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International audience; The Parkfield segment of the San Andreas Fault (SAF) sits at the transition between the locked Cholame segment to the South and the SAF creeping segment to the North. The Parkfield segment hosts regular ∼Mw $\sim {\boldsymbol{M}}\boldsymbol{w}$6 earthquakes followed by postseismic deformation. Recent studies based on geodetic data have highlighted spatial and temporal variations of aseismic slip rate in addition to postseismic slip along this section of the fault. We combine Global Navigation Satellite Systems (GNSS) and seismicity data over the 2006-2018 period to detail a comprehensive picture of transient slip events. We produce a catalog of relocated seismicity and repeating earthquakes. We use a variational Bayesian independent component analysis decomposition on GNSS data to separate geodetic deformation due to non-tectonic sources from signals of potential tectonic origin. We then reconstruct the temporal evolution of fault slip and detect potential slip transients. Those events, determined as mostly aseismic with the exception of one related to a Mw ${\boldsymbol{M}}\boldsymbol{w}$4.8 earthquake, occur more frequently during the 2004 Mw ${\boldsymbol{M}}\boldsymbol{w}$6 post-seismic period than during the subsequent inter-seismic phase. Our study illustrates the rich dynamics of seismic and aseismic slip during both post- and inter-seismic periods along active faults.

BackgroundRNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is an autosomal recessive hypomyelinating leukodystrophy characterized by neurological dysfunction, hypodontia and hypogonadotropic hypogonadism. The disease is caused by biallelic pathogenic variants inPOLR3A,POLR3B,POLR1CorPOLR3K. Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants inPOLR1C. To date, no published studies have appraised in detail the craniofacial features of patients with POLR3-HLD. In this work, the specific craniofacial characteristics of patients with POLR3-HLD associated with biallelic pathogenic variants inPOLR3A,POLR3BandPOLR1Care described.MethodsThe craniofacial features of 31 patients with POLR3-HLD were evaluated, and potential genotype–phenotype associations were evaluated.ResultsVarious craniofacial abnormalities were recognized in this patient cohort, with each individual presenting at least one craniofacial abnormality. The most frequently identified features included a flat midface (61.3%), a smooth philtrum (58.0%) and a pointed chin (51.6%). In patients withPOLR3Bbiallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants inPOLR3AandPOLR3Bwhile a higher proportion of patients withPOLR1Cbiallelic variants demonstrated bitemporal narrowing.ConclusionThrough this study, we demonstrated that craniofacial abnormalities are common in patients with POLR3-HLD. This report describes in detail the dysmorphic features of POLR3-HLD associated with biallelic variants inPOLR3A,POLR3BandPOLR1C.

Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index–4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index–4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

Cet article présente les différents mécanismes procéduraux courants dans le domaine de la solidarité internationale quant à la fourniture de l’aide, qui, en ses deux volets humanitaire et développement, met en scène plusieurs catégories d’acteurs ayant chacun un rôle stratégique. Les divers acteurs, essentiellement ici des entités morales, se déploient à titre exclusif ou complémentaire en faveur de bénéficiaires moraux ou physiques. L’exclusivité implique qu’un opérateur public ou privé intervienne seul, tandis que la complémentarité prescrit des appels d’offre ou des recours à un ou d’autres acteur(s) de la même ou d’une autre catégorie (opérateurs publics, privés solidaires ou privés marchands). Ces acteurs, qui interviennent pour certains via des mécanismes de redistribution ou de sous-traitance de type mercantiliste, agissent et interagissent à travers une pluralité d’approches. Celles-ci, modélisées, projettent un ensemble de vingt-six schémas processuels depuis les bailleurs jusqu’aux bénéficiaires et peuvent être insérées dans les quatre principes d’intégration économique de Karl Polanyi. &nbsp

