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Social innovation practices have attracted increasing attention in recent years. Especially in cities and urban areas, they have represented both a response to emerging social needs seldom addressed by declining forms of state welfare support and a platform for innovating inherited understandings of collective action and activism in cities. The authors argue that a regional perspective is needed when looking at such practices in southern European urban contexts. By looking at a variety of cases in Italian cities, this section aims to illuminate how key dimensions such as local governance models and legacies, social inclusiveness patterns, the relationship with formal and informal economies and the role of specific socio-spatial structures contribute to the shaping of social innovation practices in Italian cities.

BACKGROUND: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. METHODS: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for 'all epilepsy', 'focal epilepsy', and 'genetic generalised epilepsy' (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. FINDINGS: Cases of presumed monogenic severe epilepsy had an increased PRS for 'all epilepsy' (p<0.0001), 'focal epilepsy' (p<0.0001), and 'GGE' (p=0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. INTERPRETATION: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders. FUNDING: Science foundation Ireland, Human Genome Research Institute

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10–8): rs781716 (P = 4.71 × 10–9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10–8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10–9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10–8, OR = 0.45; P = 3.31 × 10–8, OR = 0.45; P = 1.09 × 10–8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10–8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10–6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821–55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10-8): rs781716 (P = 4.71 × 10-9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10-8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10-9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10-8, OR = 0.45; P = 3.31 × 10-8, OR = 0.45; P = 1.09 × 10-8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10-8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10-6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821-55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 × 10-11; and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 × 10-12) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development. © 2010 Nature America, Inc. All rights reserved.

Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 × 10-11; and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 × 10-12) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development. © 2010 Nature America, Inc. All rights reserved.

Locus-specific databases (LSDBs) are curated collections of sequence variants in genes associated with disease. LSDBs of cancer-related genes often serve as a critical resource to researchers, diagnostic laboratories, clinicians, and others in the cancer genetics community. LSDBs are poised to play an important role in disseminating clinical classification of variants. The IARC Working Group on Unclassified Genetic Variants has proposed a new system of five classes of variants in cancer susceptibility genes. However, standards are lacking for reporting and analyzing the multiple data types that assist in classifying variants. By adhering to standards of transparency and consistency in the curation and annotation of data, LSDBs can be critical for organizing our understanding of how genetic variation relates to disease. In this article we discuss how LSDBs can accomplish these goals, using existing databases for BRCA1, BRCA2, MSH2, MLH1, TP53, and CDKN2A to illustrate the progress and remaining challenges in this field. We recommend that: 1) LSDBs should only report a conclusion related to pathogenicity if a consensus has been reached by an expert panel. 2) The system used to classify variants should be standardized. The Working Group encourages use of the five class system described in this issue by Plon and colleagues. 3) Evidence that supports a conclusion should be reported in the database, including sources and criteria used for assignment. 4) Variants should only be classified as pathogenic if more than one type of evidence has been considered. 5) All instances of all variants should be recorded. Hum Mutat 29(11), 1273-1281, 2008. Published 2008 Wiley-Liss, Inc.

Accurate initial estimates and forecasts of radii of winds over 30 kt and 50 kt around tropical cyclones are important requirements for Navy decision-making and operations. This report describes a diagnostic study of tropical cyclone surface wind distribution that was conducted by using data extracted from tropical cyclone warnings issued by the Joint Typhoon Warning Center, Guam, during the period 1966-77. Results from two different data analyses show that: (1) The tangential wind speed along the radial axis decreases exponentially outward from the radius of maximum wind; (2) In addition to persistence, the change of a tropical cyclone's size depends only on the change of the maximum wind; and (3) The asymmetric shape of the isotachs correlates highly to the speed of movement. Based on these findings, a statistical wind-radius forecast model was formulated and tested on independent 1979 data. Results show that a time lag exists between the change of maximum wind and the change of wind radii, which suggests that the wind-pressure gradient adjustments may originate from the inner core of the storm and slowly propagate outward. The results also indicate that the statistical forecast model possesses a skill equal to that of an average JTWC forecaster's wind radius forecast. (Author)

An analog system designed to make midrange regionalized forecasts is described. The analog system uses a unique historical data base which has been formulated to reduce data handling while speeding up analog matching procedures. Tuning and verification of the system are carried out for the Greater Mediterranean region. Verification results indicate that this analog system does not perform significantly better than either persistence type forecasting or forecasts produced by the current operational FNOC (Fleet Numerical Oceanography Center) analog. Possible causes for these results are discussed. Included as an appendix is a discussion of an analog-matching technique which, using the same unique historical data base, is designed to estimate the current meteorological conditions for any possible silent data area. An experiment is described which tests the adequacy of this data base to produce matching analogs for a region covering the western U.S.S.R. Results indicate that there will have to be a substantial improvement in the historical data base if acceptable analogs are to be found.

