Pregnancy-associated atypical hemolytic uremic syndrome. Case report.

Pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) is a rare disease. There are only few reports in the literature, and most are in the puerperium period. It is a thrombotic microangiopathy (TMA) characterized for microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. We report the case of a pregnant patient at 26.3 gestation weeks, who developed clinical features of TMA, neurological alterations, and septic shock; then after fetus and placental delivery, no clinical improvement was observed; a diagnostic protocol was performed due to suspicion of P-aHUS, showing improvement after the plasma exchange sessions and eculizumab. We present here a brief review of the case since it is an entity that needs to be suspected during pregnancy when TMA features and requires an immediate diagnosis to provide timely treatment.

SARS-CoV-2 remodels the landscape of small non-coding RNAs with infection time and symptom severity.

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has significantly impacted global health, stressing the necessity of basic understanding of the host response to this viral infection. In this study, we investigated how SARS-CoV-2 remodels the landscape of small non-coding RNAs (sncRNA) from a large collection of nasopharyngeal swab samples taken at various time points from patients with distinct symptom severity. High-throughput RNA sequencing analysis revealed a global alteration of the sncRNA landscape, with abundance peaks related to species of 21-23 and 32-33 nucleotides. Host-derived sncRNAs, including microRNAs (miRNAs), transfer RNA-derived small RNAs (tsRNAs), and small nucleolar RNA-derived small RNAs (sdRNAs) exhibited significant differential expression in infected patients compared to controls. Importantly, miRNA expression was predominantly down-regulated in response to SARS-CoV-2 infection, especially in patients with severe symptoms. Furthermore, we identified specific tsRNAs derived from Glu- and Gly-tRNAs as major altered elements upon infection, with 5' tRNA halves being the most abundant species and suggesting their potential as biomarkers for viral presence and disease severity prediction. Additionally, down-regulation of C/D-box sdRNAs and altered expression of tinyRNAs (tyRNAs) were observed in infected patients. These findings provide valuable insights into the host sncRNA response to SARS-CoV-2 infection and may contribute to the development of further diagnostic and therapeutic strategies in the clinic.

Microfilaremic infection in canine filariosis in Colombia: a challenge in morphological and molecular diagnostics.

Canine filariosis is caused by filiform nematodes and affects several species of animals as well as humans. The disease produces a wide range of symptoms that can often be confused with other diseases, which increases the complexity of its diagnosis. The search for methodologies to facilitate its diagnosis is a challenge, and specific and differential identification of the parasite species causing the disease holds key to a successful diagnosis. In Colombia, there is a problem of underdiagnosis of filariosis in microfilaremic dogs infected by Dirofilaria immitis and Acanthocheilonema reconditum, and of microfilaremias not related to heartworm disease. The highest prevalences have been reported for D. immitis infections, although new cases of A. reconditum infections are beginning to appear. The aim of this study was to differentiate the microfilariae infections caused by D. immitis and A. reconditum by a morphological and molecular characterization of microfilariae so as to facilitate an accurate diagnosis of canine filariosis in the metropolitan area of Bucaramanga (Colombia). For this purpose, 400 blood samples with anticoagulants were collected from the dogs and analyzed with the help of a commercial immunochromatography kit for the detection of D. immitis circulating antigen. The Woo, Knott, and polymerase chain reaction (PCR) techniques were employed for determining the parasite count, morphological observation, and molecular identification of microfilariae present in the dogs respectively. The prevalence of microfilaremic dogs in Bucaramanga metropolitan area was 18.75% (75/400). The prevalence of dogs that tested positive for D. immitis in the antigen and in PCR tests was 1.25% (5/400) and 1% (4/400), respectively. Furthermore, the PCR test revealed that 17.75% of the microfilaremic dogs tested positive for A. reconditum (71/400) (first report in the metropolitan area of Bucaramanga), with one animal co-infected by both species, and 0% for D. repens (0/400). However, by morphological characterization, 4% of the microfilariae (3/75) corresponded to D. immitis, 20% (15/75) to D. repens, and 76% (57/75) to A. reconditum. The use of molecular diagnostic methods such as PCR aids in the specific identification of the parasite, thus making it a more accurate method than the morphological characterization of microfilariae. The identification of the parasites by PCR helps improve the veterinary diagnosis of canine filariosis in Colombia, which would lead to the establishment of an appropriate treatment protocol for each species of filaria and also to the generation of reliable data to be used at the clinical and epidemiological levels.

