Phenotyping grapevine resistance to downy mildew: deep learning as a promising tool to assess sporulation and necrosis.

BACKGROUND: Downy mildew is a plant disease that affects all cultivated European grapevine varieties. The disease is caused by the oomycete Plasmopara viticola. The current strategy to control this threat relies on repeated applications of fungicides. The most eco-friendly and sustainable alternative solution would be to use bred-resistant varieties. During breeding programs, some wild Vitis species have been used as resistance sources to introduce resistance loci in Vitis vinifera varieties. To ensure the durability of resistance, resistant varieties are built on combinations of these loci, some of which are unfortunately already overcome by virulent pathogen strains. The development of a high-throughput machine learning phenotyping method is now essential for identifying new resistance loci. RESULTS: Images of grapevine leaf discs infected with P. viticola were annotated with OIV 452-1 values, a standard scale, traditionally used by experts to assess resistance visually. This descriptor takes two variables into account the complete phenotype of the symptom: sporulation and necrosis. This annotated dataset was used to train neural networks. Various encoders were used to incorporate prior knowledge of the scale's ordinality. The best results were obtained with the Swin transformer encoder which achieved an accuracy of 81.7%. Finally, from a biological point of view, the model described the studied trait and identified differences between genotypes in agreement with human observers, with an accuracy of 97% but at a high-throughput 650% faster than that of humans. CONCLUSION: This work provides a fast, full pipeline for image processing, including machine learning, to describe the symptoms of grapevine leaf discs infected with P. viticola using the OIV 452-1, a two-symptom standard scale that considers sporulation and necrosis. If symptoms are frequently assessed by visual observation, which is time-consuming, low-throughput, tedious, and expert dependent, the method developed sweeps away all these constraints. This method could be extended to other pathosystems studied on leaf discs where disease symptoms are scored with ordinal scales.

Is childhood lying shaped by callous-unemotional traits or does lie-telling make children more callous-unemotional? A longitudinal between- and within-person perspective.

The current study aims to advance knowledge on the causal interrelationship between childhood CU traits and lying both at a between- and a within-person perspective across a significant developmental period of mid-childhood to mid-adolescence. Cross-lagged panel models and Random-intercept cross-lagged panel models were used to investigate the prospective associations between lying and the distinct subcomponents of CU traits, including Callousness, Uncaring, and Unemotional in a sample of 719 children (T1; Mage = 10.73 years, SDage = 1.38, range = 7-15 years, 54.4% girls) across four assessment points. Results supported large vulnerability effects at the between-person level across time, indicating that CU traits predominantly influence the subsequent development of lying, with Callousness and Uncaring showing most profound effects on subsequent developmental processes of lying. At the within-person level, fluctuations in CU traits and lying were overall meaningfully related, but no causal relationship could be empirically determined. These findings provide a differentiated etiological viewpoint on the intertwinement of CU traits and lying at a young age, and underscore the importance of an early identification of children with callous and uncaring tendencies in order to prevent more persistent lying in adolescence.

Chloramine Disinfection of Levofloxacin and Sulfaphenazole: Unraveling Novel Disinfection Byproducts and Elucidating Formation Mechanisms for an Enhanced Understanding of Water Treatment.

The unrestricted utilization of antibiotics poses a critical challenge to global public health and safety. Levofloxacin (LEV) and sulfaphenazole (SPN), widely employed broad-spectrum antimicrobials, are frequently detected at the terminal stage of water treatment, raising concerns regarding their potential conversion into detrimental disinfection byproducts (DBPs). However, current knowledge is deficient in identifying the potential DBPs and elucidating the precise transformation pathways and influencing factors during the chloramine disinfection process of these two antibiotics. This study conducts a comprehensive analysis of reaction pathways, encompassing piperazine ring opening/oxidation, Cl-substitution, OH-substitution, desulfurization, and S-N bond cleavage, during chloramine disinfection. Twelve new DBPs were identified in this study, exhibiting stability and persistence even after 24 h of disinfection. Additionally, an examination of DBP generation under varying disinfectant concentrations and pH values revealed peak levels at a molar ratio of 25 for LEV and SPN to chloramine, with LEV contributing 11.5% and SPN 23.8% to the relative abundance of DBPs. Remarkably, this research underscores a substantial increase in DBP formation within the molar ratio range of 1:1 to 1:10 compared to 1:10 to 1:25. Furthermore, a pronounced elevation in DBP generation was observed in the pH range of 7 to 8. These findings present critical insights into the impact of the disinfection process on these antibiotics, emphasizing the innovation and significance of this research in assessing associated health risks.

