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Abstract Thyroid cancer is the most common endocrine carcinoma and, among its different subtypes, the papillary subtype (PTC) is the most frequent. Generally, PTCs are well differentiated, but a minor percentage of PTCs are characterized by a worse prognosis and more aggressive behavior. Phytochemicals, naturally found in plant products, represent a heterogeneous group of bioactive compounds that can interfere with cell proliferation and the regulation of the cell cycle, taking part in multiple signaling pathways that are often disrupted in tumor initiation, proliferation, and progression. In this work, we focused on 15,16-dihydrotanshinone I (DHT), a tanshinone isolated from Salvia miltiorrhiza Bunge (Danshen). We first evaluated DHT biological effect on PTC cells regarding cell viability, colony formation ability, and migration capacity. All of these parameters were downregulated by DHT treatment. We then investigated gene expression changes after DHT treatment by performing RNA-seq. The analysis revealed that DHT significantly reduced the Wnt signaling pathway, which plays a role in various diseases, including cancer. Finally, we demonstrate that DHT treatment decreases protein levels of β-catenin, a final effector of canonical Wnt signaling pathway. Overall, our data suggest a possible use of this nutraceutical as an adjuvant in the treatment of aggressive papillary thyroid carcinoma.

Introduction Universal health coverage (UHC) is a global priority, ensuring equitable access to quality healthcare services without financial hardship. Many countries face challenges in progressing towards UHC. Health financing is pivotal for advancing UHC by raising revenues, enabling risk-sharing through pooling of funds and allocating resources. Digital technologies in the healthcare sector offer promising opportunities for health systems. In low-income and middle-income countries (LMICs), digital technologies for health financing (DTHF) have gained traction, supporting these three main functions of health financing for UHC. As existing information on DTHF in LMICs is limited, our scoping review aims to provide a comprehensive overview of DTHF in LMICs. Our objectives include identifying and describing existing DTHF, exploring evaluation approaches, examining their positive and negative effects, and investigating facilitating factors and barriers to implementation at the national level.Methods and analysis Our scoping review follows the six stages proposed by Arksey and O’Malley, further developed by Levac et al and the Joanna Briggs Institute. The reporting adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews framework. Eligibility criteria for studies reflect the three core elements of the search: (1) health financing, (2) digital technologies and (3) LMICs. We search multiple databases, including Medline via PubMed, EMBASE via Ovid, the Web of Science Core Collection, CENTRAL via Cochrane and the Global Index Medicus by the WHO. The extracted information is synthesised from both quantitative and qualitative studies.Ethics and dissemination As our scoping review is based solely on information gathered from previously published studies, documents and publicly available scientific literature, ethical clearance is not required for its conduct. The findings are presented and discussed in a peer-reviewed article, as well as shared at conferences relevant to the topic.

Summary: Background: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. Methods: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. Findings: We found both tau metrics significantly elevated across increasing disease stages (p

Objectives This study aimed to evaluate the effect of introduction and subsequent withdrawal of the Results-based Financing for Maternal and Newborn Health Initiative (RBF4MNH) in Malawi on utilisation of facility-based childbirths, antenatal care (ANC) and postnatal care (PNC).Design A controlled interrupted time series design was used with secondary data from the Malawian Health Management Information System.Setting Healthcare facilities at all levels identified as providing maternity services in four intervention districts and 20 non-intervention districts in Malawi.Participants Routinely collected, secondary data of total monthly service utilisation of facility-based childbirths, ANC and PNC services.Interventions The intervention is the RBF4MNH initiative, introduced by the Malawian government in 2013 to improve maternal and infant health outcomes and withdrawn in 2018 after ceasing of donor funding.Outcome measures Differences in total volume and trends of utilisation of facility-based childbirths, ANC and PNC services, compared between intervention versus non-intervention districts, for the study period of 90 consecutive months.Results No significant effect was observed, on utilisation trends for any of the three services during the first 2.5 years of intervention. In the following 2.5 years after full implementation, we observed a small positive increase for facility-based childbirths (+0.62 childbirths/month/facility) and decrease for PNC (−0.55 consultations/month/facility) trends of utilisation respectively. After withdrawal, facility-based childbirths and ANC consultations dropped both in immediate volume after removal (−10.84 childbirths/facility and −20.66 consultations/facility, respectively), and in trends of utilisation over time (−0.27 childbirths/month/facility and -1.38 consultations/month/facility, respectively). PNC utilisation levels seemed unaffected in intervention districts against a decline in the rest of the country.Conclusions Concurrent with wider literature, our results suggest that effects of complex health financing interventions, such as RBF4MNH, can take a long time to be seen. They might not be sustained beyond the implementation period if measures are not adopted to reform existing health financing structures.

