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In this manuscript, we consider well-known multi-task learning (MTL) models from the literature for linear regression problems, such as clustered MTL or weakly constrained MTL. We propose novel reformulations of the training problem for these models, based on mixed-integer quadratic programming (MIQP) techniques. We show that our approach allows to drive the optimization process up to certified global optimality, exploiting popular off-the-shelf software solvers. By computational experiments on both synthetic and real-world datasets, we show that this strategy generally leads to improvements in terms of the predictive performance of the models, if compared to the classical local optimization techniques, based on alternating minimization strategies, that are usually employed. We also suggest a number of possible extensions of our model that should further improve the quality of the obtained regressors, introducing, for example, sparsity and features selection elements.

Local and global anthropogenic pressures due to climate change and to local uses and activities are exerting significant cumulative impacts to greater extents of the oceans and seas. Coastal ecosystems are particularly threatened by the intensity and coexistence of several marine uses and pressures, including sewage and urban constructions, tourism, ship traffic, fisheries and aquaculture. Assessment of pressures and the identification of mitigation measures are key urgent actions, as already highlighted by the EU Marine Strategy Framework Directive and the United Nations Sustainable Development Goal 14. The aim of this work, developed within the Interreg-Med project SHAREMED, is to systematize existing knowledge on threats and pollution, including those of transboundary origin, for long term strategies and common action marine spatial planning, jointly developed with stakeholders. The quest is to assess coexisting environmental threats, and their propagation in space and time, at proper spatial and temporal scales, according to the type and action of each stressor (i.e. global vs. local). Cumulative pressures are tackled within a dedicated Atlas comprising three sub-basinsins of the Mediterranean Sea: the North Adriatic Sea, the Sicilian Channel and the North-Western region. The Atlas integrates information generated at the best available resolutions by 1) in-situ sampling, 2) remote observations, 3) numerical models, and 4) focusing on target ecosystems and habitat forming species. These sub-basins are subjected to multiple local and larger scale (e.g. climate) pressures that propagate in space and time, and across political boundaries, that need to be addressed through coordinated actions, based on evidence-rooted common understanding., peer-reviewed

In this paper we consider multi-objective optimization problems over a box. The problem is very relevant and several computational approaches have been proposed in the literature. They broadly fall into two main classes: evolutionary methods, which are usually very good at exploring the feasible region and retrieving good solutions even in the nonconvex case, and descent methods, which excel in efficiently approximating good quality solutions. In this paper, first we confirm, through numerical experiments, the advantages and disadvantages of these approaches. Then we propose a new method which combines the good features of both. The resulting algorithm, which we call Non-dominated Sorting Memetic Algorithm (NSMA), besides enjoying interesting theoretical properties, excels in all of the numerical tests we performed on several, widely employed, test functions., Comment: 30 pages, 8 figures

In addition to its well-established immunosuppressive actions, tryptophan 2,3-dioxygenase (TDO) appears to elicit direct effects on tumor cell function. Although TDO has been associated with cancer stemness, its involvement in melanoma stem cell biology remains largely unknown. Since we showed that by upregulating TDO, dexamethasone (dex) promotes proliferation and migration of SK-Mel-28 human melanoma cells, we sought to investigate dex effects on melanoma spherogenesis and stemness, and whether these events are mediated by TDO. We demonstrate here that dex significantly upregulates TDO in A375, a more aggressive melanoma cell line, confirming that dex effects are not limited to SK-Mel-28 cells. Moreover, dex stimulates spherogenesis of both cell lines, which is mediated by TDO, evident by its suppression with 680C91, a TDO inhibitor. The formed melanospheres appear to be enriched with embryonic stem cell marker mRNAs, the expression of which is potentiated by dex. Expression of cancer stem cell markers (CD133, CD44, ganglioside GD2) was significantly increased in A375 spheres, as detected by flow cytometry. Taken together, our results suggest that TDO could represent a promising target in the management of melanoma and that dex, routinely used as a co-medication also in advanced melanoma, may stimulate melanoma cell function/tumor-supporting properties, a rather debilitating and undesired side effect. This work was supported by grants from the University of Florence (RICATEN, Research funding UNIFI) to AP and from Tuscany Region Health Project 2018 (Bando Ricerca Salute 2018–ANTI NCT) to AC. Open Access funding provided by Qatar National Library.

