Traditional first-line treatment failure rates in neuromyelitis optica spectrum disorder patients included in the Argentinean registry (RelevarEM).

BACKGROUND: Immunosuppressive therapies as azathioprine (AZA), mycophenolate mofetil (MMF) and rituximab (RTX) are widely prescribed as first-line treatment to prevent relapses in NMOSD. However, the rate of response to these traditional therapies is unknown in Argentina. We aimed to describe and compare treatment failure rates in NMOSD patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). METHODS: A retrospective cohort study was conducted in NMOSD patients included in RelevarEM (a nationwide, longitudinal, observational, non-mandatory registry of MS and NMOSD in Argentina). NMOSD patients were defined based on validate diagnostic criteria. Only NMOSD patients who received AZA or MMF for at least 6 months or RTX for at least 1 month were included. Patients who were receiving AZA, MMF, or RTX and then switched to another 1 of these 3 therapies were included if the above-mentioned criteria for each drug were fulfilled. Data on patient demographics, clinical, neuroradiological findings, and treatments administered were collected. Treatment failure was defined as any new attack/relapse that occurred despite immunosuppressive treatment. RESULTS: We included 139 NMOSD patients who were receiving AZA (n = 105), MMF (n = 5) or RTX (n = 29) with a mean follow-up time of 41.3 ± 11.4 months and median of EDSS at treatment initiation of 3. We observed a reduction in the annualized relapse rate from pre-treatment to post-treatment of 51.1 %, 48.4 %, and 79.1 % respectively with a Hazard Risk relative to RTX (95 % CI) of 1.67 (1.34-3.54, p = 0.01) for AZA and 2.01 (1.86-4.43, p = 0.008) for MMF. AZA, MMF and RTX failure was observed in 45/105 (42.8 %), 2/5 (40 %) and 3/29 (10.3 %) patients, respectively. CONCLUSIONS: Treatment failure rates were higher for AZA and MMF than RTX in Argentinean NMOSD patients in a real-world setting. High-efficacy treatment increases the opportunity to prevent attacks of NMOSD.

Food Insecurity at Tuberculosis Treatment Initiation Is Associated With Clinical Outcomes in Rural Haiti: A Prospective Cohort Study.

BACKGROUND: Tuberculosis is a leading cause of death worldwide, and food insecurity is known to negatively influence health outcomes through multiple pathways. Few studies have interrogated the relationship between food insecurity and tuberculosis outcomes, particularly independent of nutrition. METHODS: We conducted a prospective cohort study of adults initiating first-line treatment for clinically suspected or microbiologically confirmed drug-sensitive tuberculosis at a rural referral center in Haiti. We administered a baseline questionnaire, collected clinical data, and analyzed laboratory samples. We used logistic regression models to estimate the relationship between household food insecurity (Household Hunger Scale) and treatment failure or death. We accounted for exclusion of patients lost to follow-up using inverse probability of censoring weighting and adjusted for measured confounders and nutritional status using inverse probability of treatment weighting. RESULTS: We enrolled 257 participants (37% female) between May 2020 and March 2023 with a median age (interquartile range) of 35 (25-45) years. Of these, 105 (41%) had no hunger in the household, 104 (40%) had moderate hunger in the household, and 48 (19%) had severe hunger in the household. Eleven participants (4%) died, and 6 (3%) had treatment failure. After adjustment, food insecurity was significantly associated with subsequent treatment failure or death (odds ratio 5.78 [95% confidence interval, 1.20-27.8]; P = .03). CONCLUSIONS: Household food insecurity at tuberculosis treatment initiation was significantly associated with death or treatment failure after accounting for loss to follow-up, measured confounders, and nutritional status. In addition to the known importance of undernutrition, our findings indicate that food insecurity independently affects tuberculosis treatment outcomes in Haiti.

Farnesyl Diphosphate Synthase Gene Associated with Loss of Bone Mass Density and Alendronate Treatment Failure in Patients with Primary Osteoporosis.

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = -2.21% ± 2.56; p = 0.026) and TH (CC = -2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.

Predictors of unsuccessful tuberculosis treatment outcomes in Brazil: an analysis of 259,484 patient records.