Local weather phenomena are described, and localized forecasting rules are given, for each of seven geographical areas of the Mediterranean Basin. As drawn for this study, the areas boundaries generally define the areas of occurrence of the various weather conditions and events that are found from one location to another across the region. For the operational forecaster's ease of reference, each text section addresses a particular geographical area and provides the following information for that area: an overview of local geography and seasonal, weather patterns; discussions of weather phenomena common to the area; and a series of forecasting rules cross-referenced to the phenomena discussed. Area locator maps, charts of typical weather conditions and events, satellite images, and rules-index tables are provided to enhance the operational usefulness of the information for the on-site user., See also Part 1, AD-A024 271.

This document, the product of extensive literature research, provides a single and comprehensive reference text for the operational forecaster in the Arabian Sea and Gulfs of Aden and Oman. It contains extensive climatological information, descriptions of significant meteorological phenomena and relevant forecasting aids, discussions of meteorological conditions affecting various regional ports, and a representative assortment of typical weather sequences depicted by both satellite imagery and conventional data. General information on the large-scale Asian monsoon and its relationship to the Arabian Sea region is presented. Also discussed are the significant meteorological phenomena associated with time and space variations in the Arabian Sea monsoon; forecasting aids and typical weather sequences are provided. Seasonal progressions of weather events are discussed; variations from normal conditions are described in first-hand reports from observers in the field. (Author)

The document describes a fine mesh sea-level pressure analysis scheme for the Mediterranean area with a grid length of approximately 50 n mi. The analysis scheme is an adaptation of the Fields by Information Blending methodology, Sea-Level Pressure version (FIB/SLP) for the northern hemisphere. The effect of orography is included. To test the accuracy of the fine mesh FIB/ SLP, a case study including high resolution satellite pictures from the Defense Meteorological Satellite Program (DMSP) system was compiled. This case study, which includes two of the most significant regional winds of the Mediterranean, showed that the analysis scheme is capable of distinguishing between similar pressure patterns which produce considerably different wind regimes.

The low-level cyclonic shear zone in the South China Sea is investigated as a possible precursor of tropical storm activity within the South China Sea. For tropical storm genesis in this area, it is shown that the strength of the cyclonic shear zone reaches a critical intensity approximately 24 to 48 hours before cyclogenesis takes place. Also, if the cyclonic shear zone is not present and there is either a large-scale ridge or easterly flow across the South China Sea, then tropical storm genesis does not take place for at least a week. With respect to tropical storms approaching the South China Sea from the Philippine Sea, the presence of a cyclonic shear zone is a good indication that the tropical storm will move into the area. On the other hand, when a large-scale low-level ridge is present over the area, these storm recurve northward and will not enter the South China Sea. (Author)

The research was conducted within a 3-month period in response to a COMNAVFORV requirement for a more reliable wind and sea prediction capability in Vietnam coastal waters. The purposes of this investigation were to prepare an improved wind climatology for the months of October and November, and to develop an objective technique for making short-range forecasts of the day-to-day variations in surface wind speeds for designated areas along the Vietnam coast.

The Southeast Asia (SEASIA) meteorological research program has emphasized weather phenomena and circulation features associated with synoptic events of the spring and fall transformation seasons, which have significant differences from the circulation patterns of winter and summer. Preliminary results of studies to date on the fall transformation are summarized in this paper. Climatological variations from August to November ad the characteristic synoptic events of this season are described, and a case study is presented of a typical fall-season surge.

The purposes of this current investigation were to prepare an improved wing climatology for the winter season, December through March, and to develop objective techniques for making short-range forecasts of the surface wind speeds for designated areas along the Vietnam coast.