Depression, Anxiety, and Stress Among Emerging Adult Undergraduates: A Longitudinal and Two-Cohort Study.

Mental disorders constitute one of the population's principal health problems, especially among undergraduates. This quantitative study compared levels of depression, anxiety, and stress in a sample of emerging adult university undergraduates from a gender perspective (1) during the initial and intermediate years of emerging adulthood and (2) in two different cohorts. A total of 383 Spanish emerging adult university undergraduates were monitored longitudinally (2015-2018) and two cohorts were compared (2015-2020). Participants completed the validated Spanish version of the Depression Anxiety Stress Scale-21. Mean-level and rank-order stability was found across the two waves of the longitudinal study in relation to levels of depression, anxiety, and stress. Significant differences were found between the two cohorts, indicating higher levels of psychological distress in 2020 than in 2015. Women were found to have higher levels of psychological distress, particularly stress, than men in both waves and cohorts. Results are discussed in relation to the negative effects of the COVID-19 health crisis on the emotional health of emerging adults. The present study highlights the need to establish measures designed to improve the mental health of emerging adults, which was more severely affected by the COVID-19 crisis than by the aftermath of the 2008 financial crisis. It also underscores the need to develop interventions designed to alleviate the greater degree of stress suffered by women.

Less than whole uterus irradiation for patients with locally advanced cervical cancer.

INTRODUCTION: Current consensus guidelines for definitive cervical cancer intensity modulated radiation therapy (IMRT) recommend inclusion of the entire uterus within the clinical target volume, however this is debated. We aimed to evaluate outcomes of patients with cervical cancer who were treated with less than whole uterus irradiation. METHODS: We identified 109 patients with FIGO Stage IB-IVA cervical cancer treated definitively with concurrent chemoradiation, including IMRT and brachytherapy, from 2010 to 2022 at a single institution where the practice was to include the gross cervix tumor with an internal target volume with differences in bladder filing accounted for, plus additional 5 mm planning target volume (PTV) margin. Local, regional, and distant recurrences were analyzed using competing risk methods, and a Wilcoxon rank sum test was performed to assess differences in dose to organs at risk based on the proportion of the uterus included in the PTV, with the median proportion of the uterus included (75 %) used as the cut-point. RESULTS: The median follow-up time was 65 months (range 3-352 months). The 2-year cumulative incidence of LR for the entire cohort was 4.2 % (95 % confidence interval [CI] 1.3-9.7). Compared with patients who had ≥ 75 % of the uterus included in the PTV, patients who had < 75 % of the uterus included in the PTV had significantly lower bowel D200cc (p = 0.02). The cumulative incidence of local failure (LR) was not significantly different between the two groups. CONCLUSIONS: Including less than the whole uterus for definitive cervix cancer IMRT does not seem to compromise local control. Less than whole uterus irradiation could be considered for carefully selected cervix cancer patients to decrease bowel dose and possible treatment-related toxicity.

Pelvic lymph node involvement and risk of recurrence in HPV-associated endocervical adenocarcinoma stage IA2-IB1 according to Silva's system in two Colombian cancer centers.

OBJECTIVE: To compare the pelvic lymph node involvement and risk of recurrence in patients with human papillomavirus (HPV)-associated endocervical adenocarcinoma stage IA2-IB1 undergoing hysterectomy and/or trachelectomy plus lymphadenectomy, according to Silva's classification system. METHODS: A retrospective cohort study was performed in two Colombian cancer centers. The cases were classified according to the Silva classification system. Clinical, surgical, and histopathological variables were evaluated. Recurrence risk was analyzed by patterns A, B, or C. A logistic regression model was performed for tumor recurrence. The Kaplan-Meier method was used to estimate overall survival and disease-free survival (DFS). A weighted kappa was performed to determine the degree of concordance between pathologists. RESULTS: A total of 100 patients were identified, 33% pattern A, 29% pattern B, and 38% pattern C. The median follow-up time was 42.5 months. No evidence of lymph node involvement was found in patients classified as A and B, while in the C pattern was observed in 15.8% (n = 6) of cases (P < 0.01). There were 7% of cases with recurrent disease, of which 71.5% corresponded to type C pattern. Patients with Silva pattern B and C had 1.22- and 4.46-fold increased risk of relapse, respectively, compared with pattern A. The 5-year DFS values by group were 100%, 96.1%, and 80.3% for patterns A, B, and C, respectively. CONCLUSION: For patients with early-stage HPV-associated endocervical adenocarcinoma, the type C pattern presented more lymph node involvement and risk of recurrence compared to the A and B patterns. The concordance in diagnosis of different Silva's patterns by independents pathologists were good.

