Regulatory Role of Non-Coding RNAs on Immune Responses During Sepsis

Sepsis is resulted from a systemic inflammatory response to bacterial, viral, or fungal agents. The induced inflammatory response by these microorganisms can lead to multiple organ system failure with devastating consequences. Recent studies have shown altered expressions of several non-coding RNAs such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) during sepsis. These transcripts have also been found to participate in the pathogenesis of multiple organ system failure through different mechanisms. NEAT1, MALAT1, THRIL, XIST, MIAT and TUG1 are among lncRNAs that participate in the pathoetiology of sepsis-related complications. miR-21, miR-155, miR-15a-5p, miR-494-3p, miR-218, miR-122, miR-208a-5p, miR-328 and miR-218 are examples of miRNAs participating in these complications. Finally, tens of circRNAs such as circC3P1, hsa_circRNA_104484, hsa_circRNA_104670 and circVMA21 and circ-PRKCI have been found to affect pathogenesis of sepsis. In the current review, we describe the role of these three classes of noncoding RNAs in the pathoetiology of sepsis-related complications.

Treatment-Resistant Hypercalcemia Secondary to Ectopic PTH Hypersecretion From Disseminated Ovarian Cancer

Background: Hypercalcemia of malignancy (HCM) can present secondary to hypersecretion of parathyroid hormone (PTH)-related protein (PTHrP) from malignant tumors, but rare cases of HCM have also been documented due to inappropriate PTH secretion from ectopic neoplasms. Here, we report an unusual case of HCM due to hypersecretion of PTH from a disseminated mucinous ovarian adenocarcinoma. Case Presentation: A 45-year-old female presented with confusion, constipation, fatigue, and abdominal pain two weeks after total abdominal hysterectomy with bilateral salpingo-oophorectomy and suboptimal debulking of a newly discovered left ovarian mucinous adenocarcinoma with metastasis to the bladder, parametrium, vagina, right ovary, and rectosigmoid. Subsequent CT revealed numerous bilateral pulmonary nodules, hilar adenopathy, liver lesions, and abdominal adenopathy. On exam, she was tachycardic and hypertensive with diaphoresis, dry mucous membranes, respiratory distress, guarded abdominal tenderness, and altered mental status. Her labs were significant for a serum calcium of 21.7 mg/dL, creatinine of 1.93 mg/dL, ferritin of 2,379 ng/mL, leukocytosis of 21.9 bil/L, PTH of 1,061 pg/mL, and PTHrP of 29 pmol/L. Ectopic PTH secretion was highly suspected after negative parathyroid ultrasound. Pamidronate (60 mg IV), calcitonin (200 U IM), and fluid resuscitation were unable to normalize her serum calcium, resulting in the need for dialysis and subsequent continuous renal replacement therapy. Further intervention with denosumab (120 mg SQ), etelcalcetide (5 mg IV), and cinacalcet (60 mg PO) was also attempted. Serum calcium began to decline, but repeat PTH resulted greater than 2,500 pg/mL. Unfortunately, the patient died just one week into her hospital course from septic shock and multi-organ system failure. Discussion: Hypercalcemia of malignancy typically arises from tumor secretion of PTHrP, cytokine release from osteolytic metastases, or tumor production of calcitriol. In cases of hypercalcemia due to excess PTH secretion, primary parathyroid etiologies are typically considered while ectopic PTH-secreting tumors are rare. PTH staining of biopsy specimens and total body sestamibi scan may prove useful in the early detection and treatment of these tumors, but HCM offers a poor prognosis with mean survival of 2 to 3 months and in-hospital mortality of 6.8%. Currently, there are only three cases in the reported literature of ectopic PTH-induced hypercalcemia related to ovarian cancer. To our knowledge, this is the fourth reported case. Conclusion: Ectopic PTH-secreting tumors carry a poor prognosis and should be considered in cancer patients presenting with PTH-associated hypercalcemia. Biopsy staining for PTH and total body sestamibi scan may assist in the early detection of these tumors, but current treatment strategies offer suboptimal outcomes.

Early complications and prognosis with multiple organ system failure score

Background: Acute pancreatitis is a common surgical entity with a wide clinical spectrum ranging from mild pancreatitis to severe acute pancreatitis with lethal complications. A number of scoring systems have been devised to predict and manage complications associated with severe acute pancreatitis. The objective of this study was to study the demographics, early complications of acute pancreatitis with their outcome, and to assess the efficacy of multi organ system failure score. Methods: This was a descriptive study including 120 patients of acute pancreatitis done over a period of 2 years. The management of complications and their outcome were recorded in detail. A multi organ system failure score was used to predict and assess the severity of acute pancreatitis. Results: Total 120 patients were evaluated with mean age of 40 years and male preponderance. Alcohol consumption was the most common etiological factor. Acute fluid collection was the most common local complication while shock was the most common systemic complication. MOSF scoring system had a sensitivity, specificity and positive predictive value of 96%, 92.8% and 90.5% respectively. Mortality was 5.8% seen in patients with MOSF score above 5.Conclusions: The management of early complications of acute pancreatitis is mainly conservative, with surgical management limited to only a few selected patients. MOSF score is a valuable tool to predict and assess the severity of acute pancreatitis and should be used for monitoring of high risk patients.

