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IMPORTANCE: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking. OBJECTIVE: To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up. MAIN OUTCOMES AND MEASURES: The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models. EXPOSURES: Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective). RESULTS: From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean [SD] age, 43.0 [10.7] years; 366 female patients [55.0%]), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; 95% CI, 1.13-1.55; P < .001), superimposed relapses (aHR, 2.37; 95% CI, 1.24-4.54; P = .009), and DMT exposure (aHR, 1.75; 95% CI, 1.04-2.94; P = .03) were associated with a higher risk of an EDSS score of 7.0, whereas the interaction term between DMT and superimposed relapses was associated with a reduced risk of EDSS score of 7.0 (aHR, 0.33; 95% CI, 0.16-0.71; P = .004). Similar findings were obtained when treatment according to DMT class was considered and when DMT was included as a time-dependent covariate. These results were confirmed in the subgroup of patients with available magnetic resonance imaging data. CONCLUSIONS AND RELEVANCE: Results of this comparative effectiveness research study suggest that inflammation also occurs in patients with PPMS, may contribute to long-term disability, and may be associated with a reduced risk of becoming wheelchair dependent by current licensed DMTs.

Tectonic plate motions feed the earthquake cycle—a process whereby stress along crustal faults slowly increases over decade– or century–long periods, to then suddenly drop during earthquakes. Steadiness of plate motions during such cycles has long been a central tenet in models of earthquake genesis and of faults seismic potential, and can be tested against measurements of contemporary plate motions available from Global Navigation Satellite Systems (GNSS). Here we present analyses of GNSS data from Central and Northern Italy that illuminate the motion of the Adria microplate over a period of 6 years preceding the MW6.3, 6 April 2009 L’Aquila (Italy) earthquake. We show that the motion of the whole Adria microplate changed before the 2009 earthquake, and slowed down by around 20%. We demonstrate with quantitative models that the torque required upon Adria in order to drive such a kinematic change is consistent with what is imparted to Adria by temporal stress variations occurring during the late interseismic phase of the 2009 L’Aquila earthquake cycle. The inference that plate motions can be influenced by, and thus sensitive to, earthquake cycles offers an additional perspective to assessing the seismic potential of tectonic margins. Earth's outer shell is divided into a number of units—the tectonic plates—that move relative to each other at rates of few mm to cm per year. These relative motions are at the origin of the slow accumulation, along tectonic margins, of energy that is later released suddenly via earthquakes—a decade/century–long process generally referred to as earthquake cycle. It is commonly assumed that plate motions remain steady over such cycles. This is a central assumption in virtually all models of earthquake origin and seismic hazard. The ability to measure via geodetic techniques the contemporary motions of tectonic plates over periods of few years makes it possible to test the assumption above against observations. Here we focus on the Adria microplate, a tectonic unit comprising the Northern and Central parts of Italy, and accommodating the motion of Africa toward Eurasia. We show that the geodetically–observed motion of Adria slowed down during the years immediately preceding the MW6.3 earthquake that occurred on 6 April 2009 near the city of L’Aquila, Italy, which is located along the southwestern tectonic margin of Adria. We demonstrate that the force required to slow down the Adria motion is similar to that developing along the portion of crustal fault that later generated the 2009 L’Aquila earthquake. Adria microplate motion observed from Global Navigation Satellite Systems data slowed down by around 20% in the years preceding the 2009 L'Aquila earthquakeThe slowdown is larger than what permitted by data uncertainties or the impact of data noise, and is thus deemed tectonically meaningfulThe Adria motion slowdown requires a force upon Adria consistent with that imparted to Adria by the interseismic stress gain prior to 2009 Adria microplate motion observed from Global Navigation Satellite Systems data slowed down by around 20% in the years preceding the 2009 L'Aquila earthquake The slowdown is larger than what permitted by data uncertainties or the impact of data noise, and is thus deemed tectonically meaningful The Adria motion slowdown requires a force upon Adria consistent with that imparted to Adria by the interseismic stress gain prior to 2009

