Fulminant myocarditis proven by early biopsy and outcomes.

BACKGROUND AND AIMS: While endomyocardial biopsy (EMB) is recommended in adult patients with fulminant myocarditis, the clinical impact of its timing is still unclear. METHODS: Data were collected from 419 adult patients with clinically suspected fulminant myocarditis admitted to intensive care units across 36 tertiary centres in 15 countries worldwide. The diagnosis of myocarditis was histologically proven in 210 (50%) patients, either by EMB (n = 183, 44%) or by autopsy/explanted heart examination (n = 27, 6%), and clinically suspected cardiac magnetic resonance imaging confirmed in 96 (23%) patients. The primary outcome of survival free of heart transplantation (HTx) or left ventricular assist device (LVAD) at 1 year was specifically compared between patients with early EMB (within 2 days after intensive care unit admission, n = 103) and delayed EMB (n = 80). A propensity score-weighted analysis was done to control for confounders. RESULTS: Median age on admission was 40 (29-52) years, and 322 (77%) patients received temporary mechanical circulatory support. A total of 273 (65%) patients survived without HTx/LVAD. The primary outcome was significantly different between patients with early and delayed EMB (70% vs. 49%, P = .004). After propensity score weighting, the early EMB group still significantly differed from the delayed EMB group in terms of survival free of HTx/LVAD (63% vs. 40%, P = .021). Moreover, early EMB was independently associated with a lower rate of death or HTx/LVAD at 1 year (odds ratio of 0.44; 95% confidence interval: 0.22-0.86; P = .016). CONCLUSIONS: Endomyocardial biopsy should be broadly and promptly used in patients admitted to the intensive care unit for clinically suspected fulminant myocarditis.

TTCC-2019-02: real-world evidence of first-line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck.

Objectives: The aim of this study was to confirm the efficacy of the ERBITAX scheme (paclitaxel 80 mg/m2 weekly and cetuximab 400 mg/m2 loading dose, and then 250 mg/m2 weekly) as first-line treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) who are medically unfit for cisplatin-based (PT) chemotherapy. Materials and methods: This retrospective, non-interventional study involved 16 centers in Spain. Inclusion criteria were to have started receiving ERBITAX regimen from January 2012 to December 2018; histologically confirmed SCCHN including oral cavity, oropharynx, hypopharynx, and larynx; age ≥18 years; and platinum (PT) chemotherapy ineligibility due to performance status, comorbidities, high accumulated dose of PT, or PT refractoriness. Results: A total of 531 patients from 16 hospitals in Spain were enrolled. The median age was 66 years, 82.7% were male, and 83.5% were current/former smokers. Patients were ineligible to receive PT due to ECOG 2 (50.3%), comorbidities (32%), PT cumulative dose ≥ 225 mg/m2 (10.5%), or PT refractoriness (7.2%). Response rate was 37.7%. Median duration of response was 5.6 months (95% CI: 4.4-6.6). With a median follow-up of 8.7 months (95% CI: 7.7-10.2), median PFS and OS were 4.5 months (95% CI: 3.9-5.0) and 8.9 months (95% CI: 7.8-10.3), respectively. Patients treated with immunotherapy after ERBITAX had better OS with a median of 29.8 months compared to 13.8 months for those who received other treatments. The most common grade ≥ 3 toxicities were acne-like rash in 36 patients (6.8%) and oral mucositis in 8 patients (1.5%). Five (0.9%) patients experienced grade ≥ 3 febrile neutropenia. Conclusion: This study confirms the real-world efficacy and tolerability of ERBITAX as first-line treatment in recurrent/metastatic SCCHN when PT is not feasible. Immunotherapy after treatment with ERBITAX showed remarkable promising survival, despite potential selection bias.

