Combined skin and muscle DNA priming provides enhanced humoral responses to an HIV-1 clade C envelope vaccine

Intradermal (i.d.) and intramuscular (i.m.) injections when administered with or without electroporation (EP) have the potential to tailor the immune response to DNA vaccination. This Phase I randomized controlled clinical trial in human immunodeficiency virus type 1–negative volunteers investigated whether the site and mode of DNA vaccination influences the quality of induced cellular and humoral immune responses following the DNA priming phase and subsequent protein boost with recombinant clade C CN54 gp140. A strategy of concurrent i.d. and i.m. DNA immunizations administered with or without EP was adopted. Subtle differences were observed in the shaping of vaccine-induced virus-specific CD4+ and CD8+ T cell–mediated immune responses between groups receiving: i.d.EP + i.m., i.d. + i.m.EP, and i.d.EP + i.m.EP regimens. The DNA priming phase induced 100% seroconversion in all of the groups. A single, non-adjuvanted protein boost induced a rapid and profound increase in binding antibodies in all groups, with a trend for higher responses in i.d.EP + i.m.EP. The magnitude of antigen-specific binding immunoglobulin G correlated with neutralization of closely matched clade C 93MW965 virus and Fc-dimer receptor binding (FcγRIIa and FcγRIIIa). These results offer new perspectives on the use of combined skin and muscle DNA immunization in priming humoral and cellular responses to recombinant protein

No Exit? Withdrawal Rights and the Law of Corporate Reorganizations

Bankruptcy scholarship is largely a debate about the comparative merits of a mandatory regime on one hand and bankruptcy by free design on the other. By the standard account, the current law of corporate reorganization is mandatory. Various rules that cannot be avoided ensure that investors’ actions are limited and they do not exercise their rights against specialized assets in a way that destroys the value of a business as a whole. These rules solve collective action problems and reduce the risk of bargaining failure. But there are costs to a mandatory regime. In particular, investors cannot design their rights to achieve optimal monitoring as they could in a system of bankruptcy by free design. This Article suggests that the academic debate has missed a fundamental feature of the law. Bankruptcy operates on legal entities, not on firms in the economic sense. For this reason, sophisticated investors do not face a mandatory regime at all. The ability of investors to place assets in separate entities gives them the ability to create specific withdrawal rights in the event the firm encounters financial distress. There is nothing mandatory about rules like the automatic stay when assets can be partitioned off into legal entities that are beyond the reach of the bankruptcy judge. Thus, by partitioning assets of one economic enterprise into different legal entities, investors can create a tailored bankruptcy regime. In this way, legal entities serve as building blocks that can be combined to create specific and varied but transparent investor withdrawal rights. This regime of tailored bankruptcy has been unrecognized and underappreciated and may be preferable to both mandatory and free design regimes. By allowing a limited number of investors to opt out of bankruptcy in a particular, discrete, and visible way, investors as a group may be able to both limit the risk of bargaining failure and at the same time enjoy the disciplining effect that a withdrawal right brings with it

Assessment of Brain Injury and Brain Volumes after Posthemorrhagic Ventricular Dilatation: A Nested Substudy of the Randomized Controlled ELVIS Trial

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Periventricular Hemorrhagic Infarction in Very Preterm Infants : Characteristic Sonographic Findings and Association with Neurodevelopmental Outcome at Age 2 Years

Objective: To describe the sonographic characteristics of periventricular hemorrhagic infarction (PVHI) and their association with mortality and neurodevelopmental disability in very preterm infants born in 2008-2013. Study design: Retrospective multicenter observational cohort study. Diagonal PVHI size was measured and severity score assessed. PVHI characteristics were scored and temporal trends were assessed. Neurodevelopmental outcome at 2 years of corrected age was assessed using either the Bayley Scales of Infant and Toddler Development, Third Edition or the Griffiths Mental Development Scales. Multigroup analyses were applied as appropriate. Results: We enrolled 160 infants with median gestational age of 26.6 weeks. PVHI was mostly unilateral (90%), associated with an ipsilateral grade III intraventricular hemorrhage (84%), and located in the parietal lobe (51%). Sixty-four (40%) infants with PVHI died in the neonatal period. Of the survivors assessed at 2 years of corrected age, 65% had normal cognitive and 69% had normal motor outcomes. The cerebral palsy rate was 42%. The composite outcome of death or severe neurodevelopmental disability was observed in 58%, with no trends over the study period (P = .6). Increasing PVHI severity score was associated with death (P < .001). Increasing PVHI size and severity score were negatively associated with gross motor scores (P = .01 and .03, respectively). Trigone involvement was associated with cerebral palsy (41% vs 14%; P = .004). Associated posthemorrhagic ventricular dilation (36%) was an independent risk factor for poorer cognitive and motor outcomes (P < .001 for both). Conclusions: Increasing PVHI size and severity score were predictive of less optimal gross motor outcome and death in very preterm infants

Periventricular Hemorrhagic Infarction in Very Preterm Infants : Characteristic Sonographic Findings and Association with Neurodevelopmental Outcome at Age 2 Years

Objective: To describe the sonographic characteristics of periventricular hemorrhagic infarction (PVHI) and their association with mortality and neurodevelopmental disability in very preterm infants born in 2008-2013. Study design: Retrospective multicenter observational cohort study. Diagonal PVHI size was measured and severity score assessed. PVHI characteristics were scored and temporal trends were assessed. Neurodevelopmental outcome at 2 years of corrected age was assessed using either the Bayley Scales of Infant and Toddler Development, Third Edition or the Griffiths Mental Development Scales. Multigroup analyses were applied as appropriate. Results: We enrolled 160 infants with median gestational age of 26.6 weeks. PVHI was mostly unilateral (90%), associated with an ipsilateral grade III intraventricular hemorrhage (84%), and located in the parietal lobe (51%). Sixty-four (40%) infants with PVHI died in the neonatal period. Of the survivors assessed at 2 years of corrected age, 65% had normal cognitive and 69% had normal motor outcomes. The cerebral palsy rate was 42%. The composite outcome of death or severe neurodevelopmental disability was observed in 58%, with no trends over the study period (P = .6). Increasing PVHI severity score was associated with death (P < .001). Increasing PVHI size and severity score were negatively associated with gross motor scores (P = .01 and .03, respectively). Trigone involvement was associated with cerebral palsy (41% vs 14%; P = .004). Associated posthemorrhagic ventricular dilation (36%) was an independent risk factor for poorer cognitive and motor outcomes (P < .001 for both). Conclusions: Increasing PVHI size and severity score were predictive of less optimal gross motor outcome and death in very preterm infants

Post-hemorrhagic ventricular dilatation affects white matter maturation in extremely preterm infants

Background: Data on microstructural white matter integrity in preterm infants with post-hemorrhagic ventricular dilatation (PHVD) using diffusion tensor imaging (DTI) are limited. Also, to date, no study has focused on the DTI changes in extremely preterm (EP) infants with PHVD. Methods: A case–control study of EP infants <28 weeks’ gestation with PHVD was conducted. Diffusivity and fractional anisotropy (FA) values of corticospinal tracts (CST) and corpus callosum (CC) were measured using DTI at term-equivalent age. Outcomes were assessed at 2-years-corrected age. Results: Twenty-one infants with PHVD and 21 matched-controls were assessed. FA values in the CC were lower in infants with PHVD compared with controls (mean difference, 0.05 [95% confidence interval (CI), 0.02–0.08], p < 0.001). In infants with periventricular hemorrhagic infarction, FA values in the CC were lower than in controls (mean difference, 0.05 [95% CI, 0.02–0.09], p = 0.005). The composite cognitive and motor scores were associated with the FA value of the CC (coefficient 114, p = 0.01 and coefficient 147, p = 0.004; respectively). Conclusions: Extremely preterm infants with PHVD showed lower FA values in CC. A positive correlation was also shown between the composite cognitive and motor scores and FA value of the CC at 2-years-corrected age. Impact: Extremely preterm infants with post-hemorrhagic ventricular dilatation showed lower fractional anisotropy values in their corpus callosum compared with controls reflecting the impaired microstructure of these commissural nerve fibers that are adjacent to the dilated ventricles.Impaired microstructure of the corpus callosum was shown to be associated with cognitive and motor scores at 2-years-corrected age

Corpus callosum injury after neurosurgical intervention for posthemorrhagic ventricular dilatation and association with neurodevelopmental outcome at 2 years

OBJECTIVE Direct injury to the corpus callosum (CC) due to neurosurgical interventions in infants with posthemorrhagic ventricular dilatation (PHVD) has not been reported in the literature. The authors observed a subset of infants who had suffered penetrating CC injury after neurosurgical interventions for PHVD and hypothesized that this pattern of injury may result in suboptimal CC maturation and neurodevelopmental impairment. METHODS In this multicenter, retrospective, observational study, 100 preterm and 17 full-term infants with PHVD were included and compared with 23 preterm controls. Both neonatal and postneonatal brain MRI scans were assessed for injury, and measurements were performed on postneonatal MRI scans at 2 years' corrected age. Neurodevelopmental outcome was assessed at 2 years' corrected age. RESULTS A total of 269 brain MRI scans of 140 infants were included. Of infants with PHVD, 48 (41%) had penetrating CC injury following neurosurgical interventions. The median (IQR) CC midsagittal surface area was smaller in infants with CC injury when compared with infants with PHVD who had intact CC and controls (190 mm 2 [149-262 mm 2] vs 268 mm 2 [206-318 mm 2] vs 289 mm 2 [246-320 mm 2], respectively; p < 0.001). In the univariate analysis, the area of the CC was associated with cognitive Z score (coefficient 0.009 [95% CI 0.005-0.012], p < 0.001) and motor Z score (coefficient 0.009 [95% CI 0.006-0.012], p < 0.001). In the multivariable model, CC injury was not independently associated with cognitive and motor Z score after adjusting for gestational age and presence of periventricular hemorrhagic infarction (coefficient 0.04 [95% CI -0.36 to 0.46] and -0.37 [95% CI -0.83 to 0.09], p = 0.7 and 0.1, respectively). CONCLUSIONS CC injury was not uncommon following neurosurgical interventions for PHVD in both preterm and full-term infants. At the age of 2 years, the CC midsagittal surface area was smaller in infants with injury, but CC injury was not independently associated with cognitive and motor outcomes at 2 years' corrected age

Defining discriminatory antibody fingerprints in active and latent tuberculosis

Tuberculosis (TB) is among the leading causes of death worldwide from a single infectious agent, second only to COVID-19 in 2020. TB is caused by infection with Mycobacterium tuberculosis (Mtb), that results either in a latent or active form of disease, the latter associated with Mtb spread. In the absence of an effective vaccine, epidemiologic modeling suggests that aggressive treatment of individuals with active TB (ATB) may curb spread. Yet, clinical discrimination between latent (LTB) and ATB remains a challenge. While antibodies are widely used to diagnose many infections, the utility of antibody-based tests to diagnose ATB has only regained significant traction recently. Specifically, recent interest in the humoral immune response to TB has pointed to potential differences in both targeted antigens and antibody features that can discriminate latent and active TB. Here we aimed to integrate these observations and broadly profile the humoral immune response across individuals with LTB or ATB, with and without HIV co-infection, to define the most discriminatory humoral properties and diagnose TB disease more easily. Using 209 Mtb antigens, striking differences in antigen-recognition were observed across latently and actively infected individuals that was modulated by HIV serostatus. However, ATB and LTB could be discriminated, irrespective of HIV-status, based on a combination of both antibody levels and Fc receptor-binding characteristics targeting both well characterized (like lipoarabinomannan, 38 kDa or antigen 85) but also novel Mtb antigens (including Rv1792, Rv1528, Rv2435C or Rv1508). These data reveal new Mtb-specific immunologic markers that can improve the classification of ATB versus LTB.</p