INTRODUCTION: Tuberculosis (TB) causes over 1 million deaths annually. Providing effective treatment is a key strategy for reducing TB deaths. In this study, we identified factors associated with unsuccessful treatment outcomes among individuals treated for TB in Brazil. METHODS: We obtained data on individuals treated for TB between 2015 and 2018 from Brazil's National Disease Notification System (SINAN). We excluded patients with a history of prior TB disease or with diagnosed TB drug resistance. We extracted information on patient-level factors potentially associated with unsuccessful treatment, including demographic and social factors, comorbid health conditions, health-related behaviors, health system level at which care was provided, use of directly observed therapy (DOT), and clinical examination results. We categorized treatment outcomes as successful (cure, completed) or unsuccessful (death, regimen failure, loss to follow-up). We fit multivariate logistic regression models to identify factors associated with unsuccessful treatment. RESULTS: Among 259,484 individuals treated for drug susceptible TB, 19.7% experienced an unsuccessful treatment outcome (death during treatment 7.8%, regimen failure 0.1%, loss to follow-up 11.9%). The odds of unsuccessful treatment were higher with older age (adjusted odds ratio (aOR) 2.90 [95% confidence interval: 2.62-3.21] for 85-100-year-olds vs. 25-34-year-olds), male sex (aOR 1.28 [1.25-1.32], vs. female sex), Black race (aOR 1.23 [1.19-1.28], vs. White race), no education (aOR 2.03 [1.91-2.17], vs. complete high school education), HIV infection (aOR 2.72 [2.63-2.81], vs. no HIV infection), illicit drug use (aOR 1.95 [1.88-2.01], vs. no illicit drug use), alcohol consumption (aOR 1.46 [1.41-1.50], vs. no alcohol consumption), smoking (aOR 1.20 [1.16-1.23], vs. non-smoking), homelessness (aOR 3.12 [2.95-3.31], vs. no homelessness), and immigrant status (aOR 1.27 [1.11-1.45], vs. non-immigrants). Treatment was more likely to be unsuccessful for individuals treated in tertiary care (aOR 2.20 [2.14-2.27], vs. primary care), and for patients not receiving DOT (aOR 2.35 [2.29-2.41], vs. receiving DOT). CONCLUSION: The risk of unsuccessful TB treatment varied systematically according to individual and service-related factors. Concentrating clinical attention on individuals with a high risk of poor treatment outcomes could improve the overall effectiveness of TB treatment in Brazil.

A Descriptive Study of Corneal Graft Failure in Retransplant Patients.

OBJECTIVE: To identify the main predictors for corneal graft failure in patients who underwent retransplantation. METHOD: This is a cross-sectional research with a quantitative and analytical approach, conducted based on data from secondary sources of a Human Eye Tissue Bank (HETB) in Northeast Brazil. Data were collected from the medical charts of all patients transplanted between January 2010 and December 2014. Descriptive statistics were used for the univariate analysis by means of absolute and relative frequencies and means. For the inferential analysis, the chi-square (X²) and the Fisher's Exact tests were used. RESULTS: A total of 241 records were reviewed, representing 258 keratoplasties, of which 27 (10.46%) were retransplantations due to corneal graft failure. Of the total, 55.56% of the individuals were female, with a mean age of 58.56 years, 55.56% of the population was brown, and the highest relative frequency of housing found was in the Central Mesoregion. Of the corneal graft failure cases, 88.89% were due to late failure, 30.77% of cases were classified as pseudophakic and 11.57% as aphakic. Through inferential analysis, a statistical association was obtained among the variable "corneal graft failure" and mesoregion of the state, presence of glaucoma, vascularization, and classification of the eye. CONCLUSION: The prognosis of keratoplasty is of multifactorial nature. Factors such as mesoregion of the State (place of residence), glaucoma, corneal vascularization, and aphakic eyes represent predictors for graft failure in the analyzed sample.

Natural resistance to meglumine antimoniate is associated with treatment failure in cutaneous leishmaniasis caused by Leishmania (Viannia) panamensis.

The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 µg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.

[Prognostic factors associated with failure of modular knee arthroplasty in oncologic patients]. / Factores pronósticos asociados al fracaso de la artroplastía modular de rodilla en pacientes oncológicos.

INTRODUCTION: reconstruction of large bone defects using modular knee arthroplasty (MKA) presents a significant challenge in terms of functionality. The objective of the present work was to identify the different prognostic factors associated with failure of MKA in cancer patients. MATERIAL AND METHODS: a retrospective cohort study was conducted, including patients with a diagnosis of musculoskeletal tumor in the distal femur or proximal tibia, who underwent MKA between January 1, 2010, and December 31, 2021. RESULTS: 49 patients were included, of which 25 (51.02%) were women and 24 (48.98%) men, with a mean age of 29.57 years. Of these, 14 (28.57%) patients experienced some type of MKA failure. The most frequent complication that led to failure was periprosthetic infection, observed in seven (14.29%) patients. Variables associated with MKA failure included biopsies performed outside our hospital (HR 3.2, 95% CI 1.4-6.4, p = 0.02), the length of the long axis of the tumor (HR 2.1, 95% CI 1.2-4.6, p = 0.01) and a prolonged surgical time (HR 3.37, 95% CI 1.1-8.6, p = 0.04). CONCLUSION: the most significant prognostic factors associated with MKA failure in our cohort were tumor size, prolonged surgical time, and performance of the diagnostic biopsy in a center not specialized in the management of this type of patient. These findings highlight the importance of considering these variables to improve outcomes in patients undergoing MKA.

