Fatal Episodes Research Articles

Evaluation of the "Neonatal Sequential Organ Failure Assessment" to Predict Mortality in Late-Onset Sepsis in Very Preterm Infants.

We aimed to evaluate the use of "Neonatal Sequential Organ Failure Assessment" (nSOFA) scoring in predicting mortality, to compare the accuracy of nSOFA scores at different time points in very preterm infants with late-onset sepsis (LOS), and to investigate other possible parameters that would improve the prediction. This single-center, retrospective study included preterm infants born atS<32 weeks' gestation with culture-proven LOS. The nSOFA scores of non-fatal and fatal episodes were compared at nine time points. Of 120 culture-proven LOS episodes in 106 infants, 90 (75%) episodes were non-fatal and 30 (25%) episodes were fatal. The mean birth weight (BW) of the infants who died was lower than that of survivors (p=0.038). In the fatal LOS episodes, median nSOFA scores were higher at all time points measured before sepsis evaluation, at the time of evaluation, and at all time points measured after the evaluation (p<0.001). nSOFA scores before death and at 48 hours were higher in the fatal episodes (p<0.001). At the time of sepsis assessment, nSOFA score>4 was associated with a 7- to 16-fold increased risk of mortality. Adjustment for BW, lymphocyte and monocyte counts increased the risk to 9- to 18-fold. This study demonstrated that the use of nSOFA to predict mortality and morbidity in extremely preterm infants seems feasible. The scoring system could be improved by evaluating the other parameters.

Fourteen Deaths from Suspected Heparin Overdose in an Italian Primary-Level Hospital.

Healthcare-related homicidal cases are not novel within the medical-legal landscape, but investigations are often made difficult with the scarcity of material evidence related to the crime. For this reason, it is necessary to carefully analyze the clinical documentation and employ ancillary forensic resources such as radiology, histopathology, and toxicology. In the presented scenario, the observation of 14 deaths from abnormal bleeding in a First-Level Italian Hospital revealed the administration of massive doses of heparin by a nurse. On behalf of the Judicial Authority, a multidisciplinary medical team investigated the case through the following steps: a thorough review of the clinical documentation, exhumation of the bodies belonging to the deceased patients, performing PMCT and autopsy, and collecting tissue samples for histopathological, immunohistochemical, and toxicological investigations. All the analyzed cases have been characterized by the observation of fatal hemorrhagic episodes not explained with the clinical conditions of the patients, confirmed using autopsy observations and the histological demonstration of the vitality of the lesions. However, due to the limited availability of biological material for the toxicological analysis, the indirect evidence from hematological analyses in hospitalized patients was crucial in demonstrating heparin overdose and its link to the recorded deaths. The present scenario demonstrates the fundamental importance of a multidisciplinary approach to cases of judicial interest related to the healthcare context. Therefore, the illustrated methodologies can be interpreted as an operational framework for similar future cases.

Therapeutic Nucleic Acids against Herpes Simplex Viruses

The Herpes simplex virus (HSV) causes a wide range of diseases, ranging from relatively mild primary skin lesions to severe and often fatal episodes of encephalitis. Currently, the most effective drugs for HSV-infected people are nucleoside analogs (e.g., acyclovir) targeting enzymes encoded by viral DNA. The effectiveness of nucleoside analogs is reduced because of poor solubility in water, rapid intracellular catabolism, high cellular toxicity, and the appearance of resistant viral strains. Antisense technology that exploits nucleic acid fragments (NA-based agents) is a promising alternative to antiviral therapy due to the high affinity of these agents to target nucleic acids, their high solubility in water, and lower cellular toxicity. In the last decade, antisense oligonucleotides have been investigated as potential drugs for various diseases associated with “harmful” nucleic acids. Oligonucleotides with different chemical modifications targeted at specific regions of the HSV genome have shown effectiveness in suppressing the virus. siRNA-based agents have demonstrated prolonged and effective (up to 99%) inhibition of HSV replication. Based on the publications reviewed in the review over the past 30 years, it can be concluded about the prospects of using NA-based agents to combat herpes viral infections.

