Severe Life-threatening Complications Research Articles

Expression profiling meta-analysis of ACE2 and TMPRSS2, the putative anti-inflammatory receptor and priming protease of SARS-CoV-2 in human cells, and identification of putative modulators

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in hundreds of thousands of deaths worldwide. While the majority of people with COVID-19 won't require hospitalization, those who do may experience severe life-threatening complications, including acute respiratory distress syndrome. SARS-CoV-2 infects human cells by binding to the cellular surface protein angiotensin-converting enzyme 2 (ACE2); in addition, the cellular transmembrane serine protease 2 (TMPRSS2) is needed for priming of the spike (S) protein of the virus. Virus entry may also depend on the activity of the endosomal/lysosomal cysteine proteases cathepsin B, L (CTSB, CTSL) although their activity is likely dispensable. Given that the uncertainty of how COVID-19 kills, hampers doctors' ability to choose treatments the need for a deep understanding of COVID-19 biology is urgent. Herein, we performed an expression profiling meta-analysis of ACE2, TMPRSS2 and CTSB/L genes (and proteins) in public repository databases and found that all are widely expressed in human tissues; also, the ACE2 and TMPRSS2 genes tend to be co-regulated. The ACE2 and TMPRSS genes expression is (among others) suppressed by TNF, and is induced by pro-inflammatory conditions including obesity, Barrett's esophagus, stomach infection by helicobacter pylori, diabetes, autoimmune diseases and oxidized LDL; by exercise, as well as by growth factors, viruses' infections, cigarette smoke, interferons and androgens. Regarding currently investigated therapies interferon-beta induced ACE2 gene expression in bronchial epithelial cells, while chloroquine tends to upregulate CTSB/L genes. Finally, we analyzed KEGG pathways modulated by ACE2, TMPRSS2 and CTSB/L and probed DrugBank for drugs that target modules of the affected pathways. Our data indicate possible novel high-risk groups for COVID-19; provide a rich resource for future investigations of its pathogenesis and highlight the therapeutic challenges we face.

Mitochondria, mitophagy, and metabolic disease: towards assembling the puzzle.

Dysregulation of the mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is an autosomal recessive inborn error of intermediary metabolism caused by the deficiency of methylmalonyl-CoA mutase (MMUT) — a mitochondrial enzyme that mediates the degradation of certain amino acids and lipids. The loss of MMUT activity triggers an accumulation of toxic endogenous metabolites causing severe organ dysfunctions and life-threatening complications. How MMUT deficiency instigates mitochondrial distress and tissue damage remains poorly understood. Using cell and animal-based models, we recently discovered that MMUT deficiency disables the PINK1-induced translocation of PRKN/Parkin to MMA-damaged mitochondria, impeding their delivery and subsequent dismantling by macroautophagy/autophagy-lysosome degradation systems (Luciani et al. Nat Commun. 11(1):970). This promotes an accumulation of damaged and/or dysfunctional mitochondria that spark epithelial distress and tissue damage. Using a systems biology approach based on drug-disease network perturbation modeling, we predicted targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient-derived kidney cells and ameliorates disease-relevant phenotypes in mmut-deficient zebrafish. These results unveil a link between primary MMUT deficiency, defective mitophagy, and cell distress, offering promising therapeutic avenues for MMA and other mitochondria-related diseases.

AB0567 CHARACTERIZATION OF PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY AND MYOCARDIAL INVOLVEMENT: A MONO-CENTRIC EXPERIENCE.

