A multi-mechanism approach reduces length of stay in the ICU for severe COVID-19 patients.

PURPOSE: COVID-19 pandemic has multifaceted presentations with rising evidence of immune-mediated mechanisms underplay. We sought to explore the outcomes of severe COVID-19 patients treated with a multi-mechanism approach (MMA) in addition to standard-of-care (SC) versus patients who only received SC treatment. MATERIALS AND METHODS: Data were collected retrospectively for patients admitted to the intensive care unit (ICU). This observational cohort study was performed at five institutions, 3 in the United States and 2 in Honduras. Patients were stratified for MMA vs. SC treatment during ICU stay. MMA treatment consists of widely available medications started immediately upon hospitalization. These interventions target immunomodulation, anticoagulation, viral suppression, and oxygenation. Primary outcomes included in-hospital mortality and length of stay (LOS) for the index hospitalization and were measured using logistic regression. RESULTS: Of 86 patients admitted, 65 (76%) who had severe COVID-19 were included in the study; 30 (46%) patients were in SC group, compared with 35 (54%) patients treated with MMA group. Twelve (40%) patients in the SC group died, compared with 5 (14%) in the MMA group (p-value = 0.01, Chi squared test). After adjustment for gender, age, treatment group, Q-SOFA score, the MMA group had a mean length of stay 8.15 days, when compared with SC group with 13.55 days. ICU length of stay was reduced by a mean of 5.4 days (adjusted for a mean age of 54 years, p-value 0.03) and up to 9 days (unadjusted for mean age), with no significant reduction in overall adjusted mortality rate, where the strongest predictor of mortality was the use of mechanical ventilation. CONCLUSION: The finding that MMA decreases the average ICU length of stay by 5.4 days and up to 9 days in older patients suggests that implementation of this treatment protocol could allow a healthcare system to manage 60% more COVID-19 patients with the same number of ICU beds.

Sensitisation to mitoxantrone-induced apoptosis by the oncolytic adenovirus Ad∆∆ through Bcl-2-dependent attenuation of autophagy.

Anti-apoptotic Bcl-2 is frequently activated in human malignant cells to promote cell survival and inhibit cell death. Replication-selective oncolytic adenoviruses deleted in the functional Bcl-2 homologue E1B19K potently synergise with apoptosis-inducing chemotherapeutic drugs, including mitoxantrone for prostate cancer. Here, we demonstrate that our previously generated oncolytic mutant Ad∆∆ (E1B19K- and E1ACR2-deleted) caused potent synergistic apoptotic cell death in both drug-sensitive 22Rv1, and drug-insensitive PC3 and PC3M prostate cancer cells. The synergistic cell killing was dependent on Bcl-2 expression and was prevented by Bcl-2 knockdown, which led to activation of the autophagy pathway. Mitoxantrone-induced autophagy, which was decreased in combination with Ad∆∆-infection resulting in increased apoptosis. Expression of the viral E1A12S protein alone mimicked the synergistic effects with Ad∆∆ in combination with mitoxantrone while intact wild-type virus (Ad5) had no effect. Early and late-stage inhibition of autophagy by Atg7 knockdown and chloroquine respectively, promoted apoptotic cell killing with mitoxantrone similar to Ad∆∆. These findings revealed currently unexplored actions of E1B19K-deleted oncolytic adenoviruses and the central role of Bcl-2 in the synergistic cell killing. This study suggests that cancers with functional Bcl-2 expression may be selectively re-sensitised to drugs by Ad∆∆.

Non-Coding RNAs are Differentially Expressed by Nocardia brasiliensis in Vitro and in Experimental Actinomycetoma.

INTRODUCTION: Nocardia spp. are common soil-inhabiting bacteria that frequently infect humans through traumatic injuries or inhalation routes and cause infections, such as actinomycetoma and nocardiosis, respectively. Nocardia brasiliensis is the main aetiological agent of actinomycetoma in various countries. Many bacterial non-coding RNAs are regulators of genes associated with virulence factors. OBJECTIVE: The aim of this work was to identify non-coding RNAs (ncRNAs) expressed during infection conditions and in free-living form (in vitro) in Nocardia brasiliensis. METHODS AND RESULT: The N. brasiliensis transcriptome (predominately < 200 nucleotides) was determined by RNA next-generation sequencing in both conditions. A total of seventy ncRNAs were identified in both conditions. Among these ncRNAs, 18 were differentially expressed, 12 were located within intergenic regions, and 2 were encoded as antisense of 2 different genes. Finally, 10 of these ncRNAs were studied by rapid amplification of cDNA ends and/or quantitative reverse transcription polymerase chain reaction. Interestingly, 3 transcripts corresponded to tRNA-derived fragments (tRNAsCys, Met, Thr), and one transcript was overlapped between an intergenic region and the 5´end of the 23S rRNA. Expression of these last four transcripts was increased during N. brasiliensis infection compared with the in vitro conditions. CONCLUSION: The results of this work suggest a possible role for these transcripts in the regulation of virulence genes in actinomycetoma pathogenesis.

Adenovirus-mediated sensitization to the cytotoxic drugs docetaxel and mitoxantrone is dependent on regulatory domains in the E1ACR1 gene-region.