Five-year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA-sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease-free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer-related genes (n = 14) and cancer-unrelated genes (n = 16). Three out of four down-regulated genes were cancer-related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.

Background In multiple sclerosis, the correlation between white matter lesion volumes (LV) and expanded disability status scale (EDSS) is at best moderate, leading to the “clinico-radiological paradox”, influenced by many factors, including the lack of information on the spatial localisation of each lesion on synthetic metrics such as LV. We used a probabilistic approach to provide the volume of WM tracts that may be disconnected by lesions and to evaluate its correlation with EDSS. Methods Forty-five patients (aged 37.4 ± 6.8 years, mean ± standard deviation; 30 females; 29 relapsing-remitting, 16 progressive) underwent 3-T magnetic resonance imaging. Both LV and the volume of the tracts crossing the lesioned regions (disconnectome volume, DV) were calculated using BCBtoolkit and correlated with EDSS. Results T1-weighted LV and DV significantly correlated with EDSS (p ≤ 0.006 r ≥ 0.413) as it was for T2-weighted LV and T2-weighted DV (p ≤ 0.004 r ≥ 0.430), but only T1-weighetd and T2-weighted DVs were EDSS significant predictors (p ≤ 0.001). The correlations of T1-weighted and T2-weighted LV with EDSS were significantly mediated by DV, while no effect of LV on the EDSS-DV correlation was observed. Conclusion The volume of disconnected WM bundles mediates the LV-EDSS correlation, representing the lonely EDSS predictor.

The seismic events that hit central Italy in 2016, causing extensive damage to cultural heritage and the loss of entire villages, showed the extreme fragility of the Marche territorial system with strong repercussions on the economic and social development. In the historic villages, the high inherent seismic vulnerability of the building makes it difficult to apply regulations oriented to the protection and preservation of historical and cultural values: strategies for the recovery of the buildings seem very complex. The historical building is generally characterized by a high building density, a scarcity of urban voids and an articulated accessibility system. In recent years the Marche region has developed, due to the intensification of earthquakes, a particular susceptibility to seismic risk. The historic centres have shown a scarce capability to adaptation and difficulties in hypothesizing new scenarios after the damage. In this context, we want to define an analytical method of the systemic vulnerability in the historical centres; this vulnerability is considered as a result of the complex interaction of individual structural units, aggregates and urban spaces. The aim is to compare this vulnerability with the effects that the earthquake really had on the buildings: the knowledge of the real behaviour in the historic centres will guide the research towards the definition of actions aimed at the mitigation of the seismic risk through the reduction of intrinsic vulnerabilities in the building and the implementation of the capability to face the earthquake, in order to develop a “new resilience”. The district of Camerino is taken as a case study; it’s a territorial hub of services and activities as well as being one of the largest inhabited centres affected by the 2016-2017 earthquake.

The present pilot study investigates whether an abnormal miRNA profile in NIPT plasma samples can explain the finding of a low cell-free DNA (cfDNA) fetal fraction (cfDNAff) in euploid fetuses and non-obese women. Twelve women who underwent neoBona® NIPT with a normal fetal karyotype were studied. Six with a cfDNAff &lt, 4% were matched with a control group with normal levels of cfDNAff &gt, 4%. Samples were processed using the nanostring nCounter® platform with a panel of 800 miRNAs. Four of the maternal miRNAs, miR-579, miR-612, miR-3144 and miR-6721, had a significant abnormal expression in patients. A data filtering analysis showed that miR-579, miR-612, miR-3144 and miR-6721 targeted 169, 1, 48 and 136 placenta-specific genes, respectively. miR-579, miR-3144 and miR-6721 shared placenta-specific targeted genes involved in trophoblast invasion and migration pathways (IGF2R, PTCD2, SATB2, PLAC8). Moreover, the miRNA target genes encoded proteins localized in the placenta and involved in the pathogenesis of pre-eclampsia, including chorion-specific transcription factor GCMa, PRG2, Lin-28 Homolog B and IGFBP1. In conclusion, aberrant maternal miRNA expression in circulating plasma could be a source of dysregulating trophoblast invasion and migration and could represent a novel cause of a low cfDNAff in the sera of pregnant women at the time of NIPT analysis.