Intervención educativa para mejorar la prescripción de ceftriaxona en un servicio de urgencias / Educational intervention to improve ceftriaxone prescription in an emergency department

Objetivo: Evaluar prevalencia y adecuación de ceftriaxona tras una intervención educativa en un servicio de urgencias.Métodos: Estudio cuasi experimental que incluyó un mues-treo consecutivo de consultas no programadas de pacien-tes adultos, durante dos meses preintervención y posin-tervención. Dicha intervención consistió en capacitación a médicos para limitar su indicación sólo a situaciones clínicas específicas (meningitis, enfermedad pélvica infla-matoria y abdomen agudo). Se utilizaron datos retrospecti-vos, con adicional revisión manual de historias, para validar adecuación de inicio antibiótico y apropiabilidad de droga. Se utilizó estadística descriptiva y analítica.Resultados: De un total de 28.570 consultas, 512 recibie-ron ceftriaxona (1,79%; IC95% 1,64-1,95), y sólo 60,54% se hospitalizaron. En cuanto a la comparación antes-después, se observó una reducción en la tasa de uso (de 3,66% a 0,63%; p<0,001), la adecuación en el inicio de un antimicro-biano se mantuvo (de 84,52% a 86,21%; p=0,778), aunque la adecuación de ceftriaxona aumentó en forma significativa (de 41,78% a 84,00% respectivamente; p<0,001). Adicional-mente, se redujo el tiempo de estadía hospitalaria (media-na de 6 a 5 días; p=0,014), sin diferencias en la mortalidad intrahospitalaria (19,44% vs 17,24%; p=0,691), ni en la mor-talidad a los 30 días (23,41% vs 18,96%; p=0,464).Conclusiones: Esta intervención resultó eficaz. Los hallaz-gos representan un paso fundamental en los programas de optimización del uso de antimicrobianos hospitalarios, que apuntan a reducir su sobreutilización y la consecuente resistencia.

Objective: To evaluate the prevalence and appropriateness of ceftriaxone after an educational intervention in an emergency department.Methods: Quasi-experimental study, which included a consecutive sampling of unscheduled consultations of adult patients, during 2 months pre-intervention and post-intervention. The intervention consisted of training physicians to limit its indication only to specific clinical situations (meningitis, pelvic inflammatory disease, and acute abdomen). Retrospective data were used, with additional manual chart review, to validate appropriateness of antibiotic initiation and drug appropriateness. Descriptive and analytical statistics were used.Results: Among 28570 visits, 512 received ceftriaxone (1.79%; 95%CI 1.64-1.95), and only 60.54% were hospitalized. Regarding the before-after comparison, we observed a reduction in the rate of use (from 3.66% to 0.63%; p<0.001), the appropriateness in starting an antimicrobial was maintained (from 84.52% to 86.21%; p=0.778), and the appropriateness of ceftriaxone increased significantly (from 41.78% to 84.00% respectively; p<0.001). Additionally, hospital length of stay was reduced (median 6 to 5 days; p=0.014), with no difference in in-hospital mortality (19.44% vs 17.24%; p=0.691), nor in 30-day mortality (23.41% vs 18.96%; p=0.464)

Monitoreo serológico y psicológico en personal de salud durante el comienzo de la pandemia COVID-19 / Serological and psychological monitoring of healthcare workers during the start of the COVID-19 pandemic

Introducción: el personal de salud (PdS) es esencial en la lucha contra el COVID-19. Al inicio de la pandemia, el riesgo de adquirir la enfermedad en este grupo era desconocido. Buscamos estimar incidencia y prevalencia de anticuerpos anti-SARS-CoV-2, y prevalencia de burnout en una cohorte de PdS durante la pandemia COVID-19, así como valorar la prevalencia de burnout y depresión en la cohorte. Materiales y métodos: cohorte prospectiva conformada por médicos que atendían pacientes COVID-19 desde marzo de 2020 hasta enero de 2021, en un hospital de alta complejidad de la ciudad de Buenos Aires. Se evaluó IgM e IgG anti-SARS-CoV-2 quincenalmente durante 3 meses, así como la presencia de síntomas compatibles y factores asociados a la exposición. Se remitió a participantes con alteraciones de la esfera psíquica a contacto con el equipo de salud mental del hospital. Resultados: se incluyeron 52 participantes; de ellos, 31 eran mujeres; mediana de edad 32 años (rango 25-58). La mediana de horas semanales de trabajo autoinformadas fue 48 (IIC [intervalo intercuartil] 40-69,5). Inicialmente todos fueron PCR SARS-CoV-2 negativos en hisopado nasal; 11 (21,50% IC 95%; 9,62-32,53%) tuvieron COVID-19 sintomático con anticuerpos positivos. Los factores con mayor asociación a riesgo de COVID-19 fueron anosmia/disgeusia OR 403,33 (IC 95%; 47,60-3417,02), fiebre OR 172,53 (IC 95%; 28,82-1032,65), mialgias OR 41,97 (IC 95%; 8,08-217,84), conviviente con COVID-19 OR 28,17 (IC 95%; 5,67-179,97). Cerca del 40% presentaba alteraciones en las escalas de medición de burnout o depresión. Discusión: la incidencia hallada coincide con las cifras informadas acerca de personal de salud en la etapa inicial de la pandemia en la Argentina. Otro aspecto similar fue una mayoría de infecciones de curso leve, sin ningún paciente hospitalizado. No obstante, se halló una elevada incidencia de alteraciones de la esfera psíquica, tanto al comienzo como al final del seguimiento. Conclusiones: la incidencia de positivización de anticuerpos anti-SARS-CoV-2 fue cercana al 20%. No evidenciamos infecciones presintomáticas o asintomáticas. En cambio, la prevalencia de burnout y depresión fue elevada. La salud mental es un componente del personal de salud que debe ser priorizado en situaciones futuras de impacto similar. (AU)