INTRODUCCIÓN: la reconstrucción de grandes defectos óseos mediante artroplastía modular de rodilla (AMR) representa un desafío significativo en términos de funcionalidad. El objetivo del presente trabajo fue identificar los diferentes factores pronósticos asociados al fracaso de la AMR en pacientes oncológicos. MATERIAL Y MÉTODOS: se realizó un estudio de cohorte retrospectiva, incluyendo pacientes con diagnóstico de tumor musculoesquelético en el fémur distal o la tibia proximal, que fueron sometidos a AMR entre el 1 de Enero de 2010 y el 31 de Diciembre de 2021. RESULTADOS: se incluyeron 49 pacientes, de los cuales 25 (51.02%) eran mujeres y 24 (48.98%) hombres, con una edad media de 29.57 años. De éstos, 14 (28.57%) pacientes experimentaron algún tipo de fracaso de la AMR. La complicación más frecuente que condicionó el fracaso fue la infección periprotésica, observada en siete (14.29%) pacientes. Las variables asociadas con el fracaso de las AMR incluyeron biopsias realizadas fuera de nuestro hospital (HR 3.2, IC95% 1.4-6.4, p = 0.02), longitud del eje mayor del tumor (HR 2.1, IC95% 1.2-4.6, p = 0.01) y tiempo quirúrgico prolongado (HR 3.37, IC95% 1.1-8.6, p = 0.04). CONCLUSIÓN: los factores pronósticos asociados al fracaso de las AMR en nuestra cohorte fueron el tamaño del tumor, un tiempo quirúrgico prolongado y la realización de la biopsia diagnóstica en un centro no especializado en el manejo de este tipo de pacientes. Estos hallazgos resaltan la importancia de considerar estas variables en pacientes sometidos a AMR.

Interaction between peripheral blood mononuclear cells and Trypanosoma cruzi-infected adipocytes: implications for treatment failure and induction of immunomodulatory mechanisms in adipose tissue.

Background/Introduction: Adipose tissue (AT) has been highlighted as a promising reservoir of infection for viruses, bacteria and parasites. Among them is Trypanosoma cruzi, which causes Chagas disease. The recommended treatment for the disease in Brazil is Benznidazole (BZ). However, its efficacy may vary according to the stage of the disease, geographical origin, age, immune background of the host and sensitivity of the strains to the drug. In this context, AT may act as an ally for the parasite survival and persistence in the host and a barrier for BZ action. Therefore, we investigated the immunomodulation of T. cruzi-infected human AT in the presence of peripheral blood mononuclear cells (PBMC) where BZ treatment was added. Methods: We performed indirect cultivation between T. cruzi-infected adipocytes, PBMC and the addition of BZ. After 72h of treatment, the supernatant was collected for cytokine, chemokine and adipokine assay. Infected adipocytes were removed to quantify T. cruzi DNA, and PBMC were removed for immunophenotyping. Results: Our findings showed elevated secretion of interleukin (IL)-6, IL-2 and monocyte chemoattractant protein-1 (MCP-1/CCL2) in the AT+PBMC condition compared to the other controls. In contrast, there was a decrease in tumor necrosis factor (TNF) and IL-8/CXCL-8 in the groups with AT. We also found high adipsin secretion in PBMC+AT+T compared to the treated condition (PBMC+AT+T+BZ). Likewise, the expression of CD80+ and HLA-DR+ in CD14+ cells decreased in the presence of T. cruzi. Discussion: Thus, our findings indicate that AT promotes up-regulation of inflammatory products such as IL-6, IL-2, and MCP-1/CCL2. However, adipogenic inducers may have triggered the downregulation of TNF and IL-8/CXCL8 through the peroxisome proliferator agonist gamma (PPAR-g) or receptor expression. On the other hand, the administration of BZ only managed to reduce inflammation in the microenvironment by decreasing adipsin in the infected culture conditions. Therefore, given the findings, we can see that AT is an ally of the parasite in evading the host's immune response and the pharmacological action of BZ.

Can the ROX index predict high-flow nasal cannula failure in children under 2 with lower respiratory tract infection?

OBJECTIVE: This study evaluates the ROX index's accuracy in predicting the success or failure of high-flow nasal cannula (HFNC) therapy in children under 2 years with acute respiratory failure (ARF) from lower respiratory tract infections. METHODS: From January 2018 to 2021 we conducted this multicenter retrospective cohort study, which included patients aged 2-24 months. We aimed to assess HFNC therapy outcomes as either success or failure. The analysis covered patient demographics, diagnoses, vital signs, and ROX index values at intervals from 0 to 48 h after initiating HFNC. We used bivariate analysis, repeated measures ANOVA, multivariate logistic regression, and the area under the receiver operating characteristic (AUC-ROC) curve for statistical analysis. RESULTS: The study involved 529 patients from six centers, with 198 females (37%) and a median age of 9 months (IQR: 3-15 months). HFNC therapy failed in 38% of cases. We observed significant variability in failure rates across different centers and physicians (p < .001). The ROX index was significantly associated with HFNC outcomes at all time points, showing an increasing trend in success cases over time (p < .001), but not in HFNC failure cases. Its predictive ability is limited, with AUC-ROC values ranging from 0.56 at the start to 0.67 at 48 h. CONCLUSION: While the ROX index is associated with HFNC outcomes in children under 2 years, its predictive ability is modest, impacted by significant variability among patients, physicians, and centers. These findings emphasize the need for more reliable predictive tools for HFNC therapy in this patient population.

