Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates.

Understanding SARS-CoV-2 associated immune pathology is crucial to develop pan-effective vaccines and treatments. Here we investigate the immune events from the acute state up to four weeks post SARS-CoV-2 infection, in non-human primates (NHP) with heterogeneous pulmonary pathology. We show a robust migration of CD16 expressing monocytes to the lungs occurring during the acute phase, and we describe two subsets of interstitial macrophages (HLA-DR+CD206-): a transitional CD11c+CD16+ cell population directly associated with IL-6 levels in plasma, and a long-lasting CD11b+CD16+ cell population. Trafficking of monocytes is mediated by TARC (CCL17) and associates with viral load measured in bronchial brushes. We also describe associations between disease outcomes and high levels of cell infiltration in lungs including CD11b+CD16hi macrophages and CD11b+ neutrophils. Accumulation of macrophages is long-lasting and detectable even in animals with mild or no signs of disease. Interestingly, animals with anti-inflammatory responses including high IL-10:IL-6 and kynurenine to tryptophan ratios show less severe illness. Our results unravel cellular mechanisms of COVID-19 and suggest that NHP may be appropriate models to test immune therapies.

Benchmarking of energy consumption in municipal wastewater treatment plants - a survey of over 200 plants in Italy.

One of the largest surveys in Europe about energy consumption in Italian wastewater treatment plants (WWTPs) is presented, based on 241 WWTPs and a total population equivalent (PE) of more than 9,000,000 PE. The study contributes towards standardised resilient data and benchmarking and to identify potentials for energy savings. In the energy benchmark, three indicators were used: specific energy consumption expressed per population equivalents (kWh PE-1 year-1), per cubic meter (kWh/m3), and per unit of chemical oxygen demand (COD) removed (kWh/kgCOD). The indicator kWh/m3, even though widely applied, resulted in a biased benchmark, because highly influenced by stormwater and infiltrations. Plants with combined networks (often used in Europe) showed an apparent better energy performance. Conversely, the indicator kWh PE-1 year-1 resulted in a more meaningful definition of a benchmark. High energy efficiency was associated with: (i) large capacity of the plant, (ii) higher COD concentration in wastewater, (iii) separate sewer systems, (iv) capacity utilisation over 80%, and (v) high organic loads, but without overloading. The 25th percentile was proposed as a benchmark for four size classes: 23 kWh PE-1 y-1 for large plants > 100,000 PE; 42 kWh PE-1 y-1 for capacity 10,000 < PE < 100,000, 48 kWh PE-1 y-1 for capacity 2,000 < PE < 10,000 and 76 kWh PE-1 y-1 for small plants < 2,000 PE.

The development of environmental visions and strategies at the municipal level: Case studies from the county of Östergötland in Sweden.

Sweden faces a number of environmental challenges. Municipalities can play an important role in managing these challenges. Using interviews with 13 municipalities in the county of Östergötland, the manner via which environmental visions and strategies were developed and implemented, and the challenges were explored. Differences were found in the effective development and implementation of both environmental visions and strategies due to a range of factors including the range and level of involvement of different stakeholders, variation in what constituted an environmental strategy, and the time horizons employed for the visions. Suggestions for how best to overcome the barriers are outlined.

Energy audit in small wastewater treatment plants: methodology, energy consumption indicators, and lessons learned.

Energy audits in wastewater treatment plants (WWTPs) reveal large differences in the energy consumption in the various stages, depending also on the indicators used in the audits. This work is aimed at formulating a suitable methodology to perform audits in WWTPs and identifying the most suitable key energy consumption indicators for comparison among different plants and benchmarking. Hydraulic-based stages, stages based on chemical oxygen demand, sludge-based stages and building stages were distinguished in WWTPs and analysed with different energy indicators. Detailed energy audits were carried out on five small WWTPs treating less than 10,000 population equivalent and using continuous data for 2 years. The plants have in common a low designed capacity utilization (52% on average) and equipment oversizing which leads to waste of energy in the absence of controls and inverters (a common situation in small plants). The study confirms that there are several opportunities for reducing energy consumption in small WWTPs: in addition to the pumping of influent wastewater and aeration, small plants demonstrate low energy efficiency in recirculation of settled sludge and in aerobic stabilization. Denitrification above 75% is ensured through intermittent aeration and without recirculation of mixed liquor. Automation in place of manual controls is mandatory in illumination and electrical heating.