Oncolytic adenoviruses have shown promising efficacy in clinical trials targeting prostate cancers that frequently develop resistance to all current therapies. The replication-selective mutants AdΔΔ and dl922-947, defective in pRb-binding, have been demonstrated to synergise with the current standard of care, mitoxantrone and docetaxel, in prostate cancer models. While expression of the early viral E1A gene is essential for the enhanced cell killing, the specific E1A-regions required for the effects are unknown. Here, we demonstrate that replicating mutants deleted in small E1A-domains, binding pRb (dl1108), p300/CBP (dl1104) and p400/TRRAP or p21 (dl1102) sensitize human prostate cancer cells (PC-3, DU145, 22Rv1) to mitoxantrone and docetaxel. Through generation of non-replicating mutants, we demonstrate that the small E1A12S protein is sufficient to potently sensitize all prostate cancer cells to the drugs even in the absence of viral replication and the E1A transactivating domain, conserved region (CR) 3. Furthermore, the p300/CBP-binding domain in E1ACR1 is essential for drug-sensitisation in the absence (AdE1A1104) but not in the presence of the E1ACR3 (dl1104) domain. AdE1A1104 also failed to increase apoptosis and accumulation of cells in G2/M. All E1AΔCR2 mutants (AdE1A1108, dl922-947) and AdE1A1102 or dl1102 enhance cell killing to the same degree as wild type virus. In PC-3 xenografts in vivo the dl1102 mutant significantly prolongs time to tumor progression that is further enhanced in combination with docetaxel. Neither dl1102 nor dl1104 replicates in normal human epithelial cells (NHBE). These findings suggest that additional E1A-deletions might be included when developing more potent replication-selective oncolytic viruses, such as the AdΔCR2-mutants, to further enhance potency through synergistic cell killing in combination with current chemotherapeutics.

Tumor de pancoast presentación de un caso / Pancoast´s tumor case presentation

Introducción: El Tumor de Pancoast se produce por crecimiento local de un tumor del vértice pulmonar que penetra fácilmente en el canal neural y destruye las raíces nerviosas octava cervical y primera y segunda torácicas. Su causa más frecuente es el cáncer de pulmón. Objetivo: Al presentar este caso, nuestro objetivo es mostrar de forma ilustrativa una de las formas neurológicas de presentación del cáncer de pulmón y señalar una vez más cómo este tipo de paciente casi siempre acude por Ortopedia y rara vez por Neumología o Medicina Interna. Presentación del caso: Se presentó una paciente que aquejó primeramente dolor en hombro derecho, acude al ortopédico y al reumatólogo, este último al verle las manos (uñas en vidrio de reloj y dedos hipocráticos), la remite a Neumología, se realiza radiografía de tórax, se ingresa en Medicina Interna, donde se le practica una serie de estudios, incluida cirugía de mínimo acceso por el Grupo de Tórax. Conclusiones: El estudio histológico corroboró el diagnóstico de carcinoma bronquial epidermoide, así como demostró cómo estos casos entran por Ortopedia, lo cual atrasa el accionar médico. Motivación: Tuvimos a bien presentar este caso, que ilustra cómo los pacientes con esta patología, en muchas ocasiones, entran por Ortopedia, lo cual demora el diagnóstico y, por ende, la conducta.

Introduction: Pancoast tumor refers to a tumor located in the vertex of the lung. It can easily penetrate the neural channel destroying the eight cervical and first and second thoracic nervous roots. The most frequent cause of this tumor is lung cancer. Objective: To present this case, we wants to show a neurological presentation form of lung cancer and demostrate again that this type of patient often not consult in Neumology or Internal Medicine inicially. Case presentation: Female patient complaining of pain in the right shoulder was seen in the orthopedic and rheumatology office. On Physical exam the rheumatologists detects watch glass nails and Hippocratic fingers and refers the patient to the pneumatological department. A decrease in the breath sounds of the right vertex was detected. An x-ray of the thorax was taken and the patient was admitted in the internal medicine ward. Studies carried out included minimal access thoracic surgery. Conclusions: Histologically the diagnosis was an epidermoid bronchial carcinoma, also demostrate that this type of patient often not consult in Neumology or Internal Medicine inicially. Motivation: This case shows how often patients with this pathology consult by orthopedic, retarding diagnosis and the treatment.

Postpartum hemorrhage prevention: a case study in northern rural Honduras.

Postpartum hemorrhage (PPH) is the leading cause of maternal mortality globally. Safe Motherhood policies have been directed towards the reduction of PPH by recommending active management of third-stage labor as the standard of care. One component of active management involves routine use of a uterotonic agent within 1 minute of the delivery of the baby. A case study at Clínica Materno-Infantil, a free-standing public birth center in Honduras, is presented, focusing on methods to reduce PPH. The nursing staff was trained to estimate blood loss and in methods to manage PPH, including elements of active management of the third stage of labor. Medical records were reviewed and an analysis of PPH management compared to estimated blood loss (EBL) was conducted. There was no significant correlation between PPH management techniques and EBL (r = .060; P = .368). There was a statistically significant (P < .001) correlation between oxytocin administration and lower EBL (r = -.232), indicating that there was less blood loss when oxytocin was administered. At Clínica Materno-Infantil, routine use of a uterotonic agent appears beneficial and further implementation of active management of the third stage of labor appears warranted.

Neurorretinite associada ao herpes zoster em paciente imunocompetente / Unilateral occlusive neuro-retinitis associated with herpes zoster

Os autores apresentam uma ocorrência rara de herpes zoster aftálmico associado a neurorretinite vaso-oclusiva unilateral em paciente imunocompetente e argumentam que a participaçäo viral na etiopatogênese saudáveis, deve ser bem mais frequente do que hoje supomos. Os possíveis macenismos imunopatológicos implicados no caso foram discutidos e a litaratura foi revista.