Introduction: healthcare personnel are essential in the response against COVID-19. At the beginning of the pandemic the risk of acquiring the disease in this group was unknown. We sought to estimate incidence and prevalence of anti SARS-CoV-2 antibodies, as well as burnout prevalence in a cohort of healthcare staff during the pandemic, as well as assessing the prevalence of burnout and depression in this group. Materials and methods: prospective cohort formed by physicians tending to COVID-19 patients from march 2020 to january 2021 in a high-complexity hospital in the city of Buenos Aires. We evaluated anti SARS-CoV-2 IgM and IgG each 15 days for 3 months as well as the presence of compatible symptoms and factors associated to exposition to the virus. Patients showing signs of burnout and/or depression were referred to proper care by the mental health team in the hospital. Results: we included 52 patients, 31 women, median age was 32 years (range 25 - 58). Median amount of self-reported hours worked each week was 48 (IQR 40 - 69.5). Initially all participants had a negative COVID-19 PCR nasopharyngeal swab; 11 (21.50% CI95% 9.62 - 32.53%) had symptomatic COVID-19 with positive antibodies. Factors showing stronger association with testing positive were anosmia/dysgeusia OR 403.33 (CI95% 47.60-3417.02), fever OR 172.53 (CI95% 28.82 - 1032.65), myalgia OR 41.97 (CI95% 8.08 - 217.84), cohabitation with confirmed COVID-19 case OR 28.17 (CI95% 5.67 - 179.97). Near 40% showed alterations in burnout or depression scales. Discussion: the incidence rate we found was like reported values in the initial stages of the pandemic in Argentina. Another similarity was that all cases were mild; no hospitalization was required for any participant. We found an elevated incidence of alterations in the psychic sphere, both at the beginning and end of the follow up period. Conclusions:the incidence of positive SARS-CoV-2 antibodies was around 20%. No pre or asymptomatic cases were identified. Burnout and depression incidence was high. Mental health is a component that should never be overlooked in similar situations to come. (AU)

Diagnóstico de infecciones asociadas a artroplastias / Recommendations for the diagnosis of prosthetic joint infections

Resumen La infección de prótesis articulares es la más temida de las complicaciones en estas cirugías. Su diagnóstico continúa siendo un gran desafío, debido a su presentación poco evidente y solapada, exigiendo una alta sospecha clínica para que el mismo pueda ser realizado en forma oportuna. El presente documento representa una revisión actualizada de las evidencias y recomendaciones existentes, con el objeto de proveer una herramienta que permita a los profesionales seguir un curso de acción basado en los conocimientos actuales y recursos disponibles, según la opinión de los miembros de la Comisión de Infecciones Osteoarticulares de la Sociedad Argentina de Infectología (SADI).

Abstract Prosthetic joint infection is the most feared complication of implant surgeries. Its diagnosis continues to be a challenge since its clinical presentation is usually not very evident and overlapping. A high clinical suspicion is needed to make a timely diagnosis. This document represents an updated review of the existing evidence and recommendations, in order to provide a tool that allows professionals to follow a course of action based on current knowledge and available resources, according to the opinion of the members of the Commission of Osteoarticular Infections from the Argentinean Society of Infectious Diseases (SADI).

Mucormycosis osteomyelitis after anterior cruciate ligament reconstruction: treatment and outcomes of 21 reported cases.

