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Background: Mucosal leishmaniasis (ML) is a deforming type of American Tegumentary Leishmaniasis caused by Leishmania (Viannia) braziliensis that frequently does not respond to treatment. Despite its relapsing clinical course, few parasites are usually found in mucosal lesions. Host and parasite factors may be responsible for this paradox in the pathogenesis of the disease, allowing for both a low parasite burden and the inability of the host to clear and eliminate the disease. Methods and results: In this work, we present a clinical case of relapsing ML that was treated for 25 years without success with SbV, N-methyl glucamine, sodium stibogluconate, amphotericin B deoxycholate, gabromycin, antimonial plus thalidomide, liposomal amphotericin B, Leishvacin (a vaccine made in Brazil) and miltefosine. In a comparative analysis using nanoscale liquid chromatography coupled with tandem mass spectrometry of protein extracts of L. (V.) braziliensis promastigotes isolated from the patient and from the reference strain (MHOM/BR/94/M15176), we observed increases in ATPase and HSP70 protein levels in the parasite. We also observed an impairment in the production of hydrogen peroxide by peripheral mononuclear blood monocytes (PBMCs), as assessed by the horseradish peroxidase-dependent oxidation of phenol red. Conclusions: We hypothesise that these parasite molecules may be linked to the impairment of host parasiticidal responses, resulting in Leishmania persistence in ML patients. [ABSTRACT FROM AUTHOR]

Abstract Poor-quality, substandard and falsified, medicines pose a significant public health threat, particularly in low-middle-income countries. A retrospective study was performed on Kenya's Pharmacovigilance Electronic Reporting System (2014–2021) to characterize medicine quality-related complaints and identify associations using disproportionality analysis. A total of 2767 individual case safety reports were identified, categorized into medicines with quality defects (52.1%), suspected therapeutic failure (41.6%), and suspected adverse drug reactions (6.3%). Predominantly reported were antineoplastic agents (28.6%), antivirals (11.7%), and antibacterial agents (10.8%) potentially linked to non-adherence to good manufacturing practices, inappropriate usage and supply chain degradation. Notably, analgesics (8.2%), and medical devices (3.5%) notified had quality defects, predominantly from government health facilities (60.0%). Antineoplastic agents (20.2%) and antivirals (3.7%) were frequently reported from suspected therapeutic failures and suspected adverse drug reactions, respectively, across both private for-profit facilities (26.5%) and not-for-profit facilities (5.4%). Underreporting occurred in unlicensed health facilities (8.1%), due to unawareness and reporting challenges. Pharmacists (46.1%), and pharmaceutical technicians (11.7%) predominantly reported quality defects, while medical doctors (28.0%) reported suspected therapeutic failures. Orally administered generic medicines (76.9%) were commonly reported, with tablets (5.8%) identified as potential sources of suspected adverse drug reactions, while quality defects were notified from oral solutions, suspensions, and syrups (7.0%) and medical devices (3.9%). The COVID-19 pandemic correlated with reduced reporting possibly due to prioritization of health surveillance. This study provides valuable evidence to supporting the use of medicine quality-related complaints for proactive, targeted regulatory control of high-risk medicines on the market. This approach can be strengthened by employing standardized terminology to prioritize monitoring of commonly reported suspected poor-quality medicines for risk-based sampling and testing within the supply chain.

Poor-quality, substandard and falsified, medicines pose a significant public health threat, particularly in low-middle-income countries. A retrospective study was performed on Kenya's Pharmacovigilance Electronic Reporting System (2014–2021) to characterize medicine quality-related complaints and identify associations using disproportionality analysis. A total of 2767 individual case safety reports were identified, categorized into medicines with quality defects (52.1%), suspected therapeutic failure (41.6%), and suspected adverse drug reactions (6.3%). Predominantly reported were antineoplastic agents (28.6%), antivirals (11.7%), and antibacterial agents (10.8%) potentially linked to non-adherence to good manufacturing practices, inappropriate usage and supply chain degradation. Notably, analgesics (8.2%), and medical devices (3.5%) notified had quality defects, predominantly from government health facilities (60.0%). Antineoplastic agents (20.2%) and antivirals (3.7%) were frequently reported from suspected therapeutic failures and suspected adverse drug reactions, respectively, across both private for-profit facilities (26.5%) and not-for-profit facilities (5.4%). Underreporting occurred in unlicensed health facilities (8.1%), due to unawareness and reporting challenges. Pharmacists (46.1%), and pharmaceutical technicians (11.7%) predominantly reported quality defects, while medical doctors (28.0%) reported suspected therapeutic failures. Orally administered generic medicines (76.9%) were commonly reported, with tablets (5.8%) identified as potential sources of suspected adverse drug reactions, while quality defects were notified from oral solutions, suspensions, and syrups (7.0%) and medical devices (3.9%). The COVID-19 pandemic correlated with reduced reporting possibly due to prioritization of health surveillance. This study provides valuable evidence to supporting the use of medicine quality-related complaints for proactive, targeted regulatory control of high-risk medicines on the market. This approach can be strengthened by employing standardized terminology to prioritize monitoring of commonly reported suspected poor-quality medicines for risk-based sampling and testing within the supply chain. [ABSTRACT FROM AUTHOR]

Simple Summary: Response to treatment and prognosis after 223Ra treatment varies among patients. Using a combination of clinical, biochemical, and radiomic data from bone scintigraphy and 18F-Fluorocholine PET/CT obtained from our prospective ChoPET-Rad study, we identified predictive and prognostic variables. The goal was to create a nomogram able to predict therapeutic failure and overall survival, aiding in the selection of more suitable candidates for this treatment. Purpose: We aimed to develop a nomogram able to predict treatment failure, skeletal events, and overall survival (OS) in patients with castration-resistant prostate cancer with bone metastases (CRPC-BM) treated with Radium-223 dichloride (223Ra). Patients and Methods: Patients from the Castilla-La Mancha Spanish region were prospectively included in the ChoPET-Rad multicenter study from January 2015 to December 2022. Patients underwent baseline, interim, and end-of-treatment bone scintigraphy (BS) and 18F-Fluorocholine PET/CT (FCH PET/CT) scans, obtaining multiple imaging radiomics as well as clinical and biochemical variables during follow-up and studying their association with the previously defined end-points. Survival analysis was performed using the Kaplan–Meier method and Cox regression. Multivariate logistic and Cox regression models were calculated, and these models were depicted by means of nomograms. Results: Median progression-free survival (PFS) and OS were 4 and 14 months (mo), respectively. The variables that showed independent and significant association with therapeutic failure were baseline alkaline phosphatase (AP) levels (p = 0.022) and the characteristics of BM on the CT portion of PET/CT (p = 0.017). In the case of OS, the significant variables were therapeutic failure (p = 0.038), the number of lines received after 223Ra (p < 0.001), average SUVmax (p = 0.002), bone marrow infiltration in FCH PET/CT (p = 0.006), and interim FCH PET/CT response (p = 0.048). Final nomograms included these variables, showing good discrimination among the 100 patients included in our study. In the study of skeletal events, only OS showed a significant association in the multivariate analysis, resulting in an inconsistent nomogram design. Conclusions: FCH PET/CT appears to be a good tool for evaluating patients eligible for treatment with 223Ra, as well as for their follow-up. Thus, findings derived from it, such as the morphological characteristics of BM in the CT, bone marrow infiltration, or the response to 223Ra in the interim study, have proven to be solid and useful variables in the creation of nomograms for predicting therapeutic failure and OS. [ABSTRACT FROM AUTHOR]

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The main objective of this study was to evaluate the variables influencing the efficacy of different approaches to addressing the problem of drug use among juvenile offenders. A longitudinal study was conducted with 79 adolescent internees at the Teresa de Calcuta CEMJ (Centro de Ejecución de Medidas Judiciales) in Madrid. Therapeutic interventions were conducted with adolescents with severe drug-related problems. For data analysis, binary logistic regression analysis was used. Therapeutic success after a three-month follow-up period was 53.2%. The regression analysis correctly classified 86.1% of the cases, effectively predicting 85.7% of therapeutic success and 86.5% of therapeutic failure. The analysis identified 4 predictive factors: the number of criminal charges resulting in internment, number of minor infractions committed during detention, prior consumption of ecstasy and risk factors in personality and/or behavioural issues. The results suggest that judicial and therapeutic interventions should be based on the chronicity of delinquency and other individual personality traits. [ABSTRACT FROM AUTHOR]