Prevented perinatal HIV infections in the era of antiretroviral prophylaxis and treatment, United States, 1994-2020.

OBJECTIVE: The primary aim of this serial cross-sectional analysis is to estimate the total number of prevented perinatal HIV transmissions from the time of the initial recommendation for perinatal zidovudine (ZDV) prophylaxis in 1994 through 2020 in the US. METHODS: The estimated number of prevented transmissions was calculated as annual differences between expected and observed numbers of perinatal HIV transmissions. Annual expected number of transmissions was estimated by multiplying the annual number of births to women with HIV by 0.2255 (22.55%), i.e., the transmission rate of the control group in the ACTG Protocol 076 trial. We used published point estimates or, if only ranges were given, the midpoints of those ranges as the best estimates of the annual numbers of births to women with HIV and infants with perinatal HIV. When data were not available, we linearly interpolated or extrapolated the available data to obtain estimated numbers for each year. RESULTS: Between 1978 and 2020, the approximate number of live births to women with HIV was 191 267 (95% confidence interval [CI] 190 392-192 110) and for infants with diagnosed perinatal HIV, it was 21 379 (95% CI 21 088-21 695). Since 1994, the annual number of infants born with HIV decreased from 1263 (95% CI 1194-1333) to 33 in 2019 (95% CI 22-45) and 36 in 2020 (95% CI 25-48), corresponding to a 97% reduction. Cumulatively, an estimated total of 22 732 (95% CI 21 340-24 462) perinatal HIV infections were prevented from 1994 through to 2020. CONCLUSION: The elimination of perinatal HIV transmission-accompanied by the cumulative number of prevented cases exceeding that of perinatal HIV infections-is a major public health achievement in the US.

Kinetic and proteomic studies in milk show distinct patterns among major Listeria monocytogenes clones.

Listeria monocytogenes, a contaminant of raw milk, includes hypervirulent clonal complexes (CC) like CC1, CC4, and CC6, highly overrepresented in dairy products when compared to other food types. Whether their higher prevalence in dairy products is the consequence of a growth advantage in this food remains unknown. We examined growth kinetics of five L. monocytogenes isolates (CC1, CC4, CC6, CC9, and CC121) at 37 and 4 °C in ultra-high temperature (UHT) milk and raw milk. At 4 °C, hypovirulent CC9 and CC121 isolates exhibit better growth parameters in UHT milk compared to the hypervirulent CC1, CC4, and CC6 isolates. CC9 isolate in raw milk at 4 °C exhibited the fastest growth and the highest final concentrations. In contrast, hypervirulent isolates (CC1, CC4, and CC6) displayed better growth rates in UHT milk at 37 °C, the mammalian host temperature. Proteomic analysis of representative hyper- (CC1) and hypovirulent (CC9) isolates showed that they respond to milk cues differently with CC-specific traits. Proteins related to metabolism (such as LysA or different phosphotransferase systems), and stress response were upregulated in both isolates during growth in UHT milk. Our results show that there is a Listeria CC-specific and a Listeria CC-common response to the milk environment. These findings shed light on the overrepresentation of hypervirulent L. monocytogenes isolates in dairy products, suggesting that CC1 and CC4 overrepresentation in dairy products made of raw milk may arise from contamination during or after milking at the farm and discard an advantage of hypervirulent isolates in milk products when stored at refrigeration temperatures.

Rhodococcus infection: a 10-year retrospective analysis of clinical experience and antimicrobial susceptibility profile.

