Challenges and opportunities for access to Advanced Therapy Medicinal Products in Brazil.

BACKGROUND AIMS: The marketing authorization of Advanced Therapy Medicinal Products (ATMPs) in Brazil is recent. The features of these therapies impose specialized regulatory action and are consequently challenging for developers. The goal of this study was to identify the industry's experience in clinical development, marketing authorization and access to ATMPs through the Unified Health System (SUS, acronym in Portuguese), from a regulatory perspective. METHODS: A survey containing structured questions was conducted among research participants who work at companies that commercialize ATMPs. A descriptive analysis was performed. RESULTS: We invited 15 foreign pharmaceutical companies, of which 10 agreed to participate. Overall, participants assessed that Brazil has a well-established regulatory system, especially the sanitary registration by the National Health Surveillance Agency (Anvisa), which ensures the quality, safety, and efficacy of the products. The Agency's good interaction with the regulated sector, the harmonization of sanitary and ethical assessment systems with other countries, and the analysis time in the biosafety assessment of Genetically Modified Organisms (GMOs) stand out as positive in industry's evaluation. On the other hand, it is important to advance the pricing regulation for these products since Brazilian regulations do not establish specific criteria for ATMP. One of the biggest challenges is the difficulty for the SUS in reimbursing these very high-cost therapies, especially using current Health Technology Assessment (HTA) methods. CONCLUSIONS: Considering the increasing number of approvals of cell and gene therapies in Brazil in the coming years, a close dialogue between the industry and the public sector is recommended to advance regulatory improvements (pricing and HTA). Additionally, the construction of policies to promote the national Health Economic-Industrial Complex, based on a mission-oriented vision that encourages innovative models of financing, especially those that consider risk-sharing and co-financing technologies, will help provide the population with universal, equitable and sustainable access to ATMP in the SUS.

Genetic Epidemiology and Clinical Characteristics of Patients with Spinocerebellar Ataxias in an Unexplored Brazilian State, Using Strategies for Resource-Limited Settings.

Spinocerebellar ataxias (SCAs) have a worldwide average prevalence of 2.7 cases per 100,000 individuals, with significant geographic variability. This study aimed to develop resource-limited strategies to detect and characterize the frequency and genetic-clinical profile of SCAs in an unexplored population from Alagoas State, a low Human Development Index state in northeastern Brazil. Active search strategies were employed to identify individuals with a diagnosis or clinical suspicion of SCAs, and a protocol for clinical and molecular evaluation was applied in collaboration with a reference center in Neurogenetics. A total of 73 individuals with SCAs were identified, with a minimum estimated prevalence of 2.17 cases per 100,000 inhabitants. SCA3 was the most common type (75.3%), followed by SCA7 (15.1%), SCA1 (6.8%), and SCA2 (2.7%). Patients with SCA3 subphenotype 2 were the most predominant. Detailed analysis of patients with SCA3 and SCA7 revealed age at onset and clinical features congruent with other studies, with gait disturbance and reduced visual capacity in SCA7 as the main initial manifestations. The study also identified many asymptomatic individuals at risk of developing SCAs. These findings demonstrate that simple and collaborative strategies can enhance the detection capacity of rare diseases such as SCAs in resource-limited settings and that Alagoas State has a minimum estimated prevalence of SCAs similar to the world average.

Orthognathic surgery associated with reconstruction of the temporomandibular joint with a customized prosthesis: a case report.

