Coherent and Dissipative Coupling in a Magnetomechanical System.

Hybrid elastic and spin waves hold promises for energy-efficient and versatile generation and detection of magnetic signals, with potentially long coherence times. Here we report on the combined elastic and magnetic dynamics in a one-dimensional magnetomechanical crystal composed of an array of magnetic nanostripes. Phononic and magnonic modes are impulsively excited by an optical ultrafast trigger and their decay is monitored by time-resolved magneto-optical Kerr effect. Complementary Brillouin light scattering measurements and micromagnetic simulations concur in a unified picture, in which the strength and degree of mixing of coherent and dissipative coupling of the quasiparticles are determined quantitatively.

Identifying internalizing transdiagnostic profiles through motivational and cognitive control systems: Relations with symptoms, functionality, and quality of life.

BACKGROUND: The diversity of patients' symptomatology among people seeking treatment on community-based mental health services poses significant challenges to traditional models of care. Recent approaches favor identifying transdiagnostic factors that allow a better understanding of patient heterogeneity and designing more effective and quality interventions. This study examines the heterogeneity of patients with internalizing symptoms based on profiles identified with cognitive and motivational control variables. Differences between these profiles on dimensional measures of psychopathology and quality of life are examined. METHODS: 263 patients were selected by non-probabilistic sampling procedures on mental health services in the province of Huelva (Spain). A latent class analysis on the standardized scale scores of The Behavioral Inhibition/Behavioral Activation System Scales and the Effortful Control Scale of the Adult Temperament Questionnaire Short-Form was conducted. Profiles were compared on the scores of the Inventory of Depression and Anxiety Symptoms-II, the WHO Disability Assessment Schedule II, and the Health Assessment Questionnaire SF-36. RESULTS: The four latent profile solution is the one that showed the best fit indicators and substantive interpretability, with a kappa of 0.94 in the cross-validation procedure with 75% of the sample. No sex differences were found between the profiles (χ32 5.17, p = .160). Profiles #1 and #3, both characterized by an imbalance between low activation and high inhibition, had lower well-being, lower functionality, and quality of life. When comparing profile #2 (featuring the highest inhibitory control) lower scores on most internalizing scales are observed, specially claustrophobia, social anxiety, panic mania. Profile #4 (low control, high activation, and high inhibition) showed greater scores on both mania and euphoria and lower scores on emotional role. CONCLUSIONS: We identified four distinctive profiles that had overly increased behavioral inhibition (as expected in internalizing disorders) and differed in the degree of imbalance between inhibition and activation systems, and between motivational systems and top-down cognitive control. The profile characterized by high activation and reduced cognitive (inhibitory) control was the one showing greater mood-related symptoms and lower levels of quality of life. These profiles could be generated by treatment providers to guide clinical management in an evidence-based manner.

Improved overall survival in patients developing endocrine toxicity during treatment with nivolumab for advanced non-small cell lung cancer in a prospective study.

PURPOSE: Immune checkpoint inhibitors (ICPIs) disrupting PD-1/PD-L1 axis have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Some studies identified the development of endocrine toxicity as predictor of better survival in cancer patients treated with ICPIs. The aim of study was to evaluate survival and new onset of immune-related endocrine adverse events (irAEs) in patients treated with nivolumab for advanced NSCLC. METHODS: In a prospective study, 73 patients with previously treated advanced NSCLC received nivolumab in monotherapy. Blood samples were collected at each cycle to monitor thyroid autoimmunity, thyroid, adrenal and somatotroph axes, while thyroid morphology was evaluated by ultrasonography. RESULTS: An impaired thyroid function was recorded in 23.4% of patients (n = 15). Eight patients developed asymptomatic transient thyrotoxicosis (ATT) evolving to hypothyroidism in 50% of cases. In addition, seven patients developed overt hypothyroidism without ATT and with negative autoantibodies. Patients who developed hypothyroidism proved to have better overall survival (OS) as compared with non-developers at both univariate (p = 0.021) and multivariate analyses (p = 0.023). The survival curve of patients with reduced IGF-I at baseline, or displaying its reduction during the follow-up, showed significantly reduced median survival compared to patients with normal/high IGF-I levels (p = 0.031). CONCLUSIONS: Thyroid function abnormalities are the major irAEs in patients treated with nivolumab, and hypothyroidism onset is associated with prolonged survival. Our findings indicate that the development of hypothyroidism is a positive predictive biomarker of nivolumab antitumor efficacy in patients with NSCLC. Low IGF-I levels could represent a negative prognostic factor during nivolumab therapy.

