From Bench to Babies - Drug Development for Male Subfertility.

Infertility is estimated to affect more than 50 million couples around the world, with male factor accounting for half of these cases, yet there is a notable absence of effective treatment options for men, other than in-vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). This review considers unlicensed and empirical treatments used for male subfertility, including hormonal therapy, phosphodiesterase inhibitors, and antioxidants. Compounds generally demonstrate variable improvements in sperm function but benefits for fertility are less clear. There is a pressing need for effective treatment options for subfertile men, however, our knowledge of sperm function is limited, restricting the identification of precise treatment targets. The traditional drug discovery pathway is also notorious for its extensive resource and time requirements, often extending over decades and demanding significant financial investment. Unfortunately, a substantial number of potential therapies fail before reaching the marketplace. Furthermore, reliance on mammalian models is not possible in the drug development process for male subfertility, due to significant variability between animals and man. We review recent breakthroughs and highlight novel methods aimed at improving the effectiveness and efficiency of drug discovery for male subfertility. High-throughput screening, combinatorial chemistry, and the repurposing of established medications have great potential. These strategies offer the promise of accelerating the pace of drug development, curbing the extensive demand for resources, and, in the case of drug repurposing, diminish the demand for comprehensive pharmacokinetic and pharmacodynamic studies. As these innovative approaches are adopted, the feasibility of addressing male subfertility through scientific advancements appears to be increasingly attainable.

Influence of build direction, post-polymerization time, and aging on the fracture resistance and marginal and internal discrepancies of three-dimensional printed provisional crowns.

To evaluate the effect of build direction, post-polymerization time, and aging on the fracture resistance, failure mode, margin quality and Marginal (MD) and Internal Discrepancies (ID), and degree of conversion of tridimensional (3D) printed provisional crowns using the liquid crystal display technique (LCD). A left mandibular first molar was prepared and scanned. After, a full crown was designed (ExoCad) and exported to the LCD-printer software. One hundred and eighty crowns were printed at two build directions (30°, 90°) and post-polymerized for different periods (15, 30, 45 min). Half of the samples were aged (ST) in distilled water (37 °C/90 days). The marginal quality of the crowns was evaluated by the Schriwer method under a stereomicroscope (40x). The replica technique was used to measure the MD and ID and measured under a stereomicroscope (10x), through 20 reference points defined in 5 regions: Occlusal (O), Cusp (CP), Axial (AX), Chamfer (CH), and Finish Line (F). After, the crowns were cemented onto the respective dies using temporary cement and submitted to compression test (ISO150, 1 mm/min, 100 kgf).The failure mode was classified by Burke's fracture mode. The degree of conversion was evaluated through Fourier Transform Infrared Spectroscopy. The data (µm) of MD and ID and fracture resistance (N) were subjected to ANOVA (3 factors) and Tukey's test (5%); Weibull analysis was also performed for fracture resistance data (N). For MD, ID and fracture resistance ANOVA revealed that all factors (P < .001) were significant. For aged groups, the crowns printed at 30° showed lower MD (Tukey). The O_90_30 min (172.13A µm) and O_90_15 min (170.20A µm) groups showed the highest ID values. Higher resistance values were observed for the 30_45 min (844.30A N), 30_30 min (835.35A N), and 90_30 min (820.62A N) groups (Tukey). In the margin analysis, 98.6% of the crowns printed at 30° showed smooth margins without defects. The most prevalent fracture mode (41.7%) was Burke type 5. The degree of conversion (DC) increased with increasing post-polymerization time and aging. Printing provisional crowns at 30° provided lower crown MD and ID, as well as higher fracture resistance. A post-polymerization time of 30 min resulted in higher crown fracture resistance, while aging reduced the resistance of the crowns.

Effect of different surface treatments and adhesive cementation on the surface topography and flexural strength of translucent and ultra-translucent monolithic zirconia.

