Towards individualised and optimalised positioning of non-ventilated COVID-19 patients: Putting the affected parts of the lung(s) on top?

The outbreak of COVID-19 led to an unprecedented inflow of hospitalised patients with severe acute respiratory syndrome (SARS), requiring high-flow non-invasive oxygenation, if not invasive mechanical ventilation. While the best option in terms of non-invasive systems of oxygen delivery is still a matter of debate, it also remains unclear as to whether or not the optimal in-bed positioning of patients might also help to improve their oxygen saturation levels. On the basis of three representative cases, it is possible to propose the following hypotheses: (i) how patients are positioned has a strong influence on their oxygen saturation levels; (ii) saturation-optimalised positions are patient-specific; (iii) prone positions require ergonomic devices; and (iv) saturation-optimalised positions should aim to place the most affected part(s) of the lung(s) on top. Considered together, these hypotheses have led us to recommend that COVID-19 patients should undergo a specific assessment at admission to determine their saturation-optimalised in-bed position. However, further studies are still needed to assess the benefits of such a strategy on clinical outcomes.

The impact of severity of initial illness, determined by SOFA score, and presence of anemia on outcomes among patients requiring Extra Corporal Membrane Oxygenation (ECMO) support: A single center experience.

INTRODUCTION: ECMO provides respiratory and circulatory support in critically ill patients. In our study, we report on a single center experience with ECMO and aim to identify the prognostic markers for survival to discharge from hospital. METHODS: A registry was maintained on all patients who underwent ECMO implantation from September 2012 till January 2016 at a single institution. The collected data was analyzed to identify baseline characteristics, outcomes including clinical variables predictive of poor outcome. RESULTS: A total of 29 patients underwent ECMO implantation. The average age of patients was 42±18years. 59% were males (N=17). 19 cases had a cardiac indication for ECMO (66%) while 10 cases had a pulmonary indication (34%). On univariate analysis; presence of Multi-organ failure, SOFA score more than 18 and hemoglobin less than 10g/dl at baseline and after ECMO removal were associated with increased 30day mortality. Pearson correlation with 30day mortality showed a positive correlation with MOF (+0.562, p=0.002) and SOFA score >18 (+0.448, p=0.015) and a negative correlation with anemia (-0.507, p=0.005). 15 out of the total 29 patients (52%) died within 30days of admission. Patients with MOF (log rank: 10.926, p=0.001), SOFA score >18 (log rank: 7.758, p=0.005) and hemoglobin <10g/dl (log rank: 5.595, p=0.018) had decreased survival on 30day follow up. CONCLUSIONS: Although the use of ECMO as a last line in the treatment of critical patients refractory to conventional treatment measures constitutes an important improvement in their care; with 48% overall survival; patient selection and timing of ECMO initiation remains challenging. Patients who already had signs of MOF and a high SOFA score portended a poor response. Similarly for anemic patients. Hence the importance of consideration for ECMO use earlier in course of illness rather than later. Screening and aggressive treatment of anemia in those patients may help improve the outcomes.

The importance of alpha/beta (alpha/13) interferon receptors and signaling pathways for the treatment of cervical intraepithelial neoplasias.

INTRODUCTION: Immunotherapies have been effective in treating various forms of cancer, including cervical intraepithelial neoplasias (CINs) predominantly caused by human papilloma virus (HPV). DEVELOPMENT: To establish persistent infections in stratified epithelia, HPV induces proliferative lesions. Viral gene products are able to change gene expression and cellular proteins. Interferons (IFNs) are inducible glycoproteins that have immunomodulatory, antiviral, antiproliferative, and antiangiogenic effects. In particular, interferon-alpha (IFN-alpha) has been shown to inhibit the development and progression of cervical cancer. In this review, actions of interferons alpha/beta (alpha/beta), including their receptors and signaling pathways, are described, as well as their clinical importance in the immune response against cervical lesions. CONCLUSION: The interaction of IFN-alpha/beta with its receptor results in a series of phosphorylation events. These mechanisms can be ineffective in IFN response, then it can also compromise the therapeutic effects of immunotherapy.

An evaluation of immune system cell infiltrate in the cervical stroma of patients with grade III cervical intraepithelial neoplasia after treatment with intralesional alpha-2B interferon.