Does Spinocerebellar ataxia 27B mimic cerebellar multiple system atrophy?

BACKGROUND: Whether spinocerebellar ataxia 27B (SCA27B) may present as a cerebellar multiple system atrophy (MSA-C) mimic remains undetermined. OBJECTIVES: To assess the prevalence of FGF14 (GAA)≥250 expansions in patients with MSA-C, to compare SCA27B and MSA-C clinical presentation and natural history. METHODS: FGF14 expansion screening combined with longitudinal deep-phenotyping in a prospective cohort of 195 patients with sporadic late-onset cerebellar ataxia. RESULTS: After a mean disease duration of 6.4 years, 111 patients were not meeting criteria for MSA-C while 24 and 60 patients had a final diagnosis of possible and probable MSA-C, respectively. 16 patients carried an FGF14 (GAA)≥250 expansion in the group not meeting MSA-C criteria (14.4%), 3 patients in the possible MSA-C group (12.5%), but none among probable MSA-C cases. SCA27B patients were evolving more slowly than probable MSA-C patients. CONCLUSIONS: FGF14 (GAA)≥250 expansion may account for MSA look-alike cases and should be screened among slow progressors.

Comparison of clinical outcomes over time of inpatients with healthcare-associated or community-acquired coronavirus disease 2019 (COVID-19): A multicenter, prospective cohort study.

OBJECTIVE: To compare clinical outcomes over time of inpatients with healthcare-associated coronavirus disease 2019 (HA-COVID-19) versus community-acquired COVID-19 (CA-COVID-19). DESIGN: We conducted a multicenter, prospective observational cohort study of inpatients with COVID-19. SETTING: The study was conducted across 16 acute-care hospitals in Switzerland. PARTICIPANTS AND METHODS: We compared HA-COVID-19 cases, defined as patients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) test > 5 days after hospital admission, with hospitalized CA-COVID-19 cases, defined as those who tested positive within 5 days of admission. The composite primary outcome was patient transfer to an intensive care unit (ICU) or an intermediate care unit (IMCU) and/or all-cause in-hospital mortality. We used cause-specific Cox regression and Fine-Gray regression to model the time to the composite clinical outcome, adjusting for confounders and accounting for the competing event of discharge from hospital. We compared our results to those from a conventional approach using an adjusted logistic regression model where time-varying effects and competitive risk were ignored. RESULTS: Between February 19, 2020, and December 31, 2020, we included 1,337 HA-COVID-19 cases and 9,068 CA-COVID-19 cases. HA-COVID-19 patients were significantly older: median, 80 (interquartile range [IQR], 71-87) versus median 70 (IQR, 57-80) (P < .001). A greater proportion of HA-COVID-19 patients had a Charlson comorbidity index ≥ 5 (79% vs 55%; P < .001) than did CA-COVID-19 patients. In time-varying analyses, between day 0 and 8, HA-COVID-19 cases had a decreased risk of death or ICU or IMCU transfer compared to CA-COVID-19 cases (cause-specific hazard ratio [csHR], 0.43; 95% confidence interval [CI], 0.33-0.56). In contrast, from day 8 to 30, HA-COVID-19 cases had an increased risk of death or ICU or IMCU transfer (csHR, 1.49; 95% CI, 1.20-1.85), with no significant effect on the rate of discharge (csHR, 0.83; 95% CI, 0.61-1.14). In the conventional logistic regression model, HA-COVID-19 was protective against transfer to an ICU or IMCU and/or all-cause in-hospital mortality (adjusted odds ratio [aOR], 0.79, 95% CI, 0.67-0.93). CONCLUSIONS: The risk of adverse clinical outcomes for HA-COVID-19 cases increased substantially over time in hospital and exceeded that for CA-COVID-19. Using approaches that do not account for time-varying effects or competing events may not fully capture the true risk of HA-COVID-19 compared to CA-COVID-19.

Increased Peripheral Venous Catheter Bloodstream Infections during COVID-19 Pandemic, Switzerland.