Rhodococcus equi is an opportunistic pathogen known to cause pulmonary and extrapulmonary disease among immunocompromised patients. Treatment is frequently challenging due to intrinsic resistance to multiple antibiotic classes. While non-equi Rhodococcus spp. are prevalent, their clinical significance is poorly defined. There is also limited data on antibiotic susceptibility testing (AST) of Rhodococcus infection in humans. We conducted a single-center, retrospective cohort study evaluating clinical characteristics, microbiologic profile, and AST of Rhodococcus infections between June 2012 and 2022 at our tertiary academic medical center. Identification of Rhodococcus spp. was performed by Sanger 16S rRNA gene sequencing and/or matrix-assisted laser desorption ionization-time of flight mass spectrometry, and AST was performed by agar dilution. Three hundred twenty-two isolates of Rhodococcus spp. were identified from blood (50%), pulmonary (26%), and bone/joint (12%) sources. R. equi/hoagii, R. corynebacterioides, and R. erythropolis were the most frequently isolated species, with 19% of isolates identified only to genus level. One hundred ninety-nine isolates evaluated for AST demonstrated high-level resistance to amoxicillin/clavulanate, cephalosporins, and aminoglycosides. More than 95% susceptibility to imipenem, vancomycin, linezolid, rifampin, and clarithromycin was observed. Non-equi species showed a significantly more favorable AST profile relative to R. equi. Clinically significant Rhodococcus infection was rare with 10 cases diagnosed (majority due to R. equi) and managed. The majority of patients received 2- or 3-drug combination therapy for 2-6 months, with favorable clinical response. Significant differences in AST were observed between R. equi and non-equi species. Despite high antimicrobial resistance to several antibiotic classes, imipenem and vancomycin remain appropriate empiric treatment options for R. equi. Future research evaluating mechanisms underlying antimicrobial resistance is warranted.

Class size as a determinant factor in dietary changes in nursing students / El tamaño de la clase como factor determinante en los cambios dietéticos en estudiantes de enfermería

Introduction: While nursing students receive foundational education in biochemistry and nutrition during their first year of studies, the influence of nutrition education at the university level on their dietary behavior, particularly considering class size, remains unclear.Aim: The aim of this study is to assess the impact of a nutrition course on dietary changes among undergraduate nursing students, taking into account the size of the class group.Methodology: A pre-post quasi-experimental study with a within-subject design was conducted, measuring the baseline period (T0-T1) and intervention period (T1-T2). The educational intervention focused on providing basic nutritional knowledge about nutrients, balanced diets and the Mediterranean Diet within a Faculty of Medicine and Nursing. Participants included first-year undergraduate nursing students, divided into three groups based on class size: large group (n = 101), medium group (n = 70) and small group (n = 22). The frequency of recommended food group consumption for main, daily, weekly and occasional meals, as well as adherence to the Mediterranean Diet was analyzed.Findings: Only the small class group demonstrated a significant improvement in dietary quality following the educational intervention (p < 0.05), with increased consumption of fruits (p < 0.05), nuts (p < 0.001), and oily fish (p < 0.05).Discussion: Choosing the best teaching strategy can be crucial in getting nursing students to put healthy dietary knowledge into practice to improve their eating habits.Conclusions: The findings suggest that enhancing students’ personal dietary habits can contribute to the improvement of their nutrition counseling skills.(AU)

Ethanolic extract from leaves of tithonia diversifolia induces apoptosis in HCT-116 cells through oxidative stress.

Tithonia diversifolia is a perennial bushy plant found in South America with significant ethnopharmacological importance as an antimalarial, antidiabetic, antibacterial, and anticancer agent. The aim of the present study was to determine the cytotoxicity of the ethanolic extract from leaves of T. diversifolia (TdE) on human cancer cell lines (HCT-116, SNB-19, NCIH-460 and MCF-7), as well as the mechanism of action involved in cell death and cellular modulation of oxidative stress. The TdE exhibited significant activity with IC50 values ranging from 7.12 to 38.41 µg/ml, with HCT-116 being the most sensitive cell line. Subsequent experiments were conducted with HCT-116 cell line. TdE decreased the number of viable cells, followed by induction of apoptotic events, increase in mitochondrial membrane permeabilization, and enhanced G2/M phase of the cell cycle. Pro-oxidative effects including elevated acidic vesicular organelle formation, lipid peroxidation, and nitric oxide by-products, as well as reduced levels of intracellular glutathione and reactive oxygen species production were also observed following incubation with TdE, which may lead to DNA damage followed by apoptotic cell death. These results demonstrate the potential of TdE ethanolic leaf extraction for biological activity and enhance the importance of continuing to study natural sources of plants for the development of anticancer agents.

A tomato bushy stunt virus-based vector for simultaneous editing and sensing to survey the host antiviral RNA silencing machinery.

