Impact of heteroresistance on treatment outcomes of people with drug-resistant TB.

BACKGROUND: Poor treatment outcomes among people with drug-resistant TB (DR-TB) are a major concern. Heteroresistance (presence of susceptible and resistant Mycobacterium tuberculosis in the same sample) has been identified in some people with TB, but its impact on treatment outcomes is unknown. METHODS: We used targeted deep sequencing to identify mutations associated with DR-TB and heteroresistance in culture samples of 624 people with DR-TB. We evaluated the association between heteroresistance and time to unfavorable treatment outcome using Cox proportional hazards regression. RESULTS: The proportion of drug-resistant isolates with a known mutation conferring resistance was lower for streptomycin (45.2%) and second-line injectables (79.1%) than for fluoroquinolones (86.7%), isoniazid (93.2%) and rifampin (96.5%). Fifty-two (8.3%) had heteroresistance, and it was more common for fluoroquinolones (4.6%) than rifampin (2.2%), second-line injectables (1.4%), streptomycin (1.7%), or isoniazid (1.3%). There was no association between heteroresistance and time to unfavorable outcome among people with multidrug-resistant TB (adjusted hazard ratio [aHR] 1.74, 95% CI 0.39-7.72) or pre-extensively DR-TB (aHR 0.65, 95% CI 0.24-1.72). CONCLUSIONS: Heteroresistance was relatively common (8.3%) among people with DR-TB in the Philippines. However, we found insufficient evidence to demonstrate an impact on unfavorable treatment outcomes.

CONTEXTE: Les résultats médiocres du traitement chez les personnes atteintes de TB résistante aux médicaments (DR-TB, pour l'anglais « drug-resistant TB ¼) constituent une préoccupation significative. L'hétérorésistance, caractérisée par la coexistence de souches sensibles et résistantes de Mycobacterium tuberculosis dans un même échantillon, a été observée chez certains patients, mais les conséquences de cette situation sur l'efficacité des traitements demeurent incertaines. MÉTHODES: Nous avons recouru au séquençage profond ciblé afin d'identifier les mutations liées à la DR-TB et à l'hétérorésistance dans les échantillons de culture provenant de 624 personnes atteintes de DR-TB. Nous avons analysé le lien entre l'hétérorésistance et le délai jusqu'à l'issue défavorable du traitement en utilisant une régression des risques proportionnels de Cox. RÉSULTATS: La proportion d'isolats, présentant une mutation connue associée à la résistance, était inférieure pour la streptomycine (45,2%) et les médicaments injectables de deuxième ligne (79,1%) par rapport aux fluoroquinolones (86,7%), à l'isoniazide (93,2%) et à la rifampicine (96,5%). Parmi les isolats, cinquante-deux (8,3%) manifestaient une hétérorésistance, plus courante pour les fluoroquinolones (4,6%) que pour la rifampicine (2,2%), les médicaments injectables de deuxième ligne (1,4%), la streptomycine (1,7%) ou l'isoniazide (1,3%). Aucune association n'a été observée entre l'hétérorésistance et un délai d'évolution défavorable chez les patients atteints de TB multirésistante (rapport de risque ajusté [aHR] 1,74 ; IC à 95% 0,39­7,72) ou de DR-TB pré-extensive (aHR 0,65 ; IC à 95% 0,24­1,72). CONCLUSIONS: L'hétérorésistance a été observée de manière relativement fréquente (8,3%) chez les personnes atteintes de DR-TB aux Philippines. Néanmoins, nous n'avons pas identifié de preuves suffisantes pour établir un lien avec des résultats de traitement défavorables.

Challenges associated with follow-up care after implementation of an HPV screen-and-treat program with ablative therapy for cervical cancer prevention.

