HIV Drug Resistance Early Warning Indicators in Cohorts of Individuals Starting Antiretroviral Therapy Between 2004 and 2009: World Health Organization Global Report From 50 Countries

The World Health Organization developed a set of human immunodeficiency virus drug resistance (HIVDR) early warning indicators (EWIs) to assess antiretroviral therapy clinic and program factors associated with HIVDR. EWIs are monitored by abstracting data routinely recorded in clinical records, and the results enable clinics and program managers to identify problems that should be addressed to minimize preventable emergence of HIVDR in clinic populations. As of June 2011, 50 countries monitored EWIs, covering 131 686 patients initiating antiretroviral treatment between 2004 and 2009 at 2107 clinics. HIVDR prevention is associated with patient care (appropriate prescribing and patient monitoring), patient behavior (adherence), and clinic/program management efforts to reduce treatment interruptions (follow up, retention on first-line ART, procurement and supply management of antiretroviral drugs). EWIs measure these factors and the results have been used to optimize patient and population treatment outcome

Source-receiver wavefield interferometry in scattering media

Seismic or wavefield interferometry refers to a set of methods that synthesize wavefields between pairs of receivers, pairs of sources, or a source and a receiver, using wavefields propagating from and to surrounding boundaries of sources and/or receivers. Starting from cross-correlations of ambient seismic noise recordings, which provide the signal between two receivers as if one of them had been an active source, interferometric methods developed rapidly within the last decade, revolutionizing the way in which seismic, acoustic, elastic, or electromagnetic waves are used to image and monitor the interior of a medium. Only recently, an explicit link was found between the methods of source-receiver interferometry (SRI) and seismic imaging, a technique widely used in seismic exploration to map diffractors and reflectors in the subsurface, but also in more academic studies investigating, for example, deep crustal processes. This link is particularly interesting because SRI, in contrast to classical imaging schemes, does not rely on the single-scattering assumption but accounts for all multiple-scattering effects in the medium. While first non-linear imaging schemes based on SRI have been proposed, the full potential of the method remains to be explored and a number of open questions concerning, for example, the role of non-physical energy in interferometric wavefield estimates, require further investigation. The aim of this thesis is to gain more insight into the method of source-receiver interferometry in the context of wavefield construction and analysis in multiply scattering media, especially when theoretical requirements of the method (such as complete boundaries of sources and receivers, surrounding the medium of interest) are not met. First I analyse the single diffractor case using partial surface boundaries only. I find that only two out of eight terms of the SRI equation are required to construct a robust estimate of the scattered wavefield, and that one of these two terms is also used in seismic imaging. The other term provides a pseudo-physical estimate of the scattered wave; this is a new type of non-physical energy that emulates the kinematics of a physically scattered wave. I then proceed to a multiple scattering scenario, using the pseudo-physical term to predict the travel times and exact scattering paths of multiply diffracted waves. The presented algorithm is purely data-driven and fully automated and, as a by-product, provides a new tool to isolate primary diffracted waves from a complex multiply diffracted wavefield. Finally, the concept is expanded to multiply reflecting media. In reflection seismic data, multiply reflected waves should be removed prior to migration in order to avoid artefacts in the seismic image. I demonstrate how internal multiples can be estimated and attenuated using pseudo-physical energy constructed from SRI. Moreover, an explicit link is derived between the internal-multiple equation based on SRI and the internal-multiple equation derived from the inverse-scattering series (ISS), currently the most capable algorithm for internal-multiple attenuation. Using the insight provided by the SRI approach, I suggest an alternative equation that estimates internal multiples more effciently compared to the current method. Overall, this thesis improves our understanding of how physical, non-physical, and pseudo-physical wavefields are constructed in SRI, how new information about multiply scattered wavefields can be inferred, and how SRI relates to other methods of wavefield analysis, in particular seismic imaging and the ISS

Differentiation of Mesenchymal Stem Cells towards an insulin-releasing phenotype after co-culture with Pancreatic Islets

Transplantation of pancreatic islets has become a promising clinical option to treat patients with type 1 diabetes, alternative to the standard therapy with insulin injections. Islet transplantation is a minimally invasive therapeutic approach, and it allows a better metabolic control and a long-term insulin independence in more than 80% of patients (Ryan et al., 2002). However this therapeutic treatment has some side effects, such as the poor yield of pancreatic islet explants and even more the immune graft rejection, which have as a consequence the very limited lifespan of transplanted pancreatic islets. To avoid these side effects several strategies have been proposed and, besides the treatment with immunosuppressive drugs, promising results have been obtained with the use of Mesenchymal Stem cells (MSCs), already known in literature to be able to support the survival of many cell types (Scuteri et al., 2006). Several in vivo studies have demonstrated that the concurrent transplantation of pancreatic islets with MSCs reduces the number of islets required to achieve glycemic control in diabetic rats, but the mechanisms of these encouraging results are still unknown (Figliuzzi et al., 2009). For these reasons in this in vitro study we characterized the effect of co-culture of rat MSC on survival and functioning of rat pancreatic islets, by evaluating for 4 weeks: i) MSC adhesion to pancreatic islets; ii) viability of pancreatic islets co-cultured with MSCs; iii) the expression of insulin after co-culture; iv) the ability of co-cultured pancreatic islets to correctly adjust insulin release after variation of glucose concentration. Our results demonstrated that MSCs are able to adhere to pancreatic islets, but to increase only partly the pancreatic islet survival, which retain the ability to express and correctly release insulin after glucose variation in medium culture. Noteworthy that the insulin level in the medium of co-cultured pancreatic islets is always higher with respect to medium of pancreatic islets alone. The immunofluorescence analysis reveals that also MSCs (and not only pancreatic islets) are able to express insulin, but only in co-culture. These results, which justify the in vivo observation reported above, suggest that MSCs undergo to differentiation into a insulin-releasing phenotype after co-culture with pancreatic islets. We are now evaluating the molecular mechanisms which drive this effect, by analyzing the role of soluble factors and of proteins able to induce insulin expression. This study was granted by MIUR – FIRB Futuro in Ricerca 2008 RBFR08VSVI_001

