Actualización en carcinoma diferenciado de tiroides refractario a radioyodo / Update on iodine-refractory differentiated thyroid carcinoma

La terapia con radioyodo constituye un pilar fundamental en la terapia adyuvante de rutina de los pacientes con carcinoma diferenciado de tiroides de alto riesgo. Sin embargo, un porcentaje no despreciable de estos pacientes desarrollaran un estado de refractariedad a este tratamiento, mostrando un peor pronóstico, disminuyendo la supervivencia y la esperanza de vida, lo que demuestra una clara necesidad de explorar distintos abordajes terapéuticos. El tratamiento de los pacientes refractarios al radioyodo sigue siendo un desafío, disponiendo en la actualidad de distintas opciones terapéuticas novedosas que deben ser conocidas por las distintas especialidades relacionadas con el carcinoma diferenciado de tiroides (CDT). El objetivo del presente trabajo es hacer una revisión del CDT refractario al tratamiento con yodo radiactivo, centrándose especialmente en la definición de yodorrefractariedad, destacando su importancia por su elevada mortalidad, e introducir las diferentes opciones terapéuticas disponibles para estos pacientes (AU)

Radioiodine therapy represents a fundamental pillar in the routine adjuvant therapy of patients with high-risk differentiated thyroid carcinoma. However, a non-negligible percentage of these patients will develop iodine refractoriness, showing a worse prognosis, as well a lower survival, which demonstrates a clear need to explore different therapeutic approaches. Iodine refractory patient treatment continues to be a challenge, currently having different novel therapeutic options that should be known by the different specialties related to differentiated thyroid carcinoma (DTC). The aim of this work is to review iodine refractory thyroid carcinoma treatment, focusing especially on the definition of iodine refractoriness, highlighting its importance due to its high mortality, and introducing the different therapeutic options available for these patients (AU)

Update on iodine-refractory differentiated thyroid carcinoma.

Radioiodine therapy represents a fundamental pillar in the routine adjuvant therapy of patients with high-risk differentiated thyroid carcinoma. However, a non-negligible percentage of these patients will develop iodine refractoriness, showing a worse prognosis, as well a lower survival, which demonstrates a clear need to explore different therapeutic approaches. Iodine refractory patient treatment continues to be a challenge, currently having different novel therapeutic options that should be known by the different specialties related to differentiated thyroid carcinoma (DTC). The aim of this work is to review iodine refractory thyroid carcinoma treatment, focusing especially on the definition of iodine refractoriness, highlighting its importance due to its high mortality, and introducing the different therapeutic options available for these patients.

Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury.

CONTEXT.­: Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. OBJECTIVE.­: To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN.­: Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. RESULTS.­: Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. CONCLUSIONS.­: The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

Evidence of possible SARS-CoV-2 vertical transmission according to World Health Organization criteria in asymptomatic pregnant women.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vertical transmission has been investigated extensively. Recently, the World Health Organization (WHO) published strict criteria to classify the timing of mother-to-child transmission of SARS-CoV-2 into different categories. The aim of this study was to investigate the possibility of vertical transmission in asymptomatic SARS-CoV-2-positive women. METHODS: Pregnant women attending for delivery at a perinatology center in Mexico City, Mexico, who had a SARS-CoV-2-positive nasopharyngeal swab 24-48 h before delivery, were asymptomatic at the time of the test and had an obstetric indication for Cesarean section were eligible for inclusion in this study. Amniotic fluid was collected during Cesarean delivery, and neonatal oral and rectal swabs were collected at birth and at 24 h after birth. SARS-CoV-2 detection was carried out using real-time reverse-transcription polymerase chain reaction in all samples. Relevant medical information was retrieved from clinical records. The WHO criteria for classifying the timing of mother-to-child transmission of SARS-CoV-2 were applied to the study population. RESULTS: Forty-two SARS-CoV-2-positive asymptomatic pregnant women fulfilled the inclusion criteria. Twenty-five (59%) women developed mild disease after discharge. Neonatal death occurred in three (7%) cases, of which one had a positive SARS-CoV-2 test at birth and none had coronavirus disease 2019-related symptoms. There were five (12%) cases with strong evidence of intrauterine transmission of SARS-CoV-2, according to the WHO criteria, as amniotic fluid samples and neonatal samples at birth and at 24 h after birth were positive for SARS-CoV-2. Our results also showed that 40-60% of infected neonates would have been undetected if only one swab (oral or rectal) was tested. CONCLUSION: This study contributes evidence to reinforce the potential for vertical transmission of SARS-CoV-2 even in asymptomatic women and highlights the importance of testing more than one neonatal sample in order to increase the detection rate of SARS-CoV-2 in affected cases. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prevalence, clinical features, and outcomes of SARS-CoV-2 infection in pregnant women with or without mild/moderate symptoms: Results from universal screening in a tertiary care center in Mexico City, Mexico.