A tomato bushy stunt virus (TBSV)-derived vector system was applied for the delivery of CRISPR/Cas9 gene editing materials, to facilitate rapid, transient assays of host-virus interactions involved in the RNA silencing pathway. Toward this, single guide RNAs designed to target key components of the virus-induced host RNA silencing pathway (AGO2, DCL2, HEN1) were inserted into TBSV-based GFP-expressing viral vectors TBSV-GFP (TG) and its P19 defective mutant TGΔP19. This produced rapid, efficient, and specific gene editing in planta. Targeting AGO2, DCL2, or HEN1 partially rescued the lack of GFP accumulation otherwise associated with TGΔP19. Since the rescue phenotypes are normally only observed in the presence of the P19 silencing suppressor, the results support that the DCL2, HEN1, and AGO2 proteins are involved in anti-TBSV RNA silencing. Additionally, we show that knockdown of the RNA silencing machinery increases cargo expression from a nonviral binary Cas9 vector. The TBSV-based gene editing technology described in this study can be adapted for transient heterologous expression, rapid gene function screens, and molecular interaction studies in many plant species considering the wide host range of TBSV. In summary, we demonstrate that a plant virus can be used to establish gene editing while simultaneously serving as an accumulation sensor for successful targeting of its homologous antiviral silencing machinery components.

Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis on sexuality and inflammatory bowel disease. / Documento de posicionamiento. Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa sobre sexualidad y enfermedad inflamatoria intestinal.

It is widely acknowledged that inflammatory bowel disease (IBD) is associated with a high prevalence of sexual dysfunction (SD). However, there is a notable paucity of specific literature in this field. This lack of information impacts various aspects, including the understanding and comprehensive care of SD in the context of IBD. Furthermore, patients themselves express a lack of necessary attention in this area within the treatment of their disease, thus creating an unmet need in terms of their well-being. The aim of this position statement by the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) is to provide a review on the most relevant aspects and potential areas of improvement in the detection, assessment, and management of SD in patients with IBD and to integrate the approach to sexual health into our clinical practice. Recommendations are established based on available scientific evidence and expert opinion. The development of these recommendations by GETECCU has been carried out through a collaborative multidisciplinary approach involving gastroenterologists, gynecologists, urologists, surgeons, nurses, psychologists, sexologists, and, of course, patients with IBD.

Description of clinical and genetic features of 122 patients included in the Spanish Pompe registry.

Pompe disease is a rare genetic disorder with an estimated prevalence of 1:60.000. The two main phenotypes are Infantile Onset Pompe Disease (IOPD) and Late Onset Pompe Disease (LOPD). There is no published data from Spain regarding the existing number of cases, regional distribution, clinical features or, access and response to the treatment. We created a registry to collect all these data from patients with Pompe in Spain. Here, we report the data of the 122 patients registered including nine IOPD and 113 LOPD patients. There was a high variability in how the diagnosis was obtained and how the follow-up was performed among different centres. Seven IOPD patients were still alive being all treated with enzymatic replacement therapy (ERT) at last visit. Ninety four of the 113 LOPD patients had muscle weakness of which 81 were receiving ERT. We observed a progressive decline in the results of muscle function tests during follow-up. Overall, the Spanish Pompe Registry is a valuable resource for understanding the demographics, patient's journey and clinical characteristics of patients in Spain. Our data supports the development of agreed guidelines to ensure that the care provided to the patients is standardized across the country.

Considerations for future modification of The Association for the Study of Reproductive Biology embryo grading system incorporating time-lapse observations.

The Association for the Study of Reproductive Biology (ASEBIR) Interest Group in Embryology (in Spanish 'Grupo de Interés de Embriología') reviewed key morphokinetic parameters to assess the contribution of time-lapse technology (TLT) to the ASEBIR grading system. Embryo grading based on morphological characteristics is the most widely used method in human assisted reproduction laboratories. The introduction and implementation of TLT has provided a large amount of information that can be used as a complementary tool for morphological embryo evaluation and selection. As part of IVF treatments, embryologists grade embryos to decide which embryos to transfer or freeze. At the present, the embryo grading system developed by ASEBIR does not consider dynamic events observed through TLT. Laboratories that are using TLT consider those parameters as complementary data for embryo selection. The aim of this review was to evaluate review time-specific morphological changes during embryo development that are not included in the ASEBIR scoring system, and to consider them as candidates to add to the scoring system.

