There is no effective therapy for the severe acute respiratory syndrome by coronavirus 2 (SARS-CoV2) responsible for the Coronavirus disease 2019 (Covid-19). To date, dexamethasone has shown a ...decrease in mortality in patients who require oxygen, especially those with invasive mechanical ventilation. However, it is unknown if another corticosteroid can be used, the optimal dose and its duration, to achieve a better clinical outcome. The objective of the study was to compare the differences in clinical outcome and laboratory results in hospitalized patients with severe SARS-CoV2 Pneumonia treated with dexamethasone at 6 mg doses versus patients treated with high-dose methylprednisolone. Ambispective cohort study with survival analysis of 216 patients diagnosed with severe Covid-19 pneumonia confirmed by polymerase chain reaction for SARS-CoV2 by Berlin protocol, who were hospitalized in a high-complexity clinic in Medellín, Colombia. The patients should also have supplementary oxygen and radiological confirmation of Pneumonia by chest tomography. Sample size was not calculated since the total population that met the inclusion criteria was evaluated. 111 patients were treated with the institutional protocol with intravenous dexamethasone 6 mg QD for seven to 10 days if they required oxygen. Since September 15, 2020, the hospitalization protocol of the clinic was modified by the Infectious Diseases and Pulmonology service, recommending a high dose of methylprednisolone of 250 to 500 mg every day for three days with a subsequent change to oral prednisone 50 mg every day for 14 days. The protocol was not applied in the intensive care unit, where dexamethasone continued to be administered. The clinical outcome and differences in laboratory results of the patients who received dexamethasone vs. the prospective cohort that received methylprednisolone from September 15 to October 31, 2020, were evaluated. Follow-up was carried out by outpatient consultation one month after discharge or by telephone, inquiring about readmission or living-dead status. 216 patients had Covid-19 pneumonia documented by ground-glass imaging and alveolar pressure / inspired oxygen fraction (PaFi) less than 300. 111 patients received dexamethasone (DXM) and 105 received methylprednisolone (MTP). Patients in the DXM group evolved to severe ARDS in a higher proportion (26.1% vs 17.1% than the MTP group). Upon completion 4 days of treatment with parenteral corticosteroid, laboratory markers of severity decreased significantly in the group that received MTP, CRP 2.85 (2.3-3.8) vs 7.2 (5.4-9.8), (p-value < 0.0001), D-dimer 691 (612-847) vs 1083 (740-1565) (p-value = 0.04) and DHL 273 (244-289) vs 355 (270.6-422) (p-value = 0.01). After starting the corticosteroid, transfer to the intensive care unit (4.8% vs. 14.4%) and mortality (9,5% vs. 17.1%) was lower in the group that received MTP. Recovery time was shorter in patients treated with MTP, three days (3-4) vs. DXM 6 days (5-8) (p-value < 0.0001). At 30-day follow-up, 88 (92.6%) were alive in MTP vs 58 (63.1%) of those who received dexamethasone. In this study, the treatment of severe Covid-19 Pneumonia with high-dose methylprednisolone for three days followed by oral prednisone for 14 days, compared with 6 mg dexamethasone for 7 to 10 days, statistically significantly decreased the recovery time, the need for transfer to intensive care and the severity markers C-reactive protein (CRP), D-dimer and LDH. Randomized controlled studies with methylprednisolone are required to corroborate its effect, and studies in a population hospitalized in intensive care wards.
Osteomyelitis is a heterogeneous infection with regard to etiology and treatment, and currently no single management protocol exists. Management of the condition is typically an interdisciplinary ...approach between orthopedics and infectious disease; however, the orthopedist is often the person who manages treatment. The aim of the study was to determine differences in the outcome of osteomyelitis according to its treating specialty and to identify factors associated with the recurrence of the disease. An ambispective cohort study of 129 patients with osteomyelitis was conducted and the proportions for qualitative variables and central tendency and dispersion measures for quantitative variables were calculated; the latter were tested for normality using the Shapiro-Wilk test. A bivariate analysis was conducted with measures of association based on the chi square test and crude relative risk. A logistic regression model was applied and statistical significance was set at p < 0.05, including the model of relevant clinical variables that fit the Hosmer-Lemeshow test. We found that 70% of patients were treated either by orthopedics or infectious disease. Patients who were treated by an orthopedist alone presented a greater risk of relapse or reinfection (RR = 4.6; 95% CI 2.3;8.9). Risk factors of osteomyelitis recurrence as determined in the regression model included the following: age of 57 years or older (RR = 1.3; 95% 0.3;5.2), long bones (RR = 1.9; 95% CI 0.5;7.1), fracture (RR = 5.0; 95% CI 0.4;51.4), monotherapy (RR = 3.0; 95% CI 0.6;14.5), receiving less than 4 weeks of antibiotics (RR = 1.5; 95% CI 0.2;10.1), inadequate treatment (RR = 3.1; 95% CI 0.4;20.1), and receiving orthopedics treatment (RR = 5.5; 95% CI 1.6;18.2). Most patients evaluated jointly by orthopedics and infectious disease received adequate treatment for osteomyelitis and had fewer relapses.