The aim of this study was to characterize infiltrating immune cells in cervical stroma biopsy samples from patients diagnosed with cervical intraepithelial neoplasias (CINs) who were treated with IFN-alpha 2b. The authors studied 13 volunteers who were diagnosed with Cervical intraepithelial neoplasia CIN II or III and who received intra-lesional treatment with IFN-alpha 2b. They collected pre- and post-treatment biopsies from each patient. They also examined the slides under a common optical microscope with a X400 lens for biopsy sample sections that were labeled with immunohistochemistry for T lymphocyte, B lymphocyte, natural killer cell, macrophage, iNOS, and perforin markers. The presence of immune response cells in the lesion was observed after treatment with intralesional IFN-alpha 2b in patients with CIN II/III changes, a reduction in CD4+ and CD8+ T lymphocyte infiltration in the women who responded well to treatment. However, there was a significant increase in these markers in samples from women who did not respond to treatment. Nonetheless, immunotherapy with IFN-alpha 2b administered intralesionally in patients with CIN II/III yields favorable results in patients who do not smoke.

Placental and umbilical cord macroscopic changes associated with fetal and maternal events in the hypertensive disorders of pregnancy.

AIM: The purpose of this study was to identify placental and umbilical cord macroscopic changes and correlate them to maternal and fetal clinical events in hypertensive disorders of pregnancy (HDP). MATERIALS AND METHODS: The authors examined 150 placentas, 30 from each HDP group, totaling 120, and 30 from the control group. All placentas and umbilical cords were examined, recorded, and photographed. RESULTS: The mean placental weight in the control group (526.3 +/- 95.6 g) was greater than in the HDP (435.5 +/- 43.1 g). Calciphylaxis was the most common macroscopic change found in the control and HDP groups in 27 (90%) and 118 cases (98.3%), respectively. DISCUSSION: Pregnant women with HDP were relatively younger. In addition, due to low blood flow seen in HDP, the macroscopic changes found included lower placental weight, calciphylaxis in the maternal surface, and fibrin in the fetal surface. Because of all complications associated, most women with HDP had preterm infants who developed respiratory problems and had shorter umbilical cords.

Diagnosis of follicular lesions of undetermined significance in fine-needle aspirations of thyroid nodules.

Aim. We aimed to analyze the diagnostic criteria proposed by the Bethesda System for Reporting Thyroid Cytopathology for follicular lesions of undetermined significance (FLUS), the risk of cancer and diagnostic improvement with use of immunocytochemistry. Methods. For each FLUS diagnosis, we analyzed the cytological criteria (9 Bethesda criteria), secondary fine-needle aspiration (FNA) results, surgical procedures, contribution of immunocytochemistry with the antibodies cytokeratin 19 (CK19) and monoclonal anti-human mesothelial cell (HBME1). Results. Among patients with 2,210 thyroid FNAs, 244 lesions (337 nodules) were classified as FLUS (11% of all thyroid FNAs). The 3 criteria most often applied were cytological atypia suggesting papillary carcinoma (36%), microfollicular architecture but sparse cellularity (23.1%), cytological atypia (21.5%). With secondary FNA, 48.8% of nodules were reclassified as benign. For about half of all cases (41.4% for the first FNA, 57.6% for the second FNA), immunocytochemistry helped establishing a diagnosis favoring malignant or benign. No benign immunocytochemistry results were associated with a malignant lesion. In all, 22.5% of the 39 removed nodules were malignant. Conclusion. The FLUS category is supported by well-described criteria. The risk of malignancy in our series was 22.5%. Because we had no false-negative immunocytochemistry results, immunocytochemistry could be helpful in FLUS management.

IL-17 and IL-22 serum cytokine levels in patients with squamous intraepithelial lesion and invasive cervical carcinoma.