International governance structures for health-care waste management: a systematic review of scientific literature.

Significant differences exist in the management of health-care waste management, globally. This is particularly so between low, middle and high-income countries. A systematic review of scientific literature on global healthcare waste management spanning the period 2000 - current was undertaken, in order to identify key policies, practices, challenges and best practice. The findings were analysed considering the Gross National Income and the Human Development Index of each country. Effective regulation and operative definitions of waste categories are key-factors requiring improvement at the national level. The economic conditions in the country are an important factor, especially regarding treatment and disposal. Areas for improvement (e.g. the need for improved governance structures, the development of regional clusters, as well as sharps waste segregation) are suggested.

Understanding the perceptions, roles and interactions of stakeholder networks managing health-care waste: A case study of the Gaza Strip.

The sustainable management of waste requires a holistic approach involving a range of stakeholders. What can often be difficult is to understand the manner in which different types of stakeholder networks are composed and work, and how best to enhance their effectiveness. Using social network analysis and stakeholder analysis of healthcare waste management stakeholders in the case study region of the Gaza Strip, this study aimed to understand and examine the manner in which the networks functioned. The Ministry of Health was found to be the most important stakeholder, followed by municipalities and solid waste management councils. Some international agencies were also mentioned, with specific roles, while other local institutions had a limited influence. Finally while health-care facilities had a strong interest in waste management, they were generally poorly informed and had limited links to each other. The manner in which the networks operated was complicated and influenced by differences in perception, sharing of information, access to finance and levels of awareness. The lack of a clear legal framework generated various mistakes about roles and responsibilities in the system, and evidently regulation was not an effective driver for improvement. Finally stakeholders had different priorities according to the waste management issues they were involved with, however segregation at the source was identified as a key requirement by most. Areas for improving the effectiveness of the networks are suggested. The analysis utilized an innovative methodology, which involved a large number of stakeholders. Such an approach served to raise interest and awareness at different levels (public authorities, health providers, supporting actors, others), stimulate the discussion about the adoption of specific policies, and identify the effective way forward.

Glucocorticoids upregulate decreased IL-7 receptor expression in asthmatic patients and simian immunodeficiency virus-infected non-human primates.

Signaling through interleukin-7 receptor (IL-7R) is essential for regulation of T-cell homeostasis and survival. Previously, we and others have found diminished IL-7R levels in simian immunodeficiency virus (SIV) - infected non-human primates and human immunodeficiency virus (HIV) - infected patients. To date, it remains unknown whether changes in IL-7R expression could also be linked to non-infectious inflammatory diseases such as asthma or anti-inflammatory drug use. Here, we investigated through flow cytometry the levels of IL-7R expression on CD4+ and CD4- T-cells in asthmatic patients in relation to disease severity, immune status and glucocorticoid (GC) use. In addition, we sought to evaluate the effects of in vivo and in vitro GC treatment on IL-7R expression in both asthmatic patients and SIV-infected non-human primates. We demonstrated that expression of IL-7R on peripheral blood CD4+ T-cells was significantly decreased in clinically stable GC-naive mild and moderate asthmatic patients. Accordingly, the development of asthmatic reaction following bronchial allergen challenge performed in sensitized subjects was associated with a significant drop in levels of IL-7R on circulating CD4+ T-cells. In contrast, CD4+ T-cells from both, mild and moderate, but not severe asthmatics, treated with inhaled GC displayed levels of IL-7R similar to that seen in healthy controls. We did not find significant differences with serum or sputum interleukin-7 levels among healthy controls and GC-naïve and GC-treated asthmatic patients. Furthermore, both in vitro GC treatment and short-term oral GC administration to asthmatic patients resulted in a significant enhancement of IL-7R. Similarly, we demonstrated that GC-stimulated T-cells from SIV-infected non-human primates up-regulated IL-7R expression. Accordingly, experimental short-term systemic in vivo administration of GC to SIV-infected macaques led to enhancement of IL-7R expression on circulating T-cells. Our data indicate that GC bear potential to recover diminished IL-7R expression, as well in asthma as in lentiviral infection.