PURPOSE: To evaluate the effect of different surface treatments and adhesive cementation on the miniflexural strength (MFS) of monolithic zirconia. MATERIALS AND METHODS: Two-hundred and forty (240) sintered bars of translucent zirconia (ZT) and ultra-translucent zirconia (ZUT) were obtained (8 mm ×2 mm ×1 mm). The bars were divided into 16 groups (n = 15) according to the factors "Zirconia" (ZT and ZUT), "Cementation" (Cem) and "surface treatment" (Ctrl:Control, Al:Aluminum oxide/Al2O3 50 µm, Si:Silica/SiO2 coated alumina particles oxide 30 µm, Gl:Glazing+hydrofluoric acid). Half of the bars received an adhesive layer application, followed by application of resin cement and light curing. The surface roughness was measured in non-cemented groups. All the bars were subjected to the MFS test (1.0 mm/min; 100 kgf). Scanning electron microscopy was used for qualitative analyses. MFS data (MPa) and roughness (µm) were statistically evaluated by three-way and two-way ANOVA respectively and Tukey's test (5%). RESULTS: The surface treatment and the interaction were significant for roughness. Glazing promoted less roughness compared to silicatization. Regarding MFS, only the zirconia and surface treatment factors were significant. For ZT, the sandblasted groups had an increase in MFS and glazing reduced it. There was no difference between the groups without cementation for the ZUT; however, ZUT.Si/Cem, and ZUT.Al/Cem obtained superior MFS among the cemented groups. CONCLUSIONS: Sandblasting increases the flexural strength for ZT, while glaze application tends to reduce it. Applying resin cement increases the flexural strength of ZUT when associated with sandblasting. Sandblasting protocols promote greater surface roughness.

Cost-effectiveness study of therapeutic approaches for mucosal leishmaniasis.

This study aimed to estimate the cost-effectiveness of four therapeutic approaches available for mucosal leishmaniasis in Brazil: miltefosine, meglumine antimoniate, combined with and without pentoxifylline, and liposomal amphotericin B. The perspective adopted was that of the Brazilian Unified National Health System (SUS). The outcome of interest was "cured patient", which was analyzed using a decision tree model. Estimates of direct costs and effectiveness were obtained from the scientific literature. Meglumine antimoniate alone was the base comparator strategy; liposomal amphotericin B showed an incremental cost-effectiveness ratio (ICER) of USD 7,409.13 per cured patient, and the combination of meglumine antimoniate with pentoxifylline presented an ICER of USD 85.13. Miltefosine was absolutely dominated, with higher cost and similar effectiveness when compared to meglumine antimoniate. Sensitivity analyses, varying the cost by ±25%, did not change the results. However, when the cost of miltefosine was estimated at less than USD 171.23, this strategy was dominant over meglumine antimoniate alone. The results confirm that treatment with liposomal amphotericin B remains the option with the highest ICER among the approaches analyzed. Miltefosine may be cost-effective based on the variation in the acquisition price, which deserves attention because it is the only available oral option. The non-accounting of other aspects prevent the use of these results immediately to support decision-making, but they point out the need to negotiate the prices of drugs available for mucosal leishmaniasis and indicates the need of encouraging technology transfer or other actions aimed at expanding the performance of the Brazilian national industrial complex.

Models and frameworks for assessing the implementation of clinical practice guidelines: a systematic review.

BACKGROUND: The implementation of clinical practice guidelines (CPGs) is a cyclical process in which the evaluation stage can facilitate continuous improvement. Implementation science has utilized theoretical approaches, such as models and frameworks, to understand and address this process. This article aims to provide a comprehensive overview of the models and frameworks used to assess the implementation of CPGs. METHODS: A systematic review was conducted following the Cochrane methodology, with adaptations to the "selection process" due to the unique nature of this review. The findings were reported following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guidelines. Electronic databases were searched from their inception until May 15, 2023. A predetermined strategy and manual searches were conducted to identify relevant documents from health institutions worldwide. Eligible studies presented models and frameworks for assessing the implementation of CPGs. Information on the characteristics of the documents, the context in which the models were used (specific objectives, level of use, type of health service, target group), and the characteristics of each model or framework (name, domain evaluated, and model limitations) were extracted. The domains of the models were analyzed according to the key constructs: strategies, context, outcomes, fidelity, adaptation, sustainability, process, and intervention. A subgroup analysis was performed grouping models and frameworks according to their levels of use (clinical, organizational, and policy) and type of health service (community, ambulatorial, hospital, institutional). The JBI's critical appraisal tools were utilized by two independent researchers to assess the trustworthiness, relevance, and results of the included studies. RESULTS: Database searches yielded 14,395 studies, of which 80 full texts were reviewed. Eight studies were included in the data analysis and four methodological guidelines were additionally included from the manual search. The risk of bias in the studies was considered non-critical for the results of this systematic review. A total of ten models/frameworks for assessing the implementation of CPGs were found. The level of use was mainly policy, the most common type of health service was institutional, and the major target group was professionals directly involved in clinical practice. The evaluated domains differed between the models and there were also differences in their conceptualization. All the models addressed the domain "Context", especially at the micro level (8/12), followed by the multilevel (7/12). The domains "Outcome" (9/12), "Intervention" (8/12), "Strategies" (7/12), and "Process" (5/12) were frequently addressed, while "Sustainability" was found only in one study, and "Fidelity/Adaptation" was not observed. CONCLUSIONS: The use of models and frameworks for assessing the implementation of CPGs is still incipient. This systematic review may help stakeholders choose or adapt the most appropriate model or framework to assess CPGs implementation based on their specific health context. TRIAL REGISTRATION: PROSPERO (International Prospective Register of Systematic Reviews) registration number: CRD42022335884. Registered on June 7, 2022.