The objective of this case report is to describe the treatment of a dentofacial and temporomandibular joint (TMJ) deformity by means of reconstruction with a customized TMJ prosthesis and orthognathic surgery. The article discusses the therapeutic approach and the importance of functional and esthetic rehabilitation of the patient. A 22-year-old man displayed sequelae of osteomyelitis diagnosed at 6 years of age, including facial asymmetry, laterognathism, unsatisfactory occlusion, and mandibular retrognathism. Computed tomography revealed a deformity of the left mandibular condyle, ramus, and fossa. The patient underwent 1-stage surgery that involved bimaxillary orthognathic surgery and mentoplasty in conjunction with reconstruction of the left TMJ with a customized prosthesis. Postoperatively, substantial improvement was observed in the patient's facial pattern and masticatory function, and the beneficial changes have been maintained through 2 years of follow-up. The positive outcome in this patient suggests that TMJ reconstruction using a customized prosthesis in combination with computer-guided orthognathic surgery can be a satisfactory approach to correct a mandibular defect. The advantages of 1-stage surgery for the surgeon include shorter treatment time and more predictable results, while the benefits for the patient are good esthetic and functional results and improved quality of life.

Performance bonuses and the quality of primary health care delivered by family health teams in Brazil: A difference-in-differences analysis.

BACKGROUND: Pay-for-performance (P4P) programmes to incentivise health providers to improve quality of care have been widely implemented globally. Despite intuitive appeal, evidence on the effectiveness of P4P is mixed, potentially due to differences in how schemes are designed. We exploited municipality variation in the design features of Brazil's National Programme for Improving Primary Care Access and Quality (PMAQ) to examine whether performance bonuses given to family health team workers were associated with changes in the quality of care and whether the size of bonus mattered. METHODS AND FINDINGS: For this quasi-experimental study, we used a difference-in-differences approach combined with matching. We compared changes over time in the quality of care delivered by family health teams between (bonus) municipalities that chose to use some or all of the PMAQ money to provide performance-related bonuses to team workers with (nonbonus) municipalities that invested the funds using traditional input-based budgets. The primary outcome was the PMAQ score, a quality of care index on a scale of 0 to 100, based on several hundred indicators (ranging from 598 to 660) of health care delivery. We did one-to-one matching of bonus municipalities to nonbonus municipalities based on baseline demographic and economic characteristics. On the matched sample, we used ordinary least squares regression to estimate the association of any bonus and size of bonus with the prepost change over time (between November 2011 and October 2015) in the PMAQ score. We performed subgroup analyses with respect to the local area income of the family health team. The matched analytical sample comprised 2,346 municipalities (1,173 nonbonus municipalities; 1,173 bonus municipalities), containing 10,275 family health teams that participated in PMAQ from the outset. Bonus municipalities were associated with a 4.6 (95% CI: 2.7 to 6.4; p < 0.001) percentage point increase in the PMAQ score compared with nonbonus municipalities. The association with quality of care increased with the size of bonus: the largest bonus group saw an improvement of 8.2 percentage points (95% CI: 6.2 to 10.2; p < 0.001) compared with the control. The subgroup analysis showed that the observed improvement in performance was most pronounced in the poorest two-fifths of localities. The limitations of the study include the potential for bias from unmeasured time-varying confounding and the fact that the PMAQ score has not been validated as a measure of quality of care. CONCLUSIONS: Performance bonuses to family health team workers compared with traditional input-based budgets were associated with an improvement in the quality of care.

Landscape of Brazilian research and development public funding in advanced therapies: lessons learned and a roadmap for middle-income economies.