Positive effect of Mesenchymal Stem Cells therapeutic administration on chronic Experimental Autoimmune Encephalomyelitis

Multiple Sclerosis (MS) is a crippling chronic disease of the Central Nervous System caused by the presence of self-antibodies which progressively damage axonal myelin sheath, leading to axonal transmission impairment and to the development of neurological symptoms. MS is characterized by a Relapsing-Remitting course, and current therapies rely only on the use of immunosuppressive drugs, which are however unable to reverse disease progression. Encouraging results have been obtained in preclinical studies with the administration of Mesenchymal Stem Cells (MSCs) before disease onset (Zappia et al., 2005). Here, we investigate the therapeutic potential of MSC administration after disease onset into an animal model of MS, represented by Dark Agouti rats affected by chronic Relapsing-Remitting Experimental Autoimmune Encephalomyelitis (EAE) (Cavaletti et al., 2004). 106 MSC were intravenously injected in EAE rats after disease onset. Clinical score was assessed daily, and after 45 days rats were sacrificed and histological analysis of spinal cords performed to evaluate the demyelinating lesions. After the first peak of disease, no further relapses were observed in EAE rats treated with MSCs, differently from what observed in EAE group. Histological analysis demonstrated the presence of demyelinated plaques in spinal cords of EAE rats, (Luxol fast Blue staining and anti-MBP immunohystochemistry). On the contrary the therapeutic schedule with MSCs significantly reduces the number and the extension of demyelinated areas in the spinal cords, confirming clinical score evaluations. These results demonstrated that MSCs ameliorate the clinical course of EAE and hamper the disease relapsing by reducing the areas of demyelinated lesions. Granted by MIUR – FIRB Futuro in Ricerca 2008 Prot. N° RBFR08VSVI_001

Summary of Guidelines for Managing Histoplasmosis among People Living with HIV

Abstract: Histoplasmosis is a frequent fungal opportunistic infection in people living with HIV (PLHIV), associated every year to a total of 5% to 15% of AIDS-related deaths among this population. In 2020, the first global guidelines for diagnosing and managing disseminated histoplasmosis among PLHIV was published. This document recommends (1) detection of circulating Histoplasma antigens as the recommended laboratory assay to diagnose histoplasmosis among PLHIV; (2) the use of liposomal amphotericin for induction therapy in severe or moderately severe disease, followed by a maintenance therapy with itraconazole for 12 months; a shorter maintenance therapy could be considered if the patient is clinically stable and if immune status has improved; (3) antiretroviral therapy initiation as soon as possible among patients with histoplasmosis without involvement of central nervous system; and (4) that for the treatment of co-infection with histoplasmosis and tuberculosis (TB), treatment of TB should be initiated according to the World Health Organization treatment guidelines. Appropriate health education of providers, supportive supervision, and policy guidance for the care of PLHIV are required

Initial assessment of the COVID-19 vaccination's impact on case numbers, hospitalisations and deaths in people aged 80 years and older, 15 EU/EEA countries, December 2020 to May 2021

Prioritisation of elderly people in COVID-19 vaccination campaigns aimed at reducing severe outcomes in this group. Using EU/EEA surveillance and vaccination uptake, we estimated the risk ratio of case, hospitalisation and death notifications in people 80 years and older compared with 25-59-year-olds. Highest impact was observed for full vaccination uptake 80% or higher with reductions in notification rates of cases up to 65% (IRR: 0.35; 95% CI: 0.13-0.99), hospitalisations up to 78% (IRR: 0.22; 95% CI: 0.13-0.37) and deaths up to 84% (IRR: 0.16; 95% CI: 0.13-0.20).S

Estimated number of deaths directly averted in people 60 years and older as a result of COVID-19 vaccination in the WHO European Region, December 2020 to November 2021

Since December 2019, over 1.5 million SARS-CoV-2-related fatalities have been recorded in the World Health Organization European Region - 90.2% in people ≥ 60 years. We calculated lives saved in this age group by COVID-19 vaccination in 33 countries from December 2020 to November 2021, using weekly reported deaths and vaccination coverage. We estimated that vaccination averted 469,186 deaths (51% of 911,302 expected deaths; sensitivity range: 129,851-733,744; 23-62%). Impact by country ranged 6-93%, largest when implementation was early.S