An investigation into the potential for upward range expansion in high-montane species on the roof of the world.

Climate warming is occurring in high-mountain areas at a faster rate than the global average. To escape the increasing temperatures, alpine species may shift in distribution upwards, threatening cold-adapted nival plant specialists. However, little is known about the success of seedling emergence and establishment at high altitudes outside the current range, particularly in the highest mountain areas of the Himalayas. We selected four native alpine species occurring around 4000 m a.s.l. and sowed seeds at the natural growing site (GS), at a high elevation site (HS; 5000 m a.s.l.) and at high elevation with soil from the growing site (HS-S) in the Khumbu Valley, north-eastern Nepal. We monitored seedling emergence and establishment for two consecutive years. Seedling emergence and establishment varied between species. Emergence was similar between GS and HS and improved at HS-S. Establishment was low at high elevations with all but one species having high mortality after winter. Seedling emergence of low elevation plants is possible at high elevations in the Everest region, indicating species may be able to shift their distribution range upwards. However, successful establishment may be limited by the soil and high winter mortality at high elevations, although not in all species. Climate warming will potentially lead to upward migration of some Himalayan plant species, leading to altered community composition in high-mountain areas.

Age-Neutral Measurement Of Personality Functioning and Maladaptive Personality Traits.

As previous studies have shown that personality disorder (PD) assessment in older adults is often hampered because assessment tools are tailored toward younger adults, establishing the age-neutrality of novel tools is crucial. This study primarily aimed to evaluate the age-neutrality of the Level of Personality Functioning Brief Form (LPFS-BF 2.0) and the Personality Inventory for DSM-5 Modified + (PID-5-BF+M), using a sample of 254 community-dwelling adults. The analysis of Differential Item Functioning (DIF) demonstrated the age-neutrality of both instruments, with only 8.3% of LPFS-BF 2.0 items and 5.6% of PID-5-BF+M items exhibiting DIF. Differential Test Functioning (DTF) analyses revealed large DTF for the LPFS-BF 2.0 total score, indicating that age-specific norms might be necessary for this score. In summary, this study supports the use of these instruments in both older and younger adults, enhancing the assessment of PDs across the life span.

Dynamic optical coherence tomography evaluation in locally advanced basal cell carcinoma during sonidegib treatment.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in the Caucasian population. It has a multifactorial pathogenesis, in which constitutive activation of the Sonic Hedgehog signalling (SHH) pathway (via mutations in PTCH1 or SMO genes) represents by far the most common genetic aberration. The introduction of vismodegib and sonidegib, two SHH pathway inhibitors, changed the therapeutic approach of locally advanced and metastatic BCCs. EADO's (European Association of Dermato-Oncology) new staging system refers to these as 'difficult-to-treat' BCCs. OBJECTIVE: The aim was to evaluate sonidegib's effectiveness in patients affected by difficult-to-treat BCCs by using non-invasive diagnostic techniques. METHODS: We retrospectively evaluated 14 patients (4 females, 10 males; mean age 77 ± 11 years) affected by difficult-to-treat BCCs treated with oral sonidegib 200 mg/day that were followed with total body videodermoscopy (V-Track, Vidix 4.0) and dynamic optical coherence tomography (D-OCT, VivoSight Dx) since May 2022. Considering the risk of rhabdomyolysis routine blood tests, especially for creatine kinase concentrations, were performed. All treated patients were inserted in the BasoCare database, which aims to offer support to patients taking sonidegib. Complete and partial responses were evaluated by the overall reduction of the number of lesions and their individual sizes. Safety was evaluated by assessing the occurrence and severity of adverse reactions. RESULTS: Eighty per cent achieved complete clearance and 75% reduction of diameter. D-OCT scans performed at every follow-up showed concordance with clinical appearance and demonstrated reduction of hyporeflective structures, that is, islets of tumour cells and overall improvement of morphology. CONCLUSION: Sonidegib can be considered an effective treatment option in cases where surgery or radiotherapy would be unfeasible or has previously failed, although pigmented lesions did not show complete clearance, suggesting that there are factors other than the SHH pathway involved in tumour growth. Videodermoscopy and D-OCT were useful in the quick and seamless follow-up of lesions and added valuable information in assessing efficacy.