IMPORTANCE: Availability of new disease-modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear whether this improvement also involves patients with pediatric-onset MS (POMS), whose early management is more challenging. OBJECTIVE: To evaluate changes in the prognosis of POMS over time in association with changes in therapeutic and managing standards. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, multicenter, observational study. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients. Inclusion criteria were MS onset before age 18 years, diagnosis before January 2014, and disease duration of at least 3 years. Exclusion criteria were primary progressive MS, Expanded Disability Status Scale (EDSS) score of at least 8 one year after onset, unavailability of diagnosis date, and less than 2 EDSS score evaluations. Eligible patients were 4704 patients with POMS. According to these criteria, we enrolled 3198 patients, excluding 1506. EXPOSURES: We compared time to reach disability milestones by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006, and 2007-2013), adjusting for possible confounders linked to EDSS evaluations and clinical disease activity. We then analyzed the difference among the 4 diagnosis epochs regarding demographic characteristics, clinical disease activity at onset, and DMTs management. MAIN OUTCOMES AND MEASURES: Disability milestones were EDSS score 4.0 and 6.0, confirmed in the following clinical evaluation and in the last available visit. RESULTS: We enrolled 3198 patients with POMS (mean age at onset, 15.2 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), with a mean (SD) follow-up of 21.8 (11.7) years. Median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46). In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time. CONCLUSIONS AND RELEVANCE: In POMS, the risk of persistent disability has been reduced by 50% to 70% in recent diagnosis epochs, probably owing to improvement in therapeutic and managing standards.

AbstractThe creation of genetic resource cryobanks provides a crucial link between in situand ex situtechniques to improve the efficiency of conservation programs. Aim of the present review is to describe all the activities developed for the implementation of the first Italian Semen Cryobank of Autochthonous Chicken and Turkey Breeds. These activities can be classified into three main topics: (1) identification of species-specific semen freezing/thawing reference procedures; (2) drafting Standard Operative Procedures (SOP) for the implementation of the semen cryobank; (3) storage of semen doses from Italian chicken and turkey breeds to establish the cryobank. Several trials have been developed to identify a specie-specific semen cryopreservation protocol for chickens and turkeys. The major results are reviewed and a final reference protocol described. Taking into consideration the FAO guidelines for cryoconservation of animal genetic resources, SOP were drafted with the aim to provide technical guidance and logistical support on the choice of priority breeds, selection of birds for semen production, infrastructures and storage sites, birds and semen management, cryopreservation process and doses traceability. Lastly, the Italian Semen Cryobank was created. A total of 112 semen doses from 22 cockerels of three breeds, and 74 doses from 12 turkey males of three breeds were stored in the Cryobank. Breed specific semen quality parameters assessed before and after cryopreservation are reported. The described activities provide information and tools useful for the implementation of semen cryobanking in avian species and might be transferred also to other species after appropriate adaptations.HIGHLIGHTSImplementation of the first Italian Semen Cryobank of Autochthonous Chicken and Turkey BreedsDrafting Standard Operative Procedures provides technical guidance and logistical support on the design and establishment of the cryobankSemen cryobank is a precious genetic reservoir and could be useful to safeguard genetic variability in small population in vivoconserved

This study has been designed to optimize the semen freezing protocol in rabbits, in this regard we compared a Tris-citrate-glucose (TCG) extender with a commercial one (Cortalap®), that to the best of our knowledge has never been used up to now on the in vitrofreezability and fertilizing ability of cryopreserved rabbit semen. Two different inseminating semen doses were considered. Five pooled semen samples were divided into two subsamples and each of them were diluted to a ratio 1:1 (v:v) with a freezing extender composed of TCG or Cortalap®containing 16% of dimethylsulfoxide and 0.1 mol/L of sucrose. The extended semen was filled into 0.25 mL plastic straws and frozen above a liquid nitrogen surface. After thawing (50°C/10 seconds) we determined sperm motility, viability, membrane functionality, acrosome and DNA integrity. Our results showed that the Cortalap®extender significantly improved the in vitropost-thaw sperm quality, in comparison to TCG. When we compared the extenders in vivo, no significant differences in the reproductive performances were observed independently by inseminating doses used. In this study we demonstrated that Cortalap®extender can be used as an alternative to TCG. Thus, the Cortalap®being a ready to use extender, implies a reduction of time, mistakes and microbial contaminations during its preparation. This discovery results as significant because it provides beyond an important contribution to the creation of the first Italian semen cryobank of rabbit breeds and also for livestock rabbit farms based on artificial insemination (AI) program.