The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe ...pathologies, including microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virus-induced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.
Postharvest losses along food supply chains have far reaching consequences for the environment and affect the social and economic conditions of food supply chain participants, especially of those in ...developing countries. This paper explores the structural inefficiencies that lead to postharvest losses and analyses how innovative collaboration could lead to more sustainable food supply chains (FSCs) by reducing those inefficiencies. Innovative collaboration is defined as the improvement or creation of inter-organizational relationships through which FSC participants can exchange information, align incentives, engage in effective partnerships and improve their use of technology. This research distinguishes two research questions: First, how do FSC participants interact and which structural inefficiencies leading to postharvest losses can be identified in global food supply chains? And second, what are the main drivers and barriers of FSC participants to engage in innovative collaboration to reduce postharvest losses within global food supply chains? Two case studies explore the supply chain of avocados, especially due to their high susceptibility to postharvest losses, and focus on avocados from Mexico and Colombia imported into the Netherlands. Data was collected through semi-structured interviews with avocado importers, producers/exporters, packers and growers' associations, governmental organizations, and knowledge institutions. Informal interviews were held with producers and suppliers of other agricultural products traded globally. Using the software NVIVO, the collected data from interviews, documents and literature was structured allowing patterns and categories in the data to be discerned. The contribution of this paper is a typology of structural inefficiencies in global food supply chains, which provides insight into the social drivers of postharvest losses. Three categories of structural inefficiencies leading (directly or indirectly) to postharvest losses were identified: (1) corporate inefficiencies, (2) cognitive and affective inefficiencies, and (3) tangible inefficiencies. Effective partnerships were found to be the backbone of innovative collaboration, and the largest contributor to the reduction of postharvest losses, functioning as catalysts of trust, communication, cooperation and innovation, in addition to contributing to reduce structural inefficiencies along food supply chains.
•Innovative collaboration contributes positively to the sustainability of food supply chains.•Corporate, cognitive & affective, and tangible organizational inefficiencies are found.•Effective partnerships appear to be the backbone of innovative collaboration.•Effective partnerships are catalysts of trust, communication, cooperation and innovation.
Productive herpesvirus infection requires a profound, time-controlled remodeling of the viral transcriptome and proteome. To gain insights into the genomic architecture and gene expression control in ...Kaposi's sarcoma-associated herpesvirus (KSHV), we performed a systematic genome-wide survey of viral transcriptional and translational activity throughout the lytic cycle. Using mRNA-sequencing and ribosome profiling, we found that transcripts encoding lytic genes are promptly bound by ribosomes upon lytic reactivation, suggesting their regulation is mainly transcriptional. Our approach also uncovered new genomic features such as ribosome occupancy of viral non-coding RNAs, numerous upstream and small open reading frames (ORFs), and unusual strategies to expand the virus coding repertoire that include alternative splicing, dynamic viral mRNA editing, and the use of alternative translation initiation codons. Furthermore, we provide a refined and expanded annotation of transcription start sites, polyadenylation sites, splice junctions, and initiation/termination codons of known and new viral features in the KSHV genomic space which we have termed KSHV 2.0. Our results represent a comprehensive genome-scale image of gene regulation during lytic KSHV infection that substantially expands our understanding of the genomic architecture and coding capacity of the virus.