Background:Idiopathic inflammatory myopathies (IIM) are immune-mediated disorders of the skeletal muscle, with dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and immune-mediated necrotizing myopathy (IMNM) representing major subtypes. Beyond skeletal muscle, other organs may be affected and myocardial involvement may lead to severe life-threatening complications. The exact prevalence of myocardial involvement among IIM patients and its impact on other disease characteristics remain unclear.Objectives:To investigate the prevalence of myocarditis in patients affected by IIM in and to determine whether the presence and extent of myocardial involvement identify a distinct disease phenotype.Methods:42 longitudinally followed IIM patients were routinely screened for myocardial involvement during a median [IQR] follow-up time of 4.2 [2-8.5] years. Patients with secondary causes of myocardial dysfunction were not included. Patients were considered to have myocarditis in case of:i) abnormal elevation of both circulating troponin T and troponin I,ii) signs of myocardial inflammation or necrosis/fibrosis at cardiac MRI, oriii) positive myocardial tissue histology. Demographic, clinical and serologic features of patients with myocarditis were compared to those with no sign of myocardial involvement. Moreover, we determined whether the extent of myocardial involvement based on troponin levels predicts skeletal muscle disease severity.Results:57.1% (24 of 42) of patients had myocarditis. The frequency of myocardial dysfunction was similar among patients with DM, PM, IBM or IMNM and was not related to autoantibody positivity. Myocarditis was not associated with sex or ethnicity. Patients with or without myocarditis were similar in terms of age at disease onset and extra-muscular manifestations including dysphonia, dysphagia, arthralgias or arthritis, Raynaud phenomenon or interstitial lung disease. Independent of the IIM subtype, the presence of perimysial macrophages at skeletal muscle biopsy seems to protect from myocarditis development (p=0.04). Patients with myocarditis had higher median [IQR] levels of aldolase (10.9 [7.8-15.8] vs. 5.6 [4.9-8.6], p=0.014) and creatine kinase (1785 [966-5852] vs. 685 [168-2255], p=0.04) compared to patients with no myocardial dysfunction. Among patients with myocarditis, levels of troponin I negatively correlated with manual muscle testing 8 (MMT8) score (r=-1, p=0.01), strength in biceps (r=-0.95, p=0.014) and wrist extensors (r=-0.95, p=0.014) at last visit. Troponin T and troponin I titers were similar among patients with different IIM subtypes. C-reactive protein (p<0.04) but not erythrocyte sedimentation rate was found to predict myocardial involvement.Conclusion:Our findings suggest that myocarditis is a frequent occurrence among patients with IIM and should be routinely ruled out. A more severe skeletal muscle disease is associated with an increased likelihood of myocarditis development, presumably due to higher systemic disease activity or inefficient disease control. The extent of myocardial damage faithfully reflects the severity of skeletal muscle dysfunction.

Hypertension, renin–angiotensin–aldosterone system inhibition, and COVID-19

Hypertension, renin–angiotensin–aldosterone system inhibition, and COVID-19

Low lying gestation sac in early pregnancy-an algorithmic approach with ultrasound markers

The differential diagnosis of low lying gestational sac in ultrasound at early pregnancy scan varies from benign entities like cervical stage of miscarriage to morbid conditions like caesarean scar pregnancy and cervical pregnancy. Abnormal placental invasive pregnancies also manifest as low lying gestational sac at cervico-isthmic junction. Early diagnosis using simple ultrasound criteria can prevent severe life-threatening complications. Various clues on ultrasonography can easily differentiate between a caesarean scar pregnancy, cervical pregnancy, cervical stage of miscarriage or a low implanted sac which may be a precursor for morbidly adherent placenta. In this article we have reviewed the ultrasound markers in a case of inevitable abortion, a case of cervical pregnancy, 3 cases of caesarean scar pregnancy and 2 cases of morbidly adherent placenta. Comparison of anterior myometrial thickness in a low implantation of sac and caesarean scar pregnancy has been demonstrated. Sometimes a small cervical polyp can mimic a low lying gestation sac and the differential diagnosis with ultrasound has been discussed. Three dimensional ultrasound examinations for spatial location of the sac provide additional information for further management and aids in precise diagnosis. Though other investigations like MRI may also be beneficial in arriving at a diagnosis, its routine usage may be limited due to the cost and availability. Hence defining ultrasound markers in a low lying gestational sac helps in early diagnosis which can prevent fertility losses incurred due to inadvertent management

Surfactant proteins A and D: role in the pathogenesis of community-acquired pneumonia and possible predictive perspectives

Community-acquired pneumonia is one of the most common infectious diseases and remains one of the leading causes of death in this group of diseases. Studies of community-acquired pneumonia are extremely relevant for modern clinical practice. One of the important role in the pathogenesis of bacterial, viral, fungal invasion in the system of a human lung system belongs to the pulmonary surfactant, in particular, its proteins SP-A and SP-D. This article reviews the well-known mechanisms of important biological properties of immunomodulatory activity of the proteins SP-A and SP-D in response to microbial infection in the lungs. The mechanisms of participation of surfactant proteins SP-A and SP-D in the cascade of reactions that lead to severe life-threatening complications in community-acquired pneumonia are considered. The use of serum levels of surfactant proteins SP-A and SP-D can help finding new diagnostic and prognostic approaches in patients with community-acquired pneumonia.