The perinatal consequences of SARS-CoV-2 infection are still largely unknown. This study aimed to describe the features and outcomes of pregnant women with or without SARS-CoV-2 infection after the universal screening was established in a large tertiary care center admitting only obstetric related conditions without severe COVID-19 in Mexico City. This retrospective case-control study integrates data between April 22 and May 25, 2020, during active community transmission in Mexico, with one of the highest COVID-19 test positivity percentages worldwide. Only pregnant women and neonates with a SARS-CoV-2 result by quantitative RT-PCR were included in this study. Among 240 pregnant women, the prevalence of COVID-19 was 29% (95% CI, 24% to 35%); 86% of the patients were asymptomatic (95% CI, 76%-92%), nine women presented mild symptoms, and one patient moderate disease. No pregnancy baseline features or risk factors associated with severity of infection, including maternal age > 35 years, Body Mass Index >30 kg/m2, and pre-existing diseases, differed between positive and negative women. The median gestational age at admission for both groups was 38 weeks. All women were discharged at home without complications, and no maternal death was reported. The proportion of preeclampsia was higher in positive women than negative women (18%, 95% CI, 10%-29% vs. 9%, 95% CI, 5%-14%, P<0.05). No differences were found for other perinatal outcomes. SARS-CoV-2 test result was positive for nine infants of positive mothers detected within 24h of birth. An increased number of infected neonates were admitted to the NICU, compared to negative neonates (44% vs. 22%, P<0.05) and had a longer length of hospitalization (2 [2-18] days vs. 2 [2-3] days, P<0.001); these are potential proxies for illness severity. This report highlights the importance of COVID-19 detection at delivery in pregnant women living in high transmission areas.

Biopsia selectiva de ganglio centinela en el carcinoma escamoso de vulva. Análisis de seguimiento a 10 años / Sentinel lymph node biopsy procedure in squamous vulvar cancer. 10 years follow-up analysis

OBJETIVO: Aplicación de la biopsia selectiva de ganglio centinela (BSGC) en el carcinoma de vulva en estadios iniciales y análisis de los resultados, recurrencias y complicaciones. MATERIAL Y MÉTODOS: Se revisaron retrospectivamente 40 pacientes con cáncer de vulva y BSGC entre 2008 y 2018. El día de la intervención se rastrearon las cadenas ganglionares inguinales mediante sonda gammadetectora para identificar los ganglios centinela que se extirparon y remitieron para estudio anatomopatológico intraoperatorio. Posteriormente, se realizó seguimiento a largo plazo con análisis de complicaciones, recaída y mortalidad. RESULTADOS: De las 40 pacientes (edad media: 72 años [47-86]), la tasa de detección global por paciente fue del 95%, con un total de 129 ganglios centinela (GC) (3,22 GC/paciente). En tres de 25 pacientes con lesiones tumorales laterales el drenaje fue bilateral y en dos de 15 con lesiones de línea media fue unilateral. De las 40 linfogammagrafías 16 presentaban drenaje bilateral y 24 unilateral. Se obtuvieron un total de 119 GC- y 10 GC+, realizándose vaciamiento en ocho. En el grupo de GC- se incluyeron un caso de bloqueo linfático y un falso negativo. En 12 de 40 pacientes hubo complicaciones posquirúrgicas, cuatro de ellas linfedemas. Durante una mediana de seguimiento de 40 meses, recayeron seis de 10 con GC+ (40% mortalidad) y siete de 30 GC- (16% mortalidad). CONCLUSIONES: La BSGC en cáncer de vulva es la técnica de elección para una correcta estadificación y tratamiento locorregional. Es importante una adecuada estadificación ganglionar previa a la cirugía para evitar posibles bloqueos linfáticos que puedan inducir falsos negativos

