Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

Family-school connections and internalizing problems among children living with asthma in urban, low-income neighborhoods

Children with asthma living in urban environments are at risk for experiencing internalizing problems and difficulties at school due to social context and health-related stressors. Parent confidence and participation in the school and children’s attitudes about school were explored in association with children’s depressed mood and school anxiety. Forty-five parent—child dyads were recruited from urban community health centers. Most participants were members of ethnic minority groups. Hierarchical multiple regression analyses revealed that higher levels of parent confidence in the school were associated with fewer symptoms of school anxiety in children. Children’s attitudes toward school moderated the relation between parent participation in the school and children’s depressed mood. Specifically, lower levels of parent participation were associated with higher levels of depressed mood only for children with the least positive school attitudes. Although preliminary, these results suggest the importance of attending to family—school connections to optimize the school-related psychological functioning of children living with asthma in urban environments

The IMF in Starbursts

The history of the IMF in starburst regions is reviewed. The IMFs are no longer believed to be top-heavy, although some superstar clusters, whether in starburst regions or not, could be. General observations of the IMF are discussed to put the starburst results in perspective. Observed IMF variations seem to suggest that the IMF varies a little with environment in the sense that denser and more massive clusters produce more massive stars, and perhaps more brown dwarfs too, compared to intermediate mass stars.Comment: 8 pages, to be published in ``Starbursts: from 30 Doradus to Lyman Break Galaxies,'' held at Institute of Astronomy, Cambridge University, UK, September 6-10, 2004. Kluwer Academic Publishers, edited by Richard de Grijs and Rosa M. Gonzalez Delgad

Mandibular reconstruction with vascularised bone flaps: a systematic review over 25 years

To explore the techniques for mandibular reconstruction with composite free flaps and their outcomes, we systematically reviewed reports published between 1990 and 2015. A total of 9499 mandibular defects were reconstructed with 6178 fibular, 1380 iliac crest, 1127 composite radial, 709 scapular, 63 serratus anterior and rib, 32 metatarsal, and 10 lateral arm flaps including humerus. The failure rate was higher for the iliac crest (6.2%, 66/1059) than for fibular, radial, and scapular flaps combined (3.4%, 202/6018) (p<0.001). We evaluated rates of osteotomy, non-union, and fistulas. Implant-retained prostheses were used most often for rehabilitation after reconstruction with iliac crest (44%, 100/229 compared with 26%, 605/2295 if another flap was used) (p<0.001). There were no apparent changes in the choice of flap or in the complications reported. Although we were able to show some significant differences relating to the types of flap used, we were disappointed to find that fundamental outcomes such as the need for osteotomy, and rates of non-union and fistulas were under-reported. This review shows the need for more comprehensive and consistent reporting of outcomes to enable the comparison of different techniques for similar defects

Search for gravitational waves from Scorpius X-1 in the second Advanced LIGO observing run with an improved hidden Markov model

We present results from a semicoherent search for continuous gravitational waves from the low-mass x-ray binary Scorpius X-1, using a hidden Markov model (HMM) to track spin wandering. This search improves on previous HMM-based searches of LIGO data by using an improved frequency domain matched filter, the J-statistic, and by analyzing data from Advanced LIGO's second observing run. In the frequency range searched, from 60 to 650 Hz, we find no evidence of gravitational radiation. At 194.6 Hz, the most sensitive search frequency, we report an upper limit on gravitational wave strain (at 95% confidence) of h095%=3.47×10-25 when marginalizing over source inclination angle. This is the most sensitive search for Scorpius X-1, to date, that is specifically designed to be robust in the presence of spin wandering. © 2019 American Physical Society

Erratum: "A Gravitational-wave Measurement of the Hubble Constant Following the Second Observing Run of Advanced LIGO and Virgo" (2021, ApJ, 909, 218)

[no abstract available

Mapping geographical inequalities in childhood diarrhoeal morbidity and mortality in low-income and middle-income countries, 2000–17 : analysis for the Global Burden of Disease Study 2017

Background Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea. Methods We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates. Findings The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1–65·8), 17·4% (7·7–28·4), and 59·5% (34·2–86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage. Interpretation By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health