IntroductionNatalizumab (NTZ) is one of the most effective treatment options for multiple sclerosis (MS) treatment. Our study aimed to evaluate the effectiveness of NTZ when administered according to the extended dosing strategy compared with standard 4-weekly administration in a large Italian MS population.Materials and methodsThis retrospective multicentre study included patients with relapsing-remitting MS (RR-MS) who received NTZ administrations between the 1 June 2012 and the 15 May 2018 and were followed by the ‘Italian MS Register’. All patients with MS were stratified into two groups based on NTZ administration schedule: standard interval dosing (SID) patients who received infusions on average from 28 to 32 days (median 30) and extended interval dosing (EID) including patients who have been infused with interval between 33 and 49 days (median 43). Clinical data were assessed at baseline (before starting NTZ), after 12 (T1) and 24 months (T2) of treatment.ResultsOut of 5231 patients with RR-MS screened, 2092 (mean age 43.2±12.0, 60.6% women) were enrolled. A total of 1254 (59.9%) received NTZ according to SID, and 838 (40.1%) according to EID. At 12 and 24 months, no differences in terms of annualised relapse rate and disability status were found between the two groups. Progression index and confirmed disability worsening were similar between the two groups.DiscussionThe use of NTZ with an extended interval schedule showed similar effectiveness compared with SID. Unchanged clinical efficacy of EID schedule may raise the question of a possible advantage in terms of tolerability and safety.

The Milanino is a heavy Italian chicken breed and represents an important genetic resource for alternative production systems. Due to the absence of standard management guidelines for local chicken breeds, this study aims to determine the space requirement to achieve a good equilibrium between growth performance and stress response in Milanino chickens reared according to a separate-sex free-range program. A total of 140 birds (70M:70F) were reared in outdoor pens from 75 to 235 d of life according to the following experimental groups (35 birds/group): (M2) males in 2 m2/bird; (F2) females in 2 m2/bird; (M10) males in 10 m2/bird; (F10) females in 10 m2/bird. Growth performance and stress condition were recorded. Bird density affected male body weight, that was higher at the lower density of 10 m2/bird. In contrast, females showed a consistent growth rate irrespective of the bird density suggesting lower space requirements. An overall good adaptability of the breed to the separate-sex free-range system was found, irrespective of both sex and bird density. Moreover, the stress markers values assessed at the end of the growing period suggest the ability of Milanino birds to respond well to environmental stressors. The results provided in this report will be implemented into free-range management guidelines for meat production in the Milanino breed: the separate-sex rearing is recommended during the growing period in outdoor pens and the bird density has to be planned according to the sex.

The Milanino is a heavy Italian chicken breed and represents an important genetic resource for alternative production systems. In order to support its promotion in the market according to consumer expectations on healthy nutrition and animal welfare, this trial aims to study the slaughter performance and the meat quality in male and female Milanino chickens kept at different rearing density in a separate-sex free-range system. A total of 140 birds (70M:70F) were reared in outdoor pens from 75 to 235 d of life according to the following experimental groups (35 birds/group): M2) males in 2 m2/bird; F2) females in 2 m2/bird; M10) males in 10 m2/bird; F10) females in 10 m2/bird. At 235 d of age, 6 birds per group were slaughtered. Slaughter performance and meat quality were assessed. The Milanino chicken is characterized by high carcass weight and carcass yield among local chicken breeds, and a rearing density of 10 m2/bird is recommended for male birds to obtain heavier carcasses. Milanino meat appears bright and intensely colored, and it is characterized by high protein and low fat contents compared with the standard broiler meat. Total lipids of Milanino meat are characterized by a healthy fatty acid composition, corresponding to a high PUFA/SFA ratio. Milanino breast meat is a good supply of nutraceutical PUFA with a positive low n-6/n-3 PUFA ratio. The ability of the Milanino breed either to synthesize or to transfer to tissue a high quantity of PUFA relevant for human health could be a key factor for its economic valorization.