AIM: Application of sentinel lymph node biopsy (SLNB) procedure in early-stage vulvar cancer and analysis of results, recurrences and complications. MATERIAL AND METHODS: 40 patients with vulvar cancer and SLNB between 2008 and 2018 were retrospectively reviewed. During the surgical procedure the inguinofemoral lymph nodes were checked with a gamma probe to identify the sentinel nodes that were removed and referred for intraoperative pathological assessment. Subsequently, long-term patient follow-up was performed with analysis of complications, relapse and mortality. RESULTS: 40 patients (mean age: 72 years [47-86], the overall detection rate per patient was 95% and a total of 129 Sentinel Lymph Nodes (SLNs) were removed (3.22 SLN/patient). In 3 out of 25 patients with lateral tumour lesions drainage was bilateral and in 2 out of 15 with midline lesions drainage was unilateral. On lymphoscintigraphy, 16 out of 40 had bilateral drainage and 24 unilateral. A total of 119 SLN- and 10 SLN+ were obtained, in 8 out of 10 an inguinofemoral lymphadenectomy was performed. In the SLN- group, one case of lymphatic blockage and one false negative were included. In 12 out of 40 patients there were post-surgical complications, 4 of them lymphoedemas. In the median follow-up (40 months), 6 out of 10 with SLN+ (40% mortality) and 7 out of 30 SLN- (16% mortality) had recurrences. CONCLUSIONS: SLNB in vulvar cancer is the technique of choice for correct staging and locoregional therapy. Correct clinical lymph node staging is important before surgery in order to avoid potential blockage drainages which could induce a false negative SLN

Sentinel lymph node biopsy procedure in squamous vulvar cancer. 10 years follow-up analysis. / Biopsia selectiva de ganglio centinela en el carcinoma escamoso de vulva. Análisis de seguimiento a 10 años.

AIM: Application of sentinel lymph node biopsy (SLNB) procedure in early-stage vulvar cancer and analysis of results, recurrences and complications. MATERIAL AND METHODS: 40 patients with vulvar cancer and SLNB between 2008 and 2018 were retrospectively reviewed. During the surgical procedure the inguinofemoral lymph nodes were checked with a gamma probe to identify the sentinel nodes that were removed and referred for intraoperative pathological assessment. Subsequently, long-term patient follow-up was performed with analysis of complications, relapse and mortality. RESULTS: 40 patients (mean age: 72 years [47-86], the overall detection rate per patient was 95% and a total of 129 Sentinel Lymph Nodes (SLNs) were removed (3.22 SLN/patient). In 3 out of 25 patients with lateral tumour lesions drainage was bilateral and in 2 out of 15 with midline lesions drainage was unilateral. On lymphoscintigraphy, 16 out of 40 had bilateral drainage and 24 unilateral. A total of 119 SLN- and 10 SLN+ were obtained, in 8 out of 10 an inguinofemoral lymphadenectomy was performed. In the SLN- group, one case of lymphatic blockage and one false negative were included. In 12 out of 40 patients there were post-surgical complications, 4 of them lymphoedemas. In the median follow-up (40 months), 6 out of 10 with SLN+ (40% mortality) and 7 out of 30 SLN- (16% mortality) had recurrences. CONCLUSIONS: SLNB in vulvar cancer is the technique of choice for correct staging and locoregional therapy. Correct clinical lymph node staging is important before surgery in order to avoid potential blockage drainages which could induce a false negative SLN.