Babesia gibsoni Infection in a Cat with Immune-Mediated Haemolytic Anaemia and Thrombocytopenia

Tick-borne haemoparasite Babesia gibsoni has been detected rarely in cats, in surveys of apparently healthy animals. In stored blood from a 6-year-old male-neutered domestic shorthair cat in Hong Kong, B. gibsoni DNA was detected retrospectively using PCR for Babesia spp. 18S rRNA and mitochondrial cytochrome B genes, followed by sequencing and basic local alignment search tool (BLAST) analysis. The cat presented with severe haemolytic anaemia and thrombocytopenia. The cat responded to supportive care and glucocorticoids and was clinically normal despite persistent subclinical thrombocytopenia until six months after presentation, when it succumbed to a fatal haemorrhagic episode. Necropsy revealed severe intestinal and pulmonary haemorrhage and hypocellular bone marrow with megakaryocytosis but no other causes of immune-mediated thrombocytopenia (IMTP) or immune-mediated haemolytic anaemia (IMHA). Blood stored on days 158 and 180 tested PCR negative for Babesia spp. This report demonstrates that geographic range of B. gibsoni detection in cats includes Hong Kong. The exclusion of other causes suggests that B. gibsoni might have potentially played a role in triggering immune-mediated disease in this case.

Late-Onset Sepsis Mortality among Preterm Infants: Beyond Time to First Antibiotics.

Objective: To investigate the impact of timing, in vitro activity and appropriateness of empirical antimicrobials on the outcome of late-onset sepsis among preterm very low birth weight infants that are at high risk of developing meningitis. Study design: This retrospective study included 83 LOS episodes in 73 very low birth weight infants born at ≤32 weeks' gestation with positive blood and/or cerebrospinal fluid culture or polymerase chain reaction at >72 h of age. To define the appropriateness of empirical antimicrobials we considered both their in vitro activity and their ideal delivery through the blood-brain barrier when meningitis was confirmed or not ruled out through a lumbar puncture. The primary outcome was sepsis-related mortality. The secondary outcome was the development of brain lesions. Timing, in vitro activity and appropriateness of empirical antimicrobials, were compared between fatal and non-fatal episodes. Uni- and multi-variable analyses were carried out for the primary outcome. Results: Time to antibiotics and in vitro activity of empirical antimicrobials were similar between fatal and non-fatal cases. By contrast, empirical antimicrobials were appropriate in a lower proportion of fatal episodes of late-onset sepsis (4/17, 24%) compared to non-fatal episodes (39/66, 59%). After adjusting for Gram-negative vs. Gram-positive pathogen and for other supportive measures (time to volume administration), inappropriate empirical antimicrobials remained associated with mortality (aOR, 10.3; 95% CI, 1.4-76.8, p = 0.023), while timing to first antibiotics was not (aOR 0.9; 95% CI, 0.7-1.2, p = 0.408; AUC = 0.88). The association between appropriate antimicrobials and brain sequelae was also significant (p = 0.024). Conclusions: The risk of sepsis-related mortality and brain sequelae in preterm very low birth weight infants is significantly associated with the appropriateness (rather than the timing and the in vitro activity) of empirical antimicrobials. Until meningitis is ruled out through lumbar puncture, septic very low birth weight infants at high risk of mortality should receive empiric antimicrobials with high delivery through the blood-brain barrier.

SIDS classifications: issues and update

Sudden infant death syndrome (SIDS) is defined as ‘the sudden unexpected death of an infant <1 year of age, with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation, including performance of a complete autopsy and review of the circumstances of death and the clinical history’. Despite lacking pathognomonic markers, the recognition of the triple risk model and risk factors have saved many infant lives. Despite this success, use if standard SIDS definitions has declined in favour of ‘undetermined’ or ‘unascertained’.

Medications mostly associated with hematuria: assessment of the EudraVigilance and Food and Drug Administration pharmacovigilance databases entries.