AIMS: Our purpose was to describe an unusual series of 21 patients with fungal osteomyelitis after an anterior cruciate ligament reconstruction (ACL-R). METHODS: We present a case-series of consecutive patients treated at our institution due to a severe fungal osteomyelitis after an arthroscopic ACL-R from November 2005 to March 2015. Patients were referred to our institution from different areas of our country. We evaluated the amount of bone resection required, type of final reconstructive procedure performed, and Musculoskeletal Tumor Society (MSTS) functional score. RESULTS: A total of 21 consecutive patients were included in the study; 19 were male with median age of 28 years (IQR 25 to 32). All ACL-R were performed with hamstrings autografts with different fixation techniques. An oncological-type debridement was needed to control persistent infection symptoms. There were no recurrences of fungal infection after median of four surgical debridements (IQR 3 to 6). Five patients underwent an extensive curettage due to the presence of large cavitary lesions and were reconstructed with hemicylindrical intercalary allografts (HIAs), preserving the epiphysis. An open surgical debridement was performed resecting the affected epiphysis in 15 patients, with a median bone loss of 11 cm (IQR 11.5 to 15.6). From these 15 cases, eight patients were reconstructed with allograft prosthesis composites (APC); six with tumour-type prosthesis (TTP) and one required a femoral TTP in combination with a tibial APC. One underwent an above-the-knee amputation. The median MSTS functional score was 20 points at a median of seven years (IQR 5 to 9) of follow-up. CONCLUSION: This study suggests that mucormycosis infection after an ACL-R is a serious complication. Diagnosis is usually delayed until major bone destructive lesions are present. This may originate additional massive reconstructive surgeries with severe functional limitations for the patients.Level of evidence: IVCite this article: Bone Joint Open 2020;2(1):3-8.

Genetic diversity and phylogeographic analysis of human herpesvirus type 8 (HHV-8) in two distant regions of Argentina: Association with the genetic ancestry of the population.

BACKGROUND: The genetic diversity of persistent infectious agents, such as HHV-8, correlates closely with the migration of modern humans out of East Africa which makes them useful to trace human migrations. However, there is scarce data about the evolutionary history of HHV-8 particularly in multiethnic Latin American populations. OBJECTIVES: The aims of this study were to characterize the genetic diversity and the phylogeography of HHV-8 in two distant geographic regions of Argentina, and to establish potential associations with pathogenic conditions and the genetic ancestry of the population. STUDY DESIGN: A total of 101 HIV-1 infected subjects, 93 Kaposi's Sarcoma (KS) patients and 411 blood donors were recruited in the metropolitan (MET) and north-western regions of Argentina (NWA). HHV-8 DNA was detected by ORF-26 PCR in whole blood, saliva and FFPE tissues. Then, ORF-26 and ORF-K1 were analyzed for subtype assignment. Mitochondrial DNA and Y chromosome haplogroups, as well as autosomal ancestry markers were evaluated in samples in which subtypes could be assigned. Phylogeographic analysis was performed in the ORF-K1 sequences from this study combined with 388 GenBank sequences. RESULTS: HHV-8 was detected in 50.7%, 59.2% and 8% of samples from HIV-1 infected subjects, KS patients and blood donors, respectively. ORF-K1 phylogenetic analyses showed that subtypes A (A1-A5), B1, C (C1-C3) and F were present in 46.9%, 6.25%, 43.75% and 3.1% of cases, respectively. Analyses of ORF-26 fragment revealed that 81.95% of strains were subtypes A/C followed by J, B2, R, and K. The prevalence of subtype J was more commonly observed among KS patients when compared to the other groups. Among KS patients, subtype A/C was more commonly detected in MET whereas subtype J was the most frequent in NWA. Subtypes A/C was significantly associated with Native American maternal haplogroups (p = 0.004), whereas subtype J was related to non-Native American haplogroups (p < 0.0001). Sub-Saharan Africa, Europe and Latin America were the most probable locations from where HHV-8 was introduced to Argentina. CONCLUSIONS: These results give evidence of the geographic circulation of HHV-8 in Argentina, suggest the association of ORF-26 subtype J with KS development and provide new insights about its relationship with ancient and modern human migrations and identify the possible origins of this virus in Argentina.

Lower Success Rate of Débridement and Implant Retention in Late Acute versus Early Acute Periprosthetic Joint Infection Caused by Staphylococcus spp. Results from a Matched Cohort Study.