BACKGROUND: Cervical cancer is a preventable cancer; however, decreasing its prevalence requires early detection and treatment strategies that reduce rates of loss to follow-up. This study explores factors associated with loss to follow-up among HPV-positive women after implementation of a new HPV-based screen-and-treat approach for cervical cancer prevention in Iquitos, Peru. METHODS: We conducted semi-structured interviews with "obstetras" (i.e., midwives) (n = 15) working in cervical cancer prevention and women (n = 24) who were recorded as lost to follow-up after positive HPV results. We used the Health Care Access Barriers Model to guide analyses. We utilized manifest content analysis to describe barriers to follow-up according to the obstetras and thematic analysis to report themes from the women's perspectives. We also report the steps and time taken to contact women. RESULTS: We found an incomplete and fragmented patient monitoring system. This incomplete system, in conjunction with challenges in contacting some of the women, led to structural barriers for the obstetras when attempting to deliver positive results. Women in this study expressed a desire to receive treatment, however, faced cognitive barriers including a lack of understanding about HPV results and treatment procedures, fear or anxiety about HPV or treatment, and confusion about the follow-up process. Women also reported having important work matters as a barrier and reported frequently using natural medicine. Reported financial barriers were minimal. CONCLUSION: This study highlights the barriers to follow-up after implementation of a primary-level HPV-based screen-and-treat approach. While some barriers that have previously been associated with loss to follow-up were not as prominently observed in this study (e.g., financial), we emphasize the need for screen-and-treat programs to focus on strategies that can address incomplete registry systems, structural challenges in results delivery, cognitive barriers in understanding results and treatment, and work-related barriers.

The virtual multiple sclerosis patient.

Multiple sclerosis (MS) diagnosis typically involves assessing clinical symptoms, MRI findings, and ruling out alternative explanations. While myelin damage broadly affects conduction speeds, traditional tests focus on specific white-matter tracts, which may not reflect overall impairment accurately. In this study, we integrate diffusion tensor immaging (DTI) and magnetoencephalography (MEG) data into individualized virtual brain models to estimate conduction velocities for MS patients and controls. Using Bayesian inference, we demonstrated a causal link between empirical spectral changes and inferred slower conduction velocities in patients. Remarkably, these velocities proved superior predictors of clinical disability compared to structural damage. Our findings underscore a nuanced relationship between conduction delays and large-scale brain dynamics, suggesting that individualized velocity alterations at the whole-brain level contribute causatively to clinical outcomes in MS.

"The influence of auditory stimulation on whole body variability in healthy older adults during gait".

Acoustic stimulation appears to be a promising strategy in reducing the risk of falling in older adults, demonstrating effectiveness in improving stability. However, its impact on movement variability, another crucial indicator of fall risk, seems to be limited. This study aims to assess movement variability during walking in a cohort of healthy older adults exposed to three different frequencies of acoustic stimulation (90%, 100% and 110% of each subject's average cadence). Using a systemic approach based on network theory, which considers the intricate relationships between all body segments, we constructed connectivity matrices composed of nodes, represented by bony landmarks, and edges, consisting of the standardised covariance of accelerations between each pair of nodes. By introducing a new metric called Similarity Score (S-score), we quantified the ability of each individual to repeat the same motor pattern at each gait cycle under different experimental conditions. The study revealed that rhythmic auditory stimulation (RAS) at 100% and 90% of the mean cadence significantly increased the S-scores compared to the baseline. These results highlight the effects of RAS in increasing gait repeatability in healthy older adults, with a focus on global kinematics.

Economically viable bioprocess for inclusion of microalga Nannochloropsis gaditana in aquaculture feeds: Evaluation of antioxidant addition in preventing lipid oxidation during storage.

The rising prices of fishery derivatives limits their use in aquafeeds. Therefore, other alternatives are used to replace those ingredients. Among them, microalgae are of great interest both as an ingredient and as a potential stabilising agent against lipid oxidation. This study evaluates on the use of Nannochloropsis gaditana to prevent lipid oxidation in a set of 12 aquafeeds over 540 days of storage. Aquafeeds were formulated with/without 15 % N. gaditana combined with two antioxidants -butylhydroxytoluene (25-150 mg·kg-1) or vitamin E (500-3000 mg·kg-1). The effect of i) storage period, ii) presence of microalgae and iii) antioxidant addition on lipid oxidation was assessed. Results showed higher fatty acid degradation in diets lacking microalgae. The microalgae supplemented diets is enough for preserving feeds presenting the highest antioxidant effect at the end, without significant differences with the microalgae-supplemented feeds and those including antioxidants after 540 days of storage.