Drugs may have a direct causative role in triggering hematuria. The range of medications which may be responsible for hematuria is wide, but little is known on those which are most frequently involved. The aim of our study was to identify and compare drugs mostly related with hematuria. The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and the EudraVigilance (EV) database were queried to identify the drugs which were associated the most with hematuria individual reports till 30 September 2021. Rivaroxaban, aspirin, warfarin sodium, clopidogrel bisulfate, dabigatran etexilate mesylate, apixaban, warfarin, cyclophosphamide, lansoprazole, enoxaparin sodium, and ibuprofen were analyzed. Analysis per gender, age and severity was performed. Disproportional analysis was performed to compare drugs. Overall, 15,687 reports of hematuria were recorded in the FDA database and 15 007 in the EV database. Rivaroxaban and Warfarin appear to be the most dangerous medications in terms of hematuria when compared to the other medications (PRR>1, P<0.05) while apixaban is the safest one (PRR<1, P<0.05) when compared to the other medications. In terms of severity only 162/15 007 (1.08%) were fatal. Between the drugs analyzed cyclophosphamide 7.2%, enoxaparin (3%) and dabigatran (2.5%) presented a higher number of fatal hematuria episodes when compared to the other drugs (<1%). Anticoagulants and antiplatelets are more frequently related to hematuria episodes however some differences exist between them. Particularly warfarin and rivaroxaban should be prescribed with caution in patients at increased risk of hematuria. Prescribers should inform those treated with these medications about the risk of hematuria and its sequelae.

“¡Este hombre me hirió!”. Homicidio, género y lenguaje jurídico en el Jalisco decimonónico

Against the backdrop of a national civil war, this article examines a fatal episode of domestic violence in Guadalajara in 1860. Ursino Sánchez may have silenced his partner, Sista Cuevas, and fled into the night, but the victim’s surviving family members ensured that he would face punishment at the hands of the law. By examining the language deployed in the courtroom by the involved parties, I observe both how gender norms were irremediably inscribed in the legal codes governing violence, and how these norms informed testimonies and, possibly, judicial findings. Furthermore, judicial records consulted here reveal the degree to which citizens had metabolized colonial and modern legal precedents into a shared cultural understanding of gender roles that spanned decades and class divides in postcolonial Mexico.

Expert Opinion for the Management of Severe Asthma in Adults in the Gulf Region

Abstract: Asthma is a noncommunicable, chronic respiratory disease affecting 339 million individ-uals globally. The SNAPSHOT study suggests a prevalence rate of 6.4% in the Middle East region and 7.6% in the Gulf region alone, causing a significant healthcare burden. The management of se-vere asthma poses a significant challenge, thus accounting for suboptimal disease control. Diagnosis of severe asthma is quite difficult, considering the multiple factors playing a pivotal role in disease progression and management. Primary care physicians (PCPs) are predominantly involved in deci-sion-making in asthma diagnosis and control. Therefore, educating the PCPs regarding diagnostic strategies and guiding them for a timely referral to specialists can reduce fatal episodes and disease exacerbations. In this way, PCPs may ensure effective treatment and achieve optimal disease con-trol. To develop an algorithm and decision tree that may aid PCPs in the timely referral of severe asthma patients to specialists, an expert committee meeting was convened in December 2020 with leading experts from the United Arab Emirates. A three-step algorithm “CAR” was established to guide PCPs: “confirm” and check diagnosis, “assess” factors contributing to exacerbations and poor quality of life, and “refer” to a specialist. The “Severe Asthma Referral approach” conceptualized herein for the PCPs may help overcome the pragmatic challenges of early diagnosis, establish sim-ple referral criteria for specialists, and attain severe asthma treatment goals.

A Multispecialty Approach to the Identification and Diagnosis of Nonaccidental Trauma in Children.