BACKGROUND: Surgical débridement, antibiotics and implant retention (DAIR) is currently recommended by international guidelines for both early acute (postsurgical) and late acute (hematogenous) periprosthetic joint infections (PJIs). However, due to a different pathogenesis of infection, a different treatment strategy may be needed. QUESTIONS/PURPOSES: (1) Compared with early acute PJIs, are late acute PJIs associated with a higher risk of DAIR failure? (2) When stratified by microorganism, is the higher risk of failure in late acute PJI associated with Staphylocococcus aureus infection? (3) When analyzing patients with S. aureus infection, what factors are independently associated with DAIR failure? METHODS: In this multicenter observational study, early acute and late acute PJIs treated with DAIR were retrospectively evaluated and matched according to treating center, year of diagnosis, and infection-causing microorganism. If multiple matches were available, the early acute PJI diagnosed closest to the late acute PJI was selected. A total of 132 pairs were included. Treatment success was defined as a retained implant during follow-up without the need for antibiotic suppressive therapy. RESULTS: Late acute PJIs had a lower treatment success (46% [60 of 132]) compared with early acute PJIs (76% [100 of 132]), OR 3.9 [95% CI 2.3 to 6.6]; p < 0.001), but the lower treatment success of late acute PJIs was only observed when caused by Staphylococcus spp (S. aureus: 34% versus 75%; p < 0.001; coagulase-negative staphylococci: 46% versus 88%; p = 0.013, respectively). On multivariable analysis, late acute PJI was the only independent factor associated with an unsuccessful DAIR when caused by S. aureus (OR 4.52 [95% CI 1.79 to 11.41]; p < 0.001). CONCLUSIONS: Although DAIR seems to be a successful therapeutic strategy in the management of early acute PJI, its use in late acute PJI should be reconsidered when caused by Staphylococcus spp. Our results advocate the importance of isolating the causative microorganism before surgery. LEVEL OF EVIDENCE: Level III, therapeutic study.

COVID-19 y tiroxicosis / COVID-19 and thyrotoxicosis. Case report

La epidemia por COVID-19, causada por el nuevo coronavirus-2 del síndrome respiratorio agudo severo (SARS-CoV-2) ha enfrentado al equipo de salud a un abanico de presentaciones clínicas y alteraciones de las funciones órganicas a las que diagnosticar y tratar. Dentro de estas se encuentra la disfunción tiroidea.En este reporte se presenta el caso de una paciente con taquicardia persistente luego de pasado el cuadro de COVID-19, que derivó en múltiples consultas hasta que se arribó al diagnóstico de tirotoxicosis de etiología autoinmune.La tirotoxicosis asociada a COVID-19 es infrecuente, pero agrega morbilidad a la convalecencia de los pacientes, por lo que su sospecha clínica y diagnóstico rápido serían beneficiosos

The infection by the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has challenged the health care system with a new spectrum of clinical manifestations and organ disfuntions, that require proper diagnosis and treatment.In this case we report a patient with persistent tachycardia after COVID-19 acute illness. This finding led to multiple medical visits until final diagnosis of thyrotoxicosis of autoimmune etiology.Thyrotoxicosis is an unusual complication of COVID-19, that results in higher morbility in patients during the convalescent phase of the disease. Opportune clinical suspicion and early diagnosis seems to be beneficial in terms of clinical outcome

Cross Talk between eIF2α and eEF2 Phosphorylation Pathways Optimizes Translational Arrest in Response to Oxidative Stress.

The cellular stress response triggers a cascade of events leading to transcriptional reprogramming and a transient inhibition of global protein synthesis, which is thought to be mediated by phosphorylation of eukaryotic initiation factor-2α (eIF2α). Using mouse embryonic fibroblasts (MEFs) and the fission yeast S. pombe, we report that rapid translational arrest and cell survival in response to hydrogen peroxide-induced oxidative stress do not rely on eIF2α kinases and eIF2α phosphorylation. Rather, H2O2 induces a block in elongation through phosphorylation of eukaryotic elongation factor 2 (eEF2). Kinetic and dose-response analyses uncovered cross talk between the eIF2α and eEF2 phosphorylation pathways, indicating that, in MEFs, eEF2 phosphorylation initiates the acute shutdown in translation, which is maintained by eIF2α phosphorylation. Our results challenge the common conception that eIF2α phosphorylation is the primary trigger of translational arrest in response to oxidative stress and point to integrated control that may facilitate the survival of cancer cells.