BACKGROUND AIMS: Advanced therapy medicinal products (ATMPs) have reached the forefront of biotechnological innovation, partly due to public funders' efforts in the early stages of research and development (R&D). Data on investment in R&D of ATMPs are recognized as scarce, particularly in developing countries. Because of the numerous peculiarities of the Brazilian health system and the science and technology (S&T) system, the country is a good example for the evaluation of public investments in R&D of ATMPs. The aim of this study is to analyze the evolution of investments made by the Ministry of Health (MoH) of Brazil and partners in the ATMP field between 2004 and 2020. METHODS: A descriptive analysis was performed based on secondary data. The analysis was based on S&T and innovation research and support for research infrastructure in the field. The database was stratified by year of funding, ATMP type, type of study or research infrastructure project, amount invested in the project, targeted disease for which clinical trials in ATMPs were developed and financing sector (health, education, S&T and economic). RESULTS: The investments coordinated by MoH (61.5%) in partnership with the S&T, education and economic sectors (38.5%) consisted of Int$137.35 million in 282 ATMP projects. Funding included S&T and innovation research (67% of the total amount) and projects to implement or maintain infrastructure in selected research centers (32.98%). With regard to global convergence, cell therapy was the type of ATMP that most benefited from public investment, totaling 82.23% of the total funding in the analyzed period. Cardiology (29%) and neurology (21%) were the main focus of clinical trials. Following the global trend of public sector R&D funding, the number of basic and pre-clinical research projects represented 78.06% of the total number of projects. CONCLUSIONS: Despite the need to implement improvements in ATMP R&D financing policy in Brazil, the country has made important steps in the field and can serve as a benchmark for other countries with socioeconomic similarities. Among the main lessons are the prioritization of research aligned with the health needs of the population, cross-sector articulation by the health policymaker to coordinate R&D efforts of the sector and formulation of a specific sector policy (Programa Genomas Brasil, the Brazilian National Program of Genomic and Precision Medicine) to promote knowledge translation.

Advances in the Asymmetric Synthesis of BINOL Derivatives.

BINOL derivatives have shown relevant biological activities and are important chiral ligands and catalysts. Due to these properties, their asymmetric synthesis has attracted the interest of the scientific community. In this work, we present an overview of the most efficient methods to obtain chiral BINOLs, highlighting the use of metal complexes and organocatalysts as well as kinetic resolution. Further derivatizations of BINOLs are also discussed.

Epidermoid cyst mimicking a thyroglossal duct cyst in a pediatric patient: a case report.

This article presents a case of an epidermoid cyst that mimicked a thyroglossal duct cyst in a pediatric patient. An 8-year-old boy was referred for evaluation of a volumetric increase in the median cervical region with an evolution of about 4 years. The skin in the submental region was healthy and normal colored. Palpation revealed a mobile, well-circumscribed nodular lesion of soft consistency. Computed tomography of the neck showed an expansive hypodense formation extending from the base of the tongue to the upper portion of the hyoid bone, suggesting a thyroglossal duct cyst. Considering the diagnostic hypothesis, cystic enucleation via the Sistrunk procedure was planned. However, no ductal structure was identified during the surgical procedure, and the lesion was only near, but not attached to, the hyoid bone. Simple excision of the lesion was therefore performed. At the most recent follow-up examination, about 3 months postoperatively, the patient demonstrated satisfactory clinical progress. The epidermoid cyst close to the hyoid bone presented diagnostic difficulty due to its similarity to a thyroglossal duct cyst. Computed tomography provides limited information for diagnosing this type of lesion, and ultrasonography is the preferred test. In view of the uncertain diagnosis in this case, the extent of the excision was determined during the surgery, and simple excision was a satisfactory treatment associated with a good prognosis.

Public engagement in health technology assessment in Brazil: the case of the public consultation on National Clinical Guidelines for Care in Normal Birth.

BACKGROUND: There is a growing body of literature that recognizes the importance of public engagement in health technology assessment. However, there is still uncertainty regarding how the results should be recorded, analyzed, and used by decision makers. OBJECTIVE: Synthesize the contributions of the Brazilian public (women, health professionals, managers, educational institutions, and companies) about the implementation of the National Clinical Guidelines for Care in Normal Birth from the public consultation carried out in Brazil. METHOD: IRaMuTeQ software was used to organize and summarize the corpus based on three types of analysis: descriptive statistics; descending hierarchical classification; and specificities analysis. The public consultation was conducted in 2016 by the National Committee for Health Technology Incorporation (CONITEC) in the Brazilian public health system as part of the guideline development process. RESULTS: The corpus consisted of 303 texts, separated into 1233 text segments, 1081 of which were used, corresponding to retention of 87.67%. Five classes emerged from our analyses: mandatory presence of an obstetrician during labor and delivery in hospital settings; barriers and facilitators for guideline implementation; use of evidence-based practices by health professionals; progression of labor and delivery and women's rights; and mobilization to promote the guideline For each class, the most frequent words and sentences with the highest chi-squared scores were presented. Barriers were associated with lack of financial resources, training and professional motivation, and facilitators with training to change the practices of health professionals. Obstetric nurses emerged as an alternative for supervising normal births as well as the mandatory presence of an obstetrician during childbirth in hospital settings. CONCLUSION: Our findings summarize the contributions provided by the Brazilian public and shed some light on the barriers and facilitators of clinical guidelines for care in normal birth. These topics are not typically explored by quantitative studies. Including this information in the decision-making process would not only increase public engagement, but provide greater evidence for implementing the clinical guidelines nationwide.