ESOPHAGEAL STENTING FOR MALIGNANT STENOSIS (three-year outcomes)

OBJECTIVE of the study was to analyze the main problems and try to find the ways to improve the esophageal stenting for malignant stenosis with regard to our experience.METHODS AND MATERIALS. Palliative esophageal stenting for malignant dysphagia realized in 103 patients with observing all the patients till the fatal outcome.RESULTS. Early complications were observed in 9 patients (8.7 %) among which were: perforation of esophagus – 1 (0.97 %), minor bleeding – 2 (1.9 %), stent migration – 6 (5.8 %). Elimination of dysphagia as an immediate clinical effect was achieved in all of 103 patients (100 %) among all of early complications included. Delayed sequelae were found in 40 patients (38.8 %) among which were recurrent dysphagia because of tissue in-/overgrowth – 27 (26.2 %), stent migration – 2 (1.9 %), different kinds of esophageal fistulae – 5 (4.9 %), major bleeding – 6 (5.8 %). The most severe life-threatening complications developed at 109 days after stent placement. The mean survival rate was 131 days (from 12 till 546 days).CONCLUSION. Immediate clinical effect of stenting was achieved in 100 % of cases and delayed clinical effect was in 73.8 % of patients. Chemoradiotherapy conduces to increase the mean survival rate and, at the same time, to increase the most severe delayed life-threatening complications after esophageal stenting

Bronchial Artery Embolization, an Increasingly Used Method for Hemoptysis; Treatment and Avoidance.

Objectives:Hemoptysis is an alarming symptom. It may cause some severe life-threatening complications. Hypertrophic and fragile bronchial artery causes hemoptysis and occurs mostly in bronchiectasis, sarcoidosis, active or sequelae tuberculosis, aspergilloma, lung cancer or cystic fibrosis. Bronchial artery embolization is one of the angiographic methods used in diagnosis and treatment for years performed by radiologists. Hemoptysis is used mostly in patients with hemoptysis. Using this method, surgical management with high mortality and morbidity rates can be avoided or better conditions for surgery can be provided via stopping hemorrhage before surgery. We aim to share the experiences of our hospital about patients who underwent bronchial artery embolization and compare our results with the literature.Methods:Thirty-nine patients (29 male, 10 female) underwent angiography-aiming embolization. Pathologies were hemoptysis in 37 patients, Castleman disease in two patients. Embolization was performed in 33 patients; 31 for hemoptysis, two for Castleman disease. Bilateral embolization was performed in six patients.Results:Computed tomography (CT) was helpful in diagnosing the side of bleeding in 91.8% of the patients with hemoptysis. Bronchoscopy was diagnostic in 53% of patients. Polyvinyl alcohol (n=27) was mostly used for embolization. Hemoptysis recurred in six patients (19.3%). All were managed successfully, of four with re-embolization. One major complication, transient blindness, was observed.Conclusion:Bronchial artery embolization is minimally invasive, more tolerable compared to surgery can be managed with high success and lower complication rates, especially hemoptysis and in some other situations. It provides time for evaluating the underlying disease and delaying surgery for elective conditions. That is why this method has been used increasingly.

Организация хирургической помощи в многопрофильном стационаре в условиях пандемии COVID-19

The spread of caused by SARS-CoV2 acute respiratory infection associated with severe life-threatening complications has necessitated transformation of most general hospitals into infectious diseases hospitals in order to provide specialized care to infected patients, as well as the change of surgical care provision strategy. The example of surgical service reorganization has been reported for the general clinic transformed into the infectious diseases hospital capable of providing care both during the COVID-19 pandemic and after the outbreak has abated.

A Case of bacterial orbital cellulitis with complete ophthalmoplegia

Orbital cellulitis (OC) refers to acute infection of soft tissues of the orbit behind orbital septum. As many as 11% cases of OC result in visual loss. Here, we report a 60-year-old female who is a known case of Type 2 diabetes mellitus presented with complaints of right-sided headache, unable to open right eyelid, and unable to move eyeball for 1 month. Magnetic resonance imaging brain with orbit contrast done showed right-sided OC with forming abscess. Nasal endoscopy was done and nasal swab culture showed growth of Staphylococcus aureus. The patient was kept on antibiotics and was discharged after improvement. Prompt diagnosis and proper management are essential for curing the patient with OC. This is particularly important to prevent visual loss and other severe life-threatening complications.