Unusual Listeria monocytogenes hematogenous infection in total knee replacement treated with one-stage revision surgery.

Septic arthritis due to Listeria monocytogenes (LM) is extremely rare and most infections due to this organism are seen in immunocompromised patients. We describe a patient without immunological compromise, with a late total knee arthroplasty infection caused by LM treated with one-stage revision surgery. She had an elevated erythrocyte sedimentation rate (79 mm/h) and C-reactive protein (13 mg/dL). Aspiration of the knee joint yielded purulent fluid; cultures showed LM. The patient was given 6 weeks of intravenous ampicillin, followed by trimethoprim/sulfamethoxazole, and finally amoxicillin orally for 7 months. Two years after revision surgery, radiographs showed no evidence of implant loosening. This is a single case and although one-stage approach seemed to have worked, it should not be recommended on the basis of a single report.

Timing of implant-removal in late acute periprosthetic joint infection: A multicenter observational study.

OBJECTIVES: We evaluated the treatment outcome in late acute (LA) periprosthetic joint infections (PJI) treated with debridement and implant retention (DAIR) versus implant removal. METHODS: In a large multicenter study, LA PJIs of the hip and knee were retrospectively evaluated. Failure was defined as: PJI related death, prosthesis removal or the need for suppressive antibiotic therapy. LA PJI was defined as acute symptoms <3 weeks in patients more than 3 months after the index surgery and with a history of normal joint function. RESULTS: 445 patients were included, comprising 340 cases treated with DAIR and 105 cases treated with implant removal (19% one-stage revision (n = 20), 74.3% two-stage revision (n = 78) and 6.7% definitive implant removal (n = 7). Overall failure in patients treated with DAIR was 45.0% (153/340) compared to 24.8% (26/105) for implant removal (p < 0.001). Difference in failure rate remained after 1:1 propensity-score matching. A preoperative CRIME80-score ≥3 (OR 2.9), PJI caused by S. aureus (OR 1.8) and implant retention (OR 3.1) were independent predictors for failure in the multivariate analysis. CONCLUSION: DAIR is a viable surgical treatment for most patients with LA PJI, but implant removal should be considered in a subset of patients, especially in those with a CRIME80-score ≥3.

State-of-the-art diagnosis and surgical treatment of acute peri-prosthetic joint infection following primary total hip arthroplasty.

Acute peri-prosthetic joint infection (PJI) following total hip arthroplasty (THA) is a potentially devastating and undesired complication, with a prevalence of 0.3% to 2.9%. Its suspicion begins with a meticulous physical examination and anamnesis. Diagnosis should be made on the basis of the Musculoskeletal Infection Society criteria. Serum and synovial biomarkers are very useful tools when major criteria are absent.Although sometimes not possible due to medical conditions, surgery is usually the first line of treatment. Although its outcome is highly correlated with the isolated microorganism, irrigation and debridement with implant retention (DAIR) is the gold standard for treatment. Ideally, the prior approach should be proximally and distally extended to augment the field of view and remove all of the prosthetic modular components, that is, femoral head and acetabular insert.Given DAIR's unclear control of infection, with successful outcomes in the range of 30% to 95%, one- or two-stage revision protocols may play a role in certain cases of acute infections; nonetheless, further prospective, randomized studies are necessary to compare long-term outcomes between DAIR and revision surgeries.Following surgical treatment, length of antibiotherapy is in the range of six weeks to six months, without any difference in outcomes between short and long protocols. Treatment should be adjusted to the isolated bacteria and controlled further with post-operative serum biomarker levels. Cite this article: EFORT Open Rev 2018;3:434-441. DOI: 10.1302/2058-5241.3.170032.

Oxidized analogs of Di(1H-indol-3-yl)methyl-4-substituted benzenes are NR4A1-dependent UPR inducers with potent and safe anti-cancer activity.