Effects of respiratory muscular training in post-covid-19 patients: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Post-Covid-19 syndrome is defined as non-self-sustaining signs and/or symptoms lasting more than 12 weeks, occurring during or after a Covid-19 infection. The primary outcome was the analysis of the respiratory muscle training (RMT) result in respiratory muscle strength, (maximum inspiratory pressure (MIP) e maximum expiratory pressure (MEP)); and the secondary results were the analysis of lung function, dyspnea, quality of life (QoL), fatigue and functional performance. METHODS: The PICO description for this research was: P: patients diagnosed with post-Covid-19; I: RMT; C: Sham or simulated inspiratory or expiratory muscle training and usual care; O: MIP, MEP, Lung Function, level of dyspnea, QoL and functional performance. On January 15, 2024, the following databases were consulted: PubMed, Lilacs, Cochrane Library, PEDro and EMBASE. Randomized clinical trials were included without restrictions on year of publication or language. The data selection and extraction steps were carried out by two independent reviewers. RESULTS: The search in the databases resulted in a total of 14,216 studies, and after the eligibility process, 7 studies were included with a sample of 527 patients. The MIP results suffered a statistically significant increase, that is, the RMT was favorable to improve the MIP (MD = 29.55cmH2O IC 95%: 7.56cmH2O to 51.54cmH2O, p = 0,00001). For the MEP outcome, the results were statistically significant in favor of RMT (MD = 10.93cmH2O CI 95%: 3.65cmH2O to 18.21cmH2O, p = 0.00001). We also noticed a significant improvement for the group that received the RMT in the distance covered in the 6-Minute Walk Test (6MWT) MD = 40.70 m CI 95%: 18.23 m to 65.17 m%, p = 0.01). CONCLUSION: We noticed that RMT is being used in patients with respiratory diseases, including post-Covid-19. Our systematic review observed that this training provides an increase in inspiratory and expiratory muscle strength, a reduction in dyspnea levels, and an increase in the distance covered in the 6MWT and improved QoL in post-covid patients after intervention.

Confronting the Legacy of Eugenics and Ableism: Towards Anti-Ableist Bioscience Education.

Society and education are inherently ableist. Disabled people are routinely excluded from education, or have poorer outcomes within educational systems. Improving educational experiences and outcomes for people of color has required educators to design antiracist curricula that explicitly address racial inequality. Here, we explore parallel antiableist approaches to bioscience education in an essay coauthored by a disabled bioscience student and able-bodied faculty member in bioscience. Our work is underpinned by Critical Disability Theory and draws on disability and pedagogical scholarship as well as our own experiences. The biosciences has a unique need to confront its history in the discredited pseudoscience of eugenics, which has led to discrimination and human rights abuses against disabled people. We provide a brief history of the relationship between biological sciences research and eugenics and explore how this legacy impacts bioscience education today. We then present a recommended structure for antiableist biology education. Our approach goes beyond providing disability access, to a model that educates all students about disability issues and empowers them to challenge ableist narratives and practices.