PURPOSE: Several works correlate the synthesis of IL-17 and IL-22 with tumoral progression. However, there are no studies of these cytokines on cervical cancer. The authors studied the concentration of IL-17 and IL-22 on serum obtained from patients with different grades of squamous intraepithelial lesions (SILs) and invasive cervical carcinoma. MATERIALS AND METHODS: Eighty-one women were enrolled in this study, including 23 in the healthy control (with no history of infection or lesions), 11 with low-grade squamous intraepithelial lesion (LSIL), 36 with high-grade squamous intraepithelial lesion (HSIL), and 11 who were diagnosed anatomo-pathologically with invasive carcinoma. Levels of the IL-17 and IL-22 cytokines were measured in the serum obtained from these patients using the enzyme-linked immunoabsorbent assay (ELISA) method. RESULTS: IL-17 and IL-22 displayed a similar pattern of results, with an increase in the serum level of LSIL patients, when compared with serum from HSIL patients (respectively, mean- pg/ml: 22.50 vs 12.20, and 168.2 vs 61.48, p < 0.05). CONCLUSION: Concentrations of IL-17 and IL-22 in the peripheral blood of patients with LSIL were increased compared to HSIL patients.

Immune response and immunotherapy in intraepithelial and invasive lesions of the uterine cervix.

Infection with the human papillomavirus virus (HPV) induces innate and acquired immune responses in the cervical stroma, which are a delicate, balanced and generally unpredictable immunological defense. Because of the immunological breaks that the HPV virus causes, eradication of infected cells does not occur, potentially leading to development of intraepithelial and invasive lesions. Advances in our understanding of the immune system and in the definition of antigens in tumor cells has led to many new treatment strategies. As a result, immunotherapy has the potential to be the most specific treatment for tumors, and one that requires elaboration. Recently, immunotherapy with interferon and dendritc cells has been used on intrapepithelial and invasive cervical lesions with promising results.

Porphyromonas gingivalis infection at different gestation periods on fetus development and cytokines profile.

AIM: Infective agents may affect pregnancy outcomes by deregulating homeostasis. OBJECTIVES: The effects of Porphyromonas gingivalis infection before and at different gestation periods were evaluated. MATERIALS AND METHODS: Wistar rats infected via subcutaneous with P. gingivalis W83, one week before mating (BM), days 1 (PR1) and 11 of gestation (PR11), and controls were evaluated, and samples were obtained at the end of gestation. P. gingivalis was detected by PCR. Cytokine was determined by ELISA. RESULTS: Infected rats had lower maternal gain of weight. Implantation was not observed in 2/12 BM rats. PR11 presented more fetal-placental resorptions and lower placenta/fetus weight than controls. P. gingivalis was detected in placenta and fetus. IL-6 and TNF-α levels were higher in placenta and serum of infected groups, except for TNF-α in placenta of PR1. IL-1ß levels were higher in placenta of PR11, but lower in serum and placenta of PR1. There were no differences in IL-10 and PGE2 concentrations among the groups (P < 0.05). CONCLUSIONS: The experimental infection by P. gingivalis resulted in alterations in the gestational pattern and in fetal development. The consequences of infection at mid-gestation were more severe than at the beginning, possibly due to the induction of pro-inflammatory cytokines in the fetal compartment.

Immunotherapy with dendritic cells for gynecological neoplasias: a new therapeutic approach?

The immune system consists of a complex collection of mediators and cells that act in a coordinated way to eliminate neoplastic cells. One of immunotherapy's promises is the development of cellular vaccines, or more specifically, vaccines with dendritic cells. However, we still have a lot left to study and learn, since we already know that patients with tumors of the same histological grade can have completely different behaviors when given the same immunological stimulus. We believe that antitumor immunotherapy will lead to a personalized vaccine, since the scheme of treatment, the stimuli and the dosages need to be tailored to each patient.

Immunological evaluation of vaginal secretion in patients with high-grade cervical intraepithelial neoplasia treated with intralesional interferon alpha-2b.

INTRODUCTION: Conservative treatment with intralesional interferon (IFN) is a therapeutic option for cervical intraepithelial neoplasia (CIN) patients of childbearing age. MATERIALS AND METHODS: The study group was made up of patients diagnosed with a high-grade lesion and treated with intralesional human recombinant IFNalpha-2b. Vaginal secretion was collected during IFNalpha-2b treatment for analysis of cytokines and viral load. RESULTS: The initial histology diagnostic was 62.5% (n = 5) with CIN 2 and 37.5% (n = 3) with CIN 3. In terms of clinical evaluation and anatomopathology, 6.5% (n = 5) had a good clinical response, while 37.5% (n = 3) had therapeutic failure. All the patients with therapeutic failure were smokers. Interleukin 6 and tumor necrosis factor-alpha concentrations were raised at the sixth application for the patient group who failed to respond to therapy compared to the responsive group (p = 0.0357). Patients with a good response exhibited a reduction in human papillomavirus viral load (p = 0.03). CONCLUSIONS: Patients that had a good response had lower concentrations of inflammatory cytokines than did non-responders.