Prevention of complications related to peripherally inserted central catheter insertion techniques in newborns: systematic review and network meta-analysis / Prevención de complicaciones asociadas con las técnicas de inserción de catéter central de inserción periférica en recién nacidos: revisión sistemática y metaanálisis en red / Prevenção de complicações relacionadas a técnicas de inserção do cateter central de inserção periférica em recém-nascidos: revisão sistemática e metanálise em rede

Objective: to analyze the effectiveness of peripherally inserted central catheter insertion techniques in preventing the occurrence of complications related to this device in newborns. Method: a paired and network systematic literature review and meta-analysis, with its search carried out in seven databases and in the Grey Literature, including randomized and non-randomized clinical trials. The risk of bias was assessed using the Cochrane Risk of Bias 2 and Risk of Bias In Non-randomized Studies of Interventions tools. Certainty of the evidence was assessed by means of the Grading of Recommendations Assessment, Development and Evaluation. A meta-analysis was carried out with the aid of the R statistical program. Results: eight studies with 1,126 newborns were included and six insertion techniques were identified: intracavitary electrocardiogram; intracavitary electrocardiogram associated with ultrasound; ultrasound; formula; anatomical landmark; and modified anatomical landmark. Five techniques significantly decreased primary tip malpositioning when compared to the control ( p <0.05). Intracavitary electrocardiogram significantly and more effectively reduced arrhythmias, general complications and phlebitis; the technique that used a formula also reduced general complications. Infection, infiltration, secondary tip malpositioning, catheter rupture, thrombosis, occlusion and catheter-associated skin lesion were not significantly preventable events. Conclusion: intracavitary electrocardiogram and use of the formula were the most effective techniques in reducing complications.

Objetivo: analizar la efectividad de las técnicas de inserción de catéter central de inserción periférica en la prevención de la aparición de complicaciones asociadas con este dispositivo en recién nacidos. Método: revisión sistemática de la literatura y metaanálisis pareado y en red, la búsqueda se realizó en siete bases de datos y en la literatura gris, se incluyeron ensayos clínicos aleatorizados y no aleatorizados. El riesgo de sesgo se evaluó mediante las herramientas Cochrane Risk of Bias 2 y Risk of Bias In Non-randomized Studies of Interventions . La certeza de la evidencia a través de la Grading of Recommendations Assessment, Development and Evaluation . Se realizó un metaanálisis con ayuda del programa estadístico R. Resultados: se incluyeron ocho estudios, con 1126 recién nacidos, y se identificaron seis técnicas de inserción: electrocardiograma intracavitario, electrocardiograma intracavitario asociado a ultrasonido, ultrasonido, fórmula, punto anatómico de referencia y punto anatómico de referencia modificado. Cinco técnicas redujeron significativamente el mal posicionamiento primario de la punta en comparación con el control (p<0,05). El electrocardiograma intracavitario redujo de manera significativa y más efectiva las arritmias, las complicaciones generales y la flebitis; la técnica que utilizó una fórmula también redujo las complicaciones generales. La infección, la infiltración, el mal posicionamiento secundario de la punta, la rotura del catéter, la trombosis, la oclusión y las lesiones de la piel asociadas con el catéter son eventos que no se revinieron significativamente. Conclusión: el electrocardiograma intracavitario y el uso de la fórmula fueron las técnicas más efectivas para reducir las complicaciones.

Objetivo: analisar a efetividade das técnicas de inserção de cateter central de inserção periférica na prevenção da ocorrência de complicações relacionadas a este dispositivo em recém-nascidos. Método: revisão sistemática da literatura e metanálise pareada e em rede, com busca realizada em sete bases de dados e na literatura cinzenta, inclusão de ensaios clínicos aleatorizados e não aleatorizados. O risco de viés foi avaliado pelas ferramentas da Cochrane Risk of Bias 2 e o Risk of Bias In Non-randomised Studies of Interventions. A certeza da evidência pelo Grading of Recommendations Assessment, Development and Evaluation. Realizou-se metanálise com auxílio do programa estatístico R. Resultados: oito estudos, com 1126 recém-nascidos, foram incluídos e seis técnicas de inserção identificadas: eletrocardiograma intracavitário, eletrocardiograma intracavitário associado à ultrassonografia, ultrassonografia, fórmula, marco de referência anatômico e marco de referência anatômico modificado. Cinco técnicas diminuíram significativamente o mau posicionamento primário da ponta quando comparadas com o controle ( p <0,05). O eletrocardiograma intracavitário diminuiu arritmias, complicações gerais e flebite de forma significativa e mais efetiva; a técnica que utilizou uma fórmula também reduziu complicações gerais. Infecção, infiltração, mau posicionamento secundário da ponta, ruptura do cateter, trombose, oclusão e lesão de pele associada ao cateter não foram eventos prevenidos significativamente. Conclusão: eletrocardiograma intracavitário e uso da fórmula foram as técnicas mais efetivas na redução de complicações.