Child abuse is a preventable phenomenon of considerable concern resulting in significant child mortality and morbidity. We analyze various abuse lesions such as radiological (visceral and skeletal lesions and those associated with head trauma) and cutaneous (burns, bruises, bites, etc.) to enhance streamlined identification of injuries in cases of physical child abuse. For effective results, it is essential to remain mindful of all background factors, such as the caregiver setting and the prevalence of child maltreatment in the concerned community while acknowledging the possibility of natural causes (genetic diseases such as osteogenesis imperfecta and hemophilia, or acquired abnormalities) that can mimic NAT and cause confusion in diagnosis and treatment. The margin of error in cases of abuse is negligible, therefore, making its diagnosis a momentous as well as challenging clinical task. An ineffective diagnosis can have detrimental emotional consequences for the family and may even expose the child to future potentially fatal episodes of abuse. Hence, there is a need to direct special focus on the importance of accurate history taking and immediate, responsible reporting to authorities, as well as to child protective services. Therefore, considering the multifactorial approach this subject requires, this review aims to delve into prevalence statistics, various risk factors, and their effect on psychological health to offer a near-complete regulation to ensure an effective understanding of NAT on part of doctors, social workers, and other relevant authorities.

Hypoglycemic unawareness: challenges, triggers, and recommendations in patients with hypoglycemic unawareness: a case report

BackgroundHypoglycemia is a fairly common complication in diabetic patients, particularly in those on insulin therapy. Hypoglycemia symptoms are classified into two types: autonomic and neuroglycopenic symptoms. If a person develops neuroglycopenic symptoms before the appearance of autonomic symptoms or is asymptomatic until blood sugar levels are very low, the patient will develop hypoglycemic unawareness (HU).Case presentationA 25-year-old Iranian woman with HU presented with a severe hypoglycemic episode. This episode was characterized by loss of consciousness and focal neural deficits, which were unusual symptoms in the patient, who was a medical intern with type 1 diabetes and currently being treated with regular and NPH insulin.ConclusionsHypoglycemia is a common complication in diabetic patients receiving oral or insulin therapy. A patient who is unaware of their condition may experience severe and potentially fatal episodes. These incidents can negatively affect their daily lives as well as their careers and jobs. Hypoglycemia-associated autonomic failure is a possible cause for patients with multiple episodes of severe hypoglycemia. IThe use of a continuous glucose monitoring device with an alarm, if available, can be an excellent option for these patients.

Leukocyte adhesion defect: Clinical correlation with integrin expression and genetics

Objectives: Leucocyte adhesion defect 1 (LAD1) is an autosomal recessive defect in integrin expression. In this study we present a case series of 19 children with LAD1. We analysed their clinical and laboratory data and correlated it with integrin expression and underlying genetic defect. Material and Methods: Retrospective case record study of all children diagnosed with LAD1 between 2012 and 2021. Results: Ten females and 9 males were included. Eight cases were born of consanguineous marriage. 78% (15/19) had disease onset within one year of life and 8 of them were neonates. Neonates with LAD1 commonly presented with omphalitis, late-onset sepsis and respiratory infections (RTI). Most common organism isolated from blood was pseudomonas (4/8). CD11/CD18-expression ranged from severely reduced (6/8) to moderately reduced (2/8) but disease was uniformly fatal in the 7/8 patients who could not undergo hematopoietic stem cell transplant (HSCT). Seven children presented between 1month and 1year of age with RTI, bacterial sepsis and soft tissue abscess. Four expired, 1 survived after HSCT and 2 were alive at last follow up. CD11/CD18-expression ranged between 0-1.6% except in 2 cases. One child with 11%-expression is alive without transplant. Another child had 0%-CD11 but 17%-CD18-expression with very low MFI (mean florescence intensity). She succumbed at 20 months of age with perianal abscess, sepsis and RTI but prior to this fatal episode she developed autoimmune cutaneous lesions with lymphocytic infiltration. Four children presented beyond infancy. Median age at onset of symptom was 2 years with skin abscess, oral ulcers, severe periodontitis with tooth loss and pyogenic arthritis. Three of them survived without HSCT, 1 was alive at last follow up. CD11/CD18-expression ranged from 20-32% in these children. Details of cord separation was available in 17 cases and it was delayed (beyond 2 weeks of life) in 9 children. Of the 17 cases with genetic analysis of ITGB2 gene, 16 had a homozygous and 1 had compound heterozygous variant. (nonsense: 2; splice site variants:5; 8: missense variants; 2: deletion). Conclusion: Disease onset less than 1 year age was fatal, irrespective of CD11/CD18 expression. Integrin expression levels beyond 20% and splice site mutation were associated with 100% survival without HSCT but were not event free. Pseudomonas sepsis is the commonest infection in LAD1 neonates. Between 1month to 1year, RTI and gram-negative sepsis dominated and beyond 1st-year skin/perianal abscess was common. Delayed separation of cord was present only in 52% of cases.