Custo Direto do Tratamento do Acidente Vascular Cerebral Isquêmico na Perspectiva de um Hospital Público Terciário (Direct Cost of Treating Ischemic Stroke From the Perspective of a Tertiary Public Hospital).

OBJECTIVES: To measure the direct cost of treating acute ischemic stroke (IS) from the perspective of a public hospital in Brazil (HCFMB) and compare it with the reimbursement by the Unified Health System (SUS), through the Procedure Table Management System, Medicines, Orthoses/Prostheses and Special Materials of the Unified Health System (SIGTAP). METHODS: We performed a micro-costing study; four scenarios were evaluated: standard (1); alteplase (2); alteplase and mechanical thrombectomy (3); mechanical thrombectomy (4). Based on the number of patients hospitalized for ischemic stroke in 2019, hospital cost, and SUS billing were calculated for each scenario. Hospital costs were adjusted for inflation using CCEMG-EPPI-Centre Cost Converter. RESULTS: In 2019, 258 patients were hospitalized due to IS, 89.5% in scenario 1, 8% in scenario 2, 1.5% in scenario 3, 1% in scenario 4. From the hospital's perspective, the cost per patient was estimated at R$7780.13, R$15 741.23, R$28 988.49, R$25 739.79, for scenarios 1, 2, 3 and 4, respectively. The reimbursement by SIGTAP was estimated at R$3079.87, R$5417.21, R$10 901.92, R$10 286.28, respectively. If thrombectomy had been included in the SIGTAP, the last two values would be R$25 393.34 and R$24 248.89. CONCLUSIONS: The hospital cost of treating acute IS in 2019 was estimated at R$2 295 209, the SUS reimbursement at R$889 391.54. With the inclusion of thrombectomy at SIGTAP, this reimbursement would be R$975 282.44, and the loss in the cost of HCFMB per patient in relation to reimbursement by the SUS is greater in scenarios without this procedure.

First report of Tomato interveinal chlorosis virus infecting Rhynchosia minima plants in Brazil.

Tomato interveinal chlorosis virus (ToICV; Begomovirus solanumintervenae, genus Begomovirus, family Geminiviridae) has been described infecting tomato (Solanum lycopersicum) and Macroptilium lathyroides in Northeastern (NE) Brazil for more than a decade (Albuquerque et al., 2012; Silva et al., 2012). During a survey in 2020, plants of the leguminous weed Rhynchosia minima exhibiting virus-like symptoms such as mosaic and interveinal chlorosis were observed in the state of Alagoas, NE Brazil. Symptomatic leaf samples of R. minima were randomly collected (n=15; supplementary figure 1). Total DNA from each sample was used as a template for PCR amplification of partial begomoviral DNA-A sequences using the degenerate primer pair PAL1v1978 and PAR1c496, universal for geminiviruses (Rojas et al., 1993). Amplicons of ~1.2 kbp were observed from 12 samples, although this should not be considered as incidence since only symptomatic plants were collected. To identify the begomovirus associated with R. minima, viral genomes were amplified from PCR-positive samples using rolling circle amplification (RCA) (Inoue-Nagata et al., 2004). The RCA products were digested with HindIII, cloned into the pBluescript II KS+ plasmid vector and bidirectionally Sanger-sequenced (Macrogen Inc., Seoul). BLASTn searches indicated that the clones (n=4) reported here corresponded to a begomovirus DNA-A component, and pairwise comparisons showed that they shared the highest identity with ToICV, at 92.4-94.7% nucleotide sequence identity. Based on the species demarcation criteria of ≥91% nucleotide identity for the genus Begomovirus (Brown et al., 2015), the begomoviruses obtained from R. minima are new isolates of ToICV. The new DNA-A sequences of 2,619-2,623 nt in length were deposited in GenBank under accession numbers PP639092 to PP639095. Multiple nucleotide sequence alignments were prepared using the MUSCLE algorithm implemented in MEGA v.11 (Kumar et al., 2018), and a maximum likelihood (ML) tree was reconstructed in RaxML-NG (Kozlov et al., 2019), assuming a general time reversible (GTR) nucleotide substitution model with a gamma (G) model of rate heterogeneity and 1,000 bootstrap replicates. The DNA-A-based tree showed that the ToICV sequences clustered into a monophyletic group, additionally supporting these isolates as members of the species Begomovirus solanumintervenae. At least two independent interspecies recombination events were predicted among the ToICV isolates, with breakpoints located in the Rep-encoding region and ToICV (GenBank Accession JF803253), tomato mottle leaf curl virus (JF803248) and soybean blistering mosaic virus (MN486865) detected as putative parents. To the best of our knowledge, this is the first report of ToICV infecting R. minima worldwide, expanding the host range of this begomovirus. Non-cultivated plants such as R. minima play a crucial role as reservoirs and sources of inoculum for begomoviruses (Paz-Carrasco et al., 2014), reinforcing their relevance to socioeconomically important crops.