Direct from the COVID-19 crisis: research and innovation sparks in Brazil.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has spread throughout more than 160 countries, infecting millions of people worldwide. To address this health emergency, countries have organized the flow of production and innovation to reduce the impact on health. This article shows the response of the Brazilian scientific community to meet the urgent needs of the public unified health system [SUS], aiming to guarantee universal access to an estimated population of 211 million. By December 2020, Brazil had recorded more than six million cases and approximately 175,000 deaths. METHODS: We collected data on research, development and innovation projects carried out by 114 public universities (plus Oswaldo Cruz Foundation [Fiocruz] and Butantan Institute), as reported on their websites. Additionally, we examined the studies on COVID-19 approved by the National Comission for Research Ethics, as well as those reported on the Ministry of Education website as of May 15, 2020. RESULTS: The 789 identified projects were classified according to research categories as follows: development and innovation (n = 280), other types of projects (n = 226), epidemiologic research (n = 211), and basic research on disease mechanisms (n = 72). Most proposals focused on the development and innovation of personal protective equipment, medical devices, diagnostic tests, medicines and vaccines, which were rapidly identified as research priorities by the scientific community. Some promising results have been observed from phase III vaccine trials, one of which is conducted in partnership with Oxford University and another of which is performed with Sinovac Biotech. Both trials involve thousands of volunteers in their Brazilian arms and include technology transfer agreements with Fiocruz and the Butantan Institute, respectively. These vaccines proved to be safe and effective and were immediately licensed for emergency use. The provision of doses for the public health system, and vaccination, started on January 17, 2021. CONCLUSIONS: The mobilized Brazilian scientific community has generated comprehensive research, development and innovation proposals to meet the most urgent needs. It is important to emphasize that this response was only possible due to decades of investment in research, development and innovation in Brazil. We need to reinforce and protect the Brazilian science, technology and innovation system from austerity policies that disregard health and knowledge as crucial investments for Brazilian society, in line with the constitutional right of universal health access and universal health coverage.

Ultrastructural changes caused by the combination of intravenous immunoglobulin with meropenem, amikacin and colistin in multidrug-resistant Acinetobacter baumannii.

Acinetobacter baumannii is an opportunistic pathogen associated with increased morbidity and mortality in Healthcare-associated infections (HAI). Combination antimicrobial therapy, meropenem, amikacin and colistin, has been used as an alternative in multidrug-resistant (MDR) A. baumannii infections due to reduced treatment options. However, these combinations are not always effective and exhibit high toxicity. Empiric therapy of intravenous immunoglobulin (IVIG) associated with antimicrobials has shown promising results in bacterial infections, considering the immunomodulatory action of IVIG. Thus, the aim of this study was to determine the combined antimicrobial action and to describe the ultrastructural changes caused in ten MDR A. baumannii isolates submitted to IVIG alone and in combination with colistin, meropenem and amikacin. Minimum Inhibitory Concentration (MIC) of antimicrobials and checkerboard were determined. Isolates were submitted to 4 mg/mL of IVIG alone and in combination with different synergistic sub-MIC of antimicrobials tested, and processed for scanning electron microscopy. Nine bacterial isolates showed meropenem-resistant, two isolates had colistin-intermediate, and four isolates were considered intermediate to amikacin. Synergism in five isolates for meropenem/amikacin and meropenem/colistin were observed. Bacterial cells submitted to IVIG and meropenem, amikacin and colistin presented several ultrastructural changes, such as cell elongation and rupture, membrane roughness, incomplete cell division, cell surface "bubbles" and "depression". A. baumannii isolates presented high resistance to meropenem and synergism among evaluated antimicrobials. In addition, it was possible to verify in vitro that IVIG associated with meropenem, amikacin and colistin is a promising alternative for MDR A. baumannii infections. Thus, these data support the continued empirical use and stimulate in vivo analyzes with IVIG to search for new therapeutic options for HAI.