Warfarin is associated with higher rates of epistaxis compared to direct oral anticoagulants: A nationwide propensity score-weighted study.

Although epistaxis is one of the most common side effects of oral anticoagulation, it is unclear whether epistaxis rates vary between different oral anticoagulants (OAC). To compare rates of clinically relevant epistaxis between OAC. Epistaxis event rates were compared between new users of apixaban, dabigatran, rivaroxaban, and warfarin in a nationwide population-based cohort study over a 5-year study period, 2014-2019. Data was collected from the Icelandic Medicine Registry and the five major hospitals in Iceland. Inverse probability weighting (IPW) was used to yield balanced baseline characteristics, and epistaxis rates were compared using Kaplan-Meier survival estimates and Cox regression. During the study period, 2098 patients received apixaban, 474 dabigatran, 3106 rivaroxaban, and 1403 warfarin. In total, 93 patients presented with clinically relevant epistaxis, including 11 (12%) major epistaxis events and one fatal epistaxis episode. Furthermore, seven patients (9%) with non-major epistaxis later presented with major bleeding during the follow-up period. Warfarin use was associated with higher rates of epistaxis compared to apixaban (2.2 events per 100-person years (events/100-py) vs. 0.6 events/100-py, hazard ratio [HR] 4.22, 95% confidence interval [CI] 2.08-8.59, p < 0.001), rivaroxaban (2.2 events/100-py vs. 1.0 events/100-py, HR 2.26, 95% CI 1.28-4.01, p = 0.005), and dabigatran (2.2 events/100-py vs. no events, HR n/a, p < 0.001). Warfarin treatment was associated with higher rates of clinically relevant epistaxis compared to direct oral anticoagulants.

CRISPR/Cas9-mediated KLKB1 Gene Editing and Serum Kallikrein Reduction by NTLA-2002 Remains Durable in Humanized Mice Following Liver Regeneration after Partial Hepatectomy

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent, debilitating, and potentially fatal swelling episodes requiring chronic treatment. NTLA-2002 is a CRISPR/Cas9-based therapeutic candidate targeting KLKB1 as a single-dose treatment for the life-long prevention of HAE attacks. Previous studies demonstrated KLKB1 editing is sustained for at least 24 months in non-clinical animal models, suggesting the edit is permanently maintained throughout regular cell turnover. To further demonstrate durability of effect in the context of exaggerated cellular proliferation, we developed a partial hepatectomy (PHx) model to force rapid and extensive tissue regeneration following NTLA-2002 treatment.

Is The Risk of Thromboembolic Disease and Bleeding Adequately Evaluated in Patients with Glioblastoma? A Review of The Topic