Culture-negative TB: clinical characteristics, risk factors and treatment outcomes.

BACKGROUND: Although culture remains the standard for TB diagnosis, 15-20% of patients diagnosed and treated for TB are culture-negative. We explored clinical characteristics, risk factors and treatment outcomes for culture-negative TB in a Peruvian cohort.METHODS: We recruited 4,500 index TB patients and 10,160 household contacts in Lima, Peru, and enrolled 692 secondary patients diagnosed with TB during follow-up of household contacts. We analyzed smear and culture status, sociodemographic factors, clinical characteristics and TB treatment outcomes to compare culture-negative and positive patients.RESULTS: Of the 4,880 adult patients, 915 (18.8%) were culture-negative. Culture-negative patients were less likely to report symptoms of TB disease and disease of longer duration. A multivariate analysis showed no statistically significant difference in loss to follow-up, treatment failure or recurrence between the culture-negative and -positive groups but a higher rate of death among culture-negative patients with an adjusted OR of 1.65 (95% CI 1.05-2.60). In a multivariate analysis of determinants of culture negativity, older age, substance use and being a secondary case were associated with culture status.CONCLUSIONS: More recognition and awareness of culture-negative TB is key for early and correct diagnosis to reduce transmission and improve treatment outcomes.

Dolutegravir-associated resistance mutations after first-line treatment failure in Brazil.

BACKGROUND: Since January 2017, the recommended first-line antiretroviral regimen in Brazil is the fixed-dose combination of tenofovir plus lamivudine with dolutegravir (TL + D). According to the literature, integrase resistance-associated mutations (INRAMs) are rarely found upon virologic failure to first-line dolutegravir plus two nucleoside reverse transcriptase inhibitors. We evaluated the HIV antiretroviral genotypic resistance profile of patients referred for genotyping in the public health system who failed first-line TL + D after at least six months of therapy on or before December 31, 2018. METHODS: HIV Sanger sequences of the pol gene were generated from plasma of patients with confirmed virologic failure to first-line TL + D in the Brazilian public health system before December 31, 2018. RESULTS: One hundred thirteen individuals were included in the analysis. Major INRAMs were detected in seven patients (6.19%), four with R263K, one with G118R, one with E138A, and one with G140R. Four patients with major INRAMs also had the K70E and M184V mutations in the RT gene. Sixteen (14.2%) additional individuals presented minor INRAMs, and five (4,42%) patients had both major and minor INRAMS. Thirteen (11.5%) patients also presented mutations in the RT gene selected by tenofovir and lamivudine, including four with both the K70E and M184V mutations and four with only M184V. The integrase mutations L101I and T124A, which are in the in vitro pathway for integrase inhibitor resistance, were found in 48 and 19 patients, respectively. Mutations not related to TL + D, thus probable transmitted resistance mutations (TDR), were present in 28 patients (24.8%): 25 (22.1%) to nucleoside reverse transcriptase inhibitors, 19 (16.8%) to non-nucleoside reverse transcriptase inhibitors, and 6 (5.31%) to protease inhibitors. CONCLUSIONS: In marked contrast to previous reports, we report a relatively high frequency of INRAMs among selected patients failing first-line TL + D in the public health system in Brazil. Possible reasons for this discrepancy include delays in detecting virologic failure, patients inadvertently on dolutegravir monotherapy, TDR, and/or infecting subtype.

Association Between Nasopharyngeal Colonization and Clinical Outcome in Children With Acute Otitis Media.