The rapid assembly of an elliptical galaxy of 400 billion solar masses at a redshift of 2.3.

Stellar archaeology shows that massive elliptical galaxies formed rapidly about ten billion years ago with star-formation rates of above several hundred solar masses per year. Their progenitors are probably the submillimetre bright galaxies at redshifts z greater than 2. Although the mean molecular gas mass (5 × 10(10) solar masses) of the submillimetre bright galaxies can explain the formation of typical elliptical galaxies, it is inadequate to form elliptical galaxies that already have stellar masses above 2 × 10(11) solar masses at z ≈ 2. Here we report multi-wavelength high-resolution observations of a rare merger of two massive submillimetre bright galaxies at z = 2.3. The system is seen to be forming stars at a rate of 2,000 solar masses per year. The star-formation efficiency is an order of magnitude greater than that of normal galaxies, so the gas reservoir will be exhausted and star formation will be quenched in only around 200 million years. At a projected separation of 19 kiloparsecs, the two massive starbursts are about to merge and form a passive elliptical galaxy with a stellar mass of about 4 × 10(11) solar masses. We conclude that gas-rich major galaxy mergers with intense star formation can form the most massive elliptical galaxies by z ≈ 1.5.

Negative thermal expansion in crystals with the zincblende structure: an EXAFS study of CdTe.

The extended x-ray absorption fine structure (EXAFS) has been measured at both the K edges of cadmium and tellurium in CdTe, from liquid helium to room temperature, in order to investigate the local thermodynamic behaviour. The temperature dependences of the structural parameters obtained from the separate analysis of the two edges are perfectly consistent. The positive contribution to the thermal expansion due to the bond stretching and the negative contribution due to the tension effects are disentangled and quantified in terms of the bond thermal expansion and the perpendicular mean square relative displacement. The comparison with previous EXAFS results for Ge and CuCl shows that relevant correlations can be established between a number of local parameters measured by means of EXAFS and the properties of the lattice negative thermal expansion of tetrahedrally bonded semiconductors. The effective force constants derived from the EXAFS are compared with the force constants of a valence force field model.

High pressure transition in amorphous As(2)S(3) studied by EXAFS.

We report an in situ high pressure investigation of the structural change in vitreous As(2)S(3) up to 60 GPa using the diamond anvil cell and energy dispersive x-ray absorption spectroscopy. The main finding of the present study is a gradual elongation of the average As-S bond length, which takes place in the pressure range of 15-50 GPa. This change is interpreted as a signature of the coordination number increase around As atoms. The negative shift of the As K absorption edge position confirms the progressive metallization of the glass at high pressure. The observed changes are reversible after pressure release.

A new EXAFS investigation of local structural changes in amorphous and crystalline GeO(2) at high pressure.

Structural transformations at high pressure in amorphous and quartz-like crystalline GeO(2) have been investigated by using a Paris-Edinburgh press coupled to EXAFS spectroscopy. From both the germanium absorption edge position and the Ge-O distance evolution, new detailed information has been obtained about the pressure behavior of the short range order. Crystalline GeO(2) undergoes a transformation from four- to six-fold coordination at about 8.5 GPa, but at least the whole 6-12 GPa pressure range should be considered as the transition region. On the other hand, amorphous GeO(2) is characterized by a much more gradual structural change and the full octahedral state is not reached at 13 GPa as commonly believed. Furthermore, no support to the recently claimed fully pentahedral intermediate state can be given. EXAFS signals of glassy GeO(2) beyond the first Ge-O shell qualitatively confirm the continuous breakdown of the intermediate range order up to 10 GPa.

CD4+ T-cell loss and delayed expression of modulators of immune responses at mucosal sites of vaccinated macaques following SIV(mac251) infection.