Methods for the screening and diagnosis of gestational diabetes mellitus between 24 and 28 weeks of pregnancy.

The aim of this review is to provide answers to the question "How does one screen for and diagnose gestational diabetes mellitus (GDM) between 24 and 28 weeks gestation?" Two methods are currently widely used: a one-step approach (the 75g-Oral Glucose Tolerance Test, OGTT) and a two-step approach (the 50g Glucose Challenge Test, GCT, followed by 100g-OGTT). A review of the literature showed that both methods had good reproducibility (around 80%), whilst neither required preliminary diet changes. The data of the Hyperglycaemia Adverse Pregnancy Outcomes (HAPO) study on materno-foetal morbidity provided consistent support in favour of the 75g-OGTT. In addition, this one-step method presents several advantages over the two-step method, i.e. it provides a faster diagnosis time, better tolerance and it is easier to remember. We thus recommend a 75g-OGTT including three measures of the glycaemia at times 0, 1 and 2 hours for the diagnosis of GDM between 24-28 weeks of pregnancy. A discussion of alternative methods revealed that measuring Fasting Glycaemia (FG) between 24 and 28 weeks of pregnancy was unsuitable, and that measuring HbA1c, fructosamine, glycosuria, or random and postprandial plasma glucose was not advisable. This is based on the fact that too few studies have evaluated these methods, and that the studies usually involved heterogeneous populations in varying numbers, using differing criteria and sensitivity values. However, HbA1c measurements may prove useful in detecting pre-pregnancy diabetes mellitus.

[Methods of screening of gestational diabetes between 24 and 28 weeks' gestation]. / Méthodes du dépistage et du diagnostic du diabète gestationnel entre 24 et 28 semaines d'aménorrhée.

The aim of this review is to answer the question "how to detect the gestational diabetes mellitus (GDM) between 24 and 28 weeks of gestation?". Two approaches are well established: one-step approach (75 g-OGTT) and two-steps approach (50 g followed 100g-OGTT). The analysis of the literature shows that each of these methods has a good reproducibility close to 80 %, without requiring preliminary dietetics. The HAPO study provides consistent data about the 75 g-OGTT materno-fetal morbidity related. Furthermore, the one-step approach, relationship two-steps approach, has several advantages: reduction of time of diagnosis and primary care, better tolerance, simpler memorization. We recommend for the screening and the diagnosis of GDM an 75 g-OGTT with three measures: FPG, 1-h and 2-h. The various alternative methods are discussed. The measure of the fasting blood glucose isolated between 24 and 28 weeks of gestation is not a relevant approach. None of the other alternative methods (HbA1c, fructosamine, glycosuria, random and postprandial plasma glucose) cannot be recommended. Indeed, these methods have been addressed in little numerous studies, among heterogeneous populations, using variable criteria, and variable sensitivity values. Only the HbA1c might be useful to detect a pre-pregnancy diabetes mellitus.

Expression of cytokines in cervical stroma in patients with high-grade cervical intraepithelial neoplasia after treatment with intralesional interferon alpha-2b.

Conservative treatment with interferons (IFNs) has the advantage of preserving reproductive capacity in patients with grade 2 or 3 cervical intraepithelial neoplasia (CIN). The objective of this work was to study patients with high-grade CIN treated with intralesional IFN alpha-2b and to analyze the expression of Th1, Th2 and Th3 cytokines in cervical stroma. We observed that patients with a satisfactory response (60%) to treatment with IFN alpha-2b expressed more Th1 (IFN-gamma TNF-alpha, IL-2) cytokines, with a significant reduction in the viral load of high-risk human papillomavirus (p = 0.0313). All patients with therapeutic failure were smokers and had higher expression of cytokines Th2 (IL-4) or Th3 (TGF-beta2 and TGF-beta3).

The clinical use of type 1 interferon in gynecology.

