Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis

Background: Long-term safety data are of particular interest for any newly approved treatment in multiple sclerosis such as cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the integrated analysis of the safety profile of cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry. Methods: Safety data for cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (cladribine tablets versus placebo) were estimated. Results: The Monotherapy Oral cohort comprised 923 patients who received cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the cladribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference population (standardized incidence ratio, 0.88; 95% CI, 0.44-1.69). Conclusion: Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of cladribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis

Evolution of planar defects during homoepitaxial growth of β-Ga2O3 layers on (100) substrates—A quantitative model

We study the homoepitaxial growth of β-Ga2O3 (100) grown by metal-organic vapour phase as dependent on miscut-angle vs. the c direction. Atomic force microscopy of layers grown on substrates with miscut-angles smaller than 2° reveals the growth proceeding through nucleation and growth of two-dimensional islands. With increasing miscut-angle, step meandering and finally step flow growth take place. While step-flow growth results in layers with high crystalline perfection, independent nucleation of two-dimensional islands causes double positioning on the (100) plane, resulting in twin lamellae and stacking mismatch boundaries. Applying nucleation theory in the mean field approach for vicinal surfaces, we can fit experimentally found values for the density of twin lamellae in epitaxial layers as dependent on the miscut-angle. The model yields a diffusion coefficient for Ga adatoms of D = 7 × 10−9 cm2 s−1 at a growth temperature of 850 °C, two orders of magnitude lower than the values published for GaAs

Levels of diphtheria and tetanus specific IgG of Portuguese adult women, before and after vaccination with adult type Td. Duration of immunity following vaccination

<p>Abstract</p> <p>Background</p> <p>The need for tetanus toxoid decennial booster doses has been questioned by some experts. Several counter arguments have been presented, supporting the maintenance of decennial adult booster doses with tetanus and diphtheria toxoids (adult formulation of the vaccine: Td). This study aimed to evaluate the use of Td in Portuguese adult women under routine conditions. For that purpose we selected a group of women 30+ years of age to which vaccination was recommended. We intended to know if pre-vaccination antibody concentrations were associated with factors as age at first and last vaccination, number of doses and time since last revaccination. We also intended to assess the serological efficacy of Td booster.</p> <p>Methods</p> <p>Following the Portuguese guidelines 100 women were vaccinated with Td. Antitetanus toxin IgG (ATT IgG) and antidiphtheria toxin IgG (ADT IgG) levels were measured (mIU/ml) in 100 pre-vaccination and 91 post-vaccination sera. Detailed vaccination records were available from 88 participants.</p> <p>Results</p> <p>Twenty-two women (Group A) began vaccination with DPT/DT in their early childhood and their pre-vaccination ATT IgG levels increased with the number of doses received (p = 0.022) and decreased with time since last vaccination (p = 0.016). Among the 66 women who began vaccination in adolescence and adulthood (Group B), with monovalent TT, ATT IgG levels decreased with age at first dose (p < 0.001) and with time since last vaccination (p = 0.041). In Group A, antidiphtheria toxin IgG kinetics was very similar to that observed for ATT IgG. Among women not vaccinated with diphtheria toxoid, ADT IgG levels decreased with age. Serological response to both components of Td was good but more pronounced for ATT IgG.</p> <p>Conclusion</p> <p>Our study suggests that, to protect against tetanus, there is no need to administer decennial boosters to the Portuguese adults who have complied with the childhood/adolescent schedule (6 doses of tetanus toxoid). The adult booster intervals could be wider, probably of 20 years. This also seems to apply to protection against diphtheria, but issues on the herd immunity and on the circulation of toxigenic strains need to be better understood.</p

Mice Exposed to Combined Chronic Low-Dose Irradiation and Modeled Microgravity Develop Long-Term Neurological Sequelae

Spaceflight poses many challenges for humans. Ground-based analogs typically focus on single parameters of spaceflight and their associated acute effects. This study assesses the long-term transcriptional effects following single and combination spaceflight analog conditions using the mouse model: simulated microgravity via hindlimb unloading (HLU) and/or low-dose γ-ray irradiation (LDR) for 21 days, followed by 4 months of readaptation. Changes in gene expression and epigenetic modifications in brain samples during readaptation were analyzed by whole transcriptome shotgun sequencing (RNA-seq) and reduced representation bisulfite sequencing (RRBS). The results showed minimal gene expression and cytosine methylation alterations at 4 months readaptation within single treatment conditions of HLU or LDR. In contrast, following combined HLU+LDR, gene expression and promoter methylation analyses showed multiple altered pathways involved in neurogenesis and neuroplasticity, the regulation of neuropeptides, and cellular signaling. In brief, neurological readaptation following combined chronic LDR and HLU is a dynamic process that involves pathways that regulate neuronal function and structure and may lead to late onset neurological sequelae

Neonatal tetanus in Turkey; what has changed in the last decade?

dikici, bunyamin/0000-0001-7572-6525WOS: 000259222800001PubMed: 18713452Background: Neonatal tetanus (NT) is still considered as one of the major causes of neonatal death in many developing countries. The aim of the present study was to assess the characteristics of sixty-seven infants with the diagnosis of neonatal tetanus followed-up in the Pediatric Infectious Diseases Ward of Dicle University Hospital, Diyarbakir, between 1991 and 2006, and to draw attention to factors that may contribute (or may have contributed) to the elimination of the disease in Diyarbakir. Methods: The data of sixty-seven infants whose epidemiological and clinical findings were compatible with neonatal tetanus were reviewed. Patients were stratified into two groups according to whether they survived or not to assess the effect of certain factors in the prognosis. Factors having a contribution to the higher rate of tetanus among newborn infants were discussed. Results: A total of 55 cases of NT had been hospitalized between 1991 and 1996 whereas only 12 patients admitted in the last decade. All of the infants had been delivered at home by untrained traditional birth attendants (TBA), and none of the mothers had been immunized with tetanus toxoid during her pregnancy. Twenty-eight (41.8%) of the infants died during their follow-up. Lower birth weight, younger age at onset of symptoms and at the time admission, the presence of opisthotonus, risus sardonicus and were associated with a higher mortality rate. Conclusion: Although the number of neonatal tetanus cases admitted to our clinic in recent years is lower than in the last decade efforts including appropriate health education of the masses, ensurement of access to antenatal sevices and increasing the rate of tetanus immunization among mothers still should be made in our region to achieve the goal of neonatal tetanus elimination

Spin Glass and Antiferromagnetic Behaviour in a Diluted fcc Antiferromagnet

We report on a Monte Carlo study of a diluted Ising antiferromagnet on a fcc lattice. This is a typical model example of a highly frustrated antiferromagnet, and we ask, whether sufficient random dilution of spins does produce a spin glass phase. Our data strongly indicate the existence of a spin glass transition for spin--concentration $p<0.75$: We find a divergent spin glass susceptibility and a divergent spin glass correlation length, whereas the antiferromagnetic correlation length saturates in this regime. Furthermore, we find a first order phase transition to an antiferromagnet for $1\ge p>0.85$, which becomes continuous in the range $0.85>p>0.75$. Finite size scaling is employed to obtain critical exponents. We compare our results with experimental systems as diluted frustrated antiferromagnets as ${\rm Zn_{1-p}Mn_{p}Te}$.Comment: 29 pages (revtex) and 10 figures uuencoded and Z-compresse