Novel nanostructured lipid carriers loading Apigenin for anterior segment ocular pathologies.

Dry eye disease (DED) is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction and constitutes one of the most common ocular conditions worldwide. However, its treatment remains unsatisfactory. While artificial tears are commonly used to moisturize the ocular surface, they do not address the underlying causes of DED. Apigenin (APG) is a natural product with anti-inflammatory properties, but its low solubility and bioavailability limit its efficacy. Therefore, a novel formulation of APG loaded into biodegradable and biocompatible nanoparticles (APG-NLC) was developed to overcome the restricted APG stability, improve its therapeutic efficacy, and prolong its retention time on the ocular surface by extending its release. APG-NLC optimization, characterization, biopharmaceutical properties and therapeutic efficacy were evaluated. The optimized APG-NLC exhibited an average particle size below 200 nm, a positive surface charge, and an encapsulation efficiency over 99 %. APG-NLC exhibited sustained release of APG, and stability studies demonstrated that the formulation retained its integrity for over 25 months. In vitro and in vivo ocular tolerance studies indicated that APG-NLC did not cause any irritation, rendering them suitable for ocular topical administration. Furthermore, APG-NLC showed non-toxicity in an epithelial corneal cell line and exhibited fast cell internalization. Therapeutic benefits were demonstrated using an in vivo model of DED, where APG-NLC effectively reversed DED by reducing ocular surface cellular damage and increasing tear volume. Anti-inflammatory assays in vivo also showcased its potential to treat and prevent ocular inflammation, particularly relevant in DED patients. Hence, APG-NLC represent a promising system for the treatment and prevention of DED and its associated inflammation.

Diatoms in maggots; a potential tool for drowning diagnosis - A preliminary study.

Advanced putrefaction causes extensive loss of soft tissue, rendering it difficult to use the diatom test as a reliable diagnostic tool for drowning investigations. A positive diatom test in carrion insect larvae may provide significant assistance in overcoming the challenge of decomposition. The studies determined the utility of diatom test in carrion larvae on severely decomposed bodies. A modified acid digestion method involving nitric acid, K2Cr2O7 and HCl, was used to digest the blowfly larvae feeding on piglet carrion previously drowned in freshwater and sea water, respectively. Extracted diatom frustules were analysed and characterised using light microscopy coupled to a digital camera. Diatoms recovered from maggots on sea-drowned piglets were similar to diatoms from sea water (drowning medium). Centric diatoms recovered in maggots were higher (200 ± 60 diatoms/ mL) than pennate diatoms (80 ± 20 diatoms/mL). Isolated diatoms common to both maggots and water samples included Coscinodiscus sp. and Navicular spp. Albeit, there were no diatoms recovered from maggots on freshwater-drowned piglets. The findings of this study suggest that the diatom test is still a reliable diagnostic tool to determine if drowning was involved in the death of a fully decomposed body. This is the first study that isolated diatoms from maggots feeding on drowned bodies. It serves as the basis for further research into the utility of maggots for drowning investigations.

Diagnostic findings in sinonasal aspergillosis in dogs in the United Kingdom: 475 cases (2011-2021).

OBJECTIVES: To describe the diagnostic tests used and their comparative performance in dogs diagnosed with sinonasal aspergillosis in the United Kingdom. A secondary objective was to describe the signalment, clinical findings and common clinicopathologic abnormalities in sinonasal aspergillosis. MATERIALS AND METHODS: A multi-centre retrospective survey was performed involving 23 referral centres in the United Kingdom to identify dogs diagnosed with sinonasal aspergillosis from January 2011 to December 2021. Dogs were included if fungal plaques were seen during rhinoscopy or if ancillary testing (via histopathology, culture, cytology, serology or PCR) was positive and other differential diagnoses were excluded. RESULTS: A total of 662 cases were entered into the database across the 23 referral centres. Four hundred and seventy-five cases met the study inclusion criteria. Of these, 419 dogs had fungal plaques and compatible clinical signs. Fungal plaques were not seen in 56 dogs with turbinate destruction that had compatible clinical signs and a positive ancillary test result. Ancillary diagnostics were performed in 312 of 419 (74%) dogs with observed fungal plaques permitting calculation of sensitivity of cytology as 67%, fungal culture 59%, histopathology 47% and PCR 71%. CLINICAL SIGNIFICANCE: The sensitivities of ancillary diagnostics in this study were lower than previously reported challenging the clinical utility of such tests in sinonasal aspergillosis. Treatment and management decisions should be based on a combination of diagnostics including imaging findings, visual inspection, and ancillary testing, rather than ancillary tests alone.