Antimicrobial activity and biofilm inhibition of riparins I, II and III and ultrastructural changes in multidrug-resistant bacteria of medical importance.

Natural products have been used to treat various infections; however, the development of antimicrobials has made natural products in disuse. Riparin I, II and III are natural alkamide isolated from Aniba riparia (Ness) Mez (Lauraceae), that exhibit economic importance and it is used in traditional medicine, and popularly known as "louro". This study investigated the cytotoxicity, antimicrobial and antibiofilm activity, and ultrastructural changes in vitro by riparins I, II and III in Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. We analyzed the cytotoxicity by MTT assay in Vero cells and hemolytic action verified in human erythrocytes. The antimicrobial activity was determined by microdilution in broth against ATCC strains, identifying the susceptible species. Subsequently, only the MDR isolates of sensitive bacterial species were evaluated regarding its biofilm formation and ultrastructural changes. Riparin I presented low cytotoxicity and hemolytic percentage ranging from of 9.01%-12.97%. Only the riparin III that showed antimicrobial activity against MDR clinical isolates, and significant reduction in biofilm formation in S. aureus. Moreover, the riparin III promoted ultrastructural changes in bacterial cells, such as elongated cellular without bacterial septum, cells with a rugged appearance on the cell surface and cytoplasmic material extravasation. As has been noted riparin III has an inhibitory potential against biofilm formation in S. aureus, besides having antimicrobial activity and promoting ultrastructural changes in MDR clinical isolates. Thus, riparin III is an interesting alternative for further studies aiming to develop new therapeutic options.

Clinical effectiveness of enzyme replacement therapy with galsulfase in mucopolysaccharidosis type VI treatment: Systematic review.

INTRODUCTION: Mucopolysaccharidosis VI is a rare disease characterized by the arylsulfatase B enzyme deficiency, which is responsible for different clinical manifestations. The treatment consists of enzyme replacement therapy with intravenous administration of galsulfase. OBJECTIVE: Evaluate the effectiveness of the enzyme replacement therapy with galsulfase for the mucopolysaccharidosis VI treatment. METHOD: Systematic review of observational studies. The databases of PubMed, Cochrane Library, Lilacs, and Journal of Inherited Metabolic Disease were reviewed. The selection of studies, data mining, and methodological quality assessment were independently conducted by two authors. RESULTS: Eighteen studies fulfilled the inclusion criteria. Two studies were cohorts, one was longitudinal study, one was cross-sectional, one was a case-control, eight were case series, and five were case reports. A total of 362 participants with mucopolysaccharidosis type VI were evaluated, and 14 different outcomes related to the treatment effect were identified. Seven outcomes showed positive results, characterized by the patient survival, quality of life, respiratory function, joint mobility, physical resistance, reduction of urinary glycosaminoglycans, and growth. The hearing function and the cognitive development were stable after the treatment. Other outcomes related to the cardiac function, visual acuity, sleep apnea, and the size of the liver and spleen presented inconclusive outcomes. Concerning safety, light adverse reactions of hypersensitivity were reported. CONCLUSION: This review provided a broader panoramic view of the outcomes related to mucopolysaccharidosis type VI. Regardless of the inherent limitations of observational studies, the outcomes indicate that the enzyme replacement therapy has a positive effect on most of the outcomes associated to the disease.