BACKGROUND: Young children with acute otitis media (AOM) frequently exhibit nasopharyngeal colonization with either Streptococcus pneumoniae, Haemophilus influenzae or both pathogens. We aimed to determine if antibiotics could be spared or shortened in those without nasopharyngeal colonization with either pathogen. METHODS: In 2 separate randomized clinical trials in children aged 6-23 months with stringently-diagnosed AOM, we performed bacterial cultures on nasopharyngeal specimens collected at the time of diagnosis. In the first trial, we compared the efficacy of amoxicillin/clavulanate (amox/clav) administered for 10 days vs. that of placebo, and in the second trial, we compared the efficacy of amox/clav administered for 10 days vs. 5 days. In each trial, we classified children as being colonized with both S. pneumoniae and H. influenzae, S. pneumoniae alone, H. influenzae alone, or neither pathogen, and as experiencing either clinical success or clinical failure at the end-of-therapy visit, based on previously reported a priori criteria. RESULTS: We evaluated 796 children. Among children randomized to amox/clav, those colonized with either S. pneumoniae or H. influenzae or both were approximately twice as likely to experience clinical failure as children not colonized with either pathogen (odds ratio: 1.8; confidence intervals: 1.2-2.9). In contrast, among children randomized to placebo, clinical failure at the end-of-therapy visit was not associated with nasopharyngeal culture results at the time of diagnosis. CONCLUSIONS: Children colonized with either S. pneumoniae or H. influenzae or both have a greater chance of treatment failure than children colonized with neither pathogen.

Rhabdomyosarcoma in low- and middle-income countries: A report from the Asociacion de Hemato-oncología Pediatrica de Centro América (AHOPCA).

This report describes the results of an observational study dedicated to rhabdomyosarcoma developed by the Asociación de Hemato-oncología Pediatrica de Centro América (AHOPCA) between 2001 and 2018. Overall, 337 previously untreated patients < 18 years old were included in the analysis; 58% had unresected disease, and 19% were metastatic at diagnosis. With a median follow-up of 6.6 years, five-year event-free and overall survival rates were 30% and 33%, respectively. Local progression/relapse was the main cause of treatment failure.

The Role of miRNAs in Childhood Acute Lymphoblastic Leukemia Relapse and the Associated Molecular Mechanisms.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children worldwide. Although ALL patients' overall survival rates in wealthy countries currently surpass 80%, 15-20% of patients still experience relapse. The underlying mechanisms of relapse are still not fully understood, and little progress has been made in treating refractory or relapsed disease. Disease relapse and treatment failure are common causes of leukemia-related death. In ALL relapse, several gene signatures have been identified, but it is also important to study miRNAs involved in ALL relapse in an effort to avoid relapse and to achieve better survival rates since miRNAs regulate target genes that participate in signaling pathways involved in relapse, such as those related to drug resistance, survival signals, and antiapoptotic mechanisms. Several miRNAs, such as miR-24, miR-27a, miR-99/100, miR-124, miR-1225b, miR-128b, miR-142-3p, miR-155 and miR-335-3p, are valuable biomarkers for prognosis and treatment response in ALL patients. Thus, this review aimed to analyze the primary miRNAs involved in pediatric ALL relapse and explore the underlying molecular mechanisms in an effort to identify miRNAs that may be potential candidates for anti-ALL therapy soon.

Pyogenic spondylodiscitis: risk factors for therapeutic failure and recurrence / Espondilodiscite piogênica: fatores de risco para falha terapêutica e recorrência / Espondilodiscitis piógena: factores de riesgo para fracaso terapéutico y recurrencia

ABSTRACT Objective: Evaluate the prognostic factors associated with therapeutic failure and recurrence in pyogenic spondylodiscitis (PS). Methods: A historical cohort study was conducted in a reference Brazilian hospital for locomotor system and neurodevelopmental diseases. All patients with PS treated between January 1999 and December 2018 and followed for at least one year were included. PS was defined based on clinical, laboratory, and radiological criteria. Microbiological data and clinical outcomes at the end of follow-up were also collected and analyzed. Results: Fifty patients (mean age 50.94 ± 15.84 years, men 76.00%) were included. After twelve months of follow-up, therapeutic failure was observed in 24.00% (n = 12) and recurrence in 18.00% (n = 09) patients. Among those who were cured, residual symptoms were found in 50.00% (19/38). No deaths were observed. After multivariate analysis, therapeutic failure was associated with the prescription of antibiotic therapy before culture results (p = 0.0153), spinal cord compression (p = 0.0053), and sensory deficits (p = 0.0341). Furthermore, recurrence was associated with previous nonspinal surgeries (p = 0.0350) and spinal cord compression (p = 0.0447). Conclusion: PS causes significant morbidity. The prognosis depends mainly on the clinical presentation at admission, especially when associated with spinal cord compression, which reinforces the importance of early diagnosis. Level of Evidence II; Prognostic Studies.