Partial Cranial Reconstruction Using Titanium Mesh after Craniectomy: An Antiadhesive and Protective Barrier with Improved Aesthetic Outcomes.

OBJECTIVE: Describe a new, safe, technique that uses titanium mesh to partially cover skull defects immediately after decompressive craniectomy (DC). METHODS: This study is a retrospective review of 8 patients who underwent DC and placement of a titanium mesh. The mesh partially covered the defect and was placed between the temporalis muscle and the dura graft. The muscle was sutured to the mesh. All patients underwent cranioplasty at a later time. The study recorded and analyzed demographic information, time between surgeries, extra-axial fluid collections, postoperative infections, need for reoperation, cortical hemorrhages, and functional and aesthetic outcomes. RESULTS: After craniectomy, all patients underwent cranioplasty within an average of 112.5 days (30-240 days). One patient reported temporalis muscle atrophy, which was the only complication observed. During the cranioplasties, no adhesions were found between temporalis muscle, titanium mesh, and underlying dura. None of the patients showed complications in the follow-up computerized tomography scans. All patients had favorable aesthetic and functional results. CONCLUSIONS: Placing a titanium mesh as an extra step during DC could have antiadhesive and protective properties, facilitating subsequent cranioplasty by preventing adhesions and providing a clear surgical plane between the temporalis muscle and intracranial tissues. This technique also helps preserve the temporalis muscle and enhances functional and aesthetic outcomes postcranioplasty. Therefore, it represents a safe alternative to other synthetic anti-adhesive materials. Further studies are necessary to draw definitive conclusions and elucidate long-term outcomes, however, the results obtained hold great promise for the safety and efficacy of this technique.

[Cardiovascular disease before and after COVID-19 infection: One-year survival]. / Enfermedad cardiovascular previa y posterior a la infección por COVID-19. Supervivencia a un año.

AIM: To analyze the risk of COVID-19 in relation to previous morbidity; to analyze the risk of new cardiovascular events (CVE) in COVID-19 patients and one-year survival. METHODOLOGY: Case-control study and prospective cohort study. Two hundred and seventy-five randomized patients >18 years old with COVID-19 were included and matched with 825 without COVID-19 by age and sex (ratio 1:3). The main variables were diagnosis of COVID-19 and post-COVID-19 events. Sociodemographic variables, comorbidity, and previous CVD were studied. Two predictive models of factors associated with the development of COVID-19 and post-COVID-19 CVE were performed, as well as a one-year survival analysis. RESULTS: Men with a previous CVE double the risk of suffering from COVID-19 (OR 2.11; 95% CI: 1.32-3.36). In women, the risk increases with age (OR 1.01; 95% CI: 1.00-1.02), diabetes (DM) (OR 1.90; 95% CI: 1.14-3.17) and cognitive impairment (OR 4.88; 95% CI: 2.50-9.53). Immunosuppression acts as a protective factor in both sexes. Age (OR 1.02; 95% CI: 1.00-1.04), arterial hypertension (OR 2.21; 95% CI: 1.17-4.17), COVID-19 infection (OR 4.81; 95% CI: 2.89-7.98) and previous CVE (OR 4.46; 95% CI: 2.56-7.75) predict the development of a new post-COVID-19 CVE. Positive COVID-19 has lower survival (median 7 days vs. 184 days). CONCLUSIONS: Previous CVE in men and DM along with cognitive impairment in women increase the risk of presenting COVID-19. Age, arterial hypertension, previous CVE, and COVID-19 infection predict the appearance of new CVE.

Genome sequence of an Acinetobacter pittii strain obtained from a red-lored parrot with pneumonia.