Studies suggest that central venous catheter bloodstream infections (BSIs) increased during the COVID-19 pandemic. We investigated catheter-related BSIs in Switzerland and found peripheral venous catheter (PVC) BSI incidence increased during 2021-2022 compared with 2020. These findings should raise awareness of PVC-associated BSIs and prompt inclusion of PVC BSIs in surveillance systems.

Catheter size and risk of short-term peripheral venous catheter-associated bloodstream infections: an observational study.

OBJECTIVES: Short-term peripheral venous catheter-associated bloodstream infections (PVC-associated BSI) are disregarded in the literature because of their relatively low incidence. No data are available on the association between PVC diameter size and the risk of PVC-associated BSI. METHODS: Using a prospective database, we performed an observational study at the University of Geneva Hospitals from 1 January 2020 to 31 December 2021, including all patients with a PVC. We used univariable and multivariable marginal Cox regression models for clustered data to investigate the association between catheter size and PVC-associated BSI. The main variable of interest 'catheter size' was forced into our multivariable models. Confounders, which are thought to influence the risk of PVC-associated BSI, were used as adjustment factors. RESULTS: A total of 206 804 PVCs were included. In all, 10 806 of 201 413 (5.4%), 80 274 of 201 413 (39.9%), 93 047 of 201 413 (46.2%) and 17 286 of 201 413 (8.6%) PVCs measured ≤16G, 18G, 20G and ≥22G, respectively. The univariable analysis showed that diameters of ≤16G were significantly associated with a higher risk of PVC-associated BSI (hazard ratio [HR] 4.52, 95% CI, 1.14-18.00). Multivariable models confirmed these results (HR 4.65, 95% CI, 1.19-18.20). Sensitivity analyses including PVC inserted only in 2021 (HR 4.80, 95% CI, 1.21-19.10), for dwell time >2 days (HR 3.67, 95% CI, 0.92-14.65) and only in adults (HR 3.97, 95% CI, 0.97-15.39) showed similar results. DISCUSSION: Larger PVC size may increase the risk of PVC-associated BSI. Diameter size should be considered when selecting PVCs to reduce the burden of PVC-associated BSI.

Clinical and Electrophysiological Characterization of Essential Tremor in 18 Children and Adolescents.

Background: Essential tremor (ET) is considered the most frequent abnormal movement in the general population, with childhood onset in 5 to 30% of the patients. Methods: A multicenter, descriptive cross-sectional study enrolled patients ⩽18 years with a definite diagnosis of ET according to the International Parkinson and Movement Disorders Society criteria. Demographic data, clinical and electrophysiological characteristics of the tremor, neurological examination and impact on quality of life were collected. Results: 9 males and 9 females were included (mean age of 13.9 years). Tremor was characterized by : upper limb onset at a mean age of 6.5 years; at enrollment, upper limbs localization, and involvement of an additional body region in 28% of the patients; kinetic tremor in all of the patients combined with postural tremor in 17 and rest tremor in 3; tremor mean frequency of 7.6 Hz, mean burst duration of 82.7 ms; identification of mild myoclonic jerks on the polymyographic recordings in 7 patients; altered quality of life with worse emotional outcomes in girls and when a disease duration >5 years was suggested. Discussion: Childhood-onset ET is associated with delayed diagnosis and remarkable functional impact. Electromyographic identification of additional mild myoclonus is a new finding whose significance is discussed. Highlights: ET onset involved upper limbs and at inclusion, 28% of the patients exhibited involvement of an additional body region.ET impacted quality of life for all patients.Girls and patients affected for >5 years reported worse emotional outcomes.Mild myoclonic jerks were identified on 7/17 polymyographic recordings.

Case Report: Late Reactivation of Herpes B Virus After a Monkey Bite: A Case of Severe Meningoencephalitis.

Macacine alphaherpesvirus 1, also known as herpes B virus (BV), is an alphaherpesvirus endemic to several macaque species, capable of causing zoonotic infections in humans, with high mortality rates. Evidence of reactivation in humans has rarely been reported. Here we depict a case of BV reactivation after 54 years, leading to severe meningoencephalitis. This case supports the use of antiviral prophylaxis in patients surviving a confirmed BV central nervous system infection. We sequenced DNA from BV obtained from the patient's cerebrospinal fluid. Phylogenetic analysis showed significant divergence in the clustering of this particular BV strain compared with other known BVs. Therefore, additional efforts are needed to obtain a broader sequence landscape from BVs circulating in monkeys.

