive (Wistar) and hypertensive (SHR) neonate rats. After birth, ECG was recorded in the awake newborns, and they were allowed to rest on a heated surface, restricted only by the weight of the adhesive ECG electrodes. The electrodes were cut and adapted to provide more comfort to the animal, and gently placed on the newborn's skin. RR intervals were recorded over a 30-min period using an ECG system together with LabChart software (4 KHz). Three sequences of 5 min each from the ECG recording period were analyzed in time and frequency domains, using CardioSeries software. ECG data resulted in a clearly interpretable signal that was used to generate an RR interval sequence through time for the analysis of HRV. SHR neonates presented increased cardiac sympathovagal balance compared to Wistar neonates (low frequency/high frequency: 3.85±0.71 vs 0.90±0.09). In conclusion, the ECG setup here described may be used to record RR intervals to assess HRV in neonate rats, thus detecting early impairment of HRV in hypertensive newborns.

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus.

LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(TFH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications.

Role of collisionality and radiative cooling in supersonic plasma jet collisions of different materials.

Currently there is considerable interest in creating scalable laboratory plasmas to study the mechanisms behind the formation and evolution of astrophysical phenomena such as Herbig-Haro objects and supernova remnants. Laboratory-scaled experiments can provide a well diagnosed and repeatable supplement to direct observations of these extraterrestrial objects if they meet similarity criteria demonstrating that the same physics govern both systems. Here, we present a study on the role of collision and cooling rates on shock formation using colliding jets from opposed conical wire arrays on a compact pulsed-power driver. These diverse conditions were achieved by changing the wire material feeding the jets, since the ion-ion mean free path (λ_{mfp-ii}) and radiative cooling rates (P_{rad}) increase with atomic number. Low Z carbon flows produced smooth, temporally stable shocks. Weakly collisional, moderately cooled aluminum flows produced strong shocks that developed signs of thermal condensation instabilities and turbulence. Weakly collisional, strongly cooled copper flows collided to form thin shocks that developed inconsistently and fragmented. Effectively collisionless, strongly cooled tungsten flows interpenetrated, producing long axial density perturbations.

A method to assess heart rate variability in neonate rats: validation in normotensive and hypertensive animals

Several studies have focused on the heart rate variability (HRV) of murine species, while studies discussing HRV in murine neonates and infants remain scarce, since recording hemodynamic signals through invasive methods in small animals has been found to be quite challenging. Thus, this study aimed at describing and validating a novel method to assess HRV in newborn rats. An electrocardiogram (ECG) system was used to determine RR intervals in awake newborns and evaluate HRV in normotensive (Wistar) and hypertensive (SHR) neonate rats. After birth, ECG was recorded in the awake newborns, and they were allowed to rest on a heated surface, restricted only by the weight of the adhesive ECG electrodes. The electrodes were cut and adapted to provide more comfort to the animal, and gently placed on the newborn's skin. RR intervals were recorded over a 30-min period using an ECG system together with LabChart software (4 KHz). Three sequences of 5 min each from the ECG recording period were analyzed in time and frequency domains, using CardioSeries software. ECG data resulted in a clearly interpretable signal that was used to generate an RR interval sequence through time for the analysis of HRV. SHR neonates presented increased cardiac sympathovagal balance compared to Wistar neonates (low frequency/high frequency: 3.85±0.71 vs 0.90±0.09). In conclusion, the ECG setup here described may be used to record RR intervals to assess HRV in neonate rats, thus detecting early impairment of HRV in hypertensive newborns.