Background: In Equatorial Guinea, only 54 % of people living with HIV know their HIV status. There are no confirmatory or molecular diagnostic techniques for early diagnosis or monitoring of infection in the country. Rapid diagnostic tests can induce false-positive diagnoses if used as a confirmatory technique. Our study aimed to identify the challenges of early HIV diagnosis in Equatorial Guinea by analyzing the rate of false positive diagnoses, diagnostic and therapeutic delays, and treatment failures among those on antiretroviral therapy. Methods: From 2019–2022, dried blood from 341 children, adolescents and adults diagnosed in Equatorial Guinea as HIV-positive by rapid diagnostic testing, and from 54 HIV-exposed infants were collected in Bata and sent to Madrid to confirm HIV-infection by molecular (Xpert HIV-1Qual, Cepheid) and/or serological confirmatory assays (Geenius-HIV-1/2, BioRad). HIV diagnostic delay (CD4 1,000RNA-HIV-1-copies/ml) were also studied after viral quantification (XpertVL HIV-1, Cepheid). Results: False-positive diagnoses were identified in 5 % of analysed samples. HIV infection was confirmed in 90.5 % of previously diagnosed patients in Equatorial Guinea and 3.7 % of HIV-exposed children undiagnosed in the field. Two-thirds of each new HIV patient had delayed diagnosis, and one-third had advanced disease. Treatment delay occurred in 28.3 % of patients, being around four times more likely in adolescents/adults than children. More than half (56 %) of 232 treated patients presented treatment failure, being significantly higher in children/adolescents than in adults (82.9 %/90 % vs. 45.6 %, p

The advent of biologic drugs has revolutionized the treatment of Inflammatory Bowel Disease, increasing rates of response and mucosal healing in comparison to conventional therapies by allowing the treatment of corticosteroid-refractory cases and reducing corticosteroid-related side effects. However, biologic therapies (anti-TNFα inhibitors, anti-α4β7 integrin and anti-IL12/23) are still burdened by rates of response that hover around 40% (in biologic-naïve patients) or lower (for biologic-experienced patients). Moreover, knowledge of the mechanisms underlying drug resistance or loss of response is still scarce. Several cellular and molecular determinants are implied in therapeutic failure; genetic predispositions, in the form of single nucleotide polymorphisms in the sequence of cytokines or Human Leukocyte Antigen, or an altered expression of cytokines and other molecules involved in the inflammation cascade, play the most important role. Accessory mechanisms include gut microbiota dysregulation. In this narrative review of the current and most recent literature, we shed light on the mentioned determinants of therapeutic failure in order to pave the way for a more personalized approach that could help avoid unnecessary treatments and toxicities. [ABSTRACT FROM AUTHOR]

Background: Mucosal leishmaniasis (ML) is a deforming type of American Tegumentary Leishmaniasis caused by Leishmania (Viannia) braziliensis that frequently does not respond to treatment. Despite its relapsing clinical course, few parasites are usually found in mucosal lesions. Host and parasite factors may be responsible for this paradox in the pathogenesis of the disease, allowing for both a low parasite burden and the inability of the host to clear and eliminate the disease. Methods and results: In this work, we present a clinical case of relapsing ML that was treated for 25 years without success with SbV, N-methyl glucamine, sodium stibogluconate, amphotericin B deoxycholate, gabromycin, antimonial plus thalidomide, liposomal amphotericin B, Leishvacin (a vaccine made in Brazil) and miltefosine. In a comparative analysis using nanoscale liquid chromatography coupled with tandem mass spectrometry of protein extracts of L. (V.) braziliensis promastigotes isolated from the patient and from the reference strain (MHOM/BR/94/M15176), we observed increases in ATPase and HSP70 protein levels in the parasite. We also observed an impairment in the production of hydrogen peroxide by peripheral mononuclear blood monocytes (PBMCs), as assessed by the horseradish peroxidase-dependent oxidation of phenol red. Conclusions: We hypothesise that these parasite molecules may be linked to the impairment of host parasiticidal responses, resulting in Leishmania persistence in ML patients.

Community-acquired pneumonia represents the third-highest cause of mortality in industrialized countries and the first due to infection. Although guidelines for the approach to this infection model are widely implemented in international health schemes, information continually emerges that generates controversy or requires updating its management. This paper reviews the most important issues in the approach to this process, such as an aetiologic update using new molecular platforms or imaging techniques, including the diagnostic stewardship in different clinical settings. It also reviews both the Intensive Care Unit admission criteria and those of clinical stability to discharge. An update in antibiotic, in oxygen, or steroidal therapy is presented. It also analyzes the management out-of-hospital in CAP requiring hospitalization, the main factors for readmission, and an approach to therapeutic failure or rescue. Finally, the main strategies for prevention and vaccination in both immunocompetent and immunocompromised hosts are reviewed. [ABSTRACT FROM AUTHOR]

Psoriasis patients with poor therapeutic response to multiple biologic agents are not well-characterized. To describe the characteristics associated with development of multiple biologic failure (MBF) versus good clinical response (GR) to the first biologic. This prospective cohort analysis evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for ≥24 months. Multivariable logistic regression identified sociodemographic, clinical, and patient-reported outcomes that differed between MBF (discontinued ≥2 biologics of different classes, each used for ≥90 days, due to inadequate efficacy) and GR (continued use of first biologic for ≥2 years) patients. One thousand thirty-nine patients were analyzed (490 GR [47.2%], 65 MBF [6.3%]). Female sex, shorter psoriasis duration, earlier year of biologic initiation, prior nonbiologic systemic therapy use, history of hyperlipidemia, and Medicaid insurance were significantly associated with MBF, though the latter 2 variables exhibited wider confidence intervals, indicating a lower level of support. The first-to-second biologic sequence most observed with MBF was Tumor necrosis factor-α inhibitor to IL-17 inhibitor use. Biologic adherence between visits was not evaluated. Approximately 6% of psoriasis patients met MBF criteria. The results identify characteristics associated with MBF that may distinguish patients warranting more frequent follow-up. [ABSTRACT FROM AUTHOR]

Nosocomial pneumonia, or hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) are important health problems worldwide, with both being associated with substantial morbidity and mortality. HAP is currently the main cause of death from nosocomial infection in critically ill patients. Although guidelines for the approach to this infection model are widely implemented in international health systems and clinical teams, information continually emerges that generates debate or requires updating in its management. This scientific manuscript, written by a multidisciplinary team of specialists, reviews the most important issues in the approach to this important infectious respiratory syndrome, and it updates various topics, such as a renewed etiological perspective for updating the use of new molecular platforms or imaging techniques, including the microbiological diagnostic stewardship in different clinical settings and using appropriate rapid techniques on invasive respiratory specimens. It also reviews both Intensive Care Unit admission criteria and those of clinical stability to discharge, as well as those of therapeutic failure and rescue treatment options. An update on antibiotic therapy in the context of bacterial multiresistance, in aerosol inhaled treatment options, oxygen therapy, or ventilatory support, is presented. It also analyzes the out-of-hospital management of nosocomial pneumonia requiring complete antibiotic therapy externally on an outpatient basis, as well as the main factors for readmission and an approach to management in the emergency department. Finally, the main strategies for prevention and prophylactic measures, many of them still controversial, on fragile and vulnerable hosts are reviewed. [ABSTRACT FROM AUTHOR]

Antibiotic resistance is a major Public Health challenge worldwide. Mechanisms other than resistance are described as contributors to therapeutic failure. These include heteroresistance and tolerance, which escape the standardized procedures used for antibiotic treatment decision-making as they do not involve changes in minimal inhibitory concentration (MIC). Haemophilus influenzae causes chronic respiratory infection and is associated with exacerbations suffered by chronic obstructive pulmonary disease (COPD) patients. Although resistance to imipenem is rare in this bacterial species, heteroresistance has been reported, and antibiotic tolerance cannot be excluded. Moreover, development of antibiotic heteroresistance or tolerance during within-host H. influenzae pathoadaptive evolution is currently unknown. In this study, we assessed imipenem resistance, heteroresistance and tolerance in a previously sequenced longitudinal collection of H. influenzae COPD respiratory isolates. The use of Etest, disc diffusion, population analysis profiling, tolerance disc (TD)-test methods, and susceptibility breakpoint criteria when available, showed a significant proportion of imipenem heteroresistance with differences in terms of degree among strains, absence of imipenem tolerance, and no specific trends among serial and clonally related strains could be established. Analysis of allelic variation in the ftsI, acrA, acrB, and acrR genes rendered a panel of polymorphisms only found in heteroresistant strains, but gene expression and genome-wide analyses did not show clear genetic traits linked to heteroresistance. In summary, a significant proportion of imipenem heteroresistance was observed among H. influenzae strains isolated from COPD respiratory samples over time. These data should be useful for making more accurate clinical recommendations to COPD patients.