Prolactin decreases LPS-induced inflammatory cytokines by inhibiting TLR-4/NFκB signaling in the human placenta.

Prolactin (PRL) plays an important role in trophoblast growth, placental angiogenesis and immunomodulation within the feto-maternal interface, where different cell types secrete PRL and express its receptor. During pregnancy, inflammatory signalling is a deleterious event that has been associated with poor fetal outcomes. The placenta is highly responsive to the inflammatory stimulus; however, the actions of PRL in placental immunity and inflammation remain largely unknown. The aim of this study was to evaluate PRL effects on the TLR4/NFkB signalling cascade and associated inflammatory targets in cultured explants from healthy term human placentas. An in utero inflammatory scenario was mimicked using lipopolysaccharides (LPS) from Escherichia coli. PRL significantly reduced LPS-dependent TNF-α, IL-1ß and IL-6 secretion and intracellular levels. Mechanistically, PRL prevented LPS-mediated upregulation of TLR-4 expression and NFκB phosphorylation. In conclusion, PRL limited inflammatory responses to LPS in the human placenta, suggesting that this hormone could be critical in inhibiting exacerbated immune responses to infections that could threaten pregnancy outcome. This is the first evidence of a mechanism for anti-inflammatory activity of PRL in the human placenta, acting as a negative regulator of TLR-4/NFkB signaling.

The BeWo cell line derived from a human placental choriocarcinoma is permissive for respiratory syncytial virus infection.

The respiratory syncytial virus (RSV) is the main pathogen associated with upper respiratory tract infections during early childhood. Vertical transmission of this virus has been suggested in humans, based on observations recorded during animal studies that revealed an association of RSV with persistent structural and functional changes in the developing lungs of the offspring. However, human placentas have not yet been evaluated for susceptibility to RSV infection. In this study, we examined the capacity of RSV to infect a human trophoblast model, the BeWo cell line. Our results suggest that BeWo cells are susceptible to RSV infection since they allow RNA viral replication, viral protein translation, leading to the production of infectious RSV particles. In this report, we demonstrate that a human placenta model system, consisting of BeWo cells, is permissive to RSV infection. Thus, the BeWo cell line may represent a useful model for studies that aim to characterize the events of a possible RSV infection at the human maternal-fetal interface.

Captación de 131I en calcinosis tumoral en un paciente en hemodiálisis tratado de cáncer de tiroides / 131I uptake in tumoral calcinosis in a patient on hemodialysis treated for thyroid cancer

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Progesterone suppresses the lipopolysaccharide-induced pro-inflammatory response in primary mononuclear cells isolated from human placental blood.

Progesterone is an essential hormone that induces deep immune adaptations favoring pregnancy maintenance. We aimed at evaluating the effects of progesterone on the synthesis of pro- and anti-inflammatory cytokines by mononuclear cells isolated from human placental blood stimulated with lipopolysaccharide, emulating an infection-inflammation environment. Mononuclear cells isolated form human placental blood were obtained from nine women undergoing elective cesarean delivery at term (not in labor), isolated by density gradient sedimentation, cultured and co-stimulated with lipopolysaccharide (500 ng/ml) from Escherichia coli in the presence or not of progesterone (0.01, 0.1, or 1.0 µM) for 24 h. Culture supernatants were assayed for pro-inflammatory (IL-1ß, TNFα, IL-6), anti-inflammatory (IL-10) cytokines, chemokines (IL-8, MIP-1α) and total MMP-9 by ELISA. In comparison with basal conditions, lipopolysaccharide treatment induced IL-1ß, TNFα, IL-6, IL-8, MIP-1α, and MMP-9 synthesis. lipopolysaccharide co-treatment with progesterone significantly decreased the bacterial endotoxin-induced IL-1ß, TNF-α, IL-6, IL-8, and MIP-1α secretion. In contrast, co-treatment with progesterone increased the level of IL-10 secreted to the culture medium. The present results support the concept that progesterone can modulate--partially--the inflammatory response of professional immune cells isolated from placental blood. Therefore, progesterone might be part of the natural compensatory mechanism that limits the cytotoxic effects associated with an intrauterine infection process during gestation.