Abstract Psychological-distress increased at the onset of the COVID-19 pandemic in Argentina. Longitudinal studies in developing countries are scarce. Particularly, Argentina had one of the longest lockdowns. Differences in preventive measures against the virus spread between countries may differentially affect the mental health of the populations. Here we aimed to characterize distinct psychological-distress and related-symptoms trajectories associated with the pandemic and explore risk/protective factors. In this longitudinal study, data from 832 Argentineans were collected every 3–5 months, between April 2020–August 2021. Mean psychological-distress levels and related-symptoms tended to increase over time. However, latent-class analysis identified four distinct psychological-distress trajectories. Most individuals had consistently good mental health (Resilient). Two classes showed psychological-distress worsening during the initial phase of the pandemic and recovered at different time points (Fast Recovery; Slow Recovery). The remaining class maintained a mild -level of psychological-distress and began to deteriorate in March 2021 (Deteriorating) continuously. Individuals who are younger, female, have pre-existing psychiatric diagnoses, or have high neuroticism or lower resilience were more likely to experiencing fluctuations in psychological-distress. The mental health trajectory during the pandemic had a complex dynamic. Although most participants remained resilient, a vulnerable group was detected, which deteriorated over time and should be considered by health-services.

Abstract Background The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

Background: Estimates of ‘brain-predicted age’ quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD) but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored. Methods: We trained three models to predict age from FC, structural (S), or multimodal MRI (S+FC) in 390 amyloid-negative cognitively normal (CN/A−) participants (18–89 years old). In independent samples of 144 CN/A−, 154 CN/A+, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid and tau, as well as a global cognitive composite. Results: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG was significantly reduced in CN/A+ participants compared to CN/A−. In CI participants only, elevated S-BAG and S+FC BAG were associated with more advanced AD pathology and lower cognitive performance. Conclusions: Both FC-BAG and S-BAG are elevated in CI participants. However, FC and structural MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to presymptomatic AD pathology, while S-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model improves sensitivity to healthy age differences. Funding: This work was supported by the National Institutes of Health (P01-AG026276, P01- AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, and U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimer’s Association (SG-20-690363-DIAN).

Introduction Gender-based discrimination (GBD) is generally defined as unequal or disadvantageous treatment based on one’s gender. Emerging evidence suggests that exposure to GBD in its various forms can yield negative consequences for women’s health, including delaying access to healthcare services and lowering the quality of nutrition. Although consensus exists around the theoretical definitions of GBD, current studies are limited on how to measure GBD empirically in order to assess its true impact on women’s health. Our mixed-methods scoping review aims at synthesising existing evidence by answering the question How is gender-based discrimination defined and measured in the health literature, with specific reference to Low and Middle-Income Countries (LMICs)?. Our ambition is to identify commonalities across definitions and measures to generate a dialogue towards reaching consensus around the development of a single standardised tool to be applied in health studies.Methods and analysis Our mixed-method scoping review includes quantitative, qualitative and mixed-methods studies and unfolds according to the six stages proposed by Levac et al. Eligibility criteria for studies were defined in order to reflect the three core elements of the search, namely (1) the discrimination based on the gender, (2) the link to health outcomes and (3) the developing countries context. Four databases (PubMed, Web of Science, Cinahl and Econlit) were searched. We will extract and synthesise information from quantitative and qualitative studies following the framework proposed by Hong and use the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping review tool as a guide.Ethics and dissemination Since our scoping review relies exclusively on information extracted from published articles, its conduct is not subjected to ethical clearance. Results will be described and discussed in a peer-reviewed article and presented at relevant workshops and conferences.

Introduction Major haemorrhage after injury is the leading cause of preventable death for trauma patients. Recent advancements in trauma care suggest damage control resuscitation (DCR) should start in the prehospital phase following major trauma. In Italy, Helicopter Emergency Medical Services (HEMS) assist the most complex injuries and deliver the most advanced interventions including DCR. The effect size of DCR delivered prehospitally on survival remains however unclear.Methods and analysis This is an investigator-initiated, large, national, prospective, observational cohort study aiming to recruit >500 patients in haemorrhagic shock after major trauma. We aim at describing the current practice of hypotensive trauma management as well as propose the creation of a national registry of patients with haemorrhagic shock. Primary objective: the exploration of the effect size of the variation in clinical practice on the mortality of hypotensive trauma patients. The primary outcome measure will be 24 hours, 7-day and 30-day mortality. Secondary outcomes include: association of prehospital factors and survival from injury to hospital admission, hospital length of stay, prehospital and in-hospital complications, hospital outcomes; use of prehospital ultrasound; association of prehospital factors and volume of first 24-hours blood product administration and evaluation of the prevalence of use, appropriateness, haemodynamic, metabolic and effects on mortality of prehospital blood transfusions. Inclusion criteria: age >18 years, traumatic injury attended by a HEMS team including a physician, a systolic blood pressure