COVID-19 and Social Isolation Endangering Psychological Health of Older Adults: Implications for Telepsychiatry

Coronavirus disease-19 (COVID-19) has created a public health emergency and had claimed 911,877 lives at the time of writing this manuscript (September 12, 2020). While everybody is at the risk of acquiring infection following the exposure to SARS-CoV-2, older adults are significantly more likely to experience severe illness, life-threatening complications, hospitalizations, and deaths. As the pandemic evolved, social distancing or shielding efforts as primary prevention were instituted to protect the physical health status of the vulnerable population, with no or limited consideration to the psychological health of the older population. Social isolation and loneliness are the long-standing public health concerns among older adults, which appear to be exacerbating amidst the COVID-19 pandemic. Given the pre-existing risk of late-life psychiatric disorders among older individuals, it is critical to determine challenges posed by COVID-19 and associated social distancing protocols as it relates to the psychosocial well-being of the aging population. Such information is imperative to design targeted interventions to fulfill the unmet needs of the older population. Therefore, this review endeavors to identify the healthcare and emotional needs of the aging population during the COVID-19 pandemic in the context of psychological health and social capital. Additionally, this review also identifies the barriers in the uptake of telepsychiatry and highlights the need for promoting remote counseling services among older people to promote their psychosocial well-being.

Association between disease-related malnutrition and innate immunity gene expression in critically ill patients at intensive care unit admission

The aim of the study was to analyse the relationship between nutritional disorders and the expression of innate antibacterial response genes in patients admitted to the intensive care unit (ICU). In 46 patients with severe malnutrition and life-threatening surgical complications, nutritional status tests were performed on the basis of the NRS 2002 (Nutritional Risk Screening) scale, cytokine, albumin, C-reactive protein concentrations, anthropometric tests, and body composition analysis. Concurrently, the expression of Toll-like receptor 2, NOD1, TRAF6, and HMGB1 genes was determined in peripheral blood leukocytes at the mRNA level using real-time polymerase chain reaction. It was found that both the nutritional status and the gene expression changed depending on the group of patients studied (including the group of survivors vs. non-survivors). Significant correlations were found between the results of routine tests used in the diagnostics of malnutrition (including NRS 2002, resistance, reactance, phase angle, excess of extracellular water) and the expression of the studied genes. Moreover, the expression of TRAF6 and HMGB1 genes correlated with the Acute Physiology and Chronic Health Evaluation II scale and the age of the patients. The results of the research suggest that the expression of innate antibacterial response genes may be a new diagnostic tool complementing the assessment of nutritional disorders in surgical patients admitted to the ICU. These tests may be helpful in providing more accurate diagnostics of the genetic effects of malnutrition and in the monitoring of patients for whom nutritional treatment is planned to support the functions of the immune system, thereby increasing the effectiveness of this type of treatment in the ICU.

Orbital cellulitis: early intervention saves vision

Orbital cellulitis describes an infection involving the soft tissues posterior to the orbital septum including the fat and muscle within the bony orbit. This condition is associated with severe sight and life-threatening complications. Distinguishing it from preseptal cellulitis is difficult, but important. Acute sinusitis is the commonest predisposing factor. Clinical findings alone are not specific enough to distinguish between preseptal and post septal orbital cellulitis. Early diagnosis using CT orbit is important to rule out complications such as orbital cellulitis, subperiosteal abscess. The most common location of subperiosteal abscess is the medial wall of the orbit. Transnasal endoscopic drainage of the abscess is a functional and minimally invasive technique and is the treatment of choice at present. Early diagnosis and intervention are mandatory to prevent the visual loss and life-threatening complication.Here, the authors describe a 2 months old infant with orbital cellulitis and medial subperiosteal abscess and treated with transnasal endoscopic drainage of the subperiosteal abscess.

Immunological and Clinical Impact of Manipulated and Unmanipulated DLI after Allogeneic Stem Cell Transplantation of AML Patients.

Allogeneic stem cell transplantation (allo-SCT) is the preferred curative treatment for several hematological malignancies. The efficacy of allo-SCT depends on the graft-versus-leukemia (GvL) effect. However, the prognosis of patients with relapsed acute myeloid leukemia (AML) following allo-SCT is poor. Donor lymphocyte infusion (DLI) is utilized after allo-SCT in this setting to prevent relapse, to prolong progression free survival, to establish full donor chimerism and to restore the GvL effect in patients with hematological malignancies. Thus, there are different options for the administration of DLI in AML patients. DLI is currently used prophylactically and in the setting of an overt relapse. In addition, in the minimal residual disease (MRD) setting, DLI may be a possibility to improve overall survival. However, DLI might increase the risk of severe life-threatening complications such as graft-versus-host disease (GvHD) as well as severe infections. The transfusion of lymphocytes has been tested not only for the treatment of hematological malignancies but also chronic infections. In this context, manipulated DLI in a prophylactic or therapeutic approach are an option, e.g., virus-specific DLI using different selection methods or antigen-specific DLI such as peptide-specific CD8+ cytotoxic T lymphocytes (CTLs). In addition, T cells are also genetically engineered, using both chimeric antigen receptor (CAR) genetically modified T cells and T cell receptor (TCR) genetically modified T cells. T cell therapies in general have the potential to enhance antitumor immunity, augment vaccine efficacy, and limit graft-versus-host disease after allo-SCT. The focus of this review is to discuss the different strategies to use donor lymphocytes after allo-SCT. Our objective is to give an insight into the functional effects of DLI on immunogenic antigen recognition for a better understanding of the mechanisms of DLI. To ultimately increase the GvL potency without raising the risk of GvHD at the same time.

Improved Anti-Tumor Response of Chimeric Antigen Receptor T Cell (CART) Therapy after GM-CSF Inhibition Is Mechanistically Supported By a Novel Direct Interaction of GM-CSF with Activated Carts

Despite the remarkable activity of CD19 directed chimeric antigen receptor T cell (CART19) therapy in the treatment of B cell malignancies, the therapy is limited by the development of severe life-threatening complications such as neurotoxicity (NT) and cytokine release syndrome (CRS). Additionally, durable efficacy following CART19 therapy is not optimal. Emerging literature suggests that inhibitory myeloid cells and their cytokines play an important role in inducing CAR-T cell toxicities and also contribute to the inhibition of their effector functions. Specifically, GM-CSF was identified as a critical cytokine in the development of NT and CRS after CART19 therapy. Neutralization of GM-CSF in preclinical models has been shown to prevent CRS and enhance CART anti-tumor activity through modulation of myeloid cell behavior, resulting in reduction of tumor associated macrophages. In addition to the predominant effect of GM-CSF on myeloid cells, there appears to be a direct effect on CART19 cells. In this study, we aimed to evaluate the direct effect of GM-CSF on CART cells. Our initial finding of enhanced anti-tumor activity of CART19 cells after GM-CSF inhibition suggested a direct effect of GM-CSF on CART cells (Sterner et al. 2019, Blood). In these experiments, a guide RNA (gRNA) targeting exon 3 of GM-CSF in a CRISPR-Cas9 lentiviral vector was used to knock out GM-CSF during CART cell manufacturing. This resulted in a disruption efficiency of approximately 70% of the GM-CSF gene. Using a high tumor burden xenograft model for relapsed acute lymphoblastic leukemia established through the engraftment of the CD19+ luciferase+ NALM6 cell line (1x106 cells intravenously) in immunocompromised NOD-SCID-γ-/- mice, treatment with low doses of GM-CSFk/o CART19 resulted in improved anti-tumor activity and overall survival compared to GM-CSFwt CART19. The lack of myeloid cells in this model pointed to an intrinsic effect of GM-CSF on CAR-T cells. To ensure that this was not related to an off-target effect of the gRNA, whole exome sequencing (WES) of the modified cells was performed. There was no difference in the single nucleotide variants or indel counts between GM-CSFk/o CART19 and GM-CSFwt CART19 (Figure 1A). WES was significant for only two alterations in the exon 3 targeted by the gRNA (Figure 1B). The high efficiency and accuracy of targeting exon 3 of GM-CSF indicated that the improvement in CART function is unlikely related to an off-target effect of the gRNA and suggested the possibility of a direct interaction between GM-CSF and CART cells as a potential mechanism behind the improved anti-tumor activity. To investigate this interaction, we first assessed the expression of GM-CSF receptors on CART cells. While resting CART cells do not express any GM-CSF receptors, our analysis robustly indicates that activated CART cells significantly upregulate both α and β subunits of the GM-CSF receptor. This finding was significant both when CART cells are activated through their T cell receptor with CD3/CD28 beads (Figure 1C) or through the CAR with irradiated NALM6 cells (Figure 1D). Additionally, activated GM-CSFk/o CART19 cells also upregulated GM-CSF receptors, indicating this upregulation is induced by T cell stimulation. These results suggest a direct interaction between GM-CSF and upregulated GM-CSFR on activated CART cells. Having demonstrated that 1) GM-CSF depletion enhances CART19 efficacy in xenograft models in the absence of monocytes and 2) T cell activation increases GM-CSF receptor expression, we sought to uncover the downstream changes resulting from this effect. Transcriptome interrogation of GM-CSFk/o CART19 revealed a distinct signature including a significant inhibition of the Fas death pathway, a known critical pathway in inducing CART cell apoptosis. This suggests a potential mechanism for enhanced CART19 activity following GM-CSF depletion (Figure 1E). In summary, our results strongly indicate that CART cells increase expression of GM-CSF receptor subunits when activated, resulting in modulation of CART cell functions. Furthermore, GM-CSFk/o CART19 revealed a distinct transcriptome signature compared to GM-CSFwt CART19. These results illuminate a novel mechanism for a direct modulatory effect of GM-CSF on activated CART cells. Disclosures Cox: Humanigen: Patents & Royalties. Sterner:Humanigen: Patents & Royalties. Sakemura:Humanigen: Patents & Royalties. Ahmed:Humanigen: Employment. Chappell:Humanigen: Employment. Durrant:Humanigen: Employment. Parikh:Acerta Pharma: Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Lentigen: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Kite/Gilead: Research Funding; Morphosys: Research Funding.