Health conditions and occupational risks in a novel group: waste pickers in the largest open garbage dump in Latin America.

BACKGROUND: The inadequate management of solid waste impacts populations' health and quality of life, and disproportionately affects developing countries. This study aims to describe a protocol for epidemiological diagnosis, the purpose being to estimate the prevalence of chronic and communicable and non communicable diseases in waste pickers, and the occupational and environmental risk factors to which these are exposed. METHODS: This is a cross-sectional study, based on survey design in an area of extreme social vulnerability - the largest garbage dump in Latin America. Using a multidimensional research protocol, divided in three stages: 1- The identification of the subjects, and the scheduling of tests; 2- Situational diagnosis through interviews, anthropometric evaluation, measuring blood pressure, collecting hair and nail samples to detect exposure to heavy metals and undertaking laboratory tests; 3- The return of the waste pickers to receive the test results, followed by referral to the health team and to report occupational accidents. RESULTS: One thousand twenty-five waste pickers undertook tests and interviews. The majority were women (67.0%), with 36-45 years old (45.7%), and 96.0% had children. In total, 27.3% of the participants did not attend to any school and 47.7% were educated only up to primary level. The majority of waste pickers (68.70%) reported accidents and most of them (89.69%) were related to sharp objects. The mean time working in this open dump was 15 years. According the anthropometric measure, 32.6% were overweight and 21.1% were obese. The most common reported diseases were: osteomuscular disorders (78.7%); arboviruses (28.6%); episodic diarrhea (24.9%); hypertension (24.2%); bronchitis (14.3%); intestinal worms (12.6%) and diabetes (10.1%). According to the blood tests, the values outside the reference limits were: Uric acid (23.89%); creatinine (54.06%); GGT range (16.04%); SGOT - Serum Glutamic Oxaloacetic Transaminase (5.29%); SGPT - serum Glutamic-Pyruvic Transaminase (35.52%). CONCLUSIONS: This study is the first to evaluate multiple risks and diseases in the majority of waste pickers working in the largest garbage dump of a continent. These findings highlight the importance to address urgently the environmental, social and health impacts related to the management of solid waste in developmental countries to protect these workers and their families.

Public engagement in health technology assessment in Brazil: the case of the Trastuzumab public consultation.

BACKGROUND: Public engagement in health technology assessment (HTA) is increasing worldwide. There are several forms of public engagement and it is not always possible to determine which stakeholders participate in the HTA process and how they contribute. Our objective was to investigate which types of social representatives contributed to the public consultation on the incorporation of Trastuzumab for early-stage breast cancer treatment within the public health system in Brazil, held in 2012 by the National Committee for Health Technology Incorporation (CONITEC). METHODS: A mixed methods approach was used to analyze social representativeness and the composition of the corpus from the public consultation, which consisted of 127 contributions. Three types of analysis were performed using IRaMuTeQ software: classic lexical analysis, descending hierarchical classification and specificities analysis. The contributions were clustered according to the main categories of discourse observed, into four social representation categories: 1) patient representation/advocacy; 2) pharmaceutical industry/advocacy; 3) healthcare professionals; and 4) individual contributions. RESULTS: Category 1 contained words related to increased survival due to use of the drug and a low score for words pertaining to studies on Trastuzumab. The word "safety" obtained a positive score only in category 2, which was also the only category that exhibited a negative score for the word "risk". Category 3 displayed the lowest scores for "diagnosis" and "safety". The word "efficacy" had a negative score only in category 4. CONCLUSIONS: Each category exhibited different results for words related to health systems and to key concepts linked to HTA. Our analysis enabled the identification of the most prominent contributions for each category. Despite the promising results obtained, further research is needed to validate this software for use in analyzing public contributions.