Objective To estimate the economic cost associated with implementing the Results Based Financing for Maternal and Newborn Health (RBF4MNH) Initiative in Malawi. No specific hypotheses were formulated ex-ante.Setting Primary and secondary delivery facilities in rural Malawi.Participants Not applicable. The study relied almost exclusively on secondary financial data.Intervention The RBF4MNH Initiative was a results-based financing (RBF) intervention including both a demand and a supply-side component.Primary and secondary outcome measures Cost per potential and for actual beneficiaries.Results The overall economic cost of the Initiative during 2011–2016 amounted to €12 786 924, equivalent to €24.17 per pregnant woman residing in the intervention districts. The supply side activity cluster absorbed over 40% of all resources, half of which were spent on infrastructure upgrading and equipment supply, and 10% on incentives. Costs for the demand side activity cluster and for verification were equivalent to 14% and 6%, respectively of the Initiative overall cost.Conclusion Carefully tracing resource consumption across all activities, our study suggests that the full economic cost of implementing RBF interventions may be higher than what was previously reported in published cost-effectiveness studies. More research is urgently needed to carefully trace the costs of implementing RBF and similar health financing innovations, in order to inform decision-making in low-income and middle-income countries around scaling up RBF approaches.

BackgroundHealth systems are complex systems involving a vast range of actors. In West Africa, they are often not accessible or responsive. Burkina Faso has widely expressed, in its public health policy, the need to improve both access to quality care and health system responsiveness. There is also a strong wish to give more voice to citizens. To support Burkinabè institutions in achieving these goals, we have developed an action research (AR) protocol. ObjectiveThis paper presents the protocol that will address citizens’ participation in health policies and their empowerment through the expression of opinions, for accountability, as well as the strengthening of the health system using information and communication technologies (ICTs). MethodsOur approach will consist of (1) enabling people to express their opinions on the health system by means of a toll-free (TF) service coupled with an interactive voice server (IVS); (2) building an information base with anonymous and reliable data; and (3) conducting information awareness-raising activities, including knowledge transfer (KT) and advocacy, social integration activities, development of OpenData platforms, and the capitalization and media coverage of governance issues. For this purpose, the AR project will be implemented in Burkina Faso. The design uses a concurrent mixed-methods approach. This AR project will evaluate the acceptability, process, effectiveness, and economic costs of the device’s implementation. We will also analyze the potential for the data collected by the device to be used to improve practices. ResultsData collection is in progress; the TF number was officially launched on July 1, 2020, and data collection is planned to continue throughout 2021. By using mixed methods, our AR will be approached from a variety of perspectives. Mixed methods will support us in combining the partial insights into sophisticated realities from qualitative inquiries with the data analyses produced by quantitative research. ConclusionsThis AR is expected to add knowledge on how to increase the empowerment of the population, especially the most vulnerable, to participate in democratic processes and enjoy and exercise their human rights. This protocol recommends implementing a low-cost, contextually adapted technology, associated with an evidence-based approach and carried out on a significant scale. The originality of this approach lies in the fact that it introduces a real AR dimension with local communities and nongovernmental organizations (NGOs), combined with an integrated strategy of KT and application throughout the project for all stakeholders. International Registered Report Identifier (IRRID)DERR1-10.2196/28780

Low back pain continues to be a major clinical challenge with high direct and indirect societal costs. It is a complex disease with complex pathophysiology both for acute and chronic low back pain. Although there is consistent evidence about multidisciplinary treatment of low back pain, several different approaches and techniques are proposed, with different results often conflicting among them. In fact, even though the multidisciplinary approach is widely accepted, it is generally applied in different steps involving only one health care providing for each approach. This approach not only does not guarantee a real multidisciplinary vision of this disease but also lacks evaluation of the dynamic changes of the disease according to real patients’ needs. In our hospital setting we have developed a “simultaneous multidisciplinary care” of low back pain patients in order to overcome these problems and to satisfy all patients’ needs by evaluating and treating all problems causing and related to low back pain. Starting from the existing literature we propose our approach as a new pathway to treat low back patients with a simultaneous multidisciplinary approach.

Climate change is one of today's major challenges, and among the causes of population movement and international migration. Climate migrants impact health systems and how their ability to respond and adapt to their needs and patterns. To date, the resilience of health systems in the context of climate change has barely been explored. The purpose of this article is to show the importance of studying the relationship between climate change, migration, and the resilience of health systems from an interdisciplinary perspective. Resilience is an old concept, notably in the field of psychology, and is increasingly applied to the study of health systems. Yet, no research has analysed the resilience of health systems in the context of climate change. While universal health coverage is a major international goal, little research to date focused on the existing links between climate, migration, health systems and resilience. We propose an interdisciplinary approach relying on the concept of health system resilience to study adaptive and transformative strategies to articulate climate change, migration and health systems.