Sensorization of microfluidic brain-on-a-chip devices: Towards a new generation of integrated drug screening systems.

Brain-on-a-chip (BoC) devices show typical characteristics of brain complexity, including the presence of different cell types, separation in different compartments, tissue-like three-dimensionality, and inclusion of the extracellular matrix components. Moreover, the incorporation of a vascular system mimicking the blood-brain barrier (BBB) makes BoC particularly attractive, since they can be exploited to test the brain delivery of different drugs and nanoformulations. In this review, we introduce the main innovations in BoC and BBB-on-a-chip models, especially focusing sensorization: electrical, electrochemical, and optical biosensors permit the real-time monitoring of different biological phenomena and markers, such as the release of growth factors, the expression of specific receptors/biomarkers, the activation of immune cells, cell viability, cell-cell interactions, and BBB crossing of drugs and nanoparticles. The recent improvements in signal amplification, miniaturization, and multiplication of the sensors are discussed in an effort to highlight their benefits versus limitations and delineate future challenges in this field.

Natural History and Phenotypic Spectrum of GAA-FGF14 Sporadic Late-Onset Cerebellar Ataxia (SCA27B).

BACKGROUND: Heterozygous GAA expansions in the FGF14 gene have been related to autosomal dominant cerebellar ataxia (SCA27B-MIM:620174). Whether they represent a common cause of sporadic late-onset cerebellar ataxia (SLOCA) remains to be established. OBJECTIVES: To estimate the prevalence, characterize the phenotypic spectrum, identify discriminative features, and model longitudinal progression of SCA27B in a prospective cohort of SLOCA patients. METHODS: FGF14 expansions screening combined with longitudinal deep-phenotyping in a prospective cohort of 118 SLOCA patients (onset >40 years of age, no family history of cerebellar ataxia) without a definite diagnosis. RESULTS: Prevalence of SCA27B was 12.7% (15/118). Higher age of onset, higher Spinocerebellar Degeneration Functional Score, presence of vertigo, diplopia, nystagmus, orthostatic hypotension absence, and sensorimotor neuropathy were significantly associated with SCA27B. Ataxia progression was ≈0.4 points per year on the Scale for Assessment and Rating of Ataxia. CONCLUSIONS: FGF14 expansion is a major cause of SLOCA. Our natural history data will inform future FGF14 clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Infantile-onset parkinsonism, dyskinesia, and developmental delay: do not forget polyglutamine defects!

We present the phenotype of an infant with the largest ATN1 CAG expansion reported to date (98 repeats). He presented at 4 months with developmental delay, poor eye contact, acquired microcephaly, failure to thrive. He progressively developed dystonia-parkinsonism with paroxysmal oromandibular and limbs dyskinesia and fatal outcome at 17 months. Cerebral MRI disclosed globus pallidus T2-WI hyperintensities and brain atrophy. Molecular analysis was performed post-mortem following the diagnosis of dentatorubral-pallidoluysian atrophy (DRPLA) in his symptomatic father. Polyglutamine expansion defects should be considered when neurodegenerative genetic disease is suspected even in infancy and parkinsonism can be a presentation of infantile-onset DRPLA.

Gene therapy for aromatic L-amino acid decarboxylase deficiency: Requirements for safe application and knowledge-generating follow-up.

The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2-based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally-delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow-up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality-assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long-term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are necessary.

The present and future of blood virome in allogeneic hematopoietic cell transplant recipients.

PURPOSE OF REVIEW: Allogeneic hematopoietic cell transplantation (allogeneic HCT) is a highly effective therapy for a broad range of hematological diseases and its use is increasing worldwide. Despite advances in antiviral prophylaxis and treatment, viral infections are still one of the leading causes of post-HCT morbidity and mortality. In this patient population, metagenomic next-generation sequencing (mNGS) revealed a much larger diversity of viruses than previously suspected via the targeted screening approach. In the context of profound immunosuppression, these viral infections may cause transient viremia or protracted replication and potentially be associated with yet unrecognized or unspecific clinical manifestations. On the contrary, by constantly interacting with the immune system, viral infections may have a significant impact on posttransplant outcomes. Here, we review the latest advances in research assessing the role of the blood virome in the development of post-HCT complications. RECENT FINDINGS: Research efforts are under way to uncover the potential role of several previously undetected viruses in the development of allogeneic HCT complications and their impact on transplant outcomes. SUMMARY: The identification of viral actors impacting post-HCT morbidity and survival is key to optimize monitoring and infection prevention/treatment strategies.