Introduction: Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor, with an aggressive course and a short life expectancy despite standard treatment (chemotherapy and radiotherapy). The possibility of the development of thrombotic events (VTE) with this type of cancer is frequent. Objective: To determine the risk of presenting VTE and haemorrhagic events in patients affected by GBM. Methods: Observational retrospective study of patients with GBM diagnosis at the General University Hospital of Ciudad Real between 2012 and 2015. The demographic characteristics of patients were studied, predictive models were compared, and a survival analysis was performed. Results: 77 patients were studied, 42 (55.3%) / 34 (44.7%), men and women respectively, with an average age of 66.42 years. 13 (16.9%) presented VTE; of which 10 (61.54%) in the form of deep venous thrombosis (DVT), 3 (23.08%) pulmonary embolism (PE) and 2 (15.38%) mixed events. The quality of life according to the performance status ECOG scale at the moment of diagnosis was 1 in 42 (15.38%) patients, and at the time of VTE, 5 (41.7%) had a value of 2, and 4 (33.3.3 %) registered 3. In the group that developed VTE according to the predictive model of risk for thrombosis in Khorana 5 (38.5%) had low risk and 8 (61.5%) intermediate; on the ASCO 2013 modified scale 5 (38.5%) had an Intermediate risk and 8 (61.5%) high. With a median, 1 year follow-up, 64 (84.2%) patients died, with an average time after the diagnosis of 279.09 days (216.6-341.6) (SE 31,8). 2 (2.6%) of the patients presented a greater haemorrhagic event and 7 (7.9%) cerebral haemorrhage, of which 4 (44.4%) had prophylactic Low molecular weight heparins (LMWHs). In the survival analysis of Kaplan Meyer, patients who received prophylactic treatment with LMWHs had a higher survival rate with an average of 298.5 days compared to 239.3 of those who did not (p&gt; 0.05). There were no significant variables in the multivariate analysis for thrombotic or haemorrhagic events. Conclusion and Discussion: The demographic and clinical characteristics of our patients were similar to those reported in other international publications. The predictive scale of Khorana was not validated in our study, in contrast, the modified ASCO 2013 scale was closer to our results. The creation of a precise predictive model would help to delineate the benefit of prophylactic anticoagulation in high-risk patients. Long-term prophylaxis with LMWHs has demonstrated a reduction of thrombotic events without significantly increasing the fatal haemorrhagic episodes, also demonstrating greater long-term survival, independent of thrombotic events. Randomized prospective studies are needed to demonstrate its benefits.

Safety of Direct Acting Oral Anticoagulants (DOACs) in Comparison to Low Molecular Weight Heparin (LWMH) in Gastrointestinal and Genito-Urinary Cancers

Introduction:DOACs are absorbed in the gastrointestinal (GI) tract and DOAC elimination is primarily through the GI and genitourinary (GU) systems. The safety of DOACs in cancer associated thrombosis in subjects with malignant lesions in GI and GU malignancies has been of concern. Studies have been sparse and data conflicting.Methods:We identified patients with active GI and GU malignancies from July 2001 to July 2020 with confirmed VTE at our institution. Patients who received either enoxaparin or a DOAC (apixaban or rivaroxaban) were included in the study. Demographic, disease characteristics, VTE data and events were extracted from electronic medical records (EMR). Date of anticoagulation (AC) initiation was based on the first order and/or prescription of the anticoagulant. Patients were followed either to the earliest bleeding event (BE) or one year from initiation, whichever occurred first. BEs were categorized based on ISTH guidelines. Variables were compared between LMWH and DOAC cohorts, as well as between the apixaban and rivaroxaban cohorts, using t-tests for continuous variables and chi-squared tests or Fisher's exact test for categorical variables.Results:We identified a total of 206 patients, 159 in the DOAC and 47 in the LWMH groups. Table 1 describes the baseline characteristics of the study populations. Median age of patients, gender and BMI were comparable for all groups. When evaluated for type of cancer, 66.6% of patients had active GI malignancy while 33.3% had active GU tumors. The majority of the patients given DOACs had a better ECOG status than those in the LMWH group (p=0.0023), but no difference was noted for ECOG status between DOACs (p=0.69). Most patients had metastatic disease. The majority of the VTE events were in the form of DVTs. Concomitant aspirin intake was 9.4% in DOAC and 4.2% in LMWH groups. Cancer subtypes and AC choice data are given in detail in Table 2.LMWH use was higher in blacks and somewhat lower in the Hispanic population (Table 1). When anticoagulation choice was examined by primary tumor site (Table 2), disproportionately more patients with GU tumors were placed on LMWH while more GI cancers were given a DOAC (p=0.014). Extent and stage of the cancer did not appear to bias anticoagulant choice (p=0.62). Within the DOACs, rivaroxaban use was higher in the GI cancers but considerably less used in the GU malignancies (p=0.00049).There was one recurrent thrombosis in each of the apixaban (1/86) and the rivaroxaban (1/73) cohorts. There were no recurrent events in the LMWH (0/47) cohort.The majority of patients in the DOAC and LMWH groups, 88.1% and 86.4%, had no CRNMB or major bleeding events in the 1-year period after the initiation of the therapeutic AC (Table 3). Combined BE (clinically relevant non-major bleeding [CRNMB] and major bleeding rates) with apixaban, rivaroxaban and LMWH were 17.4% (15/86), 20.5% (15/73), and 19.1% (9/47) respectively. There were no fatal bleeding episodes in any of the groups. Most of the bleeding events on DOACs and LMWHs occurred in the same organ system as the primary cancer (Table 3) but there was no statistically significant difference in bleeding events between patients on DOACs or LMWH for GI, GU or all cancer types (p=0.63, 0.75 and 0.97 respectively). Within DOACs, we also noted no statistically significant difference in the bleeding events with apixaban as compared to rivaroxaban in patients with GI primary, GU primary or all cancer types together, (p=0.47, 0.94 and 0.62 respectively).Conclusion:No significant differences in major/CRNM bleeding events were found for patients with GI or GU cancer associated thrombosis given DOACs (apixaban/rivaroxaban) vs enoxaparin. The tumor site is often the site of bleeding, but no differences in tumor-specific site bleeding could be shown by anticoagulant choice. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Anticoagulation for the Treatment of Acute Venous Thromboembolism a Systematic Review and Network Meta-Analysis