CMV Management with Specific Immunoglobulins: A Multicentric Retrospective Analysis on 92 Allotransplanted Patients.

CMV represents one of the most severe life-threatening complications of allogeneic stem cell transplantation (allo-SCT). Pre-emptive treatment is highly effective, but toxicity and repetitive reactivation of CMV represent a significant challenge in the clinical practice. The use of anti-CMV specific immunoglobulins (Megalotect) is controversial.We retrospectively collected data on 92 patients submitted to allo-SCT for hematological malignancies, in whom Megalotect was used either for prophylaxis (n=14) or with pre-emptive therapy, together with an anti-CMV specific drug (n=78). All the patients were considered at high-risk, due to the presence of at least one risk factor for CMV reactivation.The treatment was well tolerated, with no reported infusion reactions, nor other adverse events, none of the 14 cases treated with Megalotect as prophylaxis developed CMV reactivation. 51/78 (65%) patients who received Megalotect during pre-emptive treatment achieved complete clearance of CMV viremia, and 14/51 patients (29%) developed a breakthrough CMV infection. 7/78 patients (9%) developed CMV disease. The projected 1-year OS, 1-year TRM, and 1-year RR is 74%, 15%, and 19%, respectively. No differences were observed in terms of OS, TRM, and RR by comparing patients who achieved a complete response after treatment versus those who did not.These retrospective data suggest that Megalotect is safe and well-tolerated. When used as prophylaxis, no CMV reactivation was recorded. Further prospective trials are warranted to identify the best set of patients who can benefit from Megalotect alone or in addition to anti-CMV specific drugs.

Pregnancy outcomes in patients with primary antiphospholipid syndrome: A systematic review and meta-analysis.