Objetivo: La fibromialgia ( FM ) es un síndrome de dolor crónico generalizado, asociado a alteraciones emocionales y comportamentales. El objetivo de este estudio fue identificar los síntomas afectivo-conductuales y las estrategias cognitivas de afrontamiento en la percepción de dolor de pacientes con FM . Material y métodos: Se realizó un estudio de corte transversal, con análisis de casos y controles, con una muestra de dos grupos de mujeres, en la ciudad de Barranquilla (Colombia): 34 con diagnóstico de FM y 30 controles, a quienes se les realizó evaluación de síntomas psicológicos y de percepción de dolor. Resultados: Los pacientes con FM presentan significativamente mayores síntomas afectivo- conductuales (ansiedad, depresión, insomnio, somatización y disfunción social) que los sujetos controles (p

Results-based financing (RBF) schemes-including performance based financing (PBF) and conditional cash transfers (CCT)-are increasingly being used to encourage use and improve quality of institutional health care for pregnant women in order to reduce maternal and neonatal mortality in low-income countries. While there is emerging evidence that RBF can increase service use and quality, little is known on the impact of RBF on costs and time to seek care for obstetric complications, although the two represent important dimensions of access. We conducted this study to fill the existing gap in knowledge by investigating the impact of RBF (PBF+CCT) on household costs and time to seek care for obstetric complications in four districts in Malawi. The analysis included data on 2,219 women with obstetric complications from three waves of a population-based survey conducted at baseline in 2013 and repeated in 2014(midline) and 2015(endline). Using a before and after approach with controls, we applied generalized linear models to study the association between RBF and household costs and time to seek care. Results indicated that receipt of RBF was associated with a significant reduction in the expected mean time to seek care for women experiencing an obstetric complication. Relative to non-RBF, time to seek care in RBF areas decreased by 27.3% (95%CI: 28.4-25.9) at midline and 34.2% (95%CI: 37.8-30.4) at endline. No substantial change in household costs was observed. We conclude that the reduced time to seek care is a manifestation of RBF induced quality improvements, prompting faster decisions on care seeking at household level. Our results suggest RBF may contribute to timely emergency care seeking and thus ultimately reduce maternal and neonatal mortality in beneficiary populations.

Breakthrough cancer Pain (BTcP) has a high prevalence in cancer population. Patients with BTcP reported relevant health care costs and poor quality of life. The study assessed the cost-effectiveness of the available Oral Fentanyl Formulations (OFFs) for BTcP in Italy. A decision-analytical model was developed to estimate costs and benefits associated with treatments, from the Italian NHS perspective. Expected reductions in pain intensity per BTcP episodes were translated into, percentage of BTcP reduction, resource use and Quality-Adjusted-Life-Years (QALYs). Relative efficacy, resources used and unit costs data were derived from the literature and validated by clinical experts. Probabilistic and deterministic sensitivity analyses were performed. At base-case analysis, Sublingual Fentanyl Citrate (FCSL) compared to other oral formulations reported a lower patient's cost (€1,960.8) and a higher efficacy (18.7% of BTcP avoided and 0.0507 QALYs gained). The sensitivity analyses confirmed the main results in all tested scenarios, with the highest impact reported by BTcP duration and health care resources consumption parameters. Between OFFs, FCSL is the cost-effective option due to faster reduction of pain intensity. However, new research is needed to better understand the economic and epidemiologic impact of BTcP, and to collect more robust data on economic and quality of life impact of the different fentanyl formulations. Different fentanyl formulations are available to manage BTcP in cancer population. The study is the first that assesses the different impact in terms of cost and effectiveness of OFFs, providing new information to better allocate the resources available to treat BTcP and highlighting the need of better data.

Chronic low back pain (CLBP) is one of the most common medical conditions, ranking as the greatest contributor to global disability and accounting for huge societal costs based on the Global Burden of Disease 2010 study. Large genetic and -omics studies provide a promising avenue for the screening, development and validation of biomarkers useful for personalized diagnosis and treatment (precision medicine). Multicentre studies are needed for such an effort, and a standardized and homogeneous approach is vital for recruitment of large numbers of participants among different centres (clinical and laboratories) to obtain robust and reproducible results. To date, no validated standard operating procedures (SOPs) for genetic/-omics studies in chronic pain have been developed. In this study, we validated an SOP model that will be used in the multicentre (5 centres) retrospective "PainOmics" study, funded by the European Community in the 7th Framework Programme, which aims to develop new biomarkers for CLBP through three different -omics approaches: genomics, glycomics and activomics. The SOPs describe the specific procedures for (1) blood collection, (2) sample processing and storage, (3) shipping details and (4) cross-check testing and validation before assays that all the centres involved in the study have to follow. Multivariate analysis revealed the absolute specificity and homogeneity of the samples collected by the five centres for all genetics, glycomics and activomics analyses. The SOPs used in our multicenter study have been validated. Hence, they could represent an innovative tool for the correct management and collection of reliable samples in other large-omics-based multicenter studies.