Patients with cutaneous leishmaniasis (CL) present an exacerbated inflammatory response associated with tissue damage and ulcer development. In recent years, higher rates of failure to pentavalent antimoniate therapy have been observed, yet the underlying reason remains poorly understood. We hypothesize that the eicosanoid PGE2 favours the establishment of infection by L. braziliensis, which contributes to therapeutic failure. The aim of the present study was to investigate the influence of PGE2 on the survival of L. braziliensis in macrophages and rates of therapeutic failure in CL patients. PGE2, an eicosanoid derived from the metabolism of arachidonic acid by the COX-2 enzyme, plays several roles in immune response. We found that increased PGE2 decreases the microbicidal function of macrophages and is associated with disease severity and therapeutic failure. Additionally, the neutralization of COX-2 by NS398, a selective NSAID, increases the ability of macrophages to kill L. braziliensis and protects against the pathological inflammatory response. Our data suggest that NS398 may serve as an adjunct treatment for CL patients.

Background: Kawasaki disease is a systemic vasculitis that affects small and medium-sized vessels, primarily the coronary arteries. First-line treatment includes intravenous immunoglobulin (IVIG) and acetylsalicylic acid; however, 20% do not respond adequately despite treatment. We describe a case treated with etanercept after initial IVIG failure, showing a good response. Case report: A 5-year-old female was diagnosed with classic Kawasaki disease. Echocardiography and angiotomography revealed giant and fusiform aneurysms in the coronary arteries. A first dose of IVIG therapy was administered without improvement; after the second dose, the fever persisted, so etanercept was administered, and the fever subsided. There were no new lesions in medium-caliber vessels and the previously identified coronary lesions did not progress. Conclusions: The use of etanercept in Kawasaki disease has demonstrated a clinically favorable response. Controlled clinical trials of this drug are needed to establish it as a formal therapy in cases of initial IVIG failure. [ABSTRACT FROM AUTHOR]

Objective: To evaluate parasitemia by qPCR in patients undergoing etiological treatment and followed in a Brazilian reference center. Methods: Parasite load was quantified by qPCR in 32 participants with chronic Chagas disease who were treated with benznidazole. Serological analyses were performed before and after the treatment and parasite loads were compared prior and 12/18 months post the treatment. Results: Thirty-two participants were recruited and treated with benznidazole, and 20 were followed-up. Adverse events (AE) were observed in 22 out of 29 participants that had safety data (76%), and dermatological alterations were the most frequently observed AE. Of the 20 participants analyzed, 13 and 7 completed 12 and 18 months follow-up after the treatment, respectively. 12 Months after the final treatment, Trypanosoma cruzi was detectable in 3 patients by qPCR; 18 months after the final treatment, Trypanosoma cruzi was detectable per qPCR in 4 of the 7 participants. Thus, between 12 and 18 months, 7 participants of the 20 initial follow-up cases showed positive qPCR, indicating treatment failures. Conclusions: qPCR can be used as an alternative method for evaluating the effectiveness of the etiological treatment of CD, and can be applied to analyze early therapeutic failures. The study showed that benznidazole therapy had limited effectiveness in treating chronic CD patients, thus emphasizing the importance of conducting continued research for developing more effective therapies and diagnosis for CD.

BackgroundContemporary antiretroviral therapies (ART) and management strategies have diminished both human immunodeficiency virus (HIV) treatment failure and the acquired resistance to drugs in resource-rich regions, but transmission of drug-resistant viruses has not similarly decreased. In low- and middle-income regions, ART roll-out has improved outcomes, but has resulted in increasing acquired and transmitted resistances. Our objective was to review resistance to ART drugs and methods to detect it, and to provide updated recommendations for testing and monitoring for drug resistance in HIV-infected individuals.MethodsA volunteer panel of experts appointed by the International Antiviral (formerly AIDS) Society-USA reviewed relevant peer-reviewed data that were published or presented at scientific conferences. Recommendations were rated according to the strength of the recommendation and quality of the evidence, and reached by full panel consensus.ResultsResistance testing remains a cornerstone of ART. It is recommended in newly-diagnosed individuals and in patients in whom ART has failed. Testing for transmitted integrase strand-transfer inhibitor resistance is currently not recommended, but this may change as more resistance emerges with widespread use. Sanger-based and next-generation sequencing approaches are each suited for genotypic testing. Testing for minority variants harboring drug resistance may only be considered if treatments depend on a first-generation nonnucleoside analogue reverse transcriptase inhibitor. Different HIV-1 subtypes do not need special considerations regarding resistance testing.ConclusionsTesting for HIV drug resistance in drug-naive individuals and in patients in whom antiretroviral drugs are failing, and the appreciation of the role of testing, are crucial to the prevention and management of failure of ART.

A lack of HIV viral load (VL) and HIV drug resistance (HIVDR) monitoring in sub-Saharan Africa has led to an uncontrolled circulation of HIV-strains with drug resistance mutations (DRM), compromising antiretroviral therapy (ART). This study updates HIVDR data and HIV-1 variants in Equatorial Guinea (EG), providing the first data on children/adolescents in the country. From 2019–2020, 269 dried blood samples (DBS) were collected in Bata Regional Hospital (EG) from 187 adults (73 ART-naïve/114 ART-treated) and 82 children/adolescents (25 HIV-exposed-ART-naïve/57 ART-treated). HIV-1 infection was confirmed in Madrid by molecular/serological confirmatory tests and ART-failure by VL quantification. HIV-1 pol region was identified as transmitted/acquired DRM, predicted antiretroviral susceptibility (Stanfordv9.0) and HIV-1 variants (phylogeny). HIV infection was confirmed in 88.1% of the individuals and virological failure (VL > 1000 HIV-1-RNA copies/mL) in 84.2/88.9/61.9% of 169 ART-treated children/adolescents/adults. Among the 167 subjects with available data, 24.6% suffered a diagnostic delay. All 125 treated had experienced nucleoside retrotranscriptase inhibitors (NRTI); 95.2% were non-NRTI (NNRTI); 22.4% had experienced integrase inhibitors (INSTI); and 16% had experienced protease inhibitors (PI). At sampling, they had received 1 (37.6%), 2 (32%), 3 (24.8%) or 4 (5.6%) different ART-regimens. Among the 43 treated children–adolescents/37 adults with sequence, 62.8/64.9% carried viruses with major-DRM. Most harbored DRM to NNRTI (68.4/66.7%), NRTI (55.3/43.3%) or NRTI+NNRTI (50/33.3%). One adult and one child carried major-DRM to PI and none carried major-DRM to INSTI. Most participants were susceptible to INI and PI. DRM was absent in 36.2% of treated patients with VL > 1000 cp/mL, suggesting adherence failure. TDR prevalence in 59 ART-naïve adults was high (20.3%). One-half (53.9%) of the 141 subjects with pol sequence carried CRF02_AG. The observed high rate of ART-failure and transmitted/acquired HIVDR could compromise the 95-95-95-UNAIDS targets in EG. Routine VL and resistance monitoring implementation are mandatory for early detection of ART-failure and optimal rescue therapy selection ART regimens based on PI, and INSTI can improve HIV control in EG. [ABSTRACT FROM AUTHOR]