Accuracy, adaptation and margin quality of monolithic zirconia crowns fabricated by 3D printing versus subtractive manufacturing technique: A systematic review and meta-analysis of in vitro studies.

OBJECTIVE: The purpose of this systematic review and meta-analysis was to evaluate the accuracy (trueness and precision), marginal and internal adaptation, and margin quality of zirconia crowns made by additive manufacturing compared to subtractive manufacturing technology. METHODS: The investigation adhered to the PRISMA-ScR guidelines for systematic reviews and was registered at the Prospero database (n°CRD42023452927). Four electronic databases, including PubMed, Scopus, Embase, and Web of Science and manual search was conducted to find relevant studies published until September 2023. In vitro studies that assessed the trueness and precision, marginal and internal adaptation, and margin quality of printed crowns compared to milled ones were included. Studies on crowns over implants, pontics, temporary restorations, laminates, or exclusively experimental materials were excluded. RESULTS: A total of 9 studies were included in the descriptive reporting and 7 for meta-analysis. The global meta-analysis of the trueness (P<0.74,I2=90 %) and the margin quality (P<0.61,I2=0 %) indicated no significant difference between the root mean square of printed and milled zirconia crowns. The subgroup analysis for the printing system showed a significant effect (P<0.01). The meta-analysis of the crown areas indicated no significant difference in most of the areas, except for the marginal (favoring milled crowns) and axial (favoring printed crowns) areas. For precision and adaptation, both methods showed a clinically acceptable level. CONCLUSIONS: Additive manufacturing technology produces crowns with trueness and margin quality comparable to subtractive manufacturing. Both techniques have demonstrated the ability to produce crowns with precision levels, internal discrepancy, and marginal fit within clinically acceptable limits. CLINICAL SIGNIFICANCE: 3D printing emerges as a promising and potentially applicable alternative method for manufacturing zirconia crowns, as it shows trueness and margin quality comparable to restorations produced by the subtractive method.

Treatment of Childhood Brucellosis: A Systematic Review.

BACKGROUND: Proper treatment for brucellosis is crucial to eradicate the infection and prevent complications, but there is a notable gap in evidence for pediatric treatment. This study aims to address this gap by reviewing current literature, analyzing the efficacy and safety of brucellosis treatment in children, and identifying areas that require further investigation. METHODS: A systematic review, following preferred reporting items for systematic reviews and meta-analyses and Cochrane Handbook guidelines, assessed antimicrobial regimens' efficacy and safety for treating human brucellosis in children. Original human studies with clinical outcomes after drug therapy intervention for children up to 10 years were included. Searches were conducted in Medline, Embase, Cochrane Library and LILACS databases for studies indexed until March 6, 2023. Study selection, data extraction, and bias risk assessment were performed by pairs of reviewers. The quality assessment used Joanna Briggs Institute tools and grading of recommendations assessment, development and evaluation system. Data were analyzed using R software. RESULTS: A total of 1773 records were reviewed, yielding 11 eligible studies encompassing 1156 children. All included studies presented an observational design. The most reported treatment approaches included sulfamethoxazole-trimethoprim with rifampicin or aminoglycosides, with summarized failure rates of 2% (95% confidence interval: 0.0-0.49) and 13% (95% confidence interval: 0.06-0.29), respectively (very low certainty of evidence). Adverse events and time to defervescence were not reported. CONCLUSIONS: Sulfamethoxazole-trimethoprim + rifampicin were the most prescribed antibiotics for brucellosis for pediatrics. The study highlights the need for more research with robust designs, and emphasizes uncertainty regarding the efficacy of antimicrobial regimens, emphasizing the importance of further investigations to guide specific treatment protocols for this population.