Decline in macrolide resistance rates among Streptococcus pyogenes causing pharyngitis in children isolated in Italy.

Macrolides are often used to treat group A streptococcus (GAS) infections, but their resistance rates reached high proportions worldwide. The aim of the present study was to give an update on the characteristics and contemporary prevalence of macrolide-resistant pharyngeal GAS in Central Italy. A total of 592 isolates causing pharyngitis in children were collected in the period 2012-2013. Clonality was assessed by emm typing and pulsed-field gel electrophoresis (PFGE) for all macrolide-resistant strains and for selected susceptible isolates. Genetic determinants of resistance were screened by polymerase chain reaction (PCR). Forty-four GAS were erythromycin-resistant (7.4 %). Among them, 52.3 % and 50 % were clindamycin- and tetracycline-resistant, respectively. erm(B)-positive isolates (52.3 %) expressed the constitutive cMLSB phenotype. mef(A) and its associated M phenotype were recorded in 40.9 % of the cases. The remaining erm(A)-positive isolates expressed the iMLSB phenotype. Seventeen tetracycline-resistant isolates carried tet(M) and five isolates carried tet(O). Twenty-five emm types were found among all strains, with the predominance of emm types 12, 89, 1, and 4. Eleven emm types and 12 PFGE clusters characterized macrolide-resistant strains, with almost two-thirds belonging to emm12, emm4, and emm11. Macrolide-susceptible and -resistant emm types 12, 89, 11, and 4 shared related PFGE profiles. There was a dramatic decline in macrolide resistance in Central Italy among pharyngeal GAS isolates in 2012-2013 when compared to previous studies from the same region (p < 0.05), although macrolide consumption remained stable over the past 15 years. We observed a decrease in the proportion of macrolide-resistant strains within emm types commonly associated with macrolide resistance in the past, namely emm12, 1, and 89.

Differential macrophage response to slow- and fast-growing pathogenic mycobacteria.

Nontuberculous mycobacteria (NTM) have recently been recognized as important species that cause disease even in immunocompetent individuals. The mechanisms that these species use to infect and persist inside macrophages are not well characterised. To gain insight concerning this process we used THP-1 macrophages infected with M. abscessus, M. fortuitum, M. celatum, and M. tuberculosis. Our results showed that slow-growing mycobacteria gained entrance into these cells with more efficiency than fast-growing mycobacteria. We have also demonstrated that viable slow-growing M. celatum persisted inside macrophages without causing cell damage and without inducing reactive oxygen species (ROS), as M. tuberculosis caused. In contrast, fast-growing mycobacteria destroyed the cells and induced high levels of ROS. Additionally, the macrophage cytokine pattern induced by M. celatum was different from the one induced by either M. tuberculosis or fast-growing mycobacteria. Our results also suggest that, in some cases, the intracellular survival of mycobacteria and the immune response that they induce in macrophages could be related to their growth rate. In addition, the modulation of macrophage cytokine production, caused by M. celatum, might be a novel immune-evasion strategy used to survive inside macrophages that is different from the one reported for M. tuberculosis.

Characterization of levofloxacin non-susceptible clinical Streptococcus pyogenes isolated in the central part of Italy.