Acinetobacter pittii 978-A_19 was obtained from a parrot with pneumonia. It is resistant to ampicillin, carbenicillin, cephalosporins, clindamycin, and trimethoprim + sulfamethoxazole. The genome encodes a new blaADC allele, a blaOXA-502 gene, possesses several virulence genes related to adherence and biofilm formation, and has types I, II, and IV secretion systems.

Distinctions between survivors and non-survivors with SARS-CoV-2 vaccine-induced thrombotic thrombocytopenia: A systematic review and meta-analysis.

Vaccine-inducing immune thrombocytopenia, thrombosis, and bleeding emerge as infrequent and potential complications with mortality risk in healthy subjects. However, differences between survivors and non-survivors with SARS-CoV-2 vaccine-induced thrombotic thrombocytopenia (VITT) are unclear. Methods: According to the PRISMA statement, we conducted a systematic review and meta-analysis, and the protocol was registered in PROSPERO. The main objective is to identify differences among survivors and non-survivors of SARS-CoV-2 VITT patients. We systematically searched through PubMed, Scopus, and Web of Science. We included cohorts, case series, and case reports. We classified bleeding complications according to the ISTH definition. Statistics: unpaired Student's t-test or one-way ANOVA, Wilcoxon, and Kruskal-Wallis. Results: We systematically searched from January 2021 to June 2021 and identified 51 studies that included 191 patients. Non-survivors had the most severe thrombocytopenia (p 0.02) and lower fibrinogen measurements (p 0.01). Subjects vaccinated with mRNA vaccines (BNT162b2 and mRNA-1273) had an earlier onset of adverse events following immunization (p 0.001). We identified a higher trend of overall thrombotic events (p 0.001) in recipients of viral mechanism-dependent vaccines (Table 2). Non-survivors with cerebral venous sinus thrombosis (CVST) had more severe thrombocytopenia (p 0.01) than survivors with CVST. Finally, 61 % of survivors and 50 % with thrombosis received heparin. Conclusion: We identified more severe thrombocytopenia, lower fibrinogen measurements, and a higher trend of overall thrombotic events, including CVST and thrombotic storm, particularly with viral mechanisms-dependent vaccines in non-survivors VITT patients.

Immune modulation via dendritic cells by the effect of Thymosin-alpha-1 on immune synapse in HCMV infection.

Tα1 (Thymosin-alpha-1) is a thymus-derived hormone that has been demonstrated to be effective on diverse immune cell subsets. The objective of this study was to determine the in vitro immunomodulatory effect of Tα1 in human cytomegalovirus (HCMV) infection. Dendritic cells (DCs) were isolated from peripheral blood mononuclear cells (PBMCs) by negative selection and cultured in the presence or absence of Tα1. The immunophenotyping of DCs was characterised by multiparametric flow cytometry assessing CD40, CD80, TIM-3 and PDL-1 markers, as well as intracellular TNFα production. Then, autologous CD4+ or CD8+ T-Lymphocytes (TLs) isolated by negative selection from PBMCs were co-cultured with DCs previously treated with Tα1 in the presence or absence of HCMV. Intracellular TNFα, IFNγ, IL-2 production, CD40-L and PD-1 expression were assessed through immunophenotyping, and polyfunctionality in total TLs and memory subsets were evaluated. The results showed that Tα1 increased CD40, CD80, TIM-3 and TNFα intracellular production while decreasing PDL-1 expression, particularly on plasmacytoid dendritic cells (pDCs). Therefore, Tα1 modulated the production of TNFα, IFNγ and IL-2 in both total and memory subsets of CD4+ and CD8+ TLs by upregulating CD40/CD40-L and downregulating PDL-1/PD-1 expression. Our study concludes that Tα1 enhances antigen-presenting capacity of DCs, improves TLs responses to HCMV infection, and enhances the polyfunctionality of CD8+ TLs. Consequently, Tα1 could be an alternative adjuvant for use in therapeutic cell therapy for immunocompromised patients.

Physicochemical and microbiological parameters during the manufacturing of a beer-type fermented beverage using selenized Saccharomycesboulardii.