Context 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting This was a multicenter retrospective study using information collected from 3 predominant centers. Patients A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder., Canadian Institutes of Health Research [201610PJT-377869, MOP-G2-341146-159133-BRIDG]; Fondation Les Amis d'Elliot; Leuco-Action; Fondation Lueur d'Espoir pour Ayden; Fondation le Tout pour Loo; Reseau de Medecine Genetique Appliquee of the Fonds de Recherche du Quebec-Sante; Compute Canada; Fonds de Recherche du Quebec en Sante (FRQS) Doctoral Scholarship; Fondation du Grand defi Pierre Lavoie Doctoral Scholarship; McGill Faculty of Medicine F. S.B. Miller Fellowship; Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research; Directorate of Higher Education Overseas Scholarship-Dikti Scholarship, Ministry of National Education, Republic of Indonesia; CIHR [201603PJT-148695]; BC Children's Hospital Foundation through its intramural Investigator Grant Award Program (IGAP); National Institute for Neurological Disorders and Stroke [R01NS082094]; Jakob Kamens Chair in Translational Neurotherapeutics; Fonds de Recherche du Quebec-Sante (FRQS); Canadian Institutes of Health Research; European Reference Network for Rare Neurological Disorders (ERN-RND) [739510], This study was supported by grants from the Canadian Institutes of Health Research (201610PJT-377869, MOP-G2-341146-159133-BRIDG), Fondation Les Amis d'Elliot, Leuco-Action, Fondation Lueur d'Espoir pour Ayden, Fondation le Tout pour Loo, and Reseau de Medecine Genetique Appliquee of the Fonds de Recherche du Quebec-Sante to G. Bernard. This research was enabled in part by support provided by Compute Canada (www.computecanada.ca).S.Perrier is supported by the Fonds de Recherche du Quebec en Sante (FRQS) Doctoral Scholarship, the Fondation du Grand defi Pierre Lavoie Doctoral Scholarship, the McGill Faculty of Medicine F. S.B. Miller Fellowship, and the Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research. F. K.C. is a recipient of the Directorate of Higher Education Overseas Scholarship-Dikti Scholarship, Ministry of National Education, Republic of Indonesia. W.T. G. received funding from the CIHR (201603PJT-148695) and is supported by the BC Children's Hospital Foundation through its intramural Investigator Grant Award Program (IGAP). B.L. F. was supported by the National Institute for Neurological Disorders and Stroke (R01NS082094). A.V. receives funding from the Jakob Kamens Chair in Translational Neurotherapeutics. G. Bernard has received a Research Scholar Junior 1 award from the Fonds de Recherche du Quebec-Sante (FRQS) (2012-2016) and the New Investigator Salary Award from the Canadian Institutes of Health Research (2017-2022). I.K.M., M. Synofzik, D. Tonduti, B.P.v.d.W., M.S. V.d.K., and N.I.W. are members of the European Reference Network for Rare Neurological Disorders (ERN-RND), project ID 739510.

This study presents a comparison of the spatio-temporal variability of characteristics (magnitude, duration and timing) of annual minimum daily extreme flows (AMEF) as a function of land use and the mode of management of dams. Streamflow measured at stations not affected by dams at Joliette, along the L’Assomption River (agricultural watershed, 1340 km2), and at Saint-Michel-des-Saints, on the Matawin River (forested watershed, 1390 km2) on one hand, and downstream from the Rawdon dam (regulated natural-type management mode), on the Ouareau River (1260 km2), which is the main tributary of the L’Assomption River, and from the Matawin dam (inverted-type management mode), on the Matawin River (4070 km2), on the other hand, were compared over the period from 1930 to 2010. As far as the spatial variability of natural rivers is concerned, the magnitude and duration of AMEF are higher in the forested watershed than in the agricultural watershed. In regulated rivers, AMEF magnitude is higher downstream from the dam characterized by a natural-type management mode than downstream from the dam characterized by inversion-type management. However, downstream from the latter, AMEF occur much more frequently and very early in the year. As for temporal variability, the Lombard method did not reveal any influence of land use differences on the stationarity of series of AMEF characteristics. In contrast, differences in dam management mode result in occurrences of AMEF downstream from the inversion-type dam progressively earlier in the year. The duration and timing of AMEF are not correlated with the same climate variables, be it in natural rivers or downstream from dams.

