Objective This study aims to investigate maternal, fetal, and perinatal outcomes during the 2018–2020 Ebola outbreak in Democratic Republic of Congo (DRC). Methods Mortality between pregnant and non-pregnant women of reproductive age admitted to DRC’s Mangina Ebola treatment center (ETC) were compared using propensity score matching. Propensity scores were calculated using age, initial Ebola viral load, Ebola vaccination status, and investigational therapeutic. Additionally, fetal and perinatal outcomes of pregnancies were also described. Results Twenty-seven pregnant women were admitted to the Mangina ETC during December 2018—January 2020 among 162 women of childbearing age. We found no evidence of increase mortality among pregnant women compared to non-pregnant women (relative risk:1.0, 95%CI: 0.58–1.72). Among surviving mothers, pregnancy outcomes were poor with at least 58% (11/19) experiencing loss of pregnancy while 16% (3/19) were discharged with viable pregnancy. Two mothers with viable pregnancies were vaccinated, and all received investigational therapeutics. Two live births occurred, with one infant surviving after the infant and mother received an investigational post-exposure prophylaxis and Ebola therapeutic respectively. Conclusions Pregnancy was not associated with increased mortality among women with EVD in the Mangina ETC. Fetal and perinatal outcomes remained poor in pregnancies complicated by EVD, though novel therapeutics may have potential for improving these outcomes.
Background Ebola Virus Disease (EVD) causes high case fatality rates (CFRs) in young children, yet there are limited data focusing on predicting mortality in pediatric patients. Here we present machine learning-derived prognostic models to predict clinical outcomes in children infected with Ebola virus. Methods Using retrospective data from the Ebola Data Platform, we investigated children with EVD from the West African EVD outbreak in 2014–2016. Elastic net regularization was used to create a prognostic model for EVD mortality. In addition to external validation with data from the 2018–2020 EVD epidemic in the Democratic Republic of the Congo (DRC), we updated the model using selected serum biomarkers. Findings Pediatric EVD mortality was significantly associated with younger age, lower PCR cycle threshold (Ct) values, unexplained bleeding, respiratory distress, bone/muscle pain, anorexia, dysphagia, and diarrhea. These variables were combined to develop the newly described EVD Prognosis in Children (EPiC) predictive model. The area under the receiver operating characteristic curve (AUC) for EPiC was 0.77 (95% CI: 0.74–0.81) in the West Africa derivation dataset and 0.76 (95% CI: 0.64–0.88) in the DRC validation dataset. Updating the model with peak aspartate aminotransferase (AST) or creatinine kinase (CK) measured within the first 48 hours after admission increased the AUC to 0.90 (0.77–1.00) and 0.87 (0.74–1.00), respectively. Conclusion The novel EPiC prognostic model that incorporates clinical information and commonly used biochemical tests, such as AST and CK, can be used to predict mortality in children with EVD.
Human pheochromocytoma tumor cells express glucagon receptors, and bolus i.v. glucagon injection rapidly increases plasma epinephrine levels, suggesting that glucagon can directly stimulate adrenomedullary secretion. In this study, we tested whether the catecholamine secretory response to glucagon was present in bovine chromaffin cells or exclusive to the tumor cells.Adrenomedullary cells were cultured in 24-well plates (10(6) cells per well). After 48-72 hours, wells were incubated for 1-20 minutes with (1) incubation medium (control), (2) catecholamine secretagogues (nicotine or potassium ion), or (3) glucagon (10(-8) to 10(-5) M). After incubation, catecholamine contents in medium and cells were assayed by high-pressure liquid chromatography with electrochemical detection. Fractional release rates of epinephrine, norepinephrine, and dopamine were calculated and compared to controls. Reverse-transcriptase PCR was performed to compare expression of mRNA of the glucagon receptor in chromaffin cells and pheochromocytoma cells.Nicotine and potassium evoked time-dependent release of epinephrine, norepinephrine, and dopamine. Glucagon did not affect catecholamine secretion at any concentration. Reverse-transcriptase PCR failed to detect mRNA for glucagon receptor in bovine adrenomedullary cells, but did detect it in human pheochromocytoma cells.In contrast to pheochromocytoma tumor cells, bovine adrenomedullary chromaffin cells do not express the glucagon receptor, and therefore do not secrete catecholamines in response to glucagon.
To promote equity and better ensure outbreak control in low-resource areas, International Medical Corps surveyed people in countries around the world to better understand vaccine hesitancy.
There is limited information available describing the disease burden of primary Sjögren9s Syndrome (pSS).
Objectives
This retrospective cohort study aimed to provide a descriptive analysis of the clinical characteristics and disease burden of patients with pSS and describe their healthcare resource use and associated costs.
Methods
This retrospective cohort study (HO-15–16077) was conducted in the US Truven MarketScan® Commercial database. This database reports descriptive data from employees and their families, as covered by employer-sponsored private health insurance. The primary cohort comprised patients with ≥1 diagnosis of sicca syndrome prior to 1 January 2013, and continued enrolment for ≥24 months (1 January 2012 to 31 December 2013). Patients with any conditions mimicking sicca symptoms not due to SS were excluded, as were those with connective tissue disease that may suggest secondary SS. The 1:1 matched comparator population comprised subjects without a previous diagnosis of sicca syndrome (sicca-free). The primary objective was to describe the clinical characteristics and demographics of patients with pSS, including the proportion of patients with glandular versus extra-glandular disease. The secondary objective was to describe their healthcare costs and resource utilisation compared with sicca-free subjects.