Systemic immunization of macaques with a combination of DNA-poxvirus-based vaccines confers protection from high level of both systemic and mucosal viral replication following rectal exposure to the pathogenic SIV(mac251). Here we investigated early post-infection events in rectal and vaginal tissues, and found that the loss of CCR5+CD4+ T cells was equivalent in vaccinated and control macaques, despite a three logs reduction at mucosal sites of simian immunodeficiency virus (SIV) RNA in the vaccinated group. Even though a normal CD4+ T cell number is not reconstituted at mucosal sites in either group, vaccination appeared to confer a better preservation of the CD4+ CCR5+ T cells that replenish these sites. Analysis of rectal tissues RNA following challenge exposure demonstrated a decreased expression in vaccinated macaques of transforming growth factor-beta, cytotoxic T lymphocyte antigen-4, FoxP3, and indoleamine 2,3-dioxygenase, an immune suppressive enzyme expressed by dendritic cells that converts tryptophan to kynurenine and limits T-cell responses. Accordingly, the ratio of kynurenine and tryptophan in the plasma was significantly reduced in the vaccinated animals respect to the controls. Thus, preexisting adaptive immune responses induced by these vaccine modalities, although they do not protect from CD4+ T-cell depletion, nevertheless, they contain SIV(mac251) replication and delay expression of markers of T-cell activation and/or suppression at mucosal sites.

Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques.

Loss of CD4(+) T cells in the gut is necessary but not sufficient to cause AIDS in animal models, raising the possibility that a differential loss of CD4(+) T-cell subtypes may be important. We found that CD4(+) T cells that produce interleukin (IL)-17, a recently identified lineage of effector CD4(+) T-helper cells, are infected by SIV(mac251)in vitro and in vivo, and are found at lower frequency at mucosal and systemic sites within a few weeks from infection. In highly viremic animals, Th1 cells predominates over Th17 T cells and the frequency of Th17 cells at mucosal sites is negatively correlated with plasma virus level. Because Th17 cells play a central role in innate and adaptive immune response to extracellular bacteria, our finding may explain the chronic enteropathy in human immunodeficiency virus (HIV) infection. Thus, therapeutic approaches that reconstitute an adequate balance between Th1 and Th17 may be beneficial in the treatment of HIV infection.

Einstein and Debye models for EXAFS parallel and perpendicular mean-square relative displacements.

The correlated Einstein and Debye models for EXAFS parallel mean-square relative displacement (MSRD) are derived from the general expression in terms of eigenfrequencies and eigenvectors of the dynamical matrix, without ad hoc assumptions. The two models are generalized to parameterize also the EXAFS perpendicular MSRD. The physical meaning of Einstein frequencies, as well as the application of the Debye model to crystals with more than one atom per cell, are critically discussed.

Factors associated with climacteric symptoms in women around menopause attending menopause clinics in Italy.

OBJECTIVE: To obtain data on correlates of climacteric symptoms in women around menopause attending menopause clinics in Italy. METHODS: Since 1997 a large cross sectional study has been conducted on the characteristics of women around menopause attending a network of first level menopause outpatient's clinics in Italy. A total of 66,501 (mean age 54.4 years) women are considered in the present paper. RESULTS: The odds ratios of moderate and severe hot flashes/night sweats were lower in more educated women and (for severe symptoms only) in women reporting regular physical activity. Depression, difficulty to sleep, forgetfulness and irritability tended to be less frequent in more educated women and (depression only) in women reporting regular physical activity. Parous women reported more frequently these symptoms. CONCLUSIONS: This large study confirms in Southern European population that low education, body mass index and low physical activity are associated with climacteric symptoms. Parous women are at greater risk of psychological symptoms.

Risk factors for type 2 diabetes in women attending menopause clinics in Italy: a cross-sectional study.

