Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Sacrilège et politique religieuse au Pakistan

Depuis une vingtaine d’années, le paysage religieux pakistanais est traversé par un mouvement social de grande ampleur autour de la question du blasphème. Dernier épisode en date, en octobre 2017 des manifestants outrés par un prétendu assouplissement des lois sur le blasphème ont obtenu la démission du Ministre de la justice, après des semaines de sit-in aux portes de la capitale. Depuis l’affaire des Versets sataniques1, et plus encore au cours des dix dernières années, chaque « insulte » faite au Prophète Muhammad en Occident se traduit au Pakistan par de grandes manifestations et des affrontements violents avec la police. Comme si la mise en scène, dans la rue, de l’indignation collective face à de prétendus outrages à la religion, constituait un nouveau rituel public et citoyen..

L’ethos du lutteur

Dans cette galerie de portraits de caïds rencontrés à Lahore, au Pakistan, des hors-la-loi, auteurs de crimes graves, s’efforcent de devenir des figures héroïques dans leur quartier, se positionnant parfois comme des médiateurs et redresseurs de torts. Dans un pays où le système judiciaire est souvent inopérant et inaccessible pour les plus pauvres, la réussite d’un tel renversement repose sur la capacité de ces hommes à endosser le rôle de justicier et d’évergète honorable au niveau local. Ce court texte cherche à restituer les stratégies de légitimation déployées par ces caïds et à les replacer dans l’imaginaire collectif de l’héroïsme criminel. Le bandit honorable est dans ce contexte fortement associé, aussi bien par les caïds que par les habitants des quartiers concernés, à la figure du lutteur, figure idéale véhiculant des images de masculinité puissante et de charisme social.In this portrait gallery of gangsters in Lahore, Pakistan, we meet outlaws who have committed serious crimes but who aim to become heroic figures in their neighbourhoods, sometimes by positioning themselves as mediators or redressers of wrongs. In a country where the justice system is often inoperative or inaccessible for the poorest, the success of such a role reversal rests on the capacity of these men to take on the role of benevolent and honourable bringer of justice at the local level. This short text seeks to uncover the legitimation strategies deployed by these gangsters and to locate them in their rightful context: the collective imaginary of criminal heroism. It is not only gangsters themselves but also the inhabitants of these neighbourhoods who associate the honourable bandit with the idealised figure of the fighter, mobilising images of powerful masculinity and social charisma

Sacrilège et politique religieuse au Pakistan

Depuis une vingtaine d’années, le paysage religieux pakistanais est traversé par un mouvement social de grande ampleur autour de la question du blasphème. Dernier épisode en date, en octobre 2017 des manifestants outrés par un prétendu assouplissement des lois sur le blasphème ont obtenu la démission du Ministre de la justice, après des semaines de sit-in aux portes de la capitale. Depuis l’affaire des Versets sataniques1, et plus encore au cours des dix dernières années, chaque « insulte » faite au Prophète Muhammad en Occident se traduit au Pakistan par de grandes manifestations et des affrontements violents avec la police. Comme si la mise en scène, dans la rue, de l’indignation collective face à de prétendus outrages à la religion, constituait un nouveau rituel public et citoyen..

Mafia Raj: The Rule of Bosses in South Asia

International audienc

The Economic Impact of Lower Extremity Peri-Prosthetic Fractures in a Large Hospital System.

INTRODUCTION: Peri-prosthetic fractures place a burden on hospital systems. They occur in older patients with medical comorbidities, as unplanned events requiring technically complex surgeries with expensive implants. The purpose of this study was to describe this patient population and evaluate the economic impact of peri-prosthetic fractures on a hospital system. METHODS: We conducted a retrospective study of peri-prosthetic fractures of the hip and knee between 2018 and 2019. Demographics, length of stay (LOS), and discharge disposition were collected. We performed chart and radiographic reviews to determine fracture classification and type of treatment performed. Analysis of direct inpatient costs was performed and categorized by fracture type. RESULTS: We identified 213 peri-prosthetic hip and 151 peri-prosthetic knee fractures. Mean age of hip patients was 77, and 71% were female. Average surgery time was 194 minutes, LOS was 5.01 days, and 71% were discharged to a skilled nursing facility (SNF). Mean age of knee patients was 76, and 79% were female. The average surgery time was 174 minutes, LOS was 5.12 days, and 70% were discharged to a SNF. Median direct cost of hip fractures was $17,108, with Vancouver B2 and B3 costing significantly more at$19,987 and $23,935 respectively (p-value CONCLUSION: Peri-prosthetic fractures create a significant economic impact on hospital systems. We stratified the costs of treatment based on fracture type. Significantly higher costs are associated with injuries requiring revision implants