Results
There were 12,717 eligible patients in the primary cohort: the majority (86%) were female and the mean age was 51 years. Overall, 61% of patients had claims associated with extra-glandular disease manifestations. These patients experienced a higher disease burden with 41% reporting pain, fatigue and/or insomnia, compared with 12% of patients with glandular disease only who reported pain, fatigue and/or insomnia. Patients in the primary cohort incurred greater annual healthcare service costs (1.6 times greater for all causes and 1.5 times greater for pSS-related causes) and healthcare resource utilisation compared with the sicca-free comparator cohort. The largest difference in SS-related resource utilisation was in the number of office visits (primary cohort: 5.8 visits per patient; comparator cohort: 4.7 visits per patient). Patients with extra-glandular disease also incurred greater average annual costs and used more healthcare resources than patients with glandular disease only.
Conclusions
Despite treatment, patients with pSS still experience a high disease burden. Here we have provided novel insights into the higher treatment cost and increased healthcare utilisation burden of pSS compared with the sicca-free cohort, in particular for patients with extra-glandular disease manifestations.
Acknowledgements
Study funded by GSK. Jennie Frain, PhD, Fishawack Indicia Ltd, UK, provided editorial assistance funded by GSK
Disclosure of Interest
S. Perera Shareholder of: GSK, Employee of: GSK, L. Ma Shareholder of: GSK, Employee of: GSK, R. Punwaney Shareholder of: GSK, Employee of: GSK, S. Ramachandran Shareholder of: GSK, Employee of: GSK
Mitochondrial research has influenced concepts in anthropology, human physiology and pathophysiology. We present here direct evidence that human recombinant viruses can localize in mitochondria to disrupt their integrity. This finding, while opening new perspectives in viral gene therapy, may provide new insights into the pathogenesis, prevention and treatment of viral diseases. In addition, it may advance the current understanding of cell evolution.
Recombinant adenoviruses (rAd) have been widely used as gene transfer vectors both in the laboratory and in human clinical trials. In the present study, we investigated the effects of adenoviral-mediated gene transfer in primary bovine adrenal chromaffin cells (BACC) and a murine pheochromocytoma cell line (MPC). Cells were infected with one of three nonreplicating E1/E3-deleted (E1(-)/E3(-)) rAd vectors: Ad.GFP, expressing a green fluorescent protein (GFP); Ad.null, expressing no transgene; or Ad.C2.TK, expressing the herpes simplex virus-1 thymidine kinase gene (TK). Forty-eight hours after exposure to Ad.GFP, the percentage of GFP-expressing BACC ranged from 23.5-97% in a dose-dependent manner and similarly from 1.06-84.4% in the MPC, indicating that adrenomedullary cells are a potentially valuable target for adenoviral-mediated gene transfer. Ultrastructural analysis, however, revealed profound changes in the nucleus and mitochondria of cells infected with rAd. Furthermore, infection of BACC with Ad.null was accompanied by a time- and dose-dependent decrease in cell survival due to the vector alone. Specific whole-cell norepinephrine uptake was also decreased in a time- and dose-dependent fashion in BACC. Infection of MPC cells with the Ad.C2.TK vector sensitized them to the cytotoxic effect of the antiviral drug ganciclovir, in direct proportion to the fraction of cells infected with the virus. We conclude that rAd may alter the structural and functional integrity of adrenomedullary cells, potentially interfering with the normal stress response. At the same time, in light of their ability to effectively deliver and express genes in pheochromocytoma cells, they may be applicable to the gene therapy of adrenomedullary tumors.
[131I]meta-iodobenzylguanidine ([131I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [123I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [3H]norepinephrine, [123I]MIBG, and [18F]fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [3H]norepinephrine, [123I]MIBG, and [18F]fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [18F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1±3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9±0.6%; P<0.001). Biodistribution analysis after inhibitors treatment confirmed the PET results. The uptake of [123I]MIBG was significantly increased in liver metastases 9.5±1.1% compared to 3.19±0.4% in untreated control liver metastases (P<0.05). We found that HDAC inhibitors caused an increase in the amount of norepinephrine transporter expressed in tumors. HDAC inhibitors may enhance the therapeutic efficacy of [131I]MIBG treatment in patients with advanced malignant pheochromocytoma and paraganglioma.
We compared functional imaging modalities including PET with 6-(18)F-fluorodopamine ((18)F-DA) with (123)I-metaiodobenzylguanidine ((123)I-MIBG) and somatostatin receptor scintigraphy (SRS) with (111)In-pentetreotide in nonmetastatic and metastatic pheochromocytoma (PHEO).We studied 25 men and 28 women (mean age +/- SD, 44.2 +/- 14.2 y) with biochemically proven nonmetastatic (n = 17) or metastatic (n = 36) PHEO. Evaluation included anatomic imaging with CT or MRI and functional imaging that included at least 2 nuclear medicine modalities: (18)F-DA PET, (123)I-MIBG scintigraphy, or SRS. Sensitivity of functional imaging versus anatomic imaging was assessed on a per-patient and a per-region basis.For this available cohort, on a per-patient basis overall sensitivity (combined for nonmetastatic and metastatic PHEO) was 90.2% for (18)F-DA PET, 76.0% for (123)I-MIBG scintigraphy, and 22.0% for SRS. On a per-region basis, overall sensitivity was 75.4% for (18)F-DA PET, 63.4% for (123)I-MIBG scintigraphy, and 64.0% for SRS.If available, (18)F-DA PET should be used in the evaluation of PHEO, because it is more sensitive than (123)I-MIBG scintigraphy or SRS. If (18)F-DA PET is not available, (123)I-MIBG scintigraphy (for nonmetastatic or adrenal PHEO) and SRS (for metastatic PHEO) should be the first alternative imaging methods to be used.