Background: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available. Objective: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test. Methods: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model. Results: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was significantly associated with a reduced probability of developing antibodies after COVID-19 (odds ratio (OR) = 0.20, p = 0.002). Conclusion: Patients with MS maintain the capacity to develop humoral immune response against SARS-COV-2, although to a lesser extent when treated with anti-CD20 drugs. Overall, our results are reassuring with respect to the possibility to achieve sufficient immunization with vaccination.

Background: It is unclear how multiple sclerosis (MS) affects the severity of Covid-19. Methods: Hospitalization, Intensive Care Unit (ICU) admission and death after Covid-19 diagnosis of 1362 MS patients were compared to the age and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher-risk: EDSS>3 or at least one comorbidity, lower-risk: EDSS

Background: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. Methods: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression. Findings: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128–317), p < 0·001), fingolimod (26-fold decrease (95%CI=16–42), p < 0·001) and rituximab (20-fold decrease (95%CI=10–43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46–4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days). Interpretation: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. Funding: FISM[2021/Special-Multi/001]; Italian Ministry of Health‘Progetto Z844A 5 × 1000′.

The tragic seismic events developed in the inland areas of the Marche Region, have brought out, more clearly, phenomena that were already underway for some decades: depopulation and abandonment, economic decline and consequent construction degradation. In the case of some urban settlement within the seismic zone, we witness a scenario of almost total devastation, which requires not only a reconstruction but a real new foundation. For the re-foundation of Apennine historic centers devastated by the earthquake, it is possible to assume new interpretative paradigms, starting from the public spaces, that are space of connection and aggregation. It is analyzed the main square in the historic center of Treia, a small nucleus in the inland area of the Marche Region, to verify a project strategy, which focuses on that public space.

Purpose We evaluated a series of fellow eyes (FEs) in patients affected by unilateral idiopathic epiretinal membrane (IERM) with spectral-domain optical coherence tomography (SD-OCT) and OCT angiography (OCT-A) to determine if a previous defect in the inner retina is present before the mechanical damage to the inner limiting membrane (ILM) caused by posterior vitreous detachment. Methods In patients with IERM (N = 39), ganglion cell layer (GCL) thickness in FEs was assessed with SD-OCT; in a subgroup (N = 25) the vessel density (VD) at the superficial (SCP) and deep capillary plexus (DCP) was assessed with swept-source OCT-A (SS-OCT-A). These values were then compared with 30 age-matched healthy control eyes (CEs). The statistical analyses used SPSS software version 15.0 (SPSS, Inc., Chicago, IL, USA). Data collected underwent 1-way ANOVA. A level of P < 0.05 was accepted as statistically significant. Results The GCL thickness in the FEs was significantly lower than in CEs, with a significant thinning in all sectors except temporal ones (mean P < 0.001, superior P = 0.0002, superonasal P < 0.001, inferonasal P < 0.001, and inferior P = 0.002). The VD was significantly lower in the FEs in all sectors of SCP (mean P = 0.009, inner ring P = 0.028, and outer ring P = 0.007). Conclusions GCL and SCP are significantly reduced in the FEs. These data suggest that a vascular defect in the SCP could cause a cellular loss in the inner retina that may determine the cascade events leading to the IERM proliferation; the diagnosis in a preclinical phase could provide a treatment strategy to prevent the progression of the disease.