Pulmonary hypertension as a risk assessment factor for unfavorable outcome in patients with COVID-19

Aim. To determine the predictive role of estimated pulmonary artery systolic pressure (ePASP) in COVID-19 patients.Material and methods. A retrospective study of inpatients with documented COVID-19 infection was carried out. Maximal follow-up period was 63 days. The study included 108 patients (men, 62; women, 46; mean age, 62,9±15,5 years). At admission, mean NEWS score was 6,0, blood oxygen saturation — 92%. Echocardiography was performed according to standard protocol using Vivid E9 ultrasound system (GE Healthcare). Quantitative measurements were performed according to the current ASE and EACVI guidelines. Statistical analysis was performed using the IBM SPSS Statistics v.26 software (developed by IBM Corporation).Results. Using the CHAID technique, a classification tree was developed and the strongest predictor of an unfavorable outcome was determined (ePASP). Threshold ePASP values, associated with an increased mortality risk were established (42 mm Hg and 50 mm Hg). Three groups of patients were selected based on the main predictor (<41,0 mm Hg, 42-49 mm Hg and >50 mm Hg). The increased mortality risk was noted in groups 2 and 3 compared to group 1 of patients and amounted to 31,8% and 70% versus 3,9%, respectively. There was also a correlation between the severity of CT lung parenchymal lesions according to computed tomography and the study groups of patients (36% [30-49%] — group 1, 50% [36-76%] — group 2, and 84% [56-92%] — group 3, p=0,001). In groups 2 and 3, the following complications were significantly more frequent: acute respiratory distress syndrome, acute heart failure, multiple organ system failure, venous thrombosis, disseminated intravascular coagulation. In group 3, acute renal failure and systemic inflammatory response syndrome developed significantly more often than in group 1.Conclusion. A comprehensive echocardiography has proven its availability and safety in assessing the condition of COVID-19 patients, allowing to obtain relevant information on pulmonary hemodynamics. Transthoracic echocardiography reduced the risk of complications from invasive diagnostic methods and allowed to abandon the use of the Swan-Ganz pulmonary artery catheter in the studied group of patients. As a result, a relationship was noted between the increase of ePASP and the severity of clinical performance and lung tissue damage according to computed tomography, changes in laboratory blood tests, the severity of the comorbid profile, an increase in respiratory support need.

Molecular Evidence of Hemolivia mauritanica, Ehrlichia spp. and the Endosymbiont Candidatus Midichloria Mitochondrii in Hyalomma aegyptium Infesting Testudo graeca Tortoises from Doha, Qatar

Tick-borne agents constitute a growing concern for human and animal health worldwide. Hyalomma aegyptium is a hard tick with a three-host life cycle, whose main hosts for adults are Palearctic tortoises of genus Testudo. Nevertheless, immature ticks can feed on a variety of hosts, representing an important eco-epidemiological issue regarding H. aegyptium pathogens circulation. Hyalomma aegyptium ticks are vectors and/or reservoirs of various pathogenic agents, such as Ehrlichia, Anaplasma, Babesia and Hepatozoon/Hemolivia. Ehrlichia and Anaplasma are emergent tick-borne bacteria with a worldwide distribution and zoonotic potential, responsible for diseases that cause clinical manifestations that grade from acute febrile illness to a fulminant disease characterized by multi-organ system failure, depending on the species. Babesia and Hepatozoon/Hemolivia are tick-borne parasites with increasing importance in multiple species. Testudo graeca tortoises acquired in a large animal market in Doha, Qatar, were screened for a panel of tick-borne pathogens by conventional PCR followed by bidirectional sequencing. The most prevalent agent identified in ticks was Hemolivia mauritanica (28.6%), followed by Candidatus Midichloria mitochondrii (9.5%) and Ehrlichia spp. (4.7%). All samples were negative for Babesia spp. and Hepatozoon spp. Overall, 43% of the examined adult ticks were infected with at least one agent. Only 4.7% of the ticks appeared to be simultaneously infected with two agents, i.e., Ehrlichia spp. and H. mauritanica. This is the first detection of H. mauritanica, Ehrlichia spp. and Candidatus M. mitochondrii in H. aegyptium ticks collected from pet spur-thighed tortoises, in Qatar, a fact which adds to the geographical extension of these agents. The international trade of Testudo tortoises carrying ticks infected with pathogens of veterinary and medical importance deserves strict control, in order to reduce potential exotic diseases.