Di(1H-indol-3-yl)(4-trifluoromethylphenyl)methane (DIM-Ph-4-CF3) is an analog of orphan nuclear receptor 4A1 (NR4A1) ligand cytosporone B. We have synthesized several oxidation products of DIM-Ph-4-CF3, focusing on analogs with electron-withdrawing or donating groups at their phenyl ring 4-positions, and examined their anti-cancer activity and mechanism-of-action. Mesylates (DIM-Ph-4-X+ OMs-s) having CF3, CO2Me and Cl groups were more effective inhibitors of cancer cell viability than their precursors. 19F NMR spectroscopy and differential scanning calorimetry strongly indicated interactions of DIM-Ph-4-CF3+ OMs- with the NR4A1 ligand binding domain, and compound-induced apoptosis of prostate cancer cells was dependent on NR4A1. DIM-Ph-4-CF3+ OMs- showed robust inhibition of LNCaP prostate cancer xenografts with no apparent toxicity. In vitro and in vivo, DIM-Ph-4-CF3+ OMs- activated proapoptotic unfolded protein response (UPR) signaling in prostate cancer cells. Independently of DIM-Ph-4-CF3+ OMs-, the bulk of NR4A1 localized to the cytoplasm in various cancer cell lines, suggesting a cytoplasmic mechanism-of-action of DIM-Ph-4-CF3+ OMs- in UPR induction and cell death. In summary, the data suggest that oxidized analogs of DIM-Ph-4-CF3 possess potent and safe anti-cancer activity which is mediated through UPR signaling downstream of NR4A1 binding.

Osteomielitis por mucorales (OMM) asociada a artroscopia de reparación de ligamento cruzado anterior: investigación epidemiológica y recomendaciones para su prevención / Mucor osteomyelitis after arthroscopic repair of ACL. Epidemiological investigation

OBJETIVO: Describir la investigación epidemiológica de osteomielitis por Mucorales (OMM) post reparación artroscópica de LCA (RA-LCA) en Argentina. MATERIAL Y MÉTODO: 1) Revisión de los casos; 2) Relevamiento de 3 instituciones; 3) Cultivo micológico de materiales quirúrgicos; 4) Encuesta a instrumentadoras; 5) Secuenciación de las cepas de Rhizopus y 6) Redacción de recomendaciones. RESULTADOS: Del 2005 al 2017 se identificaron 40 casos de OMM (Rhizopus sp.) post reparación artroscópica de LCA en pacientes inmunocompetentes de 12 jurisdicciones de Argentina. El diagnóstico fue por cultivo (22/31), y por anatomía patológica (9). La edad promedio fue 29 años. El 84% de 38 casos eran varones. Intervinieron 13 ortopedias. El implante fue importado en 8/20 casos y nacional en 12. En las 3 instituciones se observó: manejo inadecuado del aire de quirófano, variabilidad en la limpieza del artroscopio, en el taladro utilizado, y en el manejo de materiales que llegan de las ortopedias y falta de trazabilidad de los implantes. Los cultivos micológicos de los materiales fueron negativos. La encuesta a instrumentadores confirmó los hallazgos de los relevamientos. La secuenciación de las cepas de Rhizopus demostró predominio de policlonalidad. CONCLUSIÓN: La OMM es una complicación posible luego de la RA-LCA en instituciones privadas de Argentina. No se identificó un origen único. Se detectaron múltiples prácticas que favorecen la contaminación de la cirugía con hongos filamentosos (manejo del aire de quirófano, del artroscopio, de los materiales provenientes de ortopedia, etc.). En base a estos hallazgos la Asociación Argentina de Artroscopía sugiere medidas de prevención. Implicancia clínica: Prevención de osteomielitis por Mucorales post- cirugía artroscópica para ligamento cruzado anterior. Tipo de estudio: Serie de casos. Nivel de Evidencia: IV.

OBJECTIVE: To describe the epidemiological investigation of Mucor osteomyelitis (MO) after arthroscopic repair of ACL (ARACL) in Argentina. MATERIAL Y METHODS: 1) Review of cases; 2) Survey of 3 institutions; 3) Mycological culture of surgical materials; 4) Survey of instrumentists; 5) Sequencing of Rhizopus strains and 6) Writing of recommendations. RESULTS: From 2005 to 2017, 40 cases of MO (Rhizopus sp.) Post AR-ACL were identified in immunocompetent patients from 12 jurisdictions of Argentina. The diagnosis was made by culture (22/31), and by pathology (9). The average age was 29 years. 84% of 38 cases were male. Thirteen orthopedics intervened. The implant was imported in 8/20 cases and national in 12. In the 3 institutions it was observed: inadequate handling of the operating room air, variability in the cleaning of the arthroscope, in the drill used, and in the handling of materials that come from the orthopedics and lack of traceability of the implants. The mycological cultures of the materials were negative. The survey of instrumentists confirmed the findings of the surveys. The sequencing of Rhizopus strains showed a predominance of polyclonality. CONCLUSION: MO is a possible complication after AR-ACL in private institutions in Argentina. A unique origin was not identified. Multiple practices that favor the contamination of surgery with filamentous fungi (handling of operating room air, arthroscope, materials from orthopedics, etc.) were detected. Based on these findings, the Argentine Association of Arthroscopy suggests prevention measures. Clinical relevance: Prevention of Mucor osteomyelitis after arthroscopic surgery for anterior cruciate ligament. Type study: Cases series. Level of evidence: IV.