Interferons were initially described in terms of their role in blocking viral replication. They are important cytokines that act on various aspects of cell physiology. Importantly, they can affect cell proliferation or induce the differentiation of neoplastic cells. The exact way in which the interferon complex (IFN) acts on tumours is still unknown, although their use in clinical practice has been widely recommended, especially with tumours that are resistant to conventional treatments, or in situations where surgical removal might lead to a loss of organ function. IFN can be employed as a treatment for various chronic diseases, including tumours. Indeed interferon cytokines are the therapy of choice in certain situations. However, one of the difficulties yet to be overcome is the need for frequent administrations of the drug. We believe that the development of new formulations is needed to match the demand for its use in oncology treatment.

Production and properties of xylanases from Aspergillus terricola Marchal and Aspergillus ochraceus and their use in cellulose pulp bleaching.

Aspergillus terricola and Aspergillus ochraceus, isolated from Brazilian soil, were cultivated in Vogel and Adams media supplemented with 20 different carbon sources, at 30 degrees C, under static conditions, for 120 and 144 h, respectively. High levels of cellulase-free xylanase were produced in birchwood or oat spelt xylan-media. Wheat bran was the most favorable agricultural residue for xylanase production. Maximum activity was obtained at 60 degrees C and pH 6.5 for A. terricola, and 65 degrees C and pH 5.0 for A. ochraceus. A. terricola xylanase was stable for 1 h at 60 degrees C and retained 50% activity after 80 min, while A. ochraceus xylanase presented a t(50) of 10 min. The xylanases were stable in an alkali pH range. Biobleaching of 10 U/g dry cellulose pulp resulted in 14.3% delignification (A. terricola) and 36.4% (A. ochraceus). The brightness was 2.4-3.4% ISO higher than the control. Analysis in SEM showed defibrillation of the microfibrils. Arabinase traces and beta-xylosidase were detected which might act synergistically with xylanase.

[Mitochondrial diabetes: clinical features, diagnosis and management]. / Diagnostic clinique et biologique du diabète mitochondrial et particularités de sa prise en charge.

Mitochondrial diabetes affects up to 1% of patients with diabetes and is often unrecognised by the physicians. Maternally inherited diabetes and deafness (MIDD) resulting from the mutation 3243A>G of the mitochondrial DNA is the most frequent mutation associated with mitochondrial diabetes. This review summarizes the range of clinical phenotypes associated with MIDD and outlines the advances in genetic diagnosis, pathogenesis and management of these patients.

The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes.

CONTEXT: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue. OBJECTIVE: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes. PARTICIPANTS: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded. RESULTS: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA(1c) was also found and remained significant after adjustment for age at molecular sampling and gender. CONCLUSIONS: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

Benefits of Ophdiat, a telemedical network to screen for diabetic retinopathy: a retrospective study in five reference hospital centres.

AIM: One objective of Ophdiat, a telemedical network using digital non-mydriatic cameras in Ile-de-France, is to develop a comprehensive screening programme that provides access to annual fundus examinations to all diabetic patients. The aim of this study was to evaluate the benefits of this programme in a hospital setting. METHODS: A retrospective analysis of 500 case reports of diabetic patients hospitalized before and after Ophdiat setup was performed in five reference hospital centres. At each centre, 100 case reports (50 before, 50 after) of patients aged greater than 18 years, hospitalized for their annual check-up, with no known diabetic retinopathy (DR) before hospitalization and with the last fundus examination performed greater than 11 months previously, were randomly selected. The primary endpoint was the proportion of patients whose fundus examinations were performed during hospitalization; secondary endpoints were the number of cases of DR found and the time taken by ophthalmologists to make the diagnosis. RESULTS: The mean proportion of patients with fundus examinations was 50.4% and 72.4% before and after, respectively, Ophdiat (P<0.01). The prevalence of DR was 11.1% before and 12.7% after (not significant). The mean time taken by an ophthalmologist per diagnosis of DR was 0.90 half-day before and 0.32 half-day after Ophdiat. CONCLUSION: This evaluation shows that Ophdiat, combined with the availability of modern and effective devices, has improved DR screening in diabetology departments in hospitals. Additional human resources would certainly ensure more effective use of the system.