Assessing the temporal evolution of stresses along seismogenic faults is typically done by combining geodetic observations collected near the locations of previous large earthquakes with modeling of the interseismic, coseismic, and postseismic deformation. Here we explore whether it is feasible to link the charge phase of large earthquakes to rigid microplate motions, which can be inferred from geodetic observations that are instead collected further away from crustal faults. We use numerical simulations of the dynamics and associated kinematics of an idealized, rigid microplate subject to stress buildups and drop‐offs from a series of earthquakes. Simulations span the charging cycle of a single 6.5

The Pacific Plate is thought to be driven mainly by slab pull, associated with subduction along the Aleutians‐Japan, Marianas‐Izu‐Bonin, and Tonga‐Kermadec trenches. This implies that viscous flow within the sub‐Pacific asthenosphere is mainly generated by overlying plate motion (i.e., Couette flow) and that the associated shear stresses at the lithosphere's base are resisting such motion. Recent studies on glacial isostatic adjustment and lithosphere dynamics provide tighter constraints on the viscosity and thickness of Earth's asthenosphere and, therefore, on the amount of shear stress that asthenosphere and lithosphere mutually exchange, by virtue of Newton's third law of motion. In light of these constraints, the notion that subduction is the main driver of present‐day Pacific Plate motion becomes somewhat unviable, as the pulling force that would be required by slabs exceeds the maximum available from their negative buoyancy. Here we use coupled global models of mantle and lithosphere dynamics to show that the sub‐Pacific asthenosphere features a significant component of pressure‐driven (i.e., Poiseuille) flow and that this has driven at least 50% of the Pacific Plate motion since, at least, 15 Ma. A corollary of our models is that a sublithospheric pressure difference as high as ±50 MPa is required across the Pacific domain. Constraints on the viscosity/thickness of the asthenosphere challenge the notion that subduction is the main driver of Pacific Plate motionWe use coupled global models of mantle and lithosphere dynamics to simulate the dynamics of the Pacific Plate since 15 MaResults indicate that a strong Poiseuille (i.e., pressure driven) component of asthenospheric flow drives >50% of the Pacific Plate motion

The timing and magnitude of a Pacific plate motion change within the past 10 Ma remains enigmatic, due to the noise associated with finite‐rotation data. Nonetheless, it has been hypothesized that this change was driven by the arrival of the Ontong Java Plateau (OJP) at the Melanesian arc and the consequent subduction polarity reversal. The uncertainties associated with the timing of this event, however, make it difficult to quantitatively demonstrate a dynamical association. Here, we first reconstruct the Pacific plate's absolute motion since the mid‐Miocene (15 Ma), at high‐temporal resolution, building on previous efforts to mitigate the impact of finite‐rotation data noise. We find that the largest change in Pacific plate‐motion direction occurred between 10 and 5 Ma, with the plate rotating clockwise. We subsequently develop and use coupled global numerical models of the mantle/lithosphere system to test hypotheses on the dynamics driving this change. These indicate that the arrival of the OJP at the Melanesian arc, between 10 and 5 Ma, followed by a subduction polarity reversal that marked the initiation of subduction of the Australian plate underneath the Pacific realm, were the key drivers of this kinematic change. Noise‐reduced reconstructions of the Pacific plate's absolute motion since 15 Ma indicate significant Euler pole wander between 10 and 5 MaWe develop coupled global models of mantle and lithosphere dynamics to examine the dynamics underpinning this plate motion changeThe Ontong Java Plateau's arrival at the Melanesian arc and a consequent subduction polarity reversal were the key drivers of this change

Mantle plumes are buoyant upwellings of hot rock that transport heat from Earth’s core to its surface, generating anomalous regions of volcanism that are not directly associated with plate tectonic processes. The best-studied example is the Hawaiian–Emperor chain, but the emergence of two sub-parallel volcanic tracks along this chain, Loa and Kea, and the systematic geochemical differences between them have remained unexplained. Here we argue that the emergence of these tracks coincides with the appearance of other double volcanic tracks on the Pacific plate and a recent azimuthal change in the motion of the plate. We propose a three-part model that explains the evolution of Hawaiian double-track volcanism: first, mantle flow beneath the rapidly moving Pacific plate strongly tilts the Hawaiian plume and leads to lateral separation between high- and low-pressure melt source regions; second, the recent azimuthal change in Pacific plate motion exposes high- and low-pressure melt products as geographically distinct volcanoes, explaining the simultaneous emergence of double-track volcanism across the Pacific; and finally, secondary pyroxenite, which is formed as eclogite melt reacts with peridotite, dominates the low-pressure melt region beneath Loa-track volcanism, yielding the systematic geochemical differences observed between Loa- and Kea-type lavas. Our results imply that the formation of double-track volcanism is transitory and can be used to identify and place temporal bounds on plate-motion changes.