Selenium is an essential trace element in human health. However, it has been considered a widespread selenium deficiency worldwide, although the recommended daily intake is very low (55 µg per day). Strategies have been implemented to comply with the recommended doses, for example, through bioavailable selenium such as selenoamino acids. Thus, this research aimed to elaborate on a beer-type fermented beverage produced with previously selenized Saccharomyces boulardii. For this, the yeast was selenized by adding a minimum inhibitory concentration of Na2SeO3 (74 ppm) to YPD media. Subsequently, barley must fermentations were carried out for 120 h. Kinetic parameters of the fermentation and physicochemical parameters and selenium content of the beverage were measured. The yeast accumulated up to 25.12 mg/g of dry cell. Furthermore, selenization affected the fermentation rate, but the beverage's physicochemical parameters were not different from those of the control. Due to the final concentration of selenium in the beverage (0.378 mg/kg), it is considered a process that confers advantages for the safe intake of selenium with bioavailable potential. In conclusion, fermented beverages enriched with organic selenium could be produced through cell selenization to produce functional beverages and food.

[Anafilaxia perioperatoria a sevoflurano, un caso muy raro].

Background: Perioperative anaphylaxis can be life-threatening. The global incidence is estimated to be 1 in 10,000-20,000 procedures. The most common agents are neuromuscular blockers, latex, and antibiotics. There are very few reports of allergies to inhaled anesthetics such as sevoflurane, which is considered relatively safe in patients with drug allergies. Case report: 12-year-old patient, admitted to oncology, diagnosed with acute lymphoblastic leukemia. History of two perioperative hypersensitivity reactions. In the first event, lidocaine and rupivacaine were administered, he presented urticaria, managed with an antihistamine. On the second occasion, he received only sevoflurane and presented anaphylaxis, treated with intramuscular adrenaline. Later during intrathecal therapy, he received sevoflurane, he presented rash and arterial hypotension, managed again with adrenaline, with total remission of symptoms. Retrospectively Brighton criteria level I of certainty, classified as serious by Brown. Hypersensitivity to sevoflurane was suspected, ruling out other anesthetics such as lidocaine and rupivacaine with negative intradermal skin tests. Molecular components for latex were requested with negative results for Hev b 1, Hev b 3, Hev b 6. Due to the above and associated with the characteristics of the drug, a basophil activation test for sevoflurane was performed with an activation percentage of 50% (positive). Perioperative anaphylaxis due to sevoflurane is confirmed. Conclusion: All drugs involved in perioperative hypersensitivity reactions should be considered to establish adequate and safe treatment alternatives for this small group of patients.

Antecedentes: La anafilaxia perioperatoria puede amenazar la vida del paciente. La incidencia global se estima 1 entre 10.000-20.000 procedimientos. Los agen- tes más frecuentes son bloqueadores neuromusculares, látex y antibióticos. Hay muy pocos reportes de alergia a anestésicos inhalados como el sevoflurano, el cual se considera relativamente seguro en pacientes con alergia a fármacos. Reporte de caso: Paciente de 12 años, ingresó en oncología, diagnóstico de leucemia linfoblástica aguda. Antecedente de dos reacciones de hipersensibilidad perioperatorias. En primer evento se administró lidocaína y rupivacaína, presentó urticaria, manejado con antihistamínico. Segunda ocasión recibió sólo sevo- fluorano y presentó anafilaxia, tratado con adrenalina intramuscular. Posteriormente durante terapia intratecal, recibió sevoflurano, presentó rash e hipotensión arterial, manejo nuevamente con adrenalina, con remisión total de síntomas. Retrospectivamente criterios de Brighton nivel I de certeza, clasificada grave por Brown. Se sospechó hipersensibilidad a sevoflurano, descartando otros anestésicos como lidocaína y rupivacaina con pruebas cutáneas intradérmicas negativas. Se solicitaron componentes moleculares para látex con resultados negativos para Hev b 1, Hev b 3, Hev b 6. Por lo anterior y asociado a las características del fármaco se realiza prueba de activación de basófilos para sevoflurano con un porcentaje de activación del 50% (positivo). Se confirma anafilaxia perioperatoria por sevoflurano. Conclusión: Deben considerarse todos los fármacos involucrados en las reacciones de hipersensibilidad perioperatoria, para establecer alternativas adecuadas y seguras de tratamiento de este pequeño grupo de pacientes.