Rapid response in health technology assessment: a Delphi study for a Brazilian guideline.

BACKGROUND: Rapid response in health technology assessment is a synthesis of the best available evidence prepared in a timely manner to meet specific demands. We build a consensus among Brazilian specialists in health technology assessment to propose guidelines for the development of rapid response. METHODS: Based on a systematic review that proposed eight methodological steps to conduct rapid response, we applied a modified Delphi technique (without open questions in the first round) to reach consensus among Brazilian experts in health technology assessment. Twenty participants were invited to judge the feasibility of each methodological step in a five-point Likert scale. Consensus was reached if the step had 70% positive approval or interquartile range ≤ 1. RESULTS: The achievement of consensus was reached in the second round. Between the first and the second round, we scrutinized all points reported by the experts. The Delphi panel reached consensus of eight steps: definition of the structured question of rapid response (with a restricted scope); definition of the eligibility criteria for study types (preferably systematic reviews); search strategy (language and data limits) and sources of information (minimum two); selection of studies (independently by two responders); critical appraisal of the included studies and the risk of bias for the outcomes of interest; data extraction from the included articles; summary of evidence; and preparation of the report. CONCLUSIONS: The guidelines for rapid response in health technology assessment may help governments to make better decisions in a short period of time (35 days). The adoption of methodological processes should improve both the quality and consistency of health technology assessments of rapid decisions in the Brazilian setting.

Accuracy of Orthognathic Surgical Outcomes Using 2- and 3-Dimensional Landmarks-The Case for Apples and Oranges?

PURPOSE: To verify predicted versus obtained surgical movements in 2-dimensional (2D) and 3-dimensional (3D) measurements and compare the equivalence between these methods. MATERIALS AND METHODS: A retrospective observational study of bimaxillary orthognathic surgeries was performed. Postoperative cone-beam computed tomographic (CBCT) scans were superimposed on preoperative scans and a lateral cephalometric radiograph was generated from each CBCT scan. After identification of the sella, nasion, and upper central incisor tip landmarks on 2D and 3D images, actual and planned movements were compared by cephalometric measurements. One-sample t test was used to statistically evaluate results, with expected mean discrepancy values ranging from 0 to 2 mm. Equivalence of 2D and 3D values was compared using paired t test. RESULTS: The final sample of 46 cases showed by 2D cephalometry that differences between actual and planned movements in the horizontal axis were statistically relevant for expected means of 0, 0.5, and 2 mm without relevance for expected means of 1 and 1.5 mm; vertical movements were statistically relevant for expected means of 0 and 0.5 mm without relevance for expected means of 1, 1.5, and 2 mm. For 3D cephalometry in the horizontal axis, there were statistically relevant differences for expected means of 0, 1.5, and 2 mm without relevance for expected means of 0.5 and 1 mm; vertical movements showed statistically relevant differences for expected means of 0, 0.5, 1.5 and 2 mm without relevance for the expected mean of 1 mm. Comparison of 2D and 3D values displayed statistical differences for the horizontal and vertical axes. CONCLUSIONS: Comparison of 2D and 3D surgical outcome assessments should be performed with caution because there seems to be a difference in acceptable levels of accuracy between these 2 methods of evaluation. Moreover, 3D accuracy studies should no longer rely on a 2-mm level of discrepancy but on a 1-mm level.

Genome of Leptospira borgpetersenii strain 4E, a highly virulent isolate obtained from Mus musculus in southern Brazil.

A previous study by our group reported the isolation and characterisation of Leptospira borgpetersenii serogroup Ballum strain 4E. This strain is of particular interest because it is highly virulent in the hamster model. In this study, we performed whole-genome shotgun genome sequencing of the strain using the SOLiD sequencing platform. By assembling and analysing the new genome, we were able to identify novel features that have been previously overlooked in genome annotations of other strains belonging to the same species.

Cost of providing doctors in remote and vulnerable areas: Programa Mais Médicos in Brazil.