Powassan Virus Encephalitis: A Tertiary Center Experience.

BACKGROUND: Powassan virus (POWV) is an emerging arthropod-borne flavivirus, transmitted by Ixodes spp. ticks, which has been associated with neuroinvasive disease and poor outcomes. METHODS: A retrospective study was conducted at Mayo Clinic from 2013 to 2022. We included clinical and epidemiologic data of probable and confirmed neuroinvasive POWV cases. RESULTS: Sixteen patients with neuroinvasive POWV were identified; their median age was 63.2 years, and 62.5% were male. Six patients presented with rhombencephalitis, 4 with isolated meningitis, 3 with meningoencephalitis, 2 with meningoencephalomyelitis, and 1 with opsoclonus myoclonus syndrome. A median time of 18 days was observed between symptom onset and diagnosis. Cerebrospinal fluid analysis showed lymphocytic pleocytosis with elevated protein and normal glucose in the majority of patients. Death occurred within 90 days in 3 patients (18.8%), and residual neurologic deficits were seen in 8 survivors (72.7%). CONCLUSIONS: To our knowledge, this is the largest case series of patients with neuroinvasive POWV infection. We highlight the importance of a high clinical suspicion among patients who live in or travel to high-risk areas during the spring to fall months. Our data show high morbidity and mortality rates among patients with neuroinvasive disease.

Optimized Recovery of Viral DNA and RNA from Blood Plasma for Viral Metagenomics.

Metagenomics is vastly improving our ability to discover new viruses, as well as their possible associations with disease. However, metagenomics has also changed our understanding of viruses in general. This is because we can find viruses in healthy hosts in the absence of disease, which changes the perspective of viruses as mere pathogens and offers a new perspective in which viruses function as important components of ecosystems. In concrete, human blood metagenomics has revealed the presence of different types of viruses in apparently healthy subjects. These viruses are human anelloviruses and, to a lower extent, human pegiviruses. Viral metagenomics' major challenge is the correct isolation of the viral nucleic acids from a specific sample. For the protocol to be successful, all steps must be carefully chosen, in particular those that optimize the recovery of viral nucleic acids. Here, we present a procedure that allows the recovery of both DNA and RNA viruses from plasma samples.

Alternative ergosterol biosynthetic pathways confer antifungal drug resistance in the human pathogens within the Mucor species complex.

Mucormycoses are emerging fungal infections caused by a variety of heterogeneous species within the order Mucorales. Among the Mucor species complex, Mucor circinelloides is the most frequently isolated pathogen in mucormycosis patients and despite its clinical significance, there is an absence of established genome manipulation techniques to conduct molecular pathogenesis studies. In this study, we generated a spontaneous uracil auxotrophic strain and developed a genetic transformation procedure to analyze molecular mechanisms conferring antifungal drug resistance. With this new model, phenotypic analyses of gene deletion mutants were conducted to define Erg3 and Erg6a as key biosynthetic enzymes in the M. circinelloides ergosterol pathway. Erg3 is a C-5 sterol desaturase involved in growth, sporulation, virulence, and azole susceptibility. In other fungal pathogens, erg3 mutations confer azole resistance because Erg3 catalyzes the production of a toxic diol upon azole exposure. Surprisingly, M. circinelloides produces only trace amounts of this toxic diol and yet, it is still susceptible to posaconazole and isavuconazole due to alterations in membrane sterol composition. These alterations are severely aggravated by erg3 Δ mutations, resulting in ergosterol depletion and consequently, hypersensitivity to azoles. We also identified Erg6a as the main C-24 sterol methyltransferase, whose activity may be partially rescued by the paralogs Erg6b and Erg6c. Loss of Erg6a function diverts ergosterol synthesis to the production of cholestatype sterols, resulting in resistance to amphotericin B. Our findings suggest that mutations or epimutations causing loss of Erg6 function may arise during human infections, resulting in antifungal drug resistance to first-line treatments against mucormycoses. Importance: The Mucor species complex includes a variety of opportunistic pathogens known to cause mucormycosis, a potentially lethal fungal infection with limited therapeutic options. The only effective first-line treatments against mucormycosis consist of liposomal formulations of amphotericin B and the triazoles posaconazole and isavuconazole, all of which target components within the ergosterol biosynthetic pathway. This study uncovered M. circinelloides Erg3 and Erg6a as key enzymes to produce ergosterol, a vital constituent of fungal membranes. Absence of any of those enzymes leads to decreased ergosterol and consequently, resistance to ergosterol-binding polyenes such as amphotericin B. Particularly, losing Erg6a function pose a higher threat as the ergosterol pathway is channeled into alternative sterols similar to cholesterol, which maintain membrane permeability. As a result, erg6a mutants survive within the host and disseminate the infection, indicating that Erg6a deficiency may arise during human infections and confer resistance to the most effective treatment against mucormycoses.