Background: Therapeutic drug monitoring (TDM) has proven effectiveness in maintaining efficacy and reducing toxicities associated with vancomycin. A trough level of (15–20 mg/L) for MRSA serious infections is recommended. Therapeutic failure is of concern due to suboptimal routine vancomycin utilization in clinical practice. This study aims to identify factors of vancomycin TDM practice potentially associated with vancomycin-induced nephrotoxicity and therapeutic failure measured by the need to restart vancomycin therapy within 28-days and all-cause mortality in a tertiary hospital in Oman. Methods: A single-center retrospective cohort was conducted in a tertiary care hospital that included all adult patients aged ≥ 18 years treated with IV vancomycin for> 72 h. Results: Vancomycin therapeutic level was not achieved in 16.8% of the patients, and 47.5% had high levels (>20 mg/L). Vancomycin-induced nephrotoxicity occurred in 31.7% of the patients, it was restarted within 28-days in 18.8% of the patient, and 25.2% of the patients died during the same hospitalization. Univariate analysis showed old age (p

Background: Intra-abdominal infection (IAI) results in prolonged in-hospital length-of-stay, critical care unit requirements, and multiple surgical procedures. Several antimicrobial agents are available for treatment of IAI. In Colombia, there are no data on the comparative effectiveness of the different regimens used. Patients and Methods: A multicenter retrospective cohort study was completed in four third-level hospitals by comparing treatment effectiveness of five different antibiotic protocols (ampicillin-sulbactam, clindamycin-amikacin, piperacillin-tazobactam, amikacin-metronidazole, and cefuroxime-metronidazole) in patients with a diagnosis of IAI. Analysis was based on a composed outcome of therapeutic failure (change of antibiotic because of no clinical improvement, requirement of surgical re-intervention, post-operative infection, change of antibiotic because of antimicrobial resistance, and in-hospital mortality). Association of each antibiotic protocol to therapeutic failure was assessed through logistic regression analysis. Results: Five hundred ninety-three individuals were included. Two hundred twenty-nine were prescribed ampicillin-sulbactam; 170, clindamycin-amikacin; 77, amikacin-metronidazole; 83, piperacillin-tazobactam; and 34, cefuroxime-metronidazole. Therapeutic failure rate was 22%. Multivariable analysis showed none of the evaluated antibiotic protocols had an association with the primary outcome. Variables having an association for higher risk were age >70 years old (odds ratio [OR], 2.08; 95% confidence interval [CI], 1.04-4.18); complicated IAI (OR, 3.36; 95% CI, 1.4-8.07); and World Society of Emergency Surgery (WSES) Sepsis Severity Score (OR, 1.31; 95% CI, 1.18-1.45). Adequate source control (OR, 0.16; 95% CI, 0.05-0.45) and hospitalization at Health Center 2 (OR, 0.30; 95% CI, 0.14-0.63) were identified as protective factors. Conclusions: There are no differences between the rate of therapeutic failure among the different antibiotic protocols evaluated. This outcome depends heavily on risk factors related to disease severity when surgical intervention occurs. [ABSTRACT FROM AUTHOR]

This exploratory single session-study presents a multimodal, mixed-method description of a session of psychoanalytic psychotherapy and illustrates an in-session "failure", defined in terms of rupture in the therapeutic alliance and the process of its repair. It aims to enhance our understanding of the mechanisms implicated in therapeutic change. The research materialcomprises session's video-recording, transcript, and measurements of participants'physiological arousal, as reflected in their heart rate in the session. The analysis consisted of an iterative, multi-layered process that combines observations from verbal and nonverbal modalities of interaction for the identification of significant in-session moments. We applied quantitative descriptive analysis on participants' physiological arousal and synchronization, qualitative analysis of the clinical dialogue, and coded the in-session fluctuations in the therapeutic alliance,using the Rupture Resolution Rating System. The detailed analysis of specific interactive events in the session illustrates the shift from a "failure" in therapeutic collaboration to gradual repair; this shift entailed increased relatedness and physiological synchronization, and on a semantic level, co-created, reflective meanings in the here-and-now of the therapeutic interaction. The findings highlight ruptures as important in-session events and suggest that the therapist's empathic oscillation between interpretative and metacommunication strategies can be mutative during moments of relational rupture. Practical Implications Negotiation and resolution of in-session therapeutic ruptures may provide opportunities for therapeutic growth in terms of increased relatedness and reflectiveness. The therapist's flexible shifts between using interpretative interventions and immediate collaborative explorations in the here-and-now, in the form of metacommunication, seem to facilitate the repair of alliance rupture. Multimodal methodologies and multi-layered analyses, integrating verbal and nonverbal, physiological data in the study of therapeutic interaction can shed light on significant in-session events and mechanisms of the change process. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic disease that seriously impacts quality of life. There are known genetic and environmental factors that influence its onset and progression. Even though there is no cure for it, there are a variety of treatments available today to control its symptoms, although many of them fail to do so substantially. To identify the association of multiple sociodemographic, clinical, and pharmacological factors with therapeutic failure. Observational, descriptive, cross-sectional, retrospective, and analytical study of therapeutic failure in patients with moderate or severe psoriasis between 2020 and 2021 was performed. In total 1051 patients with moderate or severe psoriasis were evaluated. Gender (ORa: 0.579 CI 95%: 0.382–0.878), type of therapy (biologic or non-biologic; ORa: 1.939 CI 95%: 1.242–3.027), age (ORa: 1.018 CI 95%: 1.003–1.034), days of treatment (ORa: 1 CI 95%: 0.999–1) and DLQI (ORa: 1.212 CI 95%: 1.172–1.253) are significantly associated with therapeutic failure. Being male and receiving biologic therapy are associated with a higher incidence of therapeutic failure in the treatment of moderate or severe psoriasis. The increase in DLQI increase in the probability of failure, and mayor age or days of treatment decrease in the probability of failure. [ABSTRACT FROM AUTHOR]

ABSTRACT: The failure of artemisinin combination therapy (ACT) in malaria patients returning from endemic regions may be driven by parasite resistance to this treatment. ACT is used globally as the first-line treatment for Plasmodium falciparum malaria. However, artemisinin-resistant strains of P. falciparum have emerged and spread across Southeast Asia, with the risk of reaching high malaria burden regions in Africa and elsewhere. Here, we report on two malaria imported cases from Africa with possible parasite resistance to the ACT artemether-lumefantrine (AL).Case presentation: Two middle-aged males returning from Angola and Mozambique developed malaria symptoms in Portugal, where they were diagnosed and received treatment with AL as hospital inpatients. After apparent cure and discharge from hospital, these individuals returned to hospital showing signs of late clinical failure. Molecular analysis was performed across a number of drug resistance associated genes. No evidence of pfk13-mediated artemisinin resistance was found. Both subjects had complete parasite clearance after treatment with non-ACT antimalarials.Conclusion: Our case-studies highlights the need for close monitoring of signs of unsatisfactory antimalarial efficacy among AL treated patients and the possible implication of other genes or mutations in the parasite response to ACTs.

Background: Undernutrition is frequent among children living with HIV in developing countries. An interaction between malnutrition and HIV pediatric infection remains incompletely characterized in Colombia.Methodology: Retrospective longitudinal study, descriptive in nature, in 28 patients with a diagnosis of HIV infection, less than 18 years of age and receiving anti-retroviral therapy. Variables were retrieved from clinical records at start of antiretroviral therapy and after 12 months. Statistical analysis was exploratory.Results: 4 out of 28 patients were stunted (14,3%; 95%CI: 1,3 – 27,2), 2 out of 7 patients were wasted (28,6%; 95%CI: 0 – 62), 5 out of 17 patients were underweight (27,8%; 95%CI: 7,1 – 48,5) and 4 out of 28 patients had thinness (29,6%; 95%CI: 12,4 – 46,8). No clinically relevant anthropometric change was detected during follow-up. Anemia prevalence was 52% and 82% of patients had some degree of dyslipidemia. Both viral load (p=0,001) and CD4 count (p=0,01), significantly increased and the proportion of patients with therapeutic failure remained invariable during follow-up.Conclusion: Malnutrition is frequent and its prevalence might have decreased. HIV program improved medical control of the disease, with stable therapeutic failure rates that were comparable with previous reports. Nonetheless, anemia and dyslipidemia remain to be a paramount therapeutic challenge.