Background: There are several anticoagulation strategies are suggested for patients with acute venous thromboembolism (VTE), however proof, especially for cancer-associated VTE, is lacking of which strategy is optimal choice. We aimed to compare efficacy and safety outcomes among various anticoagulation strategies for patients with VTE using a systematic review and network meta-analysis. Methods: A systematic literature search was conducted using PUBMED, EMBASE, and Cochrane Library Central Register of Controlled Trials and clinical trial registries from inception through June 1, 2021. We search for randomized clinical trials (RCTs) comparing the recurrent VTE and bleeding outcomes of various anticoagulation strategies (low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux combined with vitamin K antagonists(VKA)); direct oral anticoagulants) for patients with acute VTE(noncancer or cancer-associated). Extraction of clinical outcomes were performed independently by two authors. A Bayesian network meta-analysis was applied to analyze the data. The primary efficacy endpoint was recurrent VTE episodes, the primary safety endpoint was major bleeding episodes. Secondary efficacy endpoints were fatal recurrent venous thromboembolism, the secondary safety endpoints were fatal bleeding episodes, all-cause mortality and major gastrointestinal bleeding. Results: 12117 citations were identified, 9850 unique citations, 54 RCTs met the inclusion criteria. Included trials recruited 49952 VTE participants with cancer or non-cancer. The findings showed that UFH-VKA likely increases recurrent VTE compared to LMWH-VKA (hazard ratio ((HR) 1·44(1·16,1·80), apixaban was probably the most effective strategy (surface under the cumulative ranking curve (SUCRA) 87·6%). Subgroup analysis for VTE patients with cancer shown that LMWH (HR 0·61(0·40,0·89)) and apixaban (HR 0·40(0·21,0·66)) were associated with less recurrent VTE events compared with LMWH-VKA. Apixaban (HR 0·44(0·24,0·73)) lowered the rate of major bleeding compared with the LMWH–VKA. The apixaban was probably the safest strategy (SUCRA 96·5%). For patients with cancer-associated acute VTE, although apixaban group experienced less major bleeding events compared with LMWH-VKA, it was not statically significant (HR 0·80(0·36,1·55)). Interpretation: Apixaban seems to be superior to other anticoagulation strategies for treatment of VTE with cancer. Funding: This work received research grant from The Second Hospital of Anhui Medical University(Hefei, Anhui 230601, China). Grant number: LBSART202007. Declaration of Interest: None to declare.