Chronic low back pain (CLBP) is a chronic pain syndrome in the lower back region, lasting for at least 3 months. CLBP represents the second leading cause of disability worldwide being a major welfare and economic problem. The prevalence of CLBP in adults has increased more than 100% in the last decade and continues to increase dramatically in the aging population, affecting both men and women in all ethnic groups, with a significant impact on functional capacity and occupational activities. It can also be influenced by psychological factors, such as stress, depression and/or anxiety. Given this complexity, the diagnostic evaluation of patients with CLBP can be very challenging and requires complex clinical decision-making. Answering the question “what is the pain generator” among the several structures potentially involved in CLBP is a key factor in the management of these patients, since a mis-diagnosis can generate therapeutical mistakes. Traditionally, the notion that the etiology of 80% to 90% of LBP cases is unknown has been mistaken perpetuated across decades. In most cases, low back pain can be attributed to specific pain generator, with its own characteristics and with different therapeutical opportunity. Here we discuss about radicular pain, facet Joint pain, sacro-iliac pain, pain related to lumbar stenosis, discogenic pain. Our article aims to offer to the clinicians a simple guidance to identify pain generators in a safer and faster way, relying a correct diagnosis and further therapeutical approach.

Chronic low back pain (CLBP) is a chronic pain syndrome in the lower back region, lasting for at least 3 months. CLBP represents the second leading cause of disability worldwide being a major welfare and economic problem. The prevalence of CLBP in adults has increased more than 100% in the last decade and continues to increase dramatically in the aging population, affecting both men and women in all ethnic groups, with a significant impact on functional capacity and occupational activities. It can also be influenced by psychological factors, such as stress, depression and/or anxiety. Given this complexity, the diagnostic evaluation of patients with CLBP can be very challenging and requires complex clinical decision-making. Answering the question “what is the pain generator” among the several structures potentially involved in CLBP is a key factor in the management of these patients, since a mis-diagnosis can generate therapeutical mistakes. Traditionally, the notion that the etiology of 80% to 90% of LBP cases is unknown has been mistaken perpetuated across decades. In most cases, low back pain can be attributed to specific pain generator, with its own characteristics and with different therapeutical opportunity. Here we discuss about radicular pain, facet Joint pain, sacro-iliac pain, pain related to lumbar stenosis, discogenic pain. Our article aims to offer to the clinicians a simple guidance to identify pain generators in a safer and faster way, relying a correct diagnosis and further therapeutical approach.

The aim of this study was to assess vitamin D (vit.D) levels in patients with primary antiphospholipid syndrome (PAPS), the association between hypovitaminosis D and clinical manifestations, and the effect of vit.D supplementation on serum levels. Vit.D serum levels of 115 PAPS patients, classified according to the 2006 revised criteria at the Rheumatology Department, Brescia, and of 128 voluntary healthy donors (NHD) were tested in collaboration with DiaSorin (Saluggia, Italy) using the LIAISON® chemiluminescent immunoassay. Clinical data were derived from clinical charts. Vit.D deficiency was more prevalent in PAPS than NHD (17% vs 5%). During the summer, vit.D levels were lower in PAPS than NHD (median 28 vs 40.1 ng/mL, P

Objective: It was reported by several groups that patients diagnosed as primary antiphospholipid syndrome (PAPS) had developed a full-blown systemic lupus erythematosus (SLE) even after many years of follow-up. Little is known about clinical and/or serological factors that may help predict such evolution. Antinucleosome antibodies (anti-NCS) were described to appear in early stages of SLE, in particular before anti-dsDNA antibodies. The aim of the study is to evaluate the prevalence of anti-NCS in a large cohort of PAPS patients. Methods: IgG and IgM anti-NCS antibodies were detected using a home made assay with H1-stripped chromatin as antigen. Sera from 106 PAPS patients were tested; 52 of them were also tested during the follow-up, at least 2 years apart form the basal sample. Results: Medium-high titre anti-NCS were found in nearly half of the patients (49/106, 46%), more frequently in those presenting features of “lupus like disease”. Most of patients displayed an unchanged pattern of anti-NCS over time. We describe three cases of PAPS patients that developed SLE after many years of follow-up; high titre and low titre anti-NCS were present in two and one of them respectively several years before evolving into SLE. Conclusions: A significant proportion of PAPS patients displayed medium-high titre anti-NCS, suggesting that the autoimmune response against chromatin may be a relevant event not only in patients with SLE. Further studies are warranted to explore the predictive value of anti-NCS with respect to the evolution from PAPS to SLE.