[Malignant mesothelioma in Colombia: burden of disease, overview, and subnational sociodemographic index, 2015-2020Mesotelioma maligno na Colômbia: carga de morbidade, visão geral e índice sociodemográfico subnacional, entre 2015 e 2020]. / Mesotelioma maligno en Colombia: carga de enfermedad, panorama general e índice sociodemográfico subnacional, 2015-2020.

Objective: Establish the disease burden of malignant mesothelioma (MM) in Colombia between 2015 and 2020, and its association with the subnational sociodemographic development index (SDI) and with asbestos sites. Methods: Mixed ecological study of the Colombian population diagnosed with MM (according to ICD-10) from 2015 to 2020. The global burden of disease (GBD) was estimated using the methodology proposed by Murray and Lopez, based on prevalence and mortality data obtained from official sources. The subnational (departmental level) SDI was estimated as a measure of socioeconomic development. Linear regressions were established with the GBD, SDI, and documented asbestos sites. Results: The estimated GBD of MM in Colombia during 2015-2020 was 51.71 disability-adjusted life years (DALYs) per 1 000 000 inhabitants (15 375.79 total DALYs), with predominance in people over 50 years of age (91.1%) and males (66.4%).Bogotá and Valle del Cauca were the departments with the highest number of adjusted DALYs. Bogotá had the highest SDI and Guainía and Cesar had the lowest. There was evidence of an association between DALYs and SDI, explaining 22.8% of DALYs. Conclusion: Malignant mesothelioma is the cause of a large number of DALYs, predominantly in the departments with greater socioeconomic development and with companies that used to use asbestos. However, possible underdiagnosis of MM limits analysis of the information.

Objetivo: Estabelecer o ônus da doença por mesotelioma maligno (MM) na Colômbia entre 2015 e 2020 e sua associação ao índice sociodemográfico subnacional (ISS) e locais de amianto. Métodos: Estudo ecológico misto na população colombiana diagnosticada com MM, de acordo com a CID-10 durante 2015 a 2020. A carga global da doença (CGD) foi estimada usando a metodologia proposta por Murray e López com base na prevalência e na mortalidade obtidas de fontes oficiais. O SDI subnacional (nível departamental) foi estimado como uma medida de desenvolvimento socioeconômico e foram estabelecidas regressões lineares com CGD, SDI e localizações documentadas de amianto. Resultados: A estimativa de CGD por MM na Colômbia entre 2015-2020 foi de 51,71 anos de vida ajustados por incapacidade (AVAI) por 1 000 000 de habitantes (15 375,79 AVAI totais), com predominância em pessoas com mais de 50 anos (91,1%) e do sexo masculino (66,4%).Com relação aos departamentos, Bogotá e Valle del Cauca tiveram o maior número de AVAI ajustados, enquanto Bogotá teve o maior SDI, e Guainía e Cesar, o menor. Houve uma associação entre os AVAI e o SDI, sendo que o SDI foi responsável por 22,8% dos AVAI. Conclusões: O MM é a causa de um grande número de AVAI, predominantemente em departamentos com maior desenvolvimento socioeconômico e com a presença de empresas que usavam amianto; no entanto, o possível subdiagnóstico do MM limita a análise das informações.