In Equatorial Guinea, only 54 % of people living with HIV know their HIV status. There are no confirmatory or molecular diagnostic techniques for early diagnosis or monitoring of infection in the country. Rapid diagnostic tests can induce false-positive diagnoses if used as a confirmatory technique. Our study aimed to identify the challenges of early HIV diagnosis in Equatorial Guinea by analyzing the rate of false positive diagnoses, diagnostic and therapeutic delays, and treatment failures among those on antiretroviral therapy. From 2019–2022, dried blood from 341 children, adolescents and adults diagnosed in Equatorial Guinea as HIV-positive by rapid diagnostic testing, and from 54 HIV-exposed infants were collected in Bata and sent to Madrid to confirm HIV-infection by molecular (Xpert HIV-1Qual, Cepheid) and/or serological confirmatory assays (Geenius-HIV-1/2, BioRad). HIV diagnostic delay (CD4 <350cells/mm3), advanced disease at diagnosis (CD4 <200cells/mm3) and antiretroviral treatment delay and failure (viraemia >1,000RNA-HIV-1-copies/ml) were also studied after viral quantification (XpertVL HIV-1, Cepheid). False-positive diagnoses were identified in 5 % of analysed samples. HIV infection was confirmed in 90.5 % of previously diagnosed patients in Equatorial Guinea and 3.7 % of HIV-exposed children undiagnosed in the field. Two-thirds of each new HIV patient had delayed diagnosis, and one-third had advanced disease. Treatment delay occurred in 28.3 % of patients, being around four times more likely in adolescents/adults than children. More than half (56 %) of 232 treated patients presented treatment failure, being significantly higher in children/adolescents than in adults (82.9 %/90 % vs. 45.6 %, p < 0.001). We identified some challenges of early HIV diagnosis in Equatorial Guinea, revealing a high rate of false positive diagnoses, diagnostic/treatment delays, and treatment failures that need to be addressed. The implementation of more accurate rapid diagnostic techniques and confirmatory tests, along with improving access to care, treatment, awareness, and screening, would contribute to controlling the spread of HIV in the country. [ABSTRACT FROM AUTHOR]

• Elevated levels of the kappa free light chains index (FKLCi) have emerged as a predictor for therapeutic failure (TF), defined as the occurrence of a second relapse, two or more T2 lesions, or PIRA. • An FKLCi exceeding 130 was associated with TF in both univariate and multivariate analyses, adjusted for sex, age, presence of acute inflammatory activity, EDSS at the time of sampling, administered line of treatment, and time from CSF analysis to treatment initiation. • Initiating second-line disease-modifying therapies in patients with elevated FKLCi levels would be advisable, as they have shown to be a robust protective factor against TF. • Age emerged as a weak protective factor against TF. • In contrast to findings from other studies, oligoclonal IgM Bands, Chitinase-3 Like-1, and serum neurofilament (analyzed as either raw values or age-adjusted Z-scores) were not associated with worse disease outcomes. Background: Our objective was to explore various biomarkers for predicting suboptimal responses to disease-modifying treatments (DMTs) in patients with MS (pwMS). Methods: We conducted a longitudinal, bicentric study with pwMS stratified based on their DMTs responses. Treatment failure (TF) was defined as the onset of a second relapse, presence of two or more T2 new lesions, or disability progression independent of relapse during the follow-up period. We evaluated intrathecal synthesis (ITS) of IgG and IgM using OCB, linear indices, and Reibergrams. Free kappa light chains ITS was assessed using the linear index (FKLCi). NfL and GFAP in serum and CSF, and CHI3L1 in CSF were quantified. Quantitative variables were dichotomized based on the third quartile. Predictive efficacy was assessed through bivariate and multivariate analyses, adjusting for age, sex, EDSS, acute inflammatory activity (AI) -defined as the onset of a relapse or gadolinium-enhancing lesions within a 90-day window of lumbar puncture-, treatment modality, study center, and time from disease onset to treatment initiation. In case of collinearity, multiple models were generated or confounding variables were excluded if collinearity existed between them and the biomarker. The same methodology was used to investigate the predictive potential of various combinations of two biomarkers, based on whether any of them tested positive or exceeded the third quartile. Results: A total of 137 pwMS were included. FKLCi showed no differences based on AI, no correlation with EDSS and was significantly higher in pwMS with TF (p = 0.008). FKLCi>130 was associated with TF in bivariate analysis (Log-Rank p = 0.004). Due to collinearity between age and EDSS, two different models were generated with each of them and the rest of the confounding variables, in which FKLCi>130 showed a Hazard Ratio (HR) of 2.69 (CI: 1.35–5.4) and 2.67 (CI: 1.32–5.4), respectively. The combination of either FKLC or sNfL exceeding the third quartile was also significant in bivariate (Log-Rank p = 0.04) and multivariate (HR=3.1 (CI: 1.5–6.5)) analyses. However, when analyzed independently, sNfL did not show significance, and FKLCi mirrored the pattern obtained in the previous model (HR: 3.04; CI: 1.51–6.1). Treatment with highefficacy DMTs emerged as a protective factor in all models. Discussion: Our analysis and the fact that FKLCi is independent of EDSS and AI suggest that it might be a valuable parameter for discriminating aggressive phenotypes. We propose implementing high-efficacy drugs in pwMS with elevated FKLCi. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring (TDM) has proven effectiveness in maintaining efficacy and reducing toxicities associated with vancomycin. A trough level of (15–20 mg/L) for MRSA serious infections is recommended. Therapeutic failure is of concern due to suboptimal routine vancomycin utilization in clinical practice. This study aims to identify factors of vancomycin TDM practice potentially associated with vancomycin-induced nephrotoxicity and therapeutic failure measured by the need to restart vancomycin therapy within 28-days and all-cause mortality in a tertiary hospital in Oman. A single-center retrospective cohort was conducted in a tertiary care hospital that included all adult patients aged ≥ 18 years treated with IV vancomycin for> 72 h. Vancomycin therapeutic level was not achieved in 16.8% of the patients, and 47.5% had high levels (>20 mg/L). Vancomycin-induced nephrotoxicity occurred in 31.7% of the patients, it was restarted within 28-days in 18.8% of the patient, and 25.2% of the patients died during the same hospitalization. Univariate analysis showed old age (p < 0.01), higher baseline creatinine reading (p = 0.03), high vancomycin level (p = 0.03), and vancomycin-induced nephrotoxicity (p < 0.01) were associated with increased all-cause mortality. Multivariate analysis identified overweight and vancomycin-induced nephrotoxicity were independent factors associated with increased all-cause mortality (OR:1.04; p = 0.043; 95% CI 1.00–1.08) and (OR:1.96; p = 0.049; 95% CI 1.00–21.61) respectively. Failure to achieve the recommended therapeutic vancomycin level (15–20 mg/L) is common in clinical practice and associated with poor health outcomes; hence, appropriate TDM practice is an essential exercise to improve efficacy, prevent failure and reduce serious toxicities associated with vancomycin therapy. [ABSTRACT FROM AUTHOR]

Diabetes is caused by a combination of impaired responsiveness to insulin and reduced production of insulin by the pancreas. Until recently, the decline of insulin production had been ascribed to β-cell death. But recent research has shown that β-cells do not die in diabetes, but undergo a silencing process, termed "dedifferentiation." The main implication of this discovery is that β-cells can be revived by appropriate treatments. We have shown that mitochondrial abnormalities are a key step in the progression of β-cell dysfunction towards dedifferentiation. In normal β-cells, mitochondria generate energy required to sustain insulin production and its finely timed release in response to the body's nutritional status. A normal β-cell can adapt its mitochondrial fuel source based on substrate availability, a concept known as "metabolic flexibility." This capability is the first casualty in the progress of β-cell failure. β-Cells lose the ability to select the right fuel for mitochondrial energy production. Mitochondria become overloaded, and accumulate by-products derived from incomplete fuel utilization. Energy production stalls, and insulin production drops, setting the stage for dedifferentiation. The ultimate goal of these investigations is to explore novel treatment paradigms that will benefit people with diabetes.