OBJECTIVE: To analyze risk factors for type 2 diabetes among women attending menopause clinics in Italy for counselling about the menopause. SUBJECTS: Women attending a network of first-level outpatient menopause clinics in Italy for general counselling about menopause or treatment of menopausal symptoms. METHODS: Cross-sectional study with no exclusion criteria. Type 2 diabetes was defined according to National Diabetes Data Groups Indications and the fasting blood glucose at an oral glucose tolerance test within the previous year. RESULTS: Out of the 44 694 considered in this analysis, 808 had a diagnosis of diabetes type 2 (1.8%). In comparison with women aged < 50 years, the multivariate odds ratios (OR) of type 2 diabetes were 1.31 (95% confidence interval (CI), 0.99-1.74) for women aged 50-52 years, 1.66 (95% CI, 1.27-2.17) at 53-56 years and 2.84 (95% CI, 2.20-3.67) in women aged > or = 57 years. Type 2 diabetes was less frequently reported in more educated women (OR high school/university vs. primary school = 0.44 (95% CI, 0.36-0.55)). Being overweight was associated with an increased risk of type 2 diabetes. In comparison with women reporting a low level of physical activity, the multivariate OR of type 2 diabetes was 0.67 (95% CI, 0.54-0.84) for women reporting regular physical activity. In comparison with premenopausal women, the multivariate OR of type 2 diabetes was 1.38 (95% CI, 1.03-1.84) in women with natural menopause. This finding was present also after allowing for the potential confounding effect of age. The multivariate OR of diabetes for users of hormonal replacement therapy was 0.58 (95% CI, 0.46-0.73). CONCLUSIONS: This large cross-sectional study suggests that postmenopausal women are at higher risk of type 2 diabetes after allowance for the effect of age. Other main determinants of risk of type 2 diabetes in women around menopause were low socioeconomic status and being overweight. Diabetes was found less frequently in those taking hormone replacement therapy.

The exstrophy-epispadias complex: is aesthetic appearance important?

OBJECTIVE: To show the relevance of cosmetic appearance in the adequate treatment of patients with exstrophy-epispadias complex (EEC), and to indicate that surgery by experienced teams can improve the long-term treatment forecast and the patient's body image. PATIENTS AND METHODS: From 1978 to 2002, 71 patients diagnosed with EEC were treated in the authors' institution; 24 (aged 2-23 years) were selected to undergo different surgical procedures. The criterion for surgery considered interviews conducted by the psychology team with the parents and children. The plastic surgery and paediatric urology teams carried out the procedures jointly; the follow-up was 0.33-7 years. RESULTS: Five female patients and six male had abdominoplasty to treat multiple scars; eight had intermittent catheterization conduits repositioned from the right iliac fossa to the umbilicus. Six female patients had plastic surgery of the external genitalia and three had a broad mobilization of the urogenital sinus. Thirteen male patients had a small penis and had the corpora cavernosa fully mobilized and the penis reconstructed. Five female patients and one male had anterior osteotomy. One patient with no left testis had it replaced and one patient with uterine prolapse had the uterus fixed to the posterior abdominal wall. Six patients had a second procedure, in two because the outcome of the initial operation was poor and in the others to complement the initial treatment. In all but one patient there was an improvement in the objective criteria, e.g. school absences, difficulty in establishing long-lasting social relationships and refusal to participate in sports activities. However, none of the patients would attempt sexual intercourse. CONCLUSIONS: Body image, self-esteem, sexuality, sexual function and fertility are deemed crucial by adolescents; in patients with EEC customised surgical procedures can give a satisfactory aesthetic outcome, and be a further reason for adequately following occasional urinary complications and renal function, to avoid loss to follow-up.

Altered maturation of peripheral blood dendritic cells in patients with breast cancer.

Tumours have at least two mechanisms that can alter dendritic cell (DC) maturation and function. The first affects the ability of haematopoietic progenitors to differentiate into functional DCs; the second affects their differentiation from CD14+ monocytes, promoting an early but dysfunctional maturation. The aim of this study was to evaluate the in vivo relevance of these pathways in breast cancer patients. For this purpose, 53 patients with invasive breast cancer were compared to 68 healthy controls. To avoid isolation or culture procedures for enrichment of DCs, analyses were directly performed by flow cytometry on whole-blood samples. The expression of surface antigens and intracellular accumulation of regulatory cytokines upon LPS stimulation were evaluated. The number of DCs, and in particular of the myeloid subpopulation, was markedly reduced in cancer patients (P<0.001). Patient DCs were characterized by a more mature phenotype compared with controls (P=0.016), and had impaired production of IL-12 (P<0.001). These alterations were reverted by surgical resection of the tumour. To investigate the possible role of some tumour-related immunoactive soluble factors, we measured the plasmatic levels of vascular endothelial growth factor, IL-10 and spermine. A significant inverse correlation between spermine concentration and the percentage of DCs expressing IL-12 was found. Evidence was also obtained that in vitro exposure of monocyte-derived DCs to spermine promoted their activation and maturation, and impaired their function. Taken together, our results suggest that both the above-described mechanisms could concomitantly act in breast cancer to affect DC differentiation, and that spermine could be a mediator of dysfunctional maturation of DCs.