The fortress of Arquata del Tronto: symbol of rebirth for the Marche Region affected by the earthquakeThe Fortress of Arquata del Tronto in the Marche region is an imposing structure that rises on the crag to the north of the historic center. It represents a typical example of military architecture in the Apennines Area. Its foundation is between the eleventh and the twelfth century, an initial phase of embankment which undergoes a gradual and progressive increase in structures to enhance the functionality of the fortress. The city of Ascoli Piceno, worried about consolidating the defense outposts located at its borders, soon took possession of it. From the thirteenth to the sixteenth century, the Rocca lived alternate events, clashing with nearby castles, especially with Norcia. At the end of the eighteenth century, Arquata will be absorbed in the territory of the Clitunno Department, in the ancient Duchy of Spoleto. During this period, it was partially restored, to house a stable military garrison, becoming the third fortress of the Trasimeno Department, until it returned under the Papal States. Continuous interventions make the structure suitable for military uses. At the end of the nineteenth century, Giuseppe Sacconi, as director of the Conservation Office in the Marche and Umbria Region, undertook an important restoration. The ruins of the fortress were reconfigured according to medieval forms, taken by analogy from the repertoire of fortifications in the Apennine area. A further conservative intervention was carried out in 1990 to allow a new use. Unfortunately, the seismic events in 2016-2017 have compromised the Rocca, with large collapses that currently make the complex unusable. The intention is to undertake new restoration work, setting up a school construction site; this could represent a virtuous example to favor the rebirth of Arquata del Tronto, so strongly hit by the earthquake, through a project for the enhancement of its architectural heritage.

Background and aim of the work: Every year around 275 thousand people in Europe and 420 thousand in the United States are affected by sudden cardiac arrest. Early electrical defibrillation before the arrival of emergency services can improve survival. Training the population to use the AED is essential. The training method currently in use is the BLSD course, which limits training to a population cohort and may not be enough to meet the requirements of the proposed Law no. 1839/2019. This study aims to verify the effectiveness of an online course that illustrates the practical use of the AED to a population of laypeople. Methods: An observational study was conducted to compare a lay population undergoing the view of a video spot and a cohort of people who had participated in BLSD Category A courses. The performances of the two groups were measured immediately after the course and 6 months later. Results: Overall, the video lesson reported positive results. Six months later the skills were partially retained. The cohort that followed the video lesson showed significant deterioration in the ability to correctly position the pads and in safety. Conclusions: Although improved through significant reinforcements, the video spot represents a valid alternative training method for spreading defibrillation with public access and could facilitate the culture of defibrillation as required by the new Italian law proposal. (www.actabiomedica.it).

Background and purpose : Autoimmune encephalitides (AE) include a spectrum of neurological disorders whose diagnosis revolves around the detection of neuronal antibodies (Abs). Consensus-based diagnostic criteria (AE-DC) allow clinic-serological subgrouping of AE, with unclear prognostic implications. The impact of AE-DC on patients’ management was studied, focusing on the subgroupofAb-negative-AE. Methods: This was a retrospective multicenter study on patients fulfilling AE-DC. All patients underwent Ab testing with commercial cell-based assays (CBAs) and, when available, in-house assays (immunohistochemistry, live/fixed CBAs, neuronal cultures) that contributed to defining final categories. Patients were classified as Ab-positive-AE [N-methyl-d-aspartate-receptor encephalitis (NMDAR-E), Ab-positive limbic encephalitis (LE), definite-AE] or Ab-negative-AE (Ab-negative-LE, probable-AE, possible-AE). Results: Commercial CBAs detected neuronal Abs in 70/118 (59.3%) patients. Testing 37/48 Ab-negative cases, in-house assays identified Abs in 11 patients (29.7%). A hundred and eighteen patients fulfilled the AE-DC, 81 (68.6%) with Ab-positive-AE (Ab-positive-LE, 40; NMDAR-E, 32; definite-AE, nine) and 37 (31.4%) with Ab-negative-AE (Ab-negative-LE, 17; probable/possible-AE, 20). Clinical phenotypes were similar in Ab-positive-LE versus Ab-negative-LE. Twenty-four/118 (20.3%) patients had tumors, and 19/118 (16.1%) relapsed, regardless of being Ab-positive or Ab-negative. Ab-positive-AE patients were treated earlier than Ab-negative-AE patients (P=0.045), responded more frequently to treatments (92.3% vs. 65.6%, P&nbsp