Chagas disease by Trypanosoma cruzi (T. cruzi) infection is a leading cause of myocarditis worldwide. Chagas cardiomyopathy is presented with a wide variety of conduction abnormalities including ...arrhythmias, first- and second-degree atrioventricular blockade, left ventricular systolic dysfunction and some cases heart failure leading to the death. Currently, there are no effective treatments available against advanced Chagas disease. With the advance in the development of novel therapies, it is important to utilize an animal model that can effectively replicate the diverse stages of Chagas disease, including chronic asymptomatic and symptomatic infection, that are akin to those observed in humans. Therefore, to characterize the cardiac alterations during the evolution of the infection, we evaluated the progression of cardiomyopathy caused by T. cruzi H1 infection in both BALB/c and ICR mouse models by performing electrocardiogram (ECG) studies in unanesthetized mice every month until 210 days post-infection (dpi). In the late chronic phase of infection, we also performed echocardiogram (ECHO) studies to further assess cardiac function. In conclusion, we demonstrated that ICR mice were more susceptible to cardiac alterations compared to BALB/c mice and both mouse strains are suitable experimental models to study chronic T. cruzi infection and novel treatments.
Protein synthesis is tightly regulated and alterations to translation are characteristic of many cancers.Translation regulation is largely exerted at initiation through the eukaryotic translation ...initiation factor 4 F (eIF4F). eIF4F is pivotal for oncogenic signaling as it integrates mitogenic signals to amplify production of pro-growth and pro-survival factors. Convergence of these signals on eIF4F positions this factor as a gatekeeper of malignant fate. While the oncogenic properties of eIF4F have been characterized, genome-wide evaluation of eIF4F translational output is incomplete yet critical for developing novel translation-targeted therapies.
To understand the impact of eIF4F on malignancy, we utilized a genome-wide ribosome profiling approach to identify eIF4F-driven mRNAs in MDA-MB-231 breast cancer cells. Using Silvestrol, a selective eIF4A inhibitor, we identify 284 genes that rely on eIF4A for efficient translation. Our screen confirmed several known eIF4F-dependent genes and identified many unrecognized targets of translation regulation. We show that 5′UTR complexity determines Silvestrol-sensitivity and altering 5′UTR structure modifies translational output. We highlight physiological implications of eIF4A inhibition, providing mechanistic insight into eIF4F pro-oncogenic activity.
Here we describe the transcriptome-wide consequence of eIF4A inhibition in malignant cells, define mRNA features that confer eIF4A dependence, and provide genetic support for Silvestrol’s anti-oncogenic properties. Importantly, our results show that eIF4A inhibition alters translation of an mRNA subset distinct from those affected by mTOR-mediated eIF4E inhibition. These results have significant implications for therapeutically targeting translation and underscore a dynamic role for eIF4F in remodeling the proteome toward malignancy.
Introduction: Residents of rural communities face unique geographic challenges in accessing food and healthcare, which may contribute to poor diet quality and increase the risk of diabetes. We ...compared Alternative Healthy Eating Index (aHEI) scores among residents with and without a history of diabetes from a rural county in New York known to have poor health outcomes.
Methods: In 2021, we performed a cross-sectional survey and validated food frequency questionnaire (FFQ) among residents in Sullivan County, NY, a rural county that has the second-worst health outcomes among all counties in New York. We compared overall total aHEI scores and the 11 component scores of the aHEI between 155 rural participants with diabetes and 961 without a history of diagnosed diabetes.
Results: We found statistically lower healthy eating scores among rural study participants with diabetes compared to those without diabetes (p=0.01). While the overall magnitude of this difference in total aHEI was not large (54.1 versus 56.7), our analysis of aHEI component scores found that study participants with diabetes had statistically worse eating habits for nuts/legumes, red meat, trans-fats, and alcoholic drinks (p-values of 0.036, 0.001, 0.002 and 0.002 respectively). Notably, one category where rural residents with diabetes had better eating habits than those without diabetes was for sugary beverages/juice.
Discussion: Our study found worse eating habits among rural residents with diabetes compared to those without diabetes in a rural county with particularly poor health outcomes. Additionally, this study highlights the potential need for accessible nutritional education in high-risk rural communities. While study participants with diabetes on average, consumed fewer sugary beverages and juice, more attention may need to be focused on reducing other food categories that might increase the risk of poor glycemic control.
Disclosure
M.Rony: None. C.Quintero arias: None. N.N.Wise: None. A.Prabu: None. K.Doran: None. R.Anthopolos: None. B.Elbel: None. L.Thorpe: None. D.C.Lee: None.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124400)
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