[Recommendations for prevention of surgical site infection in adult elective arthroplasty]. / Recomendaciones para la prevención de infecciones asociadas a artoplastia electiva en adultos.

Surgical site infections complicating orthopedic implant surgeries prolong hospital stay and increase risk of readmission, hospitalization costs and mortality. These recommendations are aimed at: (i) optimizing compliance and incorporating habits in all surgery phases by detecting risk factors for surgical site infections which are potentially correctable or modifiable; and (ii) optimizing preoperative antibiotic prophylaxis as well as intraoperative and postoperative care.

Recomendaciones para la prevención de infecciones asociadas a artoplastia electiva en adultos / Recommendations for prevention of surgical site infection in adult elective arthroplasty

Las infecciones del sitio quirúrgico que complican las cirugías ortopédicas con implante prolongan la estadía hospitalaria y aumentan tanto el riesgo de readmisión como el costo de la internación y la mortalidad. Las presentes recomendaciones están dirigidas a: (i) optimizar el cumplimiento de normas y la incorporación de hábitos en cada una de las fases de la cirugía, detectando factores de riesgo para infecciones del sitio quirúrgico potencialmente corregibles o modificables; y (ii) adecuar la profilaxis antibiótica preoperatoria y el cuidado intra y postoperatorio.

Surgical site infections complicating orthopedic implant surgeries prolong hospital stay and increase risk of readmission, hospitalization costs and mortality. These recommendations are aimed at: (i) optimizing compliance and incorporating habits in all surgery phases by detecting risk factors for surgical site infections which are potentially correctable or modifiable; and (ii) optimizing preoperative antibiotic prophylaxis as well as intraoperative and postoperative care.

The roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus.

We investigated the roles of IFN regulatory factor (IRF)-3 and IRF-7 in innate antiviral immunity against dengue virus (DENV). Double-deficient Irf-3(-/-)7(-/-) mice infected with the DENV2 strain S221 possessed 1,000-150,000 fold higher levels of viral RNA than wild-type and single-deficient mice 24 h postinfection (hpi); however, they remained resistant to lethal infection. IFN-α/ß was induced similarly in wild-type and Irf-3(-/-) mice post-DENV infection, whereas in the Irf-7(-/-) and Irf-3(-/-)7(-/-) mice, significantly low levels of IFN-α/ß expression was observed within 24 hpi. IFN-stimulated gene induction was also delayed in Irf-3(-/-)7(-/-) mice relative to wild-type and single-deficient mice. In particular, Cxcl10 and Ifnα2 were rapidly induced independently of both IRF-3 and IRF-7 in the Irf-3(-/-)7(-/-) mice with DENV infection. Higher levels of serum IFN-γ, IL-6, CXCL10, IL-8, IL-12 p70, and TNF were also observed in Irf-3(-/-)7(-/-) mice 24 hpi, at which time point viral titers peaked and started to be cleared. Ab-mediated blockade experiments revealed that IFN-γ, CXCL10, and CXCR3 function to restrict DENV replication in Irf-3(-/-)7(-/-) mice. Additionally, the IFN-stimulated genes Cxcl10, Ifit1, Ifit3, and Mx2 can be induced via an IRF-3- and IRF-7-independent pathway that does not involve IFN-γ signaling for protection against DENV. Collectively, these results demonstrate that IRF-3 and IRF-7 are redundant, albeit IRF-7 plays a more important role than IRF-3 in inducing the initial IFN-α/ß response; only the combined actions of IRF-3 and IRF-7 are necessary for efficient control of early DENV infection; and the late, IRF-3- and IRF-7-independent pathway contributes to anti-DENV immunity.