We investigated the prevalence, genetics, and clonality of fluoroquinolone non-susceptible isolates of Streptococcus pyogenes in the central part of Italy. S. pyogenes strains (n = 197) were isolated during 2012 from patients with tonsillopharyngitis, skin, wound or invasive infections and screened for fluoroquinolone non-susceptibility (resistance to norfloxacin and levofloxacin minimum inhibitory concentration (MIC) = 2 mg/L) following EUCAST guidelines. First-step topoisomerase parC and gyrA substitutions were investigated using sequencing analysis. Clonality was determined by pulsed field gel electrophoresis (PFGE; SmaI digestion) and by emm typing. The fluoroquinolone non-susceptible phenotype was identified in 18 isolates (9.1 %) and correlated with mutations in parC, but not in gyrA, the most frequent leading to substitution of the serine at position 79 with an alanine. Most of the fluoroquinolone non-susceptible isolates belonged to the emm-type 6, even if other emm-types were also represented (emm75, emm89, and emm2). A significant level of association was measured between PFGE and both emm type and substitutions in parC. The prevalence of fluoroquinolone non-susceptible Streptococcus pyogenes isolates in Italy is of concern and, although the well-known emm type 6 is dominant, other types are appearing and spreading.

Mycobacterium mucogenicum and other non-tuberculous mycobacteria in potable water of a trauma hospital: a potential source for human infection.

This study examined the frequency of occurrence of non-tuberculous mycobacteria (NTM) in potable water samples from a main trauma hospital in Mexico City. Sixty-nine potable water samples were collected, 23 from each source: cistern, kitchen tap and bathroom showers. Of the 69 samples, 36 harboured NTM species. Twenty-nine of the 36 isolates were Mycobacterium mucogenicum, two Mycobacterium rhodesiae, one Mycobacterium peregrinum, one Mycobacterium fortuitum and three were Mycobacterium spp. Hospital potable water harbouring NTM represents a potential source for nosocomial infections, therefore we suggest that hospital potable water microbiological guidelines should include testing for NTM species.

Differential expression of dnaA and dosR genes among members of the Mycobacterium tuberculosis complex under oxic and hypoxic conditions.

Major differences regarding the pathology and host immune response of the Beijing and Canettii genotypes of Mycobacterium tuberculosis have been reported; however, studies on the genetic expression of these genotypes during in vitro dormancy are scarce. This study examined the expression of five cell-cycle-related genes and two dormancy-related genes in M. canettii, M. tuberculosis H37Rv, and M. tuberculosis Beijing during the Wayne model of dormancy. The results showed that under hypoxic conditions the three tuberculosis genotypes were able to transcribe genes involved in DNA replication and cellular division. In addition, dosR was found to be up-regulated in M. tuberculosis Beijing during the exponential growth phase but down-regulated under hypoxic conditions. In this genotype, the replication-related gene dnaA was also strongly down-regulated. These latter two findings suggest that, compared to M. tuberculosis H37Rv and M. canettii, the Beijing genotype has a lower capacity to synthesize dosR, hspX, and dnaA mRNAs during in vitro dormancy.

Differential expression of dnaA and dosRgenes among members of the Mycobacterium tuberculosis complex under oxic and hypoxic conditions

Major differences regarding the pathology and host immune response of the Beijing and Canettii genotypes of Mycobacterium tuberculosis have been reported; however, studies on the genetic expression of these genotypes during in vitro dormancy are scarce. This study examined the expression of five cell-cycle-related genes and two dormancy-related genes in M. canettii, M. tuberculosis H37Rv, and M. tuberculosis Beijing during the Wayne model of dormancy. The results showed that under hypoxic conditions the three tuberculosis genotypes were able to transcribe genes involved in DNA replication and cellular division. In addition, dosR was found to be up-regulated in M. tuberculosis Beijing during the exponential growth phase but down-regulated under hypoxic conditions. In this genotype, the replication-related gene dnaA was also strongly down-regulated. These latter two findings suggest that, compared to M. tuberculosis H37Rv and M. canettii, the Beijing genotype has a lower capacity to synthesize dosR, hspX, and dnaA mRNAs during in vitro dormancy (AU)

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