Promoting safe and appropriate use of miltefosine to treat tegumentary leishmaniasis in Brazil: A best practice quality improvement project.

INTRODUCTION: Miltefosine is a new drug that was recently approved for the treatment of tegumentary leishmaniasis (TL) by the Brazilian health system. It has a teratogenic potential and requires follow-up of patients undergoing treatment. Improving compliance with best practices is essential to ensure the safe and appropriate use of this drug. OBJECTIVE: This project aimed to implement best practices for the safe and appropriate use of miltefosine in the treatment of TL in the state of Minas Gerais, Brazil. METHODS: This project was guided by the JBI Evidence Implementation Framework. Five best practice criteria were established based on the best available evidence. A baseline audit was conducted to measure current practice against best practice. Barriers to best practice were then identified and a follow-up audit was conducted to evaluate changes after the implementation of improvement strategies. Two sites were analyzed: a leishmaniasis reference service in Belo Horizonte, the capital of Minas Gerais, and the 28 regional offices. RESULTS: The baseline audit evaluated data from 197 miltefosine requests distributed across 13 regional sites. All requests from the reference service were compliant (100%). This is in contrast to the 60% compliance rate at the regional offices. The improvement strategies included intensifying direct communication with the regional health professionals, which increased the average compliance rate to 79.5%, 6 months after the interventions were introduced. CONCLUSION: This best practice implementation project effectively increased the compliance rate for the audited procedures. Communication from the reference site with the regional health professionals successfully increased compliance with best practices and promoted the safe and appropriate use of miltefosine. These strategies should analyzed and applied to improve other programs. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A184.

Detection of Autoantibodies Against the Acetylcholine Receptor, Evaluation of Commercially Available Methodologies: Fixed Cell-Based Assay, Radioimmunoprecipitation Assay and Enzyme-Linked Immunosorbent Assay1.

Background/Objective: Myasthenia Gravis (MG) is an autoimmune disorder characterized by pathogenic autoantibodies (AAbs) targeting nicotinic acetylcholine receptors (AChR), disrupting neuromuscular communication. RadioImmunoPrecipitation Assay (RIPA) is recommended to detect AChR AAbs, but its complexity and radioactive requirements limit widespread use. We compare non-RIPA anti-AChR immunoassays, including Cell-Based Assay (CBA) and two ELISA kits, against the gold standard RIPA. Methods/Results: 145 samples were included with medical indication for anti-AChR testing. By the RIPA method, 63 were negative (RIPA-Neg < 0.02 nmol/L), 18 were classified as Borderline (≥0.02 -1 nmol/L), and 64 were positive (RIPA-Pos > 1 nmol/L). The competitive ELISA showed poor agreement with RIPA (Kappa = 0.216). The indirect ELISA demonstrated substantial agreement with RIPA (Kappa = 0.652), with ∼76% sensitivity and ∼94% specificity for MG diagnostic. The CBA, where fixed cells expressing clustered AChR were used as substrate, exhibited almost perfect agreement with RIPA (Kappa = 0.984), yielding ∼98% sensitivity and 96% specificity for MG. In addition, a semiquantitative analysis showed a strong correlation between CBA titration, indirect ELISA, and RIPA levels (r = 0.793 and r = 0.789, respectively). Conclusions: The CBA displayed excellent analytical performance for MG diagnostic when compared to RIPA, making it a potential replacement for RIPA in clinical laboratories. Some solid-phase assays (such as the indirect ELISA applied here), as well as CBA titration, offer reliable options to estimate anti-AChR AAb levels after confirming positivity by the CBA.∥.

Efficacy of antibiotic prophylaxis to preventing brucellosis in accidental exposure: A systematic review.