Intraputaminal Gene Delivery in Two Patients with Aromatic L-Amino Acid Decarboxylase Deficiency.

Background: Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, early-onset, dyskinetic encephalopathy mostly reflecting a defective synthesis of brain dopamine and serotonin. Intracerebral gene delivery (GD) provided a significant improvement among AADCD patients (mean age, ≤6 years). Objective: We describe the clinical, biological, and imaging evolution of two AADCD patients ages >10 years after GD. Methods: Eladocagene exuparvovec, a recombinant adeno-associated virus containing the human complimentary DNA encoding the AADC enzyme, was administered into bilateral putamen by stereotactic surgery. Results: Eighteen months after GD, patients showed improvement in motor, cognitive and behavioral function, and in quality of life. Cerebral l-6-[18F] fluoro-3, 4-dihydroxyphenylalanine uptake was increased at 1 month, persisting at 1 year compared to baseline. Conclusion: Two patients with a severe form of AADCD had an objective motor and non-motor benefit from eladocagene exuparvovec injection even when treated after the age of 10 years, as in the seminal study.

Longitudinal Detection of Twenty DNA and RNA Viruses in Allogeneic Hematopoietic Stem Cell Transplant Recipients Plasma.

Metagenomics revealed novel and routinely overlooked viruses, representing sources of unrecognized infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aim to describe DNA and RNA virus prevalence and kinetics in allo-HSCT recipients' plasma for one year post HSCT. We included 109 adult patients with first allo-HSCT from 1 March 2017 to 31 January 2019 in this observational cohort study. Seventeen DNA and three RNA viral species were screened with qualitative and/or quantitative r(RT)-PCR assays using plasma samples collected at 0, 1, 3, 6, and 12 months post HSCT. TTV infected 97% of patients, followed by HPgV-1 (prevalence: 26-36%). TTV (median 3.29 × 105 copies/mL) and HPgV-1 (median 1.18 × 106 copies/mL) viral loads peaked at month 3. At least one Polyomaviridae virus (BKPyV, JCPyV, MCPyV, HPyV6/7) was detected in >10% of patients. HPyV6 and HPyV7 prevalence reached 27% and 12% at month 3; CMV prevalence reached 27%. HSV, VZV, EBV, HHV-7, HAdV and B19V prevalence remained <5%. HPyV9, TSPyV, HBoV, EV and HPg-V2 were never detected. At month 3, 72% of patients had co-infections. TTV and HPgV-1 infections were highly prevalent. BKPyV, MCPyV and HPyV6/7 were frequently detected relative to classical culprits. Further investigation is needed into associations between these viral infections and immune reconstitution or clinical outcomes.

Therapy of women with multiple sclerosis: an analysis of the use of drugs that may have adverse effects on the unborn child in the event of (unplanned) pregnancy.

Background: Although effective contraception is strongly recommended during the therapy of women with multiple sclerosis (MS) with some immunomodulatory drugs, unplanned pregnancies still occur. Adequate medication management is essential to avoid foetal harm in the event of an unplanned pregnancy. Objective: The aim was to screen for medications used in women of childbearing age with MS that may pose a risk of side effects on foetal development. Methods: Sociodemographic, clinical and medication data were collected from 212 women with MS by structured interviews, clinical examinations and medical records. Using the databases from Embryotox, Reprotox, the Therapeutic Goods Administration and on the German summaries of product characteristics, we assessed whether the taken drugs were potentially harmful regarding the foetal development. Results: The majority of patients (93.4%) were taking one or more drugs for which a possible harmful effect on the foetus is indicated in at least one of the four databases used. This proportion was even higher in patients who used hormonal contraceptives (birth control pills or vaginal rings) (PwCo, n = 101), but it was also quite high in patients who did not use such contraceptives (Pw/oCo, n = 111) (98.0% and 89.2%, respectively). PwCo were significantly more likely to take five or more medications with potential foetal risk according to at least one database than Pw/oCo (31.7% versus 6.3%). PwCo were also more severely disabled (average Expanded Disability Status Scale score: 2.8 versus 2.3) and more frequently had comorbidities (68.3% versus 54.1%) than Pw/oCo. Conclusion: Data on the most commonly used drugs in MS therapy were gathered to study the risk of possible drug effects on foetal development in female MS patients of childbearing age. We found that the majority of drugs used by patients with MS are rated as having a potential risk of interfering with normal foetal development. More effective contraception and special pregnancy information programmes regarding the therapy management during pregnancy should be implemented to reduce potential risks to mother and child. Plain Language Summary: Use of drugs not recommended during pregnancy by women with multiple sclerosis Introduction: Patients with multiple sclerosis (MS) often have to take different drugs simultaneously. During the therapy with some immunomodulatory drugs, effective contraception is strongly recommended. Nevertheless, unplanned pregnancies occur regularly in women with MS.Methods: Here, we investigated whether the 212 patients included in this study were taking drugs with known possibility of harm to the development of an unborn child. This was done using four different drug databases.Results: A subset of 111 patients was not taking hormonal contraceptives (birth control pills or vaginal rings). Of those, 99 patients were taking at least one drug that is not recommended during pregnancy according to at least one of the four databases. Most of the medications taken have the potential to affect normal foetal development.Conclusion: To ensure safe use of medications, the patients should be reminded of the importance of effective contraception.