OBJECTIVE: To evaluate the Programa Mais Médicos (More Doctors Program; PMM) in Brazil by estimating the proportional increase in the number of doctors in participating muni-cipalities and the program costs, stratified by cost component and funding source. METHODS: Official data from the 2013 edition of Demografia Médica no Brasil (Medical Demography in Brazil) was used to estimate the number of doctors prior to PMM. The number of doctors at the end of the fourth PMM recruiting cycle (July 2014) was obtained from the Ministry of Health. Cost components were identified and estimated based on PMM legislation and guidelines. The participating municipalities were chosen based on four criteria, all related to vulnerability. RESULTS: The PMM provided an additional 14 462 physicians to highly vulnerable, remote areas in 3 785 municipalities (68% of the total) and 34 Special Indigenous Sanitary Districts. There was a greater increase of physicians in the poorest regions (North and Northeast). The estimated annual cost of US$ 1.1 billion covered medical provision, continuing education, and supervision/mentoring. Funding was largely centralized at the federal level (92.6%). CONCLUSION: The cost of PMM is considered relatively moderate in comparison to its potential benefits for population health. The greater increase of doctors for the poorest and most vulnerable met the target of correcting imbalances in health worker distribution. The PMM experience in Brazil can contribute to the debate on reducing physician shortages.

A systematic review of economic evaluations of interventions to tackle tuberculosis in homeless people.

OBJECTIVE: To analyze economic evaluations of interventions related to tuberculosis (TB) diagnostics/screening, treatment, and prevention in homeless people. METHODS: A systematic review was conducted. The eligibility criteria were original studies reporting economic evaluation results. The search was not restricted by language or year. A critical appraisal approach was used. RESULTS: A total of 142 studies were identified, including five research articles (three full economic evaluations and two partial) that were selected for the final review. Most of the studies were conducted in the United States, adopted a public health perspective, and analyzed active TB. Interventions related to diagnostics/screening (the use of interferon-gamma release assay (IGRA) and mobile screening units), treatment (incentives for continuing treatment, and housing programs), and prevention (with the Bacillus Calmette-Guérin (BCG) vaccine) were identified. CONCLUSIONS: No high-quality data were found on cost-effectiveness of interventions on TB diagnostics/screening, treatment, or prevention in homeless people. However, active searching for cases via mobile screening, and financial incentives, could help increase treatment adherence, and the use of IGRA helps boost detection. TB in homeless people is neglected worldwide, especially in developing countries, where this disease tends to afflict more people made vulnerable by their precarious living conditions. Public funding mechanisms should be created to develop cross-sectoral actions targeting homeless people, as the complex dynamics of this group tend to hamper prevention and diagnosis of TB and the completion of TB treatment.

Repeated systemic administration of adipose tissue-derived mesenchymal stem cells prevents tracheal obliteration in a murine model of bronchiolitis obliterans.

OBJECTIVE: To investigate the effect of adipose tissue-derived mesenchymal stem cell (ASC) administered either systemically or locally in a murine model of bronchiolitis obliterans. RESULTS: When compared to controls, systemic treatment with 106 ASCs on D0 and a second dose on D7 significantly prevented tracheal obliteration 28 days after heterotopic tracheal transplantation (median of 94 vs. 16%; P < 0.01). A single dose tended towards less stenosis than controls, but did not reach statistical significance (28 vs. 94%; P = 0.054). On the contrary, repeated local injection was incapable of preventing tracheal obliteration when compared to a single injection or controls (37 vs. 71 vs. 87%). Two intravenous doses also tended to be better than two local injections (16 vs. 37%; P = 0.058), and were better than a single local dose (16 vs. 71%; P < 0.01). CONCLUSION: A second dose of ASC, given systemically after 7 days, reduces luminal obliteration in a heterotopic tracheal transplantation model in mice, suggesting that ASC can be used to prevent obliterative bronchiolitis after lung transplantation.