BACKGROUND: Antibiotic prophylaxis to prevent brucellosis after accidental exposure to Brucella is an important topic in public health. This study aimed to systematically review the efficacy of antibiotic prophylaxis following accidental exposure to Brucella in preventing human brucellosis disease. METHODS: The study protocol was registered in PROSPERO (CRD42023456812). The outcomes included the incidence of brucellosis disease, adverse events rate, and antibiotic prophylaxis adherence. A comprehensive literature search, conducted until 20 November, 2023, involved Medline, Embase, Cochrane Library, and LILACS databases. Descriptive analysis and meta-analysis using R software were performed, risk of bias was assessed using JBI Critical appraisal tools, and certainty of evidence was assessed using the GRADE tool. RESULTS: Among 3102 initially identified records, eight studies involving 97 individuals accidentally exposed, all focused on high-risk accidental exposure to Brucella in laboratory settings, were included in the review. All studies reported the prophylactic treatment comprising doxycycline at a dosage of 100 mg twice daily, combined with rifampicin at 600 mg, both administered over 21 days. Prophylaxis adherence was reported in 86% of cases, and incidence of brucellosis post-treatment was 0.01. Adverse events, mainly gastrointestinal, occurred in 26% of cases. Critical appraisal revealed limitations in reporting demographics and clinical information. The certainty of evidence was rated as 'very low,' emphasising the need for caution in interpreting the observed outcomes due to study design constraints and the absence of comparative groups. CONCLUSIONS: PEP is an alternative practice reported in the literature, used in accidents with high-risk exposure to Brucella. The currently available evidence of the efficacy of antibiotic prophylaxis is insufficient to support a recommendation for or against the widespread use of antibiotic prophylaxis, so caution is needed in interpreting results due to the very low certainty of evidence, primarily stemming from case series and lack of comparative groups.

Diagnosis of human brucellosis: Systematic review and meta-analysis.

BACKGROUND: Brucellosis, a widely spread zoonotic disease, poses significant diagnostic challenges due to its non-specific symptoms and underreporting. Timely and accurate diagnosis is crucial for effective patient management and public health control. However, a comprehensive comparative review of available diagnostic tests is lacking. METHODOLOGY/PRINCIPAL FINDINGS: This systematic review addressed the following question: 'What is the accuracy of the available tests to confirm human brucellosis?' Two independent reviewers examined articles published up to January 2023. The review included original studies reporting symptomatic patients with brucellosis suspicion, through any index test, with sensitivity and/or specificity as outcomes. As exclusion criteria were considered: sample size smaller than 10 patients, studies focusing on complicated brucellosis, and those lacking essential information about index or comparator tests. Sensitivity and specificity were assessed, with consideration for the index test, and 'culture' and 'culture and standard tube agglutination test (SAT)' were used as reference standards. Bias assessment and certainty of evidence were carried out using the QUADAS-2 and GRADE tools, respectively. A total of 38 studies reporting diagnostic test performance for human brucellosis were included. However, the evidence available is limited, and significant variability was observed among studies. Regarding the reference test, culture and/or SAT are deemed more appropriate than culture alone. Rose Bengal, IgG/IgM ELISA, and PCR exhibited equally high performances, indicating superior overall diagnostic accuracy, with very low certainty of the evidence. CONCLUSIONS/SIGNIFICANCE: This systematic review underscores the potential of the Rose Bengal test, IgG/IgM ELISA, and PCR as promising diagnostic tools for brucellosis. However, the successful implementation and recommendations for their use should consider the local context and available resources. The findings highlight the pressing need for standardization, improved reporting, and ongoing advancements in test development to enhance the accuracy and accessibility of brucellosis diagnosis.

Efficacy and safety of therapeutic strategies for human brucellosis: A systematic review and network meta-analysis.

BACKGROUND: Human brucellosis is a neglected, re-emerging, and endemic zoonosis in many countries. The debilitating and disabling potential of the disease is a warning about its morbidity, generating socioeconomic impact. This review aims to update the current evidence on the efficacy and safety of therapeutic options for human brucellosis using the network meta-analysis (NMA). METHODOLOGY: A systematic search was conducted in four different databases by independent reviewers to assess overall therapy failure, adverse events, and time to defervescence associated with different therapies. Randomized clinical trials (RCTs) evaluating any therapeutic drug intervention were selected, excluding non-original studies or studies related to localized forms of the disease or with less than 10 participants. Data were analyzed by frequentist statistics through NMA by random effects model. The risk of bias and certainty of evidence was assessed, this review was registered at PROSPERO. RESULTS: Thirty-one (31) RCTs involving 4167 patients were included. Three networks of evidence were identified to evaluate the outcomes of interest. Triple therapy with doxycycline + streptomycin + hydroxychloroquine for 42 days (RR: 0.08; CI 95% 0.01-0.76) had a lower failure risk than the doxycycline + streptomycin regimen. Doxycycline + rifampicin had a higher risk of failure than doxycycline + streptomycin (RR: 1.96; CI 95% 1.27-3.01). No significant difference was observed between the regimens when analyzing the incidence of adverse events and time to defervescence. In general, most studies had a high risk of bias, and the results had a very low certainty of evidence. CONCLUSIONS: This review confirmed the superiority of drugs already indicated for treating human brucellosis, such as the combination of doxycycline and aminoglycosides. The association of hydroxychloroquine to the dual regimen was identified as a potential strategy to prevent overall therapy failure, which is subject to confirmation in future studies.