Diagnosis of vascular parkinsonism: A new tool for gait hypokinesia occurring in older persons.

INTRODUCTION: Reliable diagnosis of vascular parkinsonism (VaP) in the presence of a gait hypokinesia is an issue that is encountered in geriatrics. The EVAMAR-AGEX study was focusing on the phenomenon of recurrent falls in older persons (OP) with this parkinsonian gait. The present study is focusing on the diagnosis of VaP-related parkinsonian gait by developing a diagnostic guidance model adapted to OP. METHODS: Data from baseline and the 2-year follow-up visit were used to carry out univariate analysis and calculation of odds ratios, allowing to identify relevant variables to include in the diagnostic guidance model. To evaluate the model, confusion matrices were created, evaluating true positive, false negative, false positive and true negative incidences, sensitivity and specificity, and negative and positive predictive values. RESULTS: 79 patients included 58% male; average age 81.24 years. VaP diagnosis according to Zijlmans criteria occurred in 28%; neurodegenerative parkinsonian syndromes in 72%. A 4-criteria model was established to facilitate diagnostic: lack of prior hallucinations, lack of movement disorders tremor excluded, no cognitive fluctuations, and ≥75 years of age at diagnosis. In combination of 4/4 criteria, all of them were required to disclose a specificity of 91% in the diagnosis of VaP. In combination of 3/4, in case of negative test, a negative predictive value for VaP diagnosis of 0.97 was obtained. CONCLUSION: The challenge of our tool is both to be able to rule out what is probably not a VaP and to argue what makes a VaP diagnosis probable in OP.

NRF2 in dermo-cosmetic: From scientific knowledge to skin care products.

The skin is the organ that is most susceptible to the impact of the exposome. Located at the interface with the external environment, it protects internal organs through the barrier function of the epidermis. It must adapt to the consequences of the harmful effects of solar radiation, the various chemical constituents of atmospheric pollution, and wounds associated with mechanical damage: oxidation, cytotoxicity, inflammation, and so forth. In this biological context, a capacity to adapt to the various stresses caused by the exposome is essential; otherwise, more or less serious conditions may develop accelerated aging, pigmentation disorders, atopy, psoriasis, and skin cancers. Nrf2-controlled pathways play a key role at this level. Nrf2 is a transcription factor that controls genes involved in oxidative stress protection and detoxification of chemicals. Its involvement in UV protection, reduction of inflammation in processes associated with healing, epidermal differentiation for barrier function, and hair regrowth, has been demonstrated. The modulation of Nrf2 in the skin may therefore constitute a skin protection or care strategy for certain dermatological stresses and disorders initiated or aggravated by the exposome. Nrf2 inducers can act through different modes of action. Keap1-dependent mechanisms include modification of the cysteine residues of Keap1 by (pro)electrophiles or prooxidants, and disruption of the Keap1-Nrf2 complex. Indirect mechanisms are suggested for numerous phytochemicals, acting on upstream pathways, or via hormesis. While developing novel and safe Nrf2 modulators for skin care may be challenging, new avenues can arise from natural compounds-based molecular modeling and emerging concepts such as epigenetic regulation.