Background: Ocular toxoplasmosis is an infection caused by Toxoplasma gondii. In South America, the clinical course of ocular toxoplasmosis is more severe than in Europe and North America because virulent strains of the parasite are present. Ocular toxoplasmosis is the leading cause of posterior uveitis and retinochoroiditis in Colombia, requiring timely and appropriate treatment. However, there is no standardized therapy protocol based on economic studies for the country. Purpose: To compare the cost-effectiveness of four first-line treatment regimens for active ocular toxoplasmosis in immunocompetent adults in Colombia, using the number of averted therapeutic failures as the outcome. Methods: We performed an economic and cost-effectiveness analysis to compare four first-line treatment regimens for ocular toxoplasmosis from the perspective of a third-party payer (Colombian General System of Social Security in Health). A decision analysis tree was used over a 24-week time horizon, considering only direct costs. Additionally, we performed a discrete sensitivity analysis and a probabilistic sensitivity analysis with 10,000 iterations in the Monte Carlo simulation. Results: For the base case, trimethoprim/sulfamethoxazole showed 86% effectiveness at a cost of

A lack of HIV viral load (VL) and HIV drug resistance (HIVDR) monitoring in sub-Saharan Africa has led to an uncontrolled circulation of HIV-strains with drug resistance mutations (DRM), compromising antiretroviral therapy (ART). This study updates HIVDR data and HIV-1 variants in Equatorial Guinea (EG), providing the first data on children/adolescents in the country. From 2019–2020, 269 dried blood samples (DBS) were collected in Bata Regional Hospital (EG) from 187 adults (73 ART-naïve/114 ART-treated) and 82 children/adolescents (25 HIV-exposed-ART-naïve/57 ART-treated). HIV-1 infection was confirmed in Madrid by molecular/serological confirmatory tests and ART-failure by VL quantification. HIV-1 pol region was identified as transmitted/acquired DRM, predicted antiretroviral susceptibility (Stanfordv9.0) and HIV-1 variants (phylogeny). HIV infection was confirmed in 88.1% of the individuals and virological failure (VL > 1000 HIV-1-RNA copies/mL) in 84.2/88.9/61.9% of 169 ART-treated children/adolescents/adults. Among the 167 subjects with available data, 24.6% suffered a diagnostic delay. All 125 treated had experienced nucleoside retrotranscriptase inhibitors (NRTI); 95.2% were non-NRTI (NNRTI); 22.4% had experienced integrase inhibitors (INSTI); and 16% had experienced protease inhibitors (PI). At sampling, they had received 1 (37.6%), 2 (32%), 3 (24.8%) or 4 (5.6%) different ART-regimens. Among the 43 treated children–adolescents/37 adults with sequence, 62.8/64.9% carried viruses with major-DRM. Most harbored DRM to NNRTI (68.4/66.7%), NRTI (55.3/43.3%) or NRTI+NNRTI (50/33.3%). One adult and one child carried major-DRM to PI and none carried major-DRM to INSTI. Most participants were susceptible to INI and PI. DRM was absent in 36.2% of treated patients with VL > 1000 cp/mL, suggesting adherence failure. TDR prevalence in 59 ART-naïve adults was high (20.3%). One-half (53.9%) of the 141 subjects with pol sequence carried CRF02_AG. The observed high rate of ART-failure and transmitted/acquired HIVDR could compromise the 95-95-95-UNAIDS targets in EG. Routine VL and resistance monitoring implementation are mandatory for early detection of ART-failure and optimal rescue therapy selection ART regimens based on PI, and INSTI can improve HIV control in EG.

• Artemether-lumefantrine (AL) treatment failure of imported malaria in Portugal • AL treatment failure in the presence of wild-type pfk13 and pfmdr1 • Is the standard 3-day course of AL sufficient to ensure parasite clearance? • AL increasing treatment failures urges closer immediate follow up of malaria patients The failure of artemisinin combination therapy (ACT) in malaria patients returning from endemic regions may be driven by parasite resistance to this treatment. ACT is used globally as the first-line treatment for Plasmodium falciparum malaria. However, artemisinin-resistant strains of P. falciparum have emerged and spread across Southeast Asia, with the risk of reaching high malaria burden regions in Africa and elsewhere. Here, we report on two malaria imported cases from Africa with possible parasite resistance to the ACT artemether-lumefantrine (AL). Case presentation: Two middle-aged males returning from Angola and Mozambique developed malaria symptoms in Portugal, where they were diagnosed and received treatment with AL as hospital inpatients. After apparent cure and discharge from hospital, these individuals returned to hospital showing signs of late clinical failure. Molecular analysis was performed across a number of drug resistance associated genes. No evidence of pfk13 -mediated artemisinin resistance was found. Both subjects had complete parasite clearance after treatment with non-ACT antimalarials. Conclusion: Our case-studies highlights the need for close monitoring of signs of unsatisfactory antimalarial efficacy among AL treated patients and the possible implication of other genes or mutations in the parasite response to ACTs. [ABSTRACT FROM AUTHOR]

The tegumentary leishmaniasis in Bolivia is mainly caused by L. braziliensis. The clinical manifestations are ulcerative lesions which can generate satellite lesions close to the initial one. The first choice drugs for treatment are pentavalent antimonials; although with variable effectiveness. Lack of response to these drugs leads to the use of other alternatives, considered as second-choice drugs. However, in all cases there is the possibility of therapeutic failure. The present case shows the remission of the lesions using a combined treatment of pentamidine, miltefosine and paromomycin, in a patient with a history of lack of response to monotherapy with Glucantime® The remission of the disease achieved at the end of combined therapy is probably the result of the simultaneous lytic action of the three drugs used and the restoration of the patient's immune response. Up to 21 months of post-treatment control, all the lesions remained healed and the absence of new ones. [ABSTRACT FROM AUTHOR]

BackgroundMucosal leishmaniasis (ML), the most inflammatory form of tegumentary leishmaniasis, is predominantly caused by Leishmania braziliensis. The disease is characterized by the development of lesions, mainly in the nasal mucosa. An exacerbated inflammatory response has been associated with the presence of destructive and disfiguring lesions, with stages of severity ranging from small nodulations to the complete destruction of the nasal pyramid architecture. As Leishmania is an intracellular parasite, most immunological studies have emphasized the cell-mediated immune response, while relatively few studies aimed to investigate the role antibodies in protection against, or the pathology of ML.MethodsPatients with a confirmed diagnosis of ML were classified according to clinical staging criteria. Serum levels of Leishmania-specific IgG, IgG1 and IgG2 antibodies were determined by ELISA before and after treatment with antimony or antimony plus pentoxifylline.ResultsPatients in stages IV and V produced higher concentrations of IgG and IgG1 antibodies when compared to those in stage I and II. Significant reductions were seen in the concentrations of IgG and IgG2 antibodies in most patients who responded well to treatment.ConclusionsOur data demonstrate an association between IgG antibody titers and the severity of mucosal disease. The observed reduction in antibody production after successful treatment in most patients preliminarily indicates that these tests can be used to aid in the assessment of therapeutic response.

We aimed to characterize the genetic constitution of natural T. cruzi populations involved in an Oral Chagas Disease (OCD) outbreak at a rural school of the community of Chichiriviche de la Costa, Venezuela, which affected patients did not respond to the etiological treatment. Peripheral blood samples and/or hemocultures were obtained from twenty-nine OCD patients at time of diagnosis or along nine years of Post-treatment (Tx) follow-up. The IgG serology, T. cruzi discrete typing units (DTU), satellite DNA-qPCR parasitic loads, and minicircle signatures were determined at Pre-Tx and after Tx. The serological titles and parasitic loads changed after treatment, with a significant decrease of IgG titers (Spearman’s r value= -0.961) and median parasite loads from 2.869 [IQR = 2.113 to 3.720] to 0.105 [IQR = -1.147 to 1.761] log10 par eq. /mL at Pre-Tx and Post-Tx, respectively, suggesting infection evolution from acute to chronic phase, without seroconversion or parasitological eradication, which was indicative of treatment failure. All patients were infected with T. cruzi DTU I populations. At Pre-Tx their median Jaccard genetic distances were 0.775 [IQR = 0.708 to 0.882], decreasing in genetic variability towards the end of follow-up (Mann-Whitney U test p= 0.0031). Interestingly, no Post-Tx minicircle signature was identical to its Pre-Tx counterpart population in a same patient, revealing selection of parasite subpopulations between the primary infection and Post-Tx. The parasitic populations isolated from hemocultures showed a lower number of bands in the minicircle signatures with respect to the signatures obtained directly from the patients’ blood samples, demonstrating a process of parasitic selection and reduction of the population variability that initially infected the patients. Decrease of parasitic loads after treatment as well as Pre- and Post-Tx intra-TcI diversity might be a consequence of both, natural evolution of the acute infection to the chronic phase and persistence of refractory populations due to Tx selection.