Unveiling the Electronic Structure of Pseudotetragonal WO3 Thin Films.

WO3 is a 5d compound that undergoes several structural transitions in its bulk form. Its versatility is well-documented, with a wide range of applications, such as flexopiezoelectricity, electrochromism, gating-induced phase transitions, and its ability to improve the performance of Li-based batteries. The synthesis of WO3 thin films holds promise in stabilizing electronic phases for practical applications. However, despite its potential, the electronic structure of this material remains experimentally unexplored. Furthermore, its thermal instability limits its use in certain technological devices. Here, we employ tensile strain to stabilize WO3 thin films, which we call the pseudotetragonal phase, and investigate its electronic structure using a combination of photoelectron spectroscopy and density functional theory calculations. This study reveals the Fermiology of the system, notably identifying significant energy splittings between different orbital manifolds arising from atomic distortions. These splittings, along with the system's thermal stability, offer a potential avenue for controlling inter- and intraband scattering for electronic applications.

Dual pulsed laser deposition system for the growth of complex materials and heterostructures.

Here, we present an integrated ultra-high-vacuum (UHV) apparatus for the growth of complex materials and heterostructures. The specific growth technique is the Pulsed Laser Deposition (PLD) by means of a dual-laser source based on an excimer KrF ultraviolet and solid-state Nd:YAG infra-red lasers. By taking advantage of the two laser sources-both lasers can be independently used within the deposition chambers-a large number of different materials-ranging from oxides to metals, to selenides, and others-can be successfully grown in the form of thin films and heterostructures. All of the samples can be in situ transferred between the deposition chambers and the analysis chambers by using vessels and holders' manipulators. The apparatus also offers the possibility to transfer samples to remote instrumentation under UHV conditions by means of commercially available UHV-suitcases. The dual-PLD operates for in-house research as well as user facility in combination with the Advanced Photo-electric Effect beamline at the Elettra synchrotron radiation facility in Trieste and allows synchrotron-based photo-emission as well as x-ray absorption experiments on pristine films and heterostructures.

Primary Aldosteronism and Drug Resistant Hypertension: A "Chicken-Egg" Story.

Drug-resistant arterial hypertension (RH) is a major risk factor for cardiovascular disease, often due to overlooked underlying causes. Identification of such causes poses significant clinical challenges. In this setting, primary aldosteronism (PA) is a frequent cause of RH and its prevalence in RH patients is likely higher than 20%.The pathophysiological link between PA and the development and maintenance of RH involves target organ damage and the cellular and extracellular effects of aldosterone excess that promote pro-inflammatory and pro-fibrotic changes in the kidney and vasculature.The feasibility of adrenal vein sampling in PA patients with RH, and the clinical benefit achieved by adrenalectomy, further emphasize the need to implement systematic screening for this common form of secondary hypertension in the management of a high-risk population as RH patients.: We herein review the current knowledge of the factors that contribute to the RH phenotype with a focus on PA and discuss the issues regarding the screening for PA in this setting and the therapeutic approaches (surgical and medical) aimed at resolving RH caused by PA.

The role of Zn ions in the interaction between SARS-CoV-2 orf7a protein and BST2/tetherin.

In this paper, we provide evidence that Zn 2 + ions play a role in the SARS-CoV-2 virus strategy to escape the immune response mediated by the BST2-tetherin host protein. This conclusion is based on sequence analysis and molecular dynamics simulations as well as X-ray absorption experiments [1].

Neuromuscular and cardiac adverse events associated with immune checkpoint inhibitors: pooled analysis of individual cases from multiple institutions and literature.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs. PATIENTS AND METHODS: We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor. RESULTS: This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070). CONCLUSIONS: To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment.

A dense ring of the trans-Neptunian object Quaoar outside its Roche limit.