The 2016 Kumamoto earthquake sequence occurred on the Futagawa–Hinagu fault zone near the Aso volcano on Kyushu island. The sequence was initiated with two major (M_w ≥ 6.0) foreshocks, and the mainshock (M_w = 7.0) occurred 25 h after the second major foreshock. We combine GPS, strong motion, synthetic aperture radar images, and surface offset data in a joint inversion to resolve the kinematic rupture process of the mainshock and coseismic displacement of the foreshocks. The joint inversion results reveal a unilateral rupture process for the mainshock involving sequential rupture of four major asperities. The slip area of the foreshocks and mainshock and the aftershock loci form a detailed complementary pattern. The mainshock rupture terminates near the rim of the caldera, leaving a ~10 km long gap of aftershocks. This area is characterized by high temperature and low shear wave velocity, density, and resistivity, which may be related to the partially melted geothermal condition. Ductile material property near the volcano may act as a “material barrier” to the dynamic rupture. Topographic weight of the caldera increases compressional normal stress on the fault plane, which may behave as a “stress barrier.” Long-term seismic hazard and deformation behaviors related to these two types of barriers are discussed in terms of the associated frictional mechanism. Significant postseismic creeps observed near the volcano area indicates a velocity strengthening frictional behavior near the rupture termination, which confirms that the “material barrier” mechanism is likely the dominant rupture termination mechanism.

Background Children with cerebral palsy are known to be at increased risk for visual impairment. Methods In a population-based sample drawn from a geographically defined registry, the profile of visual impairment in children with cerebral palsy was investigated. Results Close to half (49.8%; 106/213) had a visual impairment. The majority of these individuals had strabismus (55.7%; 59/106) and a slightly lesser fraction had refractive errors (20.7%; 22/106) or severe visual loss (18.9%; 20/106). The vast majority of children with severe visual loss had spastic quadriplegia (83%; 17/20) or were nonambulatory (i.e., Gross Motor Function Classification Scale IV/V, 80%; 16/20). Conclusions Knowledge of this profile will assist practitioners to heighten their appreciation of potential visual disturbances in certain subsets of children with cerebral palsy.

Firm level data for the manufacturing sector in Africa, presented in this paper, shows very low levels of investment. The importance of profit effects on investment is investigated using a flexible accelerator, a specification based on the Euler equation and a simple generalisation of these specificiations. There are controls for firm fixed effects. It is shown that the profit effect is very similar for both the accelerator and Euler equation specifications. A comparison with other studies shows that, for small firms, the effect is much smaller in Africa than for other countries. Reasons for the relative insensitivity of investment to profits in African firms are suggested. For the most general specification tested there are no significant differences in the size of the profit effect across the four countries in the study.

Leukodystrophies are a heterogeneous group of disorders associated with abnormal central nervous system white matter. The clinical features invariably include upper motor neuron signs and developmental regression with or without other neurological manifestations. The objective of this study was to characterize clinically and genetically a new form of childhood-onset leukodystrophy with ataxia and tremor. We recruited seven French-Canadian cases belonging to five families affected by an unknown form of childhood-onset leukodystrophy. Genome-wide scans (GWS) were performed using the Illumina Hap310 or Hap610 Bead Chip to identify regions of shared homozygosity that were further studied for linkage with STS markers. All cases presented between the ages of 1 and 5 years with spasticity along with other upper motor neuron signs, prominent postural tremor, and cerebellar signs. Though motor regression is a constant feature, cognitive functions are relatively preserved, even late in the course of the disease. The higher frequency of founder diseases in the French-Canadian population and the segregation in pedigrees are suggestive of a recessive mode of inheritance. By homozygosity mapping, we established linkage to a 12.6-Mb SNP-haplotyped region on chromosome 10q22.3–10q23.31 (maximum LOD score: 5.47). We describe an autosomal recessive childhood-onset leukodystrophy with ataxia and tremor mapping to a 12.6 Mb interval on chromosome 10q22.3–10q23.31. Identification of the mutated gene will allow precise diagnosis and genetic counseling and shed light on how its perturbed function leads to white matter abnormalities.

Hereditary spastic paraplegias (HSPs) are characterized by progressive lower limb spasticity and weakness. Mutations in the SPG3A gene, which encodes the large guanosine triphosphatase atlastin, are the second most common cause of autosomal dominant hereditary spastic paraplegia. In a large SPG3A screen of 70 hereditary spastic paraplegia subjects, a novel in-frame deletion, p.del436N, was identified. Characterization of this deletion showed that it affects neither the guanosine triphosphatase activity of atlastin nor interactions between atlastin and spastin. Interestingly, immunoblot analysis of lymphoblasts from affected patients demonstrated a significant reduction in atlastin protein levels, supporting a loss-of-function disease mechanism.

Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709CT [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983CG [p.Ser328(∗)] and c.6232GT [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes.