Laplace deconvolution on the basis of time domain data and its application to Dynamic Contrast Enhanced imaging

In the present paper we consider the problem of Laplace deconvolution with noisy discrete non-equally spaced observations on a finite time interval. We propose a new method for Laplace deconvolution which is based on expansions of the convolution kernel, the unknown function and the observed signal over Laguerre functions basis (which acts as a surrogate eigenfunction basis of the Laplace convolution operator) using regression setting. The expansion results in a small system of linear equations with the matrix of the system being triangular and Toeplitz. Due to this triangular structure, there is a common number $m$ of terms in the function expansions to control, which is realized via complexity penalty. The advantage of this methodology is that it leads to very fast computations, produces no boundary effects due to extension at zero and cut-off at $T$ and provides an estimator with the risk within a logarithmic factor of the oracle risk. We emphasize that, in the present paper, we consider the true observational model with possibly nonequispaced observations which are available on a finite interval of length $T$ which appears in many different contexts, and account for the bias associated with this model (which is not present when $T\rightarrow\infty$). The study is motivated by perfusion imaging using a short injection of contrast agent, a procedure which is applied for medical assessment of micro-circulation within tissues such as cancerous tumors. Presence of a tuning parameter $a$ allows to choose the most advantageous time units, so that both the kernel and the unknown right hand side of the equation are well represented for the deconvolution. The methodology is illustrated by an extensive simulation study and a real data example which confirms that the proposed technique is fast, efficient, accurate, usable from a practical point of view and very competitive.Comment: 36 pages, 9 figures. arXiv admin note: substantial text overlap with arXiv:1207.223

Mutational analysis of the PLCE1 gene in steroid-resistant nephrotic syndrome

International audienceBackground: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCε1) have been recently described in patients with early-onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. Methods: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, we performed mutational analysis in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid-resistant NS presenting at a median age of 23.0 months (range 0-373). Results: We identified homozygous or compound heterozygous mutations in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, 3 unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. Conclusion: PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although we did not identify additional variants in 19 candidate genes (16 other PLC genes, BRAF, IQGAP1 and NPHS1), we speculate that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients

Toward a New Philosophy of Preventive Nutrition: From a Reductionist to a Holistic Paradigm to Improve Nutritional Recommendations

The reductionist approach has been predominant to date in human nutrition research and has unraveled some of the fundamental mechanisms at the basis of food nutrients (e.g., those that involve deficiency diseases). In Western countries, along with progress in medicine and pharmacology, the reductionist approach helped to increase life expectancy. However, despite 40 y of research in nutrition, epidemics of obesity and diabetes are growing each year worldwide, both in developed and developing countries, leading to a decrease in healthy life years. Yet, interactions between nutrition-health relations cannot be modeled on the basis of a linear cause-effect relation between 1 food compound and 1 physiologic effect but rather from multicausal nonlinear relations. In other words, explaining the whole from the specific by a bottom-up reductionist approach has its limits. A top-down approach becomes necessary to investigate complex issues through a holistic view before addressing any specific question to explain the whole. However, it appears that both approaches are necessary and mutually reinforcing. In this review, Eastern and Western research perspectives are first presented, laying out bases for what could be the consequences of applying a reductionist versus holistic approach to research in nutrition vis-a-vis public health, environmental sustainability, breeding, biodiversity, food science and processing, and physiology for improving nutritional recommendations. Therefore, research that replaces reductionism with a more holistic approach will reveal global and efficient solutions to the problems encountered from the field to the plate. Preventive human nutrition can no longer be considered as "pharmacology" or foods as "drugs.

EXPRESSION OF DEFA1-3 AND RELATIONS WITH RISK FACTORSOF CARDIOVASCULAR DISEASES

The infiltration of immuno-inflammatory cells is one of the earliest and durable steps that lead to atherosclerosis. These cells produce many immune components that act as a double-edged sword in this inflammatory disease. Among these components, we note antimicrobial peptides, including defenses. Defenses are natural cationic peptides of the innate immune system. In Humans, these small peptides have a large antimicrobial spectrum. In addition, they play an important role in both infectious and inflammatory diseases. Our objective was to study the relation between alpha-defenses (DEFA) 1-3 genes expression and cardiovascular risk factors. This objective was built on the hypothesis that defenses may be involved in cardiovascular pathologies, and may serve as a new generation of biomarkers. To verify this hypothesis, we treated HL-60 differentiated cells with glucose decreased alphadefenses 1, 2 and 3 gene expression levels, while insulin treatment restored its expression. These findings suggest that DEFA1-3 are involved in the complex glucose-insulin metabolic pathway. In summary, DEFA1-3 genes expression is significantly correlated with glucose. These findings we suggest that DEFA1-3 could be involved in the evolution of cardiovascular complications

Cardiovascular effects of dietary salt intake in aged healthy cats: a 2-year prospective randomized, blinded, and controlled study

High salt dry expanded diets are commercially available for cats to increase water intake and urine volume, as part of the prevention or treatment of naturally occurring urinary stone formation (calcium oxalates and struvites). However, chronic high salt intake may have potential cardiovascular adverse effects in both humans, especially in aging individuals, and several animal models. The objective of this prospective, randomized, blinded, and controlled study was to assess the long-term cardiovascular effects of high salt intake in healthy aged cats. Twenty healthy neutered cats (10.1±2.4 years) were randomly allocated into 2 matched groups. One group was fed a high salt diet (3.1 g/Mcal sodium, 5.5 g/Mcal chloride) and the other group a control diet of same composition except for salt content (1.0 g/Mcal sodium, 2.2 g/Mcal chloride). Clinical examination, systolic and diastolic arterial blood pressure measurements, standard transthoracic echocardiography and conventional Doppler examinations were repeatedly performed on non-sedated cats by trained observers before and over 24 months after diet implementation. Radial and longitudinal velocities of the left ventricular free wall and the interventricular septum were also assessed in systole and diastole using 2-dimensional color tissue Doppler imaging. Statistics were performed using a general linear model. No significant effect of dietary salt intake was observed on systolic and diastolic arterial blood pressure values. Out of the 33 tested imaging variables, the only one affected by dietary salt intake was the radial early on late diastolic velocity ratio assessed in the endocardium of the left ventricular free wall, statistically lower in the high salt diet group at 12 months only (P = 0.044). In conclusion, in this study involving healthy aged cats, chronic high dietary salt intake was not associated with an increased risk of systemic arterial hypertension and myocardial dysfunction, as observed in some elderly people, salt-sensitive patients and animal models

The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease

Roles and practices of general practitioners and psychiatrists in management of depression in the community

BACKGROUND: Little is known about depressed patients' profiles and how they are managed. The aim of the study is to compare GPs and psychiatrists for 1°) sociodemographic and clinical profile of their patients considered as depressed 2°) patterns of care provision. METHODS: The study design is an observational cross-sectional study on a random sample of GPs and psychiatrists working in France. Consecutive inclusion of patients seen in consultation considered as depressed by the physician. GPs enrolled 6,104 and psychiatrists 1,433 patients. Data collected: sociodemographics, psychiatric profile, environmental risk factors of depression and treatment. All clinical data were collected by participating physicians; there was no direct independent clinical assessment of patients to check the diagnosis of depressive disorder. RESULTS: Compared to patients identified as depressed by GPs, those identified by psychiatrists were younger, more often urban (10.5% v 5.4% – OR = 2.4), educated (42.4% v 25.4% – OR = 3.9), met DSM-IV criteria for depression (94.6% v 85.6% – OR = 2.9), had been hospitalized for depression (26.1% v 15.6% – OR = 2.0) and were younger at onset of depressive problems (all adjusted p < .001). No difference was found for psychiatric and somatic comorbidity, suicide attempt and severity of current depression. Compared to GPs, psychiatrists more often prescribed tricyclics and very novel antidepressants (7.8% v 2.3% OR = 5.0 and 6.8% v 3.0% OR = 3.8) with longer duration of antidepressant treatment. GPs' patients received more "non-conventional" treatment (8.8% v 2.4% OR = 0.3) and less psychotherapy (72.2% v 89.1% OR = 3.1) (all adjusted p < .001). CONCLUSION: Differences between patients mainly concerned educational level and area of residence with few differences regarding clinical profile. Differences between practices of GPs and psychiatrists appear to reflect more the organization of the French care system than the competence of providers

Immune responses associated with mpox viral clearance in men with and without HIV in Spain : a multisite, observational, prospective cohort study

Background: Since the emergence of the global mpox outbreak in May, 2022, more than 90 000 cases have been diagnosed across 110 countries, disproportionately affecting people with HIV. The durability of mpox-specific immunity is unclear and reinfections have been reported. We aimed to compare mpox immune responses up to 6 months after diagnosis in participants with and without HIV and assess their effect on disease severity and viral clearance dynamics. Methods: This study was embedded within a prospective, observational, multicentre cohort study of viral clearance dynamics among people with mpox in Spain (MoViE). We included women and men aged 18 years or older, who had signs of mpox, and reported having symptom onset within the previous 10 days at the moment of mpox diagnosis from three sex clinics of the Barcelona metropolitan area. Samples from skin ulcers were collected weekly to estimate the time to clear monkeypox virus (MPXV) from skin lesions. Blood samples were taken at diagnosis, 29, 91, and 182 days later for immune analysis. This included quantifying IgG and IgA against three mpox antigens by ELISA, evaluating in-vitro neutralisation, and characterising mpox-specific T-cell responses using interferon γ detecting enzyme-linked immunospot (ELISpot) assay and multiparametric flow cytometry. Findings: Of the 77 originally enrolled participants, we included 33 participants recruited between July 19, and Oct 6, 2022. Participants without HIV (19 [58%] participants) and participants with HIV (14 [42%] participants) had similar clinical severity and time to MPXV clearance in skin lesions. Participants with HIV had a CD4 T-cell count median of 777 cells per μL (IQR 484-1533), and 11 (78%) of 14 were virally suppressed on antiretroviral therapy. Nine (27%) of 33 participants were age 49 years or older. 15 (45%) of 33 participants were originally from Spain, and all participants were men. Early humoral responses, particularly concentrations and breadth of IgG and IgA, were associated with milder disease and faster viral clearance. Orthopoxvirus-specific T cells count was also positively correlated with MPXV clearance. Antibody titres declined more rapidly in participants with HIV, but T-cell responses against MPXV were sustained up to day 182 after diagnosis, regardless of HIV status. Interpretation: Higher breadth and magnitude of B-cell and T-cell responses are important in facilitating local viral clearance, limiting mpox dissemination, and reducing disease severity in individuals with preserved immune system. Antibodies appear to contribute to early viral control and T-cell responses are sustained over time, which might contribute to milder presentations during reinfection. Funding: Fundació Lluita contra les Infeccions, IrsiCaixa, and Consorcio Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación e Universidades