Objective: Maternal plasma is a source of circulating placental nucleic acids. In this study, we validated previous observations on abnormal levels of circulating messenger RNA (mRNA) for the tenascin-X gene in pregnancies with ventricular septal defects in the second trimester of pregnancy. Methods: This was a bicentric retrospective study conducted from March 2016 to July 2017. Real-time polymerase chain reaction was used to identify abnormally expressed genes, comparing ten women carrying a euploid fetus with ventricular septal defects to 30 controls at 19–24 weeks of gestation. The univariable analysis was used to determine whether the mean mRNA for the tenascin-X gene values would differ from the expected values for the controls. Results: mRNA for tenascin-X gene values was higher in ventricular septal defects, 4.38 ± 3.01 versus 1.00 ± 0.80. The result was still significant even after adjustment for gestational age. Conclusions: These data confirm previous studies on the specific association of mRNA species and type of congenital heart defect and confirm that ventricular septal defects are associated with abnormal mRNA for the tenascin-X gene. The positive predictive value of this molecular marker in the general population should be assessed through prospective studies.

In this paper, we propose an innovative concept for an optical payload for Earth Observation, which operates in the medium infrared, based on two emerging technological approaches: super-resolution and compressive sensing. The aim is to improve payload performances in terms of ground spatial resolution and mitigation of some effects, such as saturation and blooming, that are often a limit for obtaining high quality level products in many application domains, such as the detection and monitoring of fire, lava, and, more generally, hotspots. Both approaches are based on the use of a Spatial Light Modulator (SLM), an optoelectronic device consisting of an array of micro-mirrors electronically actuated. The main advantages of the proposed concept consist in: (1) increased ground spatial resolution with respect to the number of pixels of the detector used; (2) expected mitigation of the blooming and saturation effects of the single pixel when high temperature hotspots are observed; (3) compressed-format capture typical of compressive sensing, which eliminates the need for a separate compression card, saving mass, memory and energy consumption.