RESUMO: Objetivo: Avaliar os fatores prognósticos associados à falha terapêutica e à recorrência na espondilodiscite piogênica (EP). Métodos: Um estudo de coorte histórica foi conduzido em um hospital brasileiro de referência nas doenças do sistema locomotor e do neurodesenvolvimento. Todos os pacientes com EP tratados entre janeiro de 1999 e dezembro de 2018 e acompanhados por pelo menos um ano foram incluídos. A EP foi definida com base em critérios clínicos, laboratoriais e radiológicos. Dados microbiológicos e desfechos clínicos ao final do tempo de seguimento também foram coletados e analisados. Resultados: Cinquenta pacientes (idade média 50,94 ± 15,84 anos, homem 76,00%) foram incluídos. Depois de doze meses de seguimento, a falha terapêutica foi observada em 24,00% (n = 12) e a recorrência em 18,00% (n = 09) dos pacientes. Entre os que curaram, sintomas residuais foram constatados em 50,00% (19/38). Nenhuma morte foi observada. Após análise multivariada, a falha terapêutica foi associada à prescrição de antibioticoterapia antes dos resultados de cultura (p = 0,0153), compressão medular (p = 0,0053) e déficits sensoriais (p = 0,0341). Além disso, a recorrência esteve associada a cirurgias não espinhais prévias (p = 0,0350) e à compressão medular (p = 0,0447). Conclusão: A EP causa morbidade significativa. O prognóstico depende principalmente da apresentação clínica na admissão, especialmente da existência de compressão medular, o que reforça a importância do diagnóstico precoce. Nível de Evidência II; Estudos de Prognóstico.

RESUMEN: Objetivo: Evaluar los factores pronósticos asociados con el fracaso terapéutico y la recurrencia en la espondilodiscitis piógena (EP). Métodos: Se realizó un estudio de cohorte histórica en un hospital de referencia brasileño para enfermedades del aparato locomotor y del neurodesarrollo. Se incluyeron todos los pacientes con EP tratados entre enero de 1999 y diciembre de 2018 y seguidos durante al menos un año. La EP se definió en base a criterios clínicos, de laboratorio y radiológicos. También se recopilaron y analizaron los datos microbiológicos y los resultados clínicos al final del tiempo de seguimiento. Resultados: Se incluyeron 50 pacientes (edad media 50,94 ± 15,84 años, sexo masculino 76,00%). A los doce meses de seguimiento, se observó fracaso terapéutico en el 24,00% (n=12) y recurrencia en el 18,00% (n=09) de los pacientes. Entre los que se curaron, se encontraron síntomas residuales en el 50,00% (19/38). No se observaron muertes. Tras el análisis multivariante, el fracaso terapéutico se asoció a la prescripción de antibioticoterapia antes de los resultados del cultivo (p = 0,0153), compresión medular (p = 0,0053) y déficits sensitivos (p = 0,0341). Además, la recurrencia se asoció con cirugías previas no espinales (p = 0,0350) y compresión medular (p = 0,0447). Se incluyeron 50 pacientes (edad media 50,94 ± 15,84 años, sexo masculino 76,00%). A los doce meses de seguimiento, se observó fracaso terapéutico en el 24,00% (n=12) y recurrencia en el 18,00% (n=09) de los pacientes. Entre los que se curaron, se encontraron síntomas residuales en el 50,00% (19/38). No se observaron muertes. Tras el análisis multivariante, el fracaso terapéutico se asoció a la prescripción de antibioticoterapia antes de los resultados del cultivo (p = 0,0153), compresión medular (p = 0,0053) y déficits sensitivos (p = 0,0341). Además, la recurrencia se asoció con cirugías previas no espinales (p = 0,0350) y compresión medular (p = 0,0447). Conclusión: La EP causa una morbilidad significativa. El pronóstico depende principalmente de la presentación clínica al ingreso, especialmente de la existencia de compresión medular, lo que refuerza la importancia del diagnóstico precoz. Nivel de Evidencia II; Estudios de Pronóstico.

Risk factors for failure after primary vitrectomy with no scleral buckling for rhegmatogenous retinal detachment / Fatores de risco para falha de tratamento após vitrectomia primária sem retinopexia com introflexão escleral

ABSTRACT Objective To assess pre-operative conditions that could influence primary anatomical success rate in a cohort of patients with rhegmatogenous retinal detachments (RRD) treated with primary vitrectomy and no scleral buckling. Methods A retrospective analysis was performed in a group of patients that underwent primary pars plana vitrectomy with gas tamponade and without scleral buckling for RRD between 2014 and 2019, with a minimum follow-up of 4 months. Results 305 eyes of 301 patients were included; 59.01% eyes were phakic, 39.01% were pseudophakic and 1.96% aphakic. 13.11% of patients had proliferative vitreoretinopathy grade B and 3.28% proliferative vitreoretinopathy grade C at the time of diagnosis while 83.61% had proliferative vitreoretinopathy grade 0 or A. 53.1% had superior breaks, 15.4% inferior breaks and 31.5% a combination of both. Primary success rate was obtained in 90.82% of eyes (95%CI 87.58-94.06). 9.18% of eyes (95%CI 5.94-12.42) re-detached. In 3.27% the cause of re-detachment was proliferative vitreoretinopathy, and in the remaining 5.90% because of a new or a missed break, the leakage of a previously treated break, or an area of shallow peripheral detachment with no detectable break. Of 181 phakic eyes, 10.49% re-detached, whereas in over 126 aphakic or pseudophakic eyes 7.75% re-detached (p=0.42). 16.39% eyes of the entire cohort had preoperative grade B or C proliferative vitreoretinopathy, whereas 32.14% of re-detached eyes had preoperative grade B or C proliferative vitreoretinopathy (95%CI 17.29-46.99; p=0.02). Th eyes that re-detached after the first surgery had a mean of 2.5 (95%CI 1.86-3.13) retinal tears, against a mean of 1.87 (95%CI 1.73-2.00) retinal tears of those that did not re-detach after the first surgery (p=0.02). Conclusion We found location of breaks and lens status to be independent factors not related to a lower single operation success rate, whereas the number or size of breaks and preoperative proliferative vitreoretinopathy stages B or C were independent factors related to a higher likelihood of re-detachment.