Background:Antiphospholipid syndrome (APS) is a rare heterogenous autoimmune disorder with severe life-threatening complications shown during pregnancy. In this analysis, we aimed to systematically compare the pregnancy outcomes (both maternal and fetal) in patients with APS.Methods:Web of Science, Google Scholar, Medicus, Cochrane Central, Embase, and Medline were searched for relevant English publications. The main inclusion criteria were based on studies that compared pregnancy outcomes in patients with APS vs a control group. Statistical analysis was carried out by the RevMan software version 5.3. This analysis involved dichotomous data, and risk ratios (RR) with 95% confidence intervals (CIs) were used to represent the analysis.Results:Eight studies consisting of a total number of 212,954 participants were included. Seven hundred seventy participants were pregnant women with APS and 212,184 participants were assigned to the control group. Pregnancy-induced hypertension was significantly higher in women with APS (RR: 1.81, 95% CI: 1.33 – 2.45; P = .0002). The risks of fetal loss (RR: 1.33, 95% CI: 1.00–1.76; P = .05), abortion (RR: 2.42, 95% CI: 1.46–4.01; P = .0006), thrombosis (RR: 2.83, 95% CI: 1.47–5.44; P = .002), and preterm delivery (RR: 1.89, 95% CI: 1.52–2.35; P = .00001) were also significantly higher in women with APS. However, placental abruption (RR: 1.35, 95% CI: 0.78–2.34; P = .29) and pulmonary embolism were not significantly different (RR: 1.47, 95% CI: 0.11–19.20; P = .77). The risk of neonatal mortality (RR: 3.95, 95% CI: 1.98–7.86; P = .0001), infants small for gestational age (RR: 1.38, 95% CI: 1.04–1.82; P = .02), premature infants (RR: 1.86, 95% CI: 1.52–2.28; P = .0001), and infants who were admitted to neonatal intensive care unit (RR: 3.35, 95% CI: 2.29–4.89; P = .00001) were also significantly higher in women with APS.Conclusion:This analysis showed APS to be associated with significantly worse pregnancy outcomes when compared to the control group. A significantly higher risk of maternal and fetal complications was observed in this category of patients. Therefore, intense care should be given to pregnant women with APS to monitor unwanted outcomes and allow a successful pregnancy.

Modeling the effect of enzyme replacement therapy on life-threatening complications in patients with Fabry disease

Fabry disease (FD) is a severe lysosome storage disease caused by congenital deficiency of the enzyme α-galactosidase A and characterized by the risk of renal failure combined with cardiovascular and CNS complications. According to the currently available information, the early start of enzyme replacement therapy (ERT) leads to a significant improvement in patient’s condition.The aim of the studyis to assess whether the timely ERT prevents severe FD complications and to calculate the number of prevented cases as depending on the time of ERT start.Materials and methods. The proposed model is based on the published results on patients with FD, receiving agalsidase alpha as ERT (no data for agalsidase beta was found). The expected number of cases with life-threatening complications was calculated for different starting timepoints and durations of the ERT.Results. In patients with FD, continuous ERT during five years reduces the number of serious cardiovascular and renal complications by 25%. An early start of ERT makes it possible to additionally (as compared with a late start) prevent the complications in more than 20% of cases.Conclusion. The early initiation of RPT in patients with FD can significantly reduce the occurrence of severe lifethreatening complications, increase the patients’ survival and improve their quality of life.

Structural and Antiviral Studies of the Human Norovirus GII.4 Protease.

Norovirus is the leading cause of acute gastroenteritis worldwide with a yearly reported 700 million cases driving a $60 billion global socioeconomic burden. With no United States Food and Drug Administration approved therapeutics and the chance for severe chronic infection and life-threatening complications, researchers have identified the protease as a potential target. However, drug development has focused on the norovirus GI.1 strain despite its accounting for less than 5% of all outbreaks. Our lab aims to change focus for norovirus drug design from GI.1 to the highly infective GII.4, responsible for more than 50% of all outbreaks worldwide. With the first published crystal structure of the norovirus GII.4 protease, we have identified several significant differences in the structure and active site that have hindered development of a potent inhibitor targeting the norovirus GII.4 protease. With these new insights, we have begun designing compounds that demonstrate increased inhibition of the clinically most relevant norovirus GII.4 strain.

Use of bispectral index monitoring to predict the outcome of patients with posterior reversible encephalopathy syndrome: Two case reports

Posterior reversible encephalopathy syndrome (PRES) is a reversible neurologic disorder characterized by a variety of symptoms such as seizures, headache, vomiting, altered mental status, and visual disturbances. Bispectral index (BIS) monitor is a kind of electroencephalography and is widely used in anesthesia depth surveillance. In intensive care units, BIS has been used to survey sedation and predict prognosis of coma patients. Here, we report two cases diagnosed radiologically with PRES that had persistent consciousness disturbance resulted from severe life-threatening complications. In our patients, they progressed with different BIS values and different outcomes. We advise that BIS should be used in intensive care as an adjunctive monitor when patients' consciousness status could not be predicted.