The complexity of multiple sclerosis (MS) treatment means that doctors and decision-makers need the best available evidence to make the best decisions for patient care. Randomized controlled trials (RCTs) are accepted as the gold standard for assessing the efficacy and safety of any new drug, but conclusions of these trials do not always aid in daily decision-making processes. Indeed, RCTs are usually conducted in ideal conditions, so can measure efficacy only in restricted and unrepresentative populations. In the past decade, a growing number of MS databases and registries have started to produce long-term outcome data from large cohorts of patients with MS treated with disease-modifying therapies in real-world settings. Such observational studies are addressing issues that are otherwise difficult or impossible to study. In this Review, we focus on the most recently published observational studies designed to identify predictors of poor outcome and treatment response or failure, and to evaluate the relative and long-term effectiveness of currently used MS treatments. We also outline the statistical approaches that are most commonly used to reduce bias and limitations in these studies, and the challenges associated with the use of 'big MS data' to facilitate the implementation of personalized medicine in MS.

The recovery, safeguarding, and valorization of autochthonous poultry breeds may contribute toward the preservation of animal biodiversity and utilization of marginal lands that otherwise offer little agricultural or industrial value. A key strategy in promoting local breeds involves the characterization of morphological traits and productive performances, which are influenced by the breed's genetic make-up as well as its environment. The Mugellese breed is an Italian local poultry breed originating in the Mugello area of north-east Tuscany. It is characterized by frugality, resilience and resistance to disease, cold, and heat stress. Moreover, these birds are particularly suitable for free-range farming. The Mugellese chicken is described as a dwarf breed with a medium neck, broad shoulders, fairly long and horizontal wings, wide, and well-developed breast (especially in the hen). Over the course of a 1-yr observation and data collection period, involving 23 breeders and 405 adult chickens, the Mugellese breed showed the following performances: 1) a hen-day egg production characterized by 2 major peaks: the first in the spring time (March–April, 65.75%), and the second in the late summer period (August–September, 51.86%); 2) high true fertility values (94.35%) throughout the entire breeding season; 3) a weight gain of 732.44 ± 117.06 g and a feed conversion ratio of 3.94 ± 2.42 at an age of 140 d; 4) a slaughter yield of 77.80% (± 3.91); v) a respective protein, fat, and mineral content in the yolk and albumen were: 27.21 ± 4.21 g, 57.77 ± 1.03 g and 3.47 ± 0.40 g per 100 g of yolk; and 82.50 ± 0.57 g, 0.12 ± 0.01 g and 5.43 ± 0.34 g per 100 g of albumen. More data are needed to validate the data obtained in this trial.

F095Allogeneic, donor-derived CD19-CAR T cells can be readily generated for the treatment of pediatric patients with relapsed/refractory BCP-ALLF095Allogeneic CD19-CAR T cells are effective and, compared to autologous CAR, they neither increase toxicity, nor induce high GvHD incidence

This review updates the current state of technologies available for turkey semen storage (hypothermic- liquid storage and cryopreservation), with special attention paid to cryopreservation. Liquid semen can be stored for up to 24 or 48 h at temperatures around 5°C, while cryopreservation allows long-term storage at -196°C. The possibility of using frozen turkey semen for artificial insemination (AI) would have practical benefits for turkey production. Reported fertility rates in response to AI using frozen/thawed semen range from 15.8 to 84.3%. Unsatisfactory fertility may be attributed to an inability of turkey spermatozoa to successfully survive the freezing/thawing process, and this, along with the high variability observed, makes this technique unacceptable for commercial breeding programs. There is therefore a need to standardize the whole freezing and thawing process to improve the post-thaw quality of turkey semen and minimize variability in results. Finding an efficient freezing protocol for turkey semen will allow for the creation of a sperm cryobank, improving current prospects for the commercial use of frozen turkey semen and also for the long-term conservation of the genetic diversity of this bird.