Titanium dioxide (TiO2) nanofibres are a novel fibrous nanomaterial with increasing applications in a variety of fields. While the biological effects of TiO2 nanoparticles have been extensively studied, the toxicological characterization of TiO2 nanofibres is far from being complete. In this study, we evaluated the toxicity of commercially available anatase TiO2 nanofibres using TiO2 nanoparticles (NP) and crocidolite asbestos as non-fibrous or fibrous benchmark materials. The evaluated endpoints were cell viability, haemolysis, macrophage activation, trans-epithelial electrical resistance (an indicator of the epithelial barrier competence), ROS production and oxidative stress as well as the morphology of exposed cells. The results showed that TiO2 nanofibres caused a cell-specific, dose-dependent decrease of cell viability, with larger effects on alveolar epithelial cells than on macrophages. The observed effects were comparable to those of crocidolite, while TiO2 NP did not decrease cell viability. TiO2 nanofibres were also found endowed with a marked haemolytic activity, at levels significantly higher than those observed with TiO2 nanoparticles or crocidolite. Moreover, TiO2 nanofibres and crocidolite, but not TiO2 nanoparticles, caused a significant decrease of the trans-epithelial electrical resistance of airway cell monolayers. SEM images demonstrated that the interaction with nanofibres and crocidolite caused cell shape perturbation with the longest fibres incompletely or not phagocytosed. The expression of several pro-inflammatory markers, such as NO production and the induction of Nos2 and Ptgs2, was significantly increased by TiO2 nanofibres, as well as by TiO2 nanoparticles and crocidolite. This study indicates that TiO2 nanofibres had significant toxic effects and, for most endpoints with the exception of pro-inflammatory changes, are more bio-active than TiO2 nanoparticles, showing the relevance of shape in determining the toxicity of nanomaterials. Given that several toxic effects of TiO2 nanofibres appear comparable to those observed with crocidolite, the possibility that they exert length dependent toxicity in vivo seems worthy of further investigation.

Nitrophorins represent a unique class of heme proteins that are able to perform the delicate transportation and release of the free-radical gaseous messenger nitric oxide (NO) in a pH-triggered manner. Besides its ability to bind to phospholipid membranes, the N-terminus of NP7, a member of the NO transporter nitrophorin family, contains an additional Leu-Pro-Gly stretch, which is a unique sequence trait, and the heme cavity is significantly altered with respect to other nitrophorins. These distinctive features encouraged us to solve the X-ray crystallographic structures of NP7 at low and high pH and bound with different heme ligands (nitric oxide, histamine, imidazole). The overall fold of the lipocalin motif is well preserved in the different X-ray structures and resembles the fold of other nitrophorins. However, a chain-like arrangement in the crystal lattice due to a number of head-to-tail electrostatic stabilizing interactions is found in NP7. Furthermore, the X-ray structures also reveal ligand-dependent changes in the orientation of the heme, as well as in specific interactions between the A-B and G-H loops, which are considered to be relevant for the biological function of nitrophorins. Fast and ultrafast laser triggered ligand rebinding experiments demonstrate the pH-dependent ligand migration within the cavities and the exit route. Finally, the topological distribution of pockets located around the heme as well as from inner cavities present at the rear of the protein provides a distinctive feature in NP7, so that while a loop gated exit mechanism to the solvent has been proposed for most nitrophorins, a more complex mechanism that involves several interconnected gas hosting cavities is proposed for NP7.

BACKGROUND:A variety of clinical process indicators exists to measure the quality of care provided by maternal and neonatal health (MNH) programs. To allow comparison across MNH programs in low- and middle-income countries (LMICs), a core set of essential process indicators is needed. Although such a core set is available for emergency obstetric care (EmOC), the 'EmOC signal functions', a similar approach is currently missing for MNH routine care evaluation. We describe a strategy for identifying core process indicators for routine care and illustrate their usefulness in a field example. METHODS:We first developed an indicator selection strategy by combining epidemiological and programmatic aspects relevant to MNH in LMICs. We then identified routine care process indicators meeting our selection criteria by reviewing existing quality of care assessment protocols. We grouped these indicators into three categories based on their main function in addressing risk factors of maternal or neonatal complications. We then tested this indicator set in a study assessing MNH quality of clinical care in 33 health facilities in Malawi. RESULTS:Our strategy identified 51 routine care processes: 23 related to initial patient risk assessment, 17 to risk monitoring, 11 to risk prevention. During the clinical performance assessment a total of 82 cases were observed. Birth attendants' adherence to clinical standards was lowest in relation to risk monitoring processes. In relation to major complications, routine care processes addressing fetal and newborn distress were performed relatively consistently, but there were major gaps in the performance of routine care processes addressing bleeding, infection, and pre-eclampsia risks. CONCLUSION:The identified set of process indicators could identify major gaps in the quality of obstetric and neonatal care provided during the intra- and immediate postpartum period. We hope our suggested indicators for essential routine care processes will contribute to streamlining MNH program evaluations in LMICs.

This study aimed to explore factors shaping the decision to undergo Human Immunodeficiency Virus (HIV) testing among men in rural Burkina Faso.The study took place in 2009 in the Nouna Health District and adopted a triangulation mixed methods design. The quantitative component relied on data collected through a structured survey on a representative sample of 1130 households. The qualitative component relied on 38 in-depth interviews, with men purposely selected to represent variation in testing decision, age, and place of residence. A two-part model was conducted, with two distinct outcome variables, i.e. "being offered an HIV test" and "having done an HIV test". The qualitative data analysis relied on inductive coding conducted by three independent analysts.Of the 937 men, 357 had been offered an HIV test and 97 had taken the test. Younger age, household wealth, living in a village under demographic surveillance, and knowing that HIV testing is available at primary health facilities were all positively associated with the probability of being offered an HIV test. Household wealth and literacy were found to be positively associated, and distance was found to be negatively associated with the probability of having taken an HIV test. Qualitative findings indicated that the limited uptake of HIV testing was linked to poor knowledge on service availability and to low risk perceptions.With only 10% of the total sample ever having tested for HIV, our study confirmed that male HIV testing remains unacceptably low in Sub-Saharan Africa. This results from a combination of health system factors, indicating general barriers to access, and motivational factors, such as one's own knowledge of service availability and risk perceptions. Our findings suggested that using antenatal care and curative services as the exclusive entry points into HIV testing may not be sufficient to reach large portions of the male population. Thus, additional strategies are urgently needed to increase service uptake.

In Sub-Saharan Africa (SSA) the disease burden of chronic non-communicable diseases (CNCDs) is rising considerably. Given weaknesses in existing financial arrangements across SSA, expenditure on CNCDs is often borne directly by patients through out-of-pocket (OOP) payments. This study explored patterns and determinants of OOP expenditure on CNCDs in Malawi. We used data from the first round of a longitudinal household health survey conducted in 2012 on a sample of 1199 households in three rural districts in Malawi. We used a two-part model to analyze determinants of OOP expenditure on CNCDs. 475 respondents reported at least one CNCD. More than 60% of the 298 individuals who reported seeking care incurred OOP expenditure. The amount of OOP expenditure on CNCDs comprised 22% of their monthly per capita household expenditure. The poorer the household, the higher proportion of their monthly per capita household expenditure was spent on CNCDs. Higher severity of disease was significantly associated with an increased likelihood of incurring OOP expenditure. Use of formal care was negatively associated with the possibility of incurring OOP expenditure. The following factors were positively associated with the amount of OOP expenditure: being female, Alomwe and household head, longer duration of disease, CNCDs targeted through active screening programs, higher socio-economic status, household head being literate, using formal care, and fewer household members living with a CNCD within a household. Our study showed that, in spite of a context where care for CNCDs should in principle be available free of charge at point of use, OOP payments impose a considerable financial burden on rural households, especially among the poorest. This suggests the existence of important gaps in financial protection in the current coverage policy.

BACKGROUND: In Switzerland, 30% of HIV-infected individuals are diagnosed late. To optimize HIV testing, the Swiss Federal Office of Public Health (FOPH) updated 'Provider Induced Counseling and Testing' (PICT) recommendations in 2010. These permit doctors to test patients if HIV infection is suspected, without explicit consent or pre-test counseling; patients should nonetheless be informed that testing will be performed. We examined awareness of these updated recommendations among emergency department (ED) doctors. METHODS: We conducted a questionnaire-based survey among 167 ED doctors at five teaching hospitals in French-Speaking Switzerland between 1(st) May and 31(st) July 2011. For 25 clinical scenarios, participants had to state whether HIV testing was indicated or whether patient consent or pre-test counseling was required. We asked how many HIV tests participants had requested in the previous month, and whether they were aware of the FOPH testing recommendations. RESULTS: 144/167 doctors (88%) returned the questionnaire. Median postgraduate experience was 6.5 years (interquartile range [IQR] 3; 12). Mean percentage of correct answers was 59 ± 11%, senior doctors scoring higher (P=0.001). Lowest-scoring questions pertained to acute HIV infection and scenarios where patient consent was not required. Median number of test requests was 1 (IQR 0-2, range 0-10). Only 26/144 (18%) of participants were aware of the updated FOPH recommendations. Those aware had higher scores (P=0.001) but did not perform more HIV tests. CONCLUSIONS: Swiss ED doctors are not aware of the national HIV testing recommendations and rarely perform HIV tests. Improved recommendation dissemination and adherence is required if ED doctors are to contribute to earlier HIV diagnoses.

BackgroundInsecticide-impregnated bed nets (ITNs) have been shown to be a highly effective tool against malaria in the endemic regions of sub-Saharan Africa (SSA). There are however different opinions about the role of ITN social marketing and ITN free distribution in the roll-out of ITN programmes. The objective of this study was to evaluate the effects of free ITN distribution through antenatal care services in addition to an ITN social marketing programme in an area typical for rural SSA.MethodsA cluster-randomised controlled ITN trial took place in the whole Kossi Province in north-western Burkina Faso, an area highly endemic for malaria. Twelve clusters were assigned to long-term ITN (Serena brand) social marketing plus free ITN (Serena brand) distribution to all pregnant women attending governmental antenatal care services (group A), and 13 clusters to ITN social marketing only (group B). The intervention took place during the rainy season of 2006 and thereafter. The trial was evaluated through a representative household survey at baseline and after one year. Serena ITN household ownership was the primary outcome measure.FindingsA total of 1052 households were visited at baseline in February 2006 and 1050 at follow-up in February 2007. Overall Serena ITN household ownership increased from 16% to 28% over the study period, with a significantly higher increase in group A (13% to 35%) than in group B (18% to 23%) (pInterpretationThe free distribution of ITNs to pregnant women through governmental antenatal care services in addition to ITN social marketing substantially improved ITN household ownership in rural Burkina Faso.Trial registrationControlled-Trials.com ISRCTN07985309.

We studied 99 patients with systemic autoimmune disease (5 males, 94 women; mean age 37 year, range 16-72): 28 Primary Antiphospholipid Syndrome, 67 Systemic lupus Erythematosus, 1 Mixed Connective Tissue Disease, 2 Undifferentiated Connective Tissue Disease and 1 Discoid Lupus. Based on the observation that native PT shows conformational changes in presence of Ca++ ions and discloses new epitopes available for binding with phospholipids, we performed 3 different methods for the detection of aPT in presence and absence of Ca++, finding a different incidence of specific autoantibodies, associated with clinical features of APS (aPT in presence of Ca++) or non associated (aPT in absence of Ca++). The presence of aPT was significantly associated also with the presence of Lupus Anticoagulant (LAC). The detection of aPT (in presence of Ca++) significantly enhances diagnostic sensibility of APS allowing the identification of a subset of patients (6/99) with clinical features of APS, but with negative LAC, aCL and aβ2-GPI; in fact (limited to thrombotic episodes) the sensibility rises from 56.2% with one test (LAC) to 81.1% with the application of LAC, aCL, aβ2GPI and aPT.

Abstract Background Nutrition has been widely recognized to influence the risk of kidney stone formation. Therefore the aim of our study was to assess: a) whether usual diet of women with idiopathic calcium nephrolithiasis (ICN) living in Parma (Northern-Italy) is different compared to healthy controls, b) how their diet differs from Italian National guidelines and c) whether it is related to nephrolithiasis clinical course. Methods 143 women with recurrent ICN (mean age 43 ± 13 ys) and 170 healthy women (mean age 42 ± 11 ys) were enrolled. All women completed a food frequency questionnaire for the last 60-days and a 3-day dietary diary analysed with a dedicated software. Results Stone formers showed a higher consumption of sausages, ham, meat and sweets than healthy controls (43.1% vs 11.1%, 29.4% vs 13.9%, 21.6% vs 4.2%, 66.7% vs 18.1%, p < 0.001). The 3-day diary analysis showed an intake of calories, carbohydrates, lipids and non-discretionary sodium about 10% higher than healthy controls (p < 0.001). Finally, after dividing the population into 3 age groups (≤30, 31-40, > 40 years), the differences described above were amplified in the class ≤30 years, where nephrolithiasis presented a more serious course (shorter recurrence interval, greater stone-rate). In this age group the intake of fruit and vegetables was notably lower than guideline recommendations. Conclusions We conclude that the usual diet of women with recurrent ICN is different from controls and characterized by low intake of fruits and vegetables and higher consumption of simple sugars and foods with high protein and salt content. This dietary imbalance could play a role in the ICN pathogenesis, especially in younger women. This work was financed by grants from Italian Ministry of University and Research as part of a larger project about the prevention of kidney stones (PRIN 2005063822) and by Fondazione per la Ricerca Scientifica Termale (FoRST). No potential conflict of interest relevant to this paper was reported.

Abstract Background Counselling on the danger signs of unpredictable obstetric complications and the appropriate management of such complications are crucial in reducing maternal mortality. The objectives of this study were to identify gaps in the provision of ANC services and knowledge of danger signs as well as the quality of care women receive in case of complications. Findings The study took place in the Rufiji District of Tanzania in 2008 and was conducted in seven health facilities. The study used (1) observations from 63 antenatal care (ANC) sessions evaluated with an ANC checklist, (2) self-assessments of 11 Health workers, (3) interviews with 28 pregnant women and (4) follow-up of 12 women hospitalized for pregnancy-related conditions. Blood pressure measurements and abdominal examinations were common during ANC visits while urine testing for albumin or sugar or haemoglobin levels was rare which was often explained as due to a lack of supplies. The reasons for measuring blood pressure or abdominal examinations were usually not explained to the women. Only 15/28 (54%) women were able to mention at least one obstetric danger sign requiring medical attention. The outcomes of ten complicated cases were five stillbirths and three maternal complications. There was a considerable delay in first contact with a health professional or the start of timely interventions including checking vital signs, using a partograph, and detailed record keeping. Conclusion Linking danger signs to clinical and laboratory examination results during ANC with the appropriate follow up and avoiding delays in emergency obstetric care are crucial to the delivery of coordinated, effective care interventions.