et al., Fast, high-throughput methods for measuring the level and duration of protective immune responses to SARS-CoV-2 are needed to anticipate the risk of breakthrough infections. Here we report the development of two quantitative PCR assays for SARS-CoV-2-specific T cell activation. The assays are rapid, internally normalized and probe-based: qTACT requires RNA extraction and dqTACT avoids sample preparation steps. Both assays rely on the quantification of CXCL10 messenger RNA, a chemokine whose expression is strongly correlated with activation of antigen-specific T cells. On restimulation of whole-blood cells with SARS-CoV-2 viral antigens, viral-specific T cells secrete IFN-γ, which stimulates monocytes to produce CXCL10. CXCL10 mRNA can thus serve as a proxy to quantify cellular immunity. Our assays may allow large-scale monitoring of the magnitude and duration of functional T cell immunity to SARS-CoV-2, thus helping to prioritize revaccination strategies in vulnerable populations., Research reported in this publication was supported in part by an ISMMS seed fund to E.G. and a Dean’s office grant to E.G. and I.M. We gratefully acknowledge use of the services and facilities of the Tisch Cancer Institute supported by the National Cancer Institute (NCI) Cancer Center Support grant (no. P30 CA196521), in particular the Hess sequencing core and the BiNGS shared facility. M.S. was supported by an NCI training grant (no. T32CA078207). J.S.Y.H. is supported by the Charles H. Revson Foundation. We acknowledge the technical contribution of D.A. Sánchez, J. Baranda, S. Baztan-Morales, M. Castillo de la Osa, A. Comins-Boo, C. del Álamo Mayo, S. Gil-Manso, B. Gonzalez, S. Hatem, J. Irure-Ventura, I. Miguens, S. Muñoz Martinez, M. Pereira, C. Rodrigues-Guerreiro, M. Rodriguez-Garcia, M.P. Rojo-Portolés and D. San Segundo. We also acknowledge Beckman Coulter for donating the equipment required for the determination of spike-specific IgG antibodies. W.M. was supported by grant no. NCI K00CA212474. This work was supported by ISMMS seed fund to J.O.; Instituto de Salud Carlos III, grant no. COV20-00668 to R.C.R.; Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 Research Call grant no. COV20/00181) cofinanced by European Development Regional Fund ‘A way to achieve Europe’ to E.P.-A.; Instituto de Salud Carlos III, Spain (grant no. COV20/00170); Government of Cantabria, Spain (grant no. 2020UIC22-PUB-0019) to M.L.H.; Instituto de Salud Carlos III (grant no. PI16CIII/00012) to P.P.; Fondo Social Europeo e Iniciativa de Empleo Juvenil YEI (grant no. PEJ2018-004557-A) to M.P.E. and grant no. REDInREN 016/009/009 ISCIII. This project has received funding from the European Union’s Horizon 2020 research and innovation program VACCELERATE under grant agreement no. 101037867 to J.O. S.G. is supported by grant nos. U24CA224319, U01DK124165 and P30 CA196521.

Unusual clinical presentations in patients with E200K familial Creutzfeldt-Jakob Disease (fCJD) have been rarely reported. Herein, we described a case of E200K fCJD presenting with subacute cranial multiple neuropathy, initially suspected to be paraneoplastic or due to a leptomeningeal carcinomatosis, considering the neoplastic comorbidity of the patient. Surprisingly, brain MRI was highly suggestive of CJD. Brain histological examination confirmed the diagnosis. Genetic tests led to the definite diagnosis of E200K fCJD. To the best of our knowledge, the current case provides the first report of a histologically-confirmed E200K fCJD starting with cranial multiple neuropathy and may widen the spectrum of the clinical variability of CJD, also in its genetic variant. Unusual presentations may lead, as in this case, to incorrect diagnostic hypothesis and unuseful therapeutic attempts in the first phase of the diagnostic process. Also in the genetic variant of CJD, brain MRI demonstrated a very high sensitivity to detect the typical abnormalities since the earliest phases of the disease.

We consider the augmented Lagrangian method (ALM) for constrained optimization problems in the presence of convex inequality and convex abstract constraints. We focus on the case where the Lagrangian sub-problems are solved up to approximate stationary points, with increasing accuracy. We analyze two different criteria of approximate stationarity for the sub-problems and we prove the global convergence to stationary points of ALM in both cases.

We consider the problem of minimizing a smooth nonconvex function over a structured convex feasible set, that is, defined by two sets of constraints that are easy to treat when considered separately. In order to exploit the structure of the problem, we define an equivalent formulation by duplicating the variables and we consider the augmented Lagrangian of this latter formulation. Following the idea of the Alternating Direction Method of Multipliers (ADMM), we propose an algorithm where a two-blocks decomposition method is embedded within an augmented Lagrangian framework. The peculiarities of the proposed algorithm are the following: (1) the computation of the exact solution of a possibly nonconvex subproblem is not required; (2) the penalty parameter is iteratively updated once an approximated stationary point of the augmented Lagrangian is determined. Global convergence results are stated under mild assumptions and without requiring convexity of the objective function. Although the primary aim of the paper is theoretical, we perform numerical experiments on a nonconvex problem arising in machine learning, and the obtained results show the practical advantages of the proposed approach with respect to classical ADMM.