Effect of ZrO2 paste, surface treatments, and storage on Weibull characteristics and resin bond strength to zirconia.

The objective is to evaluate the effect of different surface treatments and storage on the shear strength of ultratranslucent zirconia. 36 blocks of ultra-translucent zirconia were fabricated (7x7x2mm) and sintered. Then, divided into 12 groups according to the "surface treatment" (C -Primer; Al -Sandblasting with Al2O3 + Primer; Si -Silicate + Primer; Gl -Glaze + HF + Primer; Z -Zirlink; Zp -Zirlink + Primer) and "storage" factors (ST-with 150 days/37º and without). After surface treatment, five cylinders (Ø=2mm; h=2.0mm) of resin cement (n=15) were constructed in each ceramic block; at the end, the shear strength test was performed (1mm/min, 50Kgf), and analysis of surface failures. 60 additional samples (2x2x2mm) were made for extras analysis (surface roughness, MEV, and EDS). Bond strength and surface roughness data were statistically evaluated by ANOVA (2 factors/1 factor), Tukey test (5%), and Weibull analysis, respectively. ANOVA (2-way) revealed that all factors were statistically significant for bond strength. The silicatization groups (SiST: 30.47AMPa; Si: 29.21AMPa) showed the highest bond strength values, regardless of storage (Tukey's test). While the groups treated with Zirlink (ZST: 2.76FMPa; Z: 5.27EFMPa) showed the lowest values, just similar to the GlST group (5.14EFMPa). The Weibull modulus (m) showed a statistical difference between groups (p=0.000). ANOVA (1 factor) revealed that the "surface treatment" factor (p=0.0000) was statistically significant for surface roughness. Therefore, the application of Zirlink and Glaze on pre-sintered zirconia did not promote efficient adhesion of the ultratranslucent zirconia to the resin cement, even when associated with a primer containing MDP.

Quality of life of patients with cutaneous leishmaniasis: A comparative analysis of the EQ-5D-3L and CLIQ questionnaires.

PURPOSE: To evaluate the performance of the Cutaneous Leishmaniasis Impact Questionnaire (CLIQ) using the EuroQol-5 Dimension (EQ-5D-3L) as a reference standard (criterion validation); to evaluate the responsiveness of the instruments and estimate a cut-off point for the CLIQ to be able to discriminate between high and low impacts of cutaneous leishmaniasis on patients. METHODS: Between 2020 and 2022, a longitudinal validation study was conducted at a reference centre for leishmaniasis in Brazil. The EQ-5D-3L and CLIQ questionnaires were administered before, during and after treatment for cutaneous leishmaniasis. The correlation between the instruments was assessed using Spearman's correlation coefficient, responsiveness was assessed using the Wilcoxon test, and CLIQ cut-off points were proposed based on results of the EQ-5Q-3L, dichotomized between patients reporting no problems' and 'some or extreme problems'. RESULTS: There were satisfactory correlation coefficients between the two instruments before (-0.596) and during treatment (-0.551) and a low correlation between the instruments after the end of treatment (-0.389). In general, the responsiveness of the instruments was satisfactory. The CLIC scores that maximized sensitivity and specificity for recognizing impaired health status before and during treatment were 7 points and 17 points, respectively. However, at the end of treatment, based on the results for the EQ-5D-3L, the CLIC was not able to discriminate between individuals with high and low impacts of the disease. CONCLUSION: The CLIQ corresponds well with the EQ-5D-3L when applied before and during treatment but does not seem to be appropriate for follow-up evaluations after the end of treatment.