RESUMO Objetivo Avaliar condições pré-operatórias que poderiam influenciar a taxa de sucesso anatômico primário em uma coorte de pacientes com descolamento de retina regmatogênico tratada com vitrectomia primária e sem introflexão escleral. Métodos Foi realizada uma análise retrospectiva em um grupo de pacientes submetidos a vitrectomia primária pars plana com tamponamento gasoso e sem introflexão escleral por desprendimento de retina regmatogênico entre os anos 2014 e 2019, com monitoramento mínimo de 4 meses. Resultados Foram incluídos 305 olhos de 301 pacientes; 59,01% dos olhos eram fáquicos, 39,01% eram pseudofáquicos, e 1,96% era afáquico; 13,11% dos pacientes tinham vitreorretinopatia proliferativa grau B, e 3,28%, vitreorretinopatia proliferativa grau C no momento do diagnóstico, enquanto 83,61% tinham vitreorretinopatia proliferativa grau 0 ou A; 53,1% tinham rasgaduras superiores; 15,4%, rasgaduras inferiores e 31,5%, uma combinação de ambas. A taxa de sucesso primário foi obtida em 90,82% dos olhos (IC95% 87,58-94,06); 9,18% dos olhos (IC95% 5,94-12,42) se redestacaram. Em 3,27%, a causa do redescolamento foi vitreorretinopatia proliferativa e, nos 5,90% restantes, por causa de uma ruptura nova ou perdida, o vazamento de uma ruptura previamente tratada, ou uma área de descolamento periférico superficial sem ruptura detectável. Dos 181 olhos fáticos, 10,49% redestacaram-se, enquanto em mais de 126 olhos afáquicos ou pseudofáquicos 7,75% redestacaram-se (p=0,42); 16,39% dos olhos de toda a coorte tinham vitreorretinopatia proliferativa pré-operatória grau B ou C, enquanto 32,14% dos olhos redescolados tinham vitreorretinopatia proliferativa pré-operatória grau B ou C (IC95% 17,29-46,99) (p=0,02). Os olhos que se redescolaram após a primeira cirurgia tiveram média de 2,5 (IC95% 1,86-3,13) lágrimas retinianas, contra uma média de 1,87 (IC95% 1,73-2,00) lágrima retiniana daqueles que não se redestacaram após a primeira cirurgia. (p=0,02). Conclusão A localização das rasgaduras e o status da lente são fatores independentes não relacionados a uma menor taxa de sucesso da operação, enquanto o número ou o tamanho das rasgaduras e estágios vitreorretinopatia proliferativa pré-operatórios B ou C foram fatores independentes relacionados a uma maior probabilidade de redescolamento.

Pharmacokinetics of chloroquine in patients with malaria by P. vivax from the Western Brazilian Amazon basin.

The western Amazon basin is an important endemic area for malaria by P. vivax. In recent years, several reports showed the treatment failure with chloroquine, which can be related to resistance. The assessment of chloroquine resistance requires the evaluation of drug exposure, and when possible, the estimation of the pharmacokinetic parameters. However, there is no data on the pharmacokinetics of chloroquine in this endemic area. Moreover, the influence of the early reappearance of parasites in blood on the exposure to the drug was low exploited in the literature. The present study described the pharmacokinetic parameters of chloroquine in whole blood of adult patients with P. vivax malaria from the western Brazilian Amazon basin and compared the area under the curve (AUC) with the parasitological outcome at day 28. A total of 19 patients with parasite recurrence within 28 days and 20 patients with no recurrence were included in the study. Chloroquine was measured by high-performance liquid chromatography (HPLC). The pharmacokinetic parameters were estimated by non-compartmental modeling. The maximum concentration ranged from 1285 to 2030 ng/mL. The terminal half-life varied from 5.3 to 12.8 days. The volume of distribution from 1090 to 2340 L/kg, and the area under the curve to the last measurable concentration from 247 to 432 ng/mL.h. The pharmacokinetic parameters were similar in both groups, which suggests the lack of influence of early reappearance of parasites on chloroquine pharmacokinetics.