The Effects of Furosemide usage on Organ System Failure Status based on Modified Sequential Organ Failure Assessment Score in Critically ill Patient

Objectives: Eighty-six percent of patients administrated with intravenous fluid resuscitation had positive fluid accumulation. This resulted in fluid overload in 35% of all ICU patients in 2009–2012. Then, the worst consequence is multi-organs failures. Thus, one of the treatments is pharmacological diuresis to solve physiological problems. Despite of its adverse effects and fluid balance decrement on the hypoperfused organ, the organ failure resolution of furosemide usage has not been proven through any research. Hence, a research which analyzed the correlation of organ system failure status based on modified sequential organ failure assessment (MSOFA) score with furosemide usage on intensive care patient and their demographics data has been conducted. Material and Methods: The research design was a retrospective cohort which analyzed 194 subjects through ICU medical records selected by consecutive sampling method. Data of furosemide usage and MSOFA score changes were recorded. Thereafter, Chi-square test was conducted to analyze the data. Moreover, characteristics of subjects were also recorded and analyzed in this study. Results: Based on the characteristics of subjects analysis, significant factors on furosemide usage (P < 0.05) included total fluid changes, total fluid after therapy, organ system dysfunctions before therapy (including the respiratory and central nervous system), organ system dysfunction after therapy (cardiovascular), and MSOFA score before therapy. Very significant factors (P < 0.001) include total fluid before therapy, organ system dysfunction after therapy (central nervous system), and MSOFA score after therapy. There was a significant association between worsening organ system failure with furosemide usage on critically ill patients, especially in the cardiovascular and central nervous system. The relative risk result reported that furosemide usage resulted in higher MSOFA score 1.271 times more than those patients with no furosemide diuresis usage (95% CI 1.108– 1.458). Furosemide usage in this research worsens organ dysfunction, especially in cardiovascular and central nervous systems. Conclusion: The furosemide usage worsens the organ failure based on MSOFA score. Furosemide therapy should be individually adjusted, especially in those who have respiration, cardiovascular, and central nervous system dysfunction.

A Case Series: The Novel Use of Emapalumab and Ruxolitinib in Acquired Malignancy-Associated HLH in Pediatric Patients

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory syndrome that is classified into primary and acquired forms. Primary-HLH has genetic components related to defects in cytotoxic T and NK cells. The acquired form of HLH is classified based on the underlying triggers of immune dysregulation through malignancy, infections, and/or autoimmune processes. The standard of care is established with etoposide and dexamethasone, but there are currently no guidelines for refractory HLH or cases with confounding presentations with infection or malignancy. We describe cases of malignancy-associated HLH (m-HLH) in pediatric patients to discuss the intricacies in the initial diagnostic considerations, the balance of therapeutic regimens and their toxicities, and the novel use of emapalumab and ruxolitinib in refractory patients. We discuss a 16-year-old female with NK/T-cell lymphoma of the nasopharynx who presented in septic shock with pancytopenia and DIC. Diagnostic considerations included progressive lymphoma, bacteremia, and EBV viremia as possible explanations for her shock physiology. HLH was a consideration on admission given her presentation, but she did not meet criteria until HD#7 with ferritin of 740ng/mL (ref 10-291ng/mL), soluble IL-2 receptor (CD25) of 10,600pg/mL (ref &lt;1033pg/mL), sCD163 of 5,636ng/mL (ref 387-1,785ng/mL) and an abnormal NK cell function. Standard treatment with etoposide and dexamethasone showed minimal effect, as did the introduction of rituximab. Gemcitabine and oxaliplatin were started as treatment for her lymphoma as the driver of her HLH, but she developed acute decompensation with hemodynamic instability and multi-organ system failure. Her systemic inflammation worsened as evidenced by a rise in her ferritin to 15,462ng/mL and sIL-2 receptor to 28,700pg/mL. Her CXCL9, a downstream chemokine and marker of IFN-gamma activity shown to be elevated in HLH, had a dramatic increase to 106,918 pg/mL (ref &lt;121pg/mL). A decision to hold treatment for her lymphoma was made to reduce toxicities and better manage her HLH. Compassionate use of emapalumab, an IFN-gamma inhibitor indicated in primary HLH, led to dampening of her systemic inflammatory processes with resolution of fevers and signs of recovery of her hepatobiliary, renal, and gastrointestinal systems. We also describe a 17-year-old male who presented with T-ALL and bacteremia who developed HLH during induction-chemotherapy with complications from bacterial sepsis and fulminant fungemia. He represented a diagnostic conundrum throughout his induction chemotherapy with persistent fevers despite appropriate treatment and improvement of his bacteremia and fungemia. It was not until HD#50 that he met criteria for HLH with the addition of a ferritin level of 6,073ng/mL. He had limited response to treatment and had multi-system toxicities from the therapies for his HLH, ALL, and fungemia that necessitated frequent adjustments to his treatment plans. The treatment for his HLH was not standard given the toxicities. Etoposide was never in consideration given concerns for myelosuppression and dexamethasone was not given at full doses due to intolerance but was given over a prolonged duration of months. His course included a waxing and waning response to a combination of steroids and IVIG with recurrent admissions for presumed HLH flares. A trial of ruxolitinib, a JAK inhibitor, demonstrated response with stabilization of his hyperinflammatory state. Although not curative, as evidenced by his persistent hyperferritinemia, the use of ruxolitinib has allowed him to better tolerate his chemotherapy and improve his overall quality of life with a decrease in frequency of flares and hospitalizations. These cases highlight the intricacies of the management of m-HLH in pediatric patients with the spectrum of disease severity and complex diagnostic evaluations one must consider at presentation. Due to the toxicity of treatment options for often concurrent processes of malignancy, infection, and HLH, novel therapeutics such as emapalumab and ruxolitinib are required and should be evaluated in larger studies. Furthermore, guidelines for the management of pediatric m-HLH are required with inclusion of adjustments to standard therapy based on toxicity, inciting factors, concurrent processes, and the incorporation of novel therapeutics to achieve improved outcomes. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Ruxolitinib and emapalumab for refractory acquired HLH in Pediatric patients.