Left ventricular remodelling, and systolic and diastolic function in young adults with beta thalassaemia major: a Doppler echocardiographic assessment and correlation with haematological data.

OBJECTIVE: To evaluate left ventricular morphology and function in a large population of patients with beta thalassaemia. DESIGN: Echo Doppler assessment of left ventricular function and correlation of cardiovascular data with haematological data. SETTING: Thalassaemia unit in a tertiary referral centre. PATIENTS: 197 young adults with beta thalassaemia, following an adequate transfusional and chelation treatment regimen, without clinical signs of cardiopulmonary involvement. The control group consisted of 213 healthy subjects. RESULTS: Left ventricular volumes, mass index, and mass/volume ratio were increased. Diastolic and systolic shapes were different, the left ventricle maintaining an ellipsoidal shape. The ejection fraction was reduced, and was < 50% in 33 patients. Stroke volume and cardiac index were increased, and systemic vascular resistance was decreased. Fractional shortening and mean velocity of circumferential shortening were decreased. Meridional end systolic and peak systolic stress were increased, as was circumferential end systolic stress. The contractile state was reduced while the functional preload index did not differ. Left ventricular diastolic function, evaluated from the mitral inflow, showed a slightly prolonged isovolumic relaxation time, increased flow velocity integrals, and an increased E/A ratio. Among the haematological data, only serum ferritin showed a weak negative correlation with left ventricular ejection fraction. The patients with the highest serum ferritin (> 2500 ng/ml) had the lowest ejection fraction. CONCLUSIONS: Patients with beta thalassaemia on an adequate transfusion and chelation treatment regimen show abnormal left ventricular remodelling with increased volumes, mass, and mass/volume ratio. Systolic chamber function and contractile state are reduced, with a slightly increased afterload. These findings seem mainly to be related to the increased cardiac output caused by chronic anaemia. Left ventricular performance is better preserved when chelation treatment is adjusted to maintain the serum ferritin concentration at < 1000 ng/ml.

[Cytofluorimetric evaluation of peripheral blood dendritic cells in patients with Mediterranean Kaposi's sarcoma]. / Valutazione citofluorimetrica di cellule dendritiche circolanti in pazienti affetti da sarcoma di Kaposi mediterraneo.

AIM: Kaposi's sarcoma (KS) is a lympho-angioproliferative disorder characterized by angiomatous nodules and plaques that mainly affect the skin. The disease is consistently associated with human herpesvirus-8 (HHV8) and with a state of preexistent immunosuppression. Dendritic cells (DCs) have an instrumental role in the activation and function of both innate and adaptative immune responses. At least 2 distinct subsets have been characterized in peripheral blood based on phenotypic markers: myeloid DCs (CD11c+), associated with Ag uptake, T cell activation and ability to secrete IL-12, and plasmacytoid DCs, high virus-induced IFN-alpha producing cells. Because of the role of both DC subtypes in antiviral and antitumor induced responses, we hypothesized that DCs could be involved in the onset and evolution of KS. METHODS: Thirty-five patients with mediterranean KS assigned to different clinical stages were compared with 51 healthy control subjects. Peripheral blood DCs were quantified and functionally characterised by flow cytometry directly on whole blood samples. The production of the regulatory cytokines, IL-12 and IL-10, was assessed as intracellular accumulation after incubation with or without lipopolysaccharide (LPS). RESULTS: Myeloid DCs identified as lineage-/HLA-DR+/CD11c+ cells were significantly lower in KS patients than in controls (0.54+/-0.25 vs 0.69 +/-0.26% of the peripheral blood mononuclear cells; p<0.017). Furthermore, CD11c+ DCs were lower in patients with more diffuse disease. Plasmacytoid DCs, identified as lineage-/HLA-DR+/CD123+ cells, were lower in KS patients (0.23+/-0.19 vs 0.36+/-0.17; p<0.001). DCs from KS patients were more mature, as assessed by expression of the maturation marker CD83, and showed an impaired ability to produce IL-12 upon LPS stimulation, as compared with controls. CONCLUSION: The numerical and functional alterations of peripheral blood DCs observed in KS patients suggest an involvement of these cells in the onset and evolution of the disease.