Planetary rings are observed not only around giant planets1, but also around small bodies such as the Centaur Chariklo2 and the dwarf planet Haumea3. Up to now, all known dense rings were located close enough to their parent bodies, being inside the Roche limit, where tidal forces prevent material with reasonable densities from aggregating into a satellite. Here we report observations of an inhomogeneous ring around the trans-Neptunian body (50000) Quaoar. This trans-Neptunian object has an estimated radius4 of 555 km and possesses a roughly 80-km satellite5 (Weywot) that orbits at 24 Quaoar radii6,7. The detected ring orbits at 7.4 radii from the central body, which is well outside Quaoar's classical Roche limit, thus indicating that this limit does not always determine where ring material can survive. Our local collisional simulations show that elastic collisions, based on laboratory experiments8, can maintain a ring far away from the body. Moreover, Quaoar's ring orbits close to the 1/3 spin-orbit resonance9 with Quaoar, a property shared by Chariklo's2,10,11 and Haumea's3 rings, suggesting that this resonance plays a key role in ring confinement for small bodies.

Comparison between azacitidine and decitabine as front-line therapy in elderly acute myeloid leukemia patients not eligible for intensive chemotherapy.

We compared the efficacy of azacitidine (AZA) and decitabine (DEC) in elderly patients with untreated AML, diagnosed according to WHO criteria. In the two groups, we evaluated complete remission (CR), overall survival (OS) and disease free survival (DFS). The AZA and DEC groups included 139 and 186 patients, respectively. To minimize the effects of treatment selection bias, adjustments were made using the propensity-score matching method, which yielded 136 patient pairs. In the AZA and DEC cohort, median age was 75 years in both, (IQR, 71-78 and 71-77), median WBCc at treatment onset 2.5 × 109/L (IQR, 1.6-5.8) and 2.9 × 109/L (IQR, 1.5-8.1), median bone marrow (BM) blast count 30% (IQR, 24-41%) and 49% (IQR, 30-67%), 59 (43%) and 63 (46%) patients had a secondary AML, respectively. Karyotype was evaluable in 115 and 120 patients: 80 (59%) and 87 (64%) had intermediate-risk, 35 (26%) and 33 (24%) an adverse risk karyotype, respectively. Median number of cycles delivered was 6 (IQR, 3.0-11.0) and 4 (IQR, 2.0-9.0), CR rate was 24% vs 29%, median OS and 2-year OS rates 11.3 (95% CI 9.5-13.8) vs 12.0 (95% CI 7.1-16.5) months and 20% vs 24%, respectively. No differences in CR and OS were found within the following subgroup: intermediate- and adverse-risk cytogenetic, frequency of WBCc at treatment ≥ 5 × 10^9 L and < 5 × 10^9/L, de novo and secondary AML, BM blast count < and ≥ 30%. Median DFS for AZA and DEC treated patients was 9.2 vs 12 months, respectively. Our analysis indicates similar outcomes with AZA compared to DEC.

Assessing Internalizing Symptoms and Their Relation with Levels of Impairment: Evidence-Based Cutoffs for Interpreting Inventory of Depression and Anxiety Symptoms (IDAS-II) Scores.

Tests and scales measuring psychological disorders should provide information about how scores relate to other constructs such as quality of life or functional impairment. Such information is necessary to allow that their scores contribute to clinical decision making. The current study analyzes the clinical utility of the Spanish version of the Inventory for Depression and Anxiety Symptoms (IDAS-II) to discriminate between different levels of functional impairment and identify the IDAS-II scales that contribute most to explaining impairment. The total sample (N = 1390) consists of two subsamples: a community sample of the general population (n = 1072) selected by random sampling; and a sample of patients (n = 318) from public and private mental health services. The Spanish IDAS-II for measuring internalizing symptoms and WHODAS 2.0 for measuring impairment were administered to all participants. All scales show statistically significant higher scores in the patient sample, with Cohen's d effect sizes values greater than 0.30, except for well-being (d = 0.19). The cutoff values and their confidence intervals do not overlap with the means of either the community or patient sample. AUC values for most of the scales are above .70, except for appetite gain, ordering, euphoria, cleaning, and well-being. Multiple linear regression model using IDAS-II scales explain 57.1% of the variance of the WHODAS 2.0 (F 12.1377 = 155.305; p < .001). Cutoff values provided allow us to reliably differentiate between the patients and community samples. Spanish IDAS-II scores show greater sensitivity and specificity in detecting those with greater impairment. General Depression, Lassitude, Panic and Claustrophobia contribute to impairment in a greater extent. Knowledge of which symptoms are most related with impairment, allows healthcare providers to improve treatment planning based on empirical evidence.