Pregnancy Outcomes of Patients with Acute Fatty Liver of Pregnancy：A Case Control Study

Background : Limited data exists regarding the pregnancy and infant outcomes of Acute Fatty Liver of Pregnancy (AFLP). Methods: Retrospectively collected mothers with AFLP and mothers without AFLP in our center from 1/2008 to 6/2018. The primary assessment was to analyze and compare the frequency of negative maternal and fetal outcomes. The secondary assessment was to investigate the role of intrauterine balloon tamponade in reducing negative maternal outcomes. Results: Compared to 220 matched mothers, 55 AFLP mothers were younger (P<0.001), with fewer pregnancies (P=0.033), complicated with more pregnancy induced hypertension (P<0.001), twins(P=0.002), fetal growth restriction (P=0.044) and male fetus (P<0.001). 3 (5.5%) of AFLP patients were diagnosed in the postpartum period. Mean gestational week of AFLP diagnosis was 35.25±5.80 weeks. Jaundice (89.1%), nausea or vomiting (58.2%), anorexia (49.1%), fatigue (45.5%) and polydipsia (30.9%) were the main prodromal symptoms. The median duration from diagnosis to delivery was 1.55±4.62 days and 75% (39/52) pregnancy were terminated the pregnancy at the day of diagnosis. 78.8% (41/52) patients received cesarean section, 53.6% (22/41) of which received preventive plasma transfusion before surgery and no one received artificial liver support during the treatment. In comparison, higher frequency of 16 maternal complications, severe negative outcomes (27.3% vs. 0.9%) and newborn asphyxia (24.6% vs.0.9%) were observed in AFLP population. 3 mothers (mortality rates: 5.5%) died of multiple organ system failure and 6 fetus/infants (death rates: 9.8%) died of distress. When compared to those without negative outcomes, patients with negative fetal outcomes were younger (P=0.042), had more singleton rates (p=0.041), increased mean value of ALT(P=0.011) and T-Bilirubin (P=0.014), decreased prothrombin activity (P=0.011). Although no statistical significance for the small sample size, there were less refractory postpartum hemorrhage (0% vs.31.3%), hysterectomy (0% vs.12.5%), negative maternal outcomes (16.7% vs.56.3%) in patients underwent intrauterine balloon tamponade when postpartum hemorrhage exceeded 500ml. Conclusions: Several symptoms were found to be the main prodromal symptoms of AFLP. Higher frequency of adverse maternal and fetal outcomes was observed in mothers with AFLP than mothers without AFLP.We found five potential risk factors of negative fetal outcomes.

Nosocomial infections

Hospital-acquired or nosocomial infections—defined for epidemiological purposes as infections manifesting more than 48 hours after hospital admission—are common. They affect 1.4 million people worldwide, involve between 5 and 25% of hospitalized patients at any one time and are associated with considerable morbidity, mortality, and cost. The most common sites of nosocomial infection are the urinary tract, surgical wounds, and the lower respiratory tract. Most are bacterial in origin, the most common species being Escherichia coli, Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus), enterococci, Pseudomonas aeruginosa, and coagulase-negative staphylococci. The principal risk factors are extremes of age, the severity of underlying acute disease (e.g. neutropenia, organ system failure), and chronic medical conditions (especially diabetes, renal failure, and alcohol abuse).