Goal: The goal of this study is to determine the prevalence of therapeutic failure and the evolution of the biological factors after 6 and 12 months of anti‐retroviral treatment (ART) amongst human immunodefeciency virus (HIV) Patients receiving care through the Ambulatory Treatment Center in Nouakchott. Methods: The study presents a descriptive and retrospective analysis of 479 patients enrolled in ART between January 2015 and January 2019, with focus on treatment failures and related biomarkers. The average age of the patients studied was 37 ± 12.94 years. The majority (52.8%) were males, of whom (52.6%) were married. Results: The average body mass index (BMI) of the patients progressively increased after 6 and 12 months on ART. The average BMI increased from 20.3 ± 5.1 kg/m2, before treatment, to 21.7 ± 5.0 kg/m2 and 22.7 ± 5.4 kg/m2, after 6 and 12 months of treatment, respectively. Of the 479 patients, 97.3% were on 2 NRTIs + NNRTI. During the first 6 months of treatment, the clinical, immunological, and virological therapeutic failures were 0.6%, 34.10%, and 9%, respectively. After 6 and 12 months of ART, the TCD4, Hemoglobin, platelets, glycemia, creatinemia, and transaminase remained normal during the entire monitoring period. Conclusion: study demonstrated effective HIV treatment amongst the study patients. It showed clearance of virus and immune restoration can be attained after 6 and 12 months of ART. The number of patients who received the tests did decrease during the treatment period, which highlights the importance of adherence to patient management protocols, including clinical and biological monitoring. [ABSTRACT FROM AUTHOR]

We aimed to characterize the genetic constitution of natural T. cruzi populations involved in an Oral Chagas Disease (OCD) outbreak at a rural school of the community of Chichiriviche de la Costa, Venezuela, which affected patients did not respond to the etiological treatment. Peripheral blood samples and/or hemocultures were obtained from twenty-nine OCD patients at time of diagnosis or along nine years of Post-treatment (Tx) follow-up. The IgG serology, T. cruzi discrete typing units (DTU), satellite DNA-qPCR parasitic loads, and minicircle signatures were determined at Pre-Tx and after Tx. The serological titles and parasitic loads changed after treatment, with a significant decrease of IgG titers (Spearman's r value= -0.961) and median parasite loads from 2.869 [IQR = 2.113 to 3.720] to 0.105 [IQR = -1.147 to 1.761] log10 par eq. /mL at Pre-Tx and Post-Tx, respectively, suggesting infection evolution from acute to chronic phase, without seroconversion or parasitological eradication, which was indicative of treatment failure. All patients were infected with T. cruzi DTU I populations. At Pre-Tx their median Jaccard genetic distances were 0.775 [IQR = 0.708 to 0.882], decreasing in genetic variability towards the end of follow-up (Mann-Whitney U test p= 0.0031). Interestingly, no Post-Tx minicircle signature was identical to its Pre-Tx counterpart population in a same patient, revealing selection of parasite subpopulations between the primary infection and Post-Tx. The parasitic populations isolated from hemocultures showed a lower number of bands in the minicircle signatures with respect to the signatures obtained directly from the patients' blood samples, demonstrating a process of parasitic selection and reduction of the population variability that initially infected the patients. Decrease of parasitic loads after treatment as well as Pre- and Post-Tx intra-TcI diversity might be a consequence of both, natural evolution of the acute infection to the chronic phase and persistence of refractory populations due to Tx selection. [ABSTRACT FROM AUTHOR]

Background: Mucosal leishmaniasis (ML), the most inflammatory form of tegumentary leishmaniasis, is predominantly caused by Leishmania braziliensis. The disease is characterized by the development of lesions, mainly in the nasal mucosa. An exacerbated inflammatory response has been associated with the presence of destructive and disfiguring lesions, with stages of severity ranging from small nodulations to the complete destruction of the nasal pyramid architecture. As Leishmania is an intracellular parasite, most immunological studies have emphasized the cell-mediated immune response, while relatively few studies aimed to investigate the role antibodies in protection against, or the pathology of ML. Methods: Patients with a confirmed diagnosis of ML were classified according to clinical staging criteria. Serum levels of Leishmania -specific IgG, IgG1 and IgG2 antibodies were determined by ELISA before and after treatment with antimony or antimony plus pentoxifylline. Results: Patients in stages IV and V produced higher concentrations of IgG and IgG1 antibodies when compared to those in stage I and II. Significant reductions were seen in the concentrations of IgG and IgG2 antibodies in most patients who responded well to treatment. Conclusions: Our data demonstrate an association between IgG antibody titers and the severity of mucosal disease. The observed reduction in antibody production after successful treatment in most patients preliminarily indicates that these tests can be used to aid in the assessment of therapeutic response. [ABSTRACT FROM AUTHOR]

Background: Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.Objective and Rationale: We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to such treatments.Search Methods: We performed a systematic Pubmed search covering articles published since 1958 about the use of progestins, estro-progestins and selective progesterone receptor modulators, to treat endometriosis and its related symptoms. Two reviewers screened the titles and abstracts to select articles for full-text assessment.Outcomes: Progesterone receptor signalling leads to down-regulation of estrogen receptors and restrains local estradiol production through interference with aromatase and 17 beta-hydroxysteroid dehydrogenase type 1. Progestins inhibit cell proliferation, inflammation, neovascularisation and neurogenesis in endometriosis. However, progesterone receptor expression is reduced and disrupted in endometriotic lesions, with predominance of the less active isoform (PRA) over the full-length, active isoform (PRB), due to epigenetic abnormalities affecting the PGR gene transcription. Oxidative stress is another mechanism involved in progesterone resistance in endometriosis. Among the molecular targets of progesterone in the normal endometrium that resist progestin action in endometriotic cells are the nuclear transcription factor FOXO1, matrix metalloproteinases, the transmembrane gap junction protein connexin 43 and paracrine regulators of estradiol metabolism. Compared to other phenotypes, deep endometriosis appears to be more resistant to size regression upon medical treatments. Individual genetic characteristics can affect the bioavailability and pharmacodynamics of hormonal drugs used to treat endometriosis and, hence, explain part of the variability in the therapeutic response.Wider Implications: Medical treatment of endometriosis needs urgent innovation, which should start by deeper understanding of the disease core features and diverse phenotypes and idiosyncrasies, while moving from pure hormonal treatments to drug combinations or novel molecules capable of restoring the various homeostatic mechanisms disrupted by endometriotic lesions. [ABSTRACT FROM AUTHOR]

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Background: Leishmania (Viannia) braziliensis is the main etiological agent of tegumentary leishmaniasis in the Americas. Parasite molecular diversity and host immune status contribute to extensive variations in its clinical presentation within endemic areas of Brazil. Pentavalent antimonials have been used for more than 60 years as the first-line drug for all cases, despite the potential for severe side effects and refractoriness. In Rio de Janeiro, Brazil, most L. (V.) braziliensis infections are benign with a scarcity of parasites, although metastasis and refractory infections can arise. In this scenario, the use of novel molecular tools can be useful for diagnosis and to assess tissue parasitism, and is of benefit to clinical and therapeutic management. Methods: In this study, parasite load was assessed by real-time PCR based on the leishmanial small subunit ribosomal RNA gene. Results and conclusion: The data revealed a tendency to higher tissue parasitism in the skin compared to mucous lesion sites and a reduction with disease progression. Parasite load was lower in poor compared to good responders to antimonials, and was also reduced in recurrent lesions compared to primary ones. However, parasite load became higher with sequential relapses, pointing to an immune system inability to control the infection. Therefore the parasite burden does not seem to be a good predictor of disease progression.