Multidetection scheme for transient-grating-based spectroscopy.

Time-resolved optical spectroscopy represents an effective non-invasive approach to investigate the interplay of different degrees of freedom, which plays a key role in the development of novel functional materials. Here, we present magneto-acoustic data on Ni thin films on SiO2 as obtained by a versatile pump-probe setup that combines transient grating spectroscopy with time-resolved magnetic polarimetry. The possibility to easily switch from a pulsed to continuous wave probe allows probing of acoustic and magnetization dynamics on a broad time scale, in both transmission and reflection geometry.

Serum levels of autoantibodies against the angiotensin II type I receptor are not associated with serum dicarbonyl or AGE levels in patients with an aldosterone-producing adenoma.

Patients with an aldosterone-producing adenoma (APA) carry a higher risk of cardiovascular disease and commonly have high levels of autoantibodies (AT1AA) that may activate the angiotensin II type 1 receptor (AT1R). AT1R activation is linked to an increase of the glucose metabolite methylglyoxal (MGO), a potential precursor of advanced glycation endproducts (AGEs) and driver of vascular inflammation. We investigated whether serum AT1AA levels are associated with serum MGO and AGE levels in APA patients. In a case series of 26 patients with APA we measured levels of dicarbonyls MGO, glyoxal (GO) and 3-deoxyglucosone (3-DG), and dicarbonyl-derived AGEs 5-hydro-5-methylimidazolone (MG-H1), Nε-(carboxyethyl)lysine (CEL) and Nε-(carboxymethyl)lysine (CML) with UPLC-MS/MS. We also measured AT1AA by ELISA. These measurements were repeated 1-month after adrenalectomy in a subset of 14 patients. Panels of inflammation and endothelial function were also measured by immunoassays. Although baseline higher AT1AA levels tended to be correlated with higher baseline serum MGO, GO and 3-DG levels (r = 0.18, p = 0.38; r = 0.20, p = 0.33; r = 0.23, p = 0.26; respectively), these correlations were not statistically significant. We observed no obvious correlations between higher AT1AA levels and protein-bound and free MG-H1, CEL and CML levels, and markers of inflammation and endothelial function. No decrease was observed in any of the dicarbonyls, protein-bound AGE levels and markers of inflammation and endothelial function after adrenalectomy. In patients with APA the serum levels of AT1AA were not significantly correlated with serum dicarbonyls, protein-bound and free AGE levels. Increased signalling of the AT1AA receptor may therefore be unlikely to overtly increase systemic dicarbonyl levels.

Effect of follicular wave stage on potential fertility predictors and their repeatability coefficient in prepubertal Bos indicus (Nellore) and Bos taurus (Caracu) heifers.

In an attempt to develop accessible methods for the precocious individual selection based on phenotypic attributes related to reproductive superiority, this study evaluated the effects of follicular wave stages (emergence and dominance) and the repeatability coefficients of potential fertility predictors (vulvar morphometry, uterine biometry, echogenicity and echotexture, ovarian biometry, and antral follicle count - AFC) in two breeds of purebred prepubertal heifers. Nellore (n = 30) and Caracu (n = 28) heifers were submitted to a sequence of 11 evaluations conducted every 48 h (D0 - random day of the antral follicular wave until D20) to study potential fertility indicators under natural conditions. The data obtained were compared according to breed and follicular wave stage. Statistical analysis included the fixed effects of breed, evaluation day, and their statistical interaction and was performed using MIXED, GENMOD, GLM, and CORR procedures of the SAS program. Breed was found to influence rima height, ovarian area, and AFC, which were greater in Nellore heifers (P < 0.02). The follicular wave stage also influenced most of the potential predictors, highlighting AFC which was higher in the presence of a dominant follicle in both breeds (P < 0.0001). The repeatability coefficients for vulvar width (0.76 and 0.66), ovarian area (0.70 and 0.62), and AFC (0.76 and 0.74) were considered to be high in Nellore and Caracu heifers, respectively. Only ovarian biometry was able to predict AFC (Pearson correlation coefficient ≥ 0.66; P < 0.0001) in prepubertal heifers. The results indicate that most of the phenotypic reproductive parameters analyzed can be characterized throughout prepuberty using a single measure since they are intrinsic attributes of the individual.

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.