Mesotelioma maligno en Colombia: carga de enfermedad, panorama general e índice sociodemográfico subnacional, 2015-2020 / Malignant mesothelioma in Colombia: burden of disease, overview, and subnational sociodemographic index, 2015–2020 / Mesotelioma maligno na Colômbia: carga de morbidade, visão geral e índice sociodemográfico subnacional, entre 2015 e 2020

[RESUMEN]. Objetivo. Establecer la carga de enfermedad por mesotelioma maligno (MM) en Colombia entre 2015 y 2020 y su asociación con el índice sociodemográfico (SDI) subnacional y las localizaciones de asbesto. Métodos. Estudio ecológico mixto en la población colombiana con diagnóstico de MM según la CIE-10 durante 2015 a 2020. La carga global de enfermedad (GBD, por su sigla en inglés) se estimó por medio de la metodología propuesta de Murray y López a partir de la prevalencia y mortalidad obtenida de fuentes ofi- ciales. Se estimó el SDI (por su sigla en inglés) subnacional (nivel departamental) como medida de desarrollo socioeconómico y se establecieron regresiones lineales con la GBD, el SDI y las localizaciones documentadas de asbesto. Resultados. La GBD estimada por MM en Colombia durante 2015-2020 fue de 51,71 años de vida ajustados por discapacidad (AVAD) por cada 1 000 000 de habitantes (15 375,79 AVAD totales), con predominio en personas mayores de 50 años (91,1%) y de sexo masculino (66,4%). A nivel departamental, Bogotá y Valle del Cauca presentaron la mayor cantidad de AVAD ajustados; mientras que Bogotá tuvo el SDI más alto, y Guainía y Cesar el más bajo. Se evidenció una asociación entre los AVAD y el SDI, donde este último explicó 22,8% de los casos de AVAD. Conclusión. El MM es causa de una gran cantidad de AVAD, con predominio en los departamentos con mayor desarrollo socioeconómico, y con presencia de empresas que solían utilizar asbesto; no obstante, el posible subdiagnóstico de MM limita el análisis de la información.

[ABSTRACT]. Objective. Establish the disease burden of malignant mesothelioma (MM) in Colombia between 2015 and 2020, and its association with the subnational sociodemographic development index (SDI) and with asbestos sites. Methods. Mixed ecological study of the Colombian population diagnosed with MM (according to ICD-10) from 2015 to 2020. The global burden of disease (GBD) was estimated using the methodology proposed by Murray and Lopez, based on prevalence and mortality data obtained from official sources. The subnational (departmental level) SDI was estimated as a measure of socioeconomic development. Linear regressions were established with the GBD, SDI, and documented asbestos sites. Results. The estimated GBD of MM in Colombia during 2015–2020 was 51.71 disability-adjusted life years (DALYs) per 1 000 000 inhabitants (15 375.79 total DALYs), with predominance in people over 50 years of age (91.1%) and males (66.4%). Bogotá and Valle del Cauca were the departments with the highest number of adjusted DALYs. Bogotá had the highest SDI and Guainía and Cesar had the lowest. There was evidence of an association between DALYs and SDI, explaining 22.8% of DALYs. Conclusion. Malignant mesothelioma is the cause of a large number of DALYs, predominantly in the depart- ments with greater socioeconomic development and with companies that used to use asbestos. However, possible underdiagnosis of MM limits analysis of the information.

[RESUMO]. Objetivo. Estabelecer o ônus da doença por mesotelioma maligno (MM) na Colômbia entre 2015 e 2020 e sua associação ao índice sociodemográfico subnacional (ISS) e locais de amianto. Métodos. Estudo ecológico misto na população colombiana diagnosticada com MM, de acordo com a CID- 10 durante 2015 a 2020. A carga global da doença (CGD) foi estimada usando a metodologia proposta por Murray e López com base na prevalência e na mortalidade obtidas de fontes oficiais. O SDI subnacional (nível departamental) foi estimado como uma medida de desenvolvimento socioeconômico e foram estabelecidas regressões lineares com CGD, SDI e localizações documentadas de amianto. Resultados. A estimativa de CGD por MM na Colômbia entre 2015-2020 foi de 51,71 anos de vida ajustados por incapacidade (AVAI) por 1 000 000 de habitantes (15 375,79 AVAI totais), com predominância em pessoas com mais de 50 anos (91,1%) e do sexo masculino (66,4%). Com relação aos departamentos, Bogotá e Valle del Cauca tiveram o maior número de AVAI ajustados, enquanto Bogotá teve o maior SDI, e Guainía e Cesar, o menor. Houve uma associação entre os AVAI e o SDI, sendo que o SDI foi responsável por 22,8% dos AVAI. Conclusões. O MM é a causa de um grande número de AVAI, predominantemente em departamentos com maior desenvolvimento socioeconômico e com a presença de empresas que usavam amianto; no entanto, o possível subdiagnóstico do MM limita a análise das informações.