Abstract We report the case of a 32-year-old man from Rio de Janeiro, who was infected in the Amazon region of Brazil by Leishmania (Viannia) naiffi. Generally, patients with L. naiffi cutaneous leishmaniasis exhibit a good therapeutic response to either pentavalent antimonials or pentamidine. However, after pentamidine treatment, this patient’s infection evolved to therapeutic failure. To understand this clinical outcome, we investigated the presence of the Leishmania RNA virus (LRV) in parasites isolated from the cutaneous lesion; herein, we discuss the possible association between a poor response to pentamidine therapy and the presence of the LRV.

Keywords: valproate; medication administration; therapeutic failure EN valproate medication administration therapeutic failure 620 621 2 04/25/23 20230501 NES 230501 Sodium valproate is an anticonvulsant medication available as brand-name/generic tablets, capsules, and liquid (syrup). Individual doses were evaluated by high-performance liquid chromatography for valproic acid content (n = 30).[3] It is important to highlight that valproic acid content in the syrup was 97%, within acceptable pharmacopeial limits (90%-110% of the labeled amount of valproic acid).[3] The results showed that mean valproic acid content in individual doses was 81.8% for 2.5 mL/125 mg (RSD = 17.2%, n = 10), 88.3% for 5 mL/250 mg (RSD = 9.6%, n = 10), and 93.1% for 7.5 mL/375 mg of valproate (RSD = 9%, n = 10) (Figure 1). [Extracted from the article]

Les échecs thérapeutiques dans la prise en charge des carcinomes cutanés de la face ne sont pas exceptionnels, du fait de la fréquence très élevée de ces lésions. Ils se présentent sous 3 aspects : (a) la récidive tumorale sur le site d'exérèse : des rappels concernant les marges d'exérèse en chirurgie première et en cas de récidive sont faits, ainsi qu'une mise au point sur la conduite à tenir en cas de marges incomplètes ; (b) les gênes fonctionnelles liées à la chirurgie : les anomalies sont abordées par localisation anatomique (paupières et lèvres) au travers de quelques exemples et d'algorithmes décisionnels. Le nez et l'oreille sont traités dans d'autres chapitres du rapport ; (c) les séquelles esthétiques enfin sont présentées grâce à de nouveaux cas cliniques. Therapeutic failures in the management of skin carcinomas of the face are not rare, because of the very high frequency of these lesions. They come in 3 aspects: (a) tumor recurrence at the site of resection: reminders concerning the margins of excision in first surgery and in case of recurrence are made, as well as a focus on the behavior to take in case of incomplete margins; (b) Functional drawbacks related to surgery: abnormalities are addressed by anatomical location (eyelids and lips) through some examples and decisional algorithms. The nose and the ear are treated in other chapters of the book; (c) the aesthetic sequelae are finally presented thanks to new clinical cases. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) and diabetes mellitus (DM) are two chronic diseases with major impact on worldwide morbidity and mortality. DM significantly increases the risk of death, therapeutic failure and relapse of TB, requiring a much more careful monitoring of these patients. In this article we present the case of a patient with type 2 DM in the stage of major chronic complications, with numerous risk factors for TB and atypical symptomatology, pulmonary X-ray showing active TB lesions. The patient did not follow the diabetologist's recommendations, discontinuing the antidiabetic treatment on his own initiative. The glycemic imbalance and chronic alcoholism caused the failure of the anti TB therapy. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency of therapeutic failure among patients with acute and subacute brucellosis and to explore the predictors of failure.Methods: The study included 213 consecutive, naïve patients with acute and subacute brucellosis. All participants underwent clinical evaluation, chest radiography, stool microscopic examination and interferon-gamma release assay. Patients received the WHO-recommended therapy of doxycycline 200 mg/day and rifampin 900 mg/day, for 6 weeks.Results: Mean age of the study population was 39.8 ± 12.2 years; 64.8% of them were males. The therapeutic failure rate was 16.4%. Adverse effects were reported by 13.1%. Multivariate analysis of factors associated with therapeutic failure revealed latent tuberculosis infection (LTBI) (OR 3.1, 95% CI, 1.9-24.6, P: 0.009), ascariasis (OR 2.6, 95% CI 1.5-17.9, P: 0.012), and the use of acid suppressive therapy (OR 2.1, 95% CI 1.2-19.5, P: 0.037) as the predictors of therapeutic failure.Conclusions: The prevalence of therapeutic failure among the Egyptian patients with acute/subacute brucellosis is increasing. Predictors of therapeutic failure are LTBI, ascariasis, and the use of acid suppressive therapy. [ABSTRACT FROM AUTHOR]

A mathematical model based on ordinary nonlinear differential equations is proposed to interpret the effect of effective access and therapeutic failure in HIV infection among a population. The model only considers sexual transmission. The analysis is made by determining the basic reproduction number, R0, the equilibrium points of the system and their local stability. Subsequently, two thresholds are determined to stablish sufficient conditions to avoid the manifestation of infection among the population. The first threshold is relates to therapeutic failure and based on access to antiretroviral treatment; the second threshold is only related to access to treatment and other parameters of the model; in each case they are determined to be the minimum quantities that must hold to have effective access and therapeutic failure, and therefore, to guarantee smaller levels of infection. [ABSTRACT FROM AUTHOR]

In Bolivia, the drugs used for the treatment of cutaneous leishmaniasis are the antimonials by systemic application in doses / kg/weight, which cause adverse effects due to the applications in long periods and large volumes. The perilesional application of antimony has similar therapeutic efficacy than the systemic one. However, there is no documented information regarding the efficacy of perilesional treatment in patients with therapeutic failure after systemic treatment. The aim of this series of cases was to evaluate the perilesional treatment with Glucantime®, in patients with cutaneous leishmaniasis and therapeutic failure, after a first cycle of systemic treatment with antimonials. The study was conducted with eleven patients with cutaneous leishmaniasis and therapeutic failure, after the administration of a first cycle of systemic treatment with Glucantime®. from the tropical zone of Bolivia. The persistence of the lesion and the presence of parasites at the edge of the lesion were considered as therapeutic failure. The perilesional intervention consisted in the application past one day of glucantime® in five sessions. The inoculation was performed on the edge of the lesion and the dosage of the medication was calculated by multiplying the area of the lesion by the factor 0.008. All the cases presented local pain during the time of inoculation of the drug, as well as a slight enlargement of the area of the lesion after the first inoculation of the drug. In the following inoculations the progressive reduction of the area of the lesion was observed until its complete healing. [ABSTRACT FROM AUTHOR]

Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. Results: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. Conclusion: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.

Visceral leishmaniasis (VL) caused by the protozoan parasite Leishmania infantum, is one of the most important zoonotic diseases affecting dogs and humans in the Mediterranean area. The presence of infected dogs as the main reservoir host of L. infantum is regarded as the most significant risk for potential human infection. We have studied the susceptibility profile to antimony and other anti-leishmania drugs (amphotericin B, miltefosine, paromomycin) in Leishmania infantum isolates extracted from a dog before and after two therapeutic interventions with meglumine antimoniate (subcutaneous Glucantime®, 100 mg/kg/day for 28 days). After the therapeutic intervention, these parasites were significantly less susceptible to antimony than pretreatment isolate, presenting a resistance index of 6-fold to SbIII for promastigotes and >3-fold to SbIII and 3-fold to SbV for intracellular amastigotes. The susceptibility profile of this resistant L. infantum line is related to a decreased antimony uptake due to lower aquaglyceroporin-1 expression levels. Additionally, other mechanisms including an increase in thiols and overexpression of enzymes involved in thiol metabolism, such as ornithine decarboxylase, trypanothione reductase, mitochondrial tryparedoxin and mitochondrial tryparedoxin peroxidase, could contribute to the resistance as antimony detoxification mechanisms. A major contribution of this study in a canine L. infantum isolate is to find an antimony-resistant mechanism similar to that previously described in other human clinical isolates.