Risk of Thromboembolic Disease and Hemorrhage in Patients with Multiform Glioblastoma

Introduction: Glioblastoma Multiforme (GBM) is the most frequent malignant brain tumor, with an aggressive course and a short life expectancy despite standard treatment (chemotherapy and radiotherapy). The possibility of the development of Thrombotic Events (VTE) with this type of cancer is frequent. We designed this study to determine the risk of presenting VTE and hemorrhagic events in patients affected by GBM. Methods: Observational retrospective study of patients with GBM diagnosis at the General University Hospital of Ciudad Real between 2012 and 2015. The demographic characteristics of patients were studied, predictive models were compared, and a survival analysis was performed. Results: 77 patients were studied, 42 (55.3%)/34 (44.7%), men and women respectively, with an average age of 66.42 years. 13 (16.9%) presented VTE; of which 10 (61.54%) in the form of Deep Venous Thrombosis (DVT), 3 (23.08%) Pulmonary Embolism (PE) and 2 (15.38%) mixed events. The quality of life according to the performance status ECOG scale at the moment of diagnosis was 1 in 42 (15.38%) patients, and at the time of VTE, 5 (41.7%) had a value of 2, and 4 (33.3.3 %) registered 3. In the group that developed VTE according to the predictive model of risk for thrombosis in Khorana 5 (38.5%) had low risk and 8 (61.5%) intermediate; on the ASCO 2013 modified scale 5 (38.5%) had an Intermediate risk and 8 (61.5%) high. With a median, 1 year follow-up, 64 (84.2%) patients died, with an average time after the diagnosis of 279.09 days (216.6-341.6) (SE 31,8). 2 (2.6%) of the patients presented a greater haemorrhagic event and 7 (7.9%) cerebral haemorrhage, of which 4 (44.4%) had prophylactic Low Molecular Weight Heparins (LMWHs). In the survival analysis of Kaplan Meyer, patients who received prophylactic treatment with LMWHs had a higher survival rate with an average of 298.5 days compared to 239.3 of those who did not (p &gt;0.05). There were no significant variables in the multivariate analysis for thrombotic or haemorrhagic events. Conclusion and Discussion: The demographic and clinical characteristics of our patients were similar to those reported in other international publications. The predictive scale of Khorana was not validated in our study, in contrast, the modified ASCO 2013 scale was closer to our results. The creation of a precise predictive model would help to delineate the benefit of prophylactic anticoagulation in high-risk patients. Long-term prophylaxis with LMWHs has demonstrated a reduction of thrombotic events without significantly increasing the fatal haemorrhagic episodes, also demonstrating greater long-term survival, independent of thrombotic events. Randomized prospective studies are needed to demonstrate its benefits.

Current Diagnosis and Management of Primary Chylomicronemia

Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher. PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-of-function mutations in LPL pathway genes ( LPL , LMF1 , GPIHBP1 , APOC2 , and APOA5 ). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive.The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life.Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease.Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.

Tumor lysis syndrome risk in outpatient versus inpatient administration of venetoclax and hypomethlators for acute myeloid leukemia.

Venetoclax along with hypomethylating agents (HMAs) is the new standard therapy for older patients with acute myeloid leukemia (AML) not fit for intensive frontline induction chemotherapy. Venetoclax is associated with fatal episodes of tumor lysis syndrome (TLS) in chronic lymphocytic leukemia (CLL), and recommendations are for its initiation for CLL and AML in the inpatient setting with close monitoring. Herein, we evaluated the safety of outpatient venetoclax ramp up when given in addition to HMAs for the treatment of AML. We conducted a retrospective review of patients diagnosed with AML at our institution from 12/1/2016 until 7/1/2020. We identified patients who received HMAs and venetoclax for AML, either as frontline or relapsed/refractory therapy. Records were reviewed for evidence of laboratory or clinical tumor lysis episodes in all patients. Between 12/1/2016 and 7/1/2020 43, patients at our institution received venetoclax/HMA for the treatment of AML. Thirty-nine patients (91%) had venetoclax initiation and ramp up in the outpatient setting. One episode of laboratory TLS (2.5%) was identified. This patient required admission to the hospital for rasburicase and IV fluids with resolution of the laboratory effects without resultant clinical TLS. There were no episodes of clinical TLS in either group. Thirty-day mortality from venetoclax initiation was 0% in both groups. Our experience with HMAs and venetoclax showed that outpatient ramp up of venetoclax is safe with a very low risk of laboratory TLS (2.5%) and no evidence of clinical TLS within our cohort.