Multiple Organ Failure Research Articles

Генетически-фенотипический профиль детей с атипичным гемолитико-уремическим синдромом

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease caused by dysregulation of the alternative complement pathway as a result of mutations in complement genes or the formation of antibodies (AB) to some of the complement factors. Identification of the gene mutations incidence and the corresponding phenotypic features in pediatric patients with aHUS in Russia is aimed at improving the diagnosis and prognosis of the disease as well as treatment tactics planning for patient management. The purpose of this research was to determine the patterns of progression, prognosis and outcomes of aHUS in children depending on their genetic profile. Materials and methods used: the Article represents data from a retro- and prospective analyses of the characteristics of the course of aHUS in 172 children depending on their genetic profile performed in Jan. 2012-Feb. 2022. The sporadic form of aHUS was diagnosed after exclusion of the other forms of thrombotic microangiopathy (TMA), the familial form (in cases with the familial records), the acquired (CFH-Ab HUS) in cases with AB increase to factor H. AutoAb against factor H was determined by enzyme-linked immunosorbent assay (ELISA-VIDITEST anti-complement factor H). The search for mutations (n=167) was carried out using Next-generation Sequencing (NGS) and Sanger sequencing methods. Results: the sporadic form of aHUS was diagnosed in 96.9% of cases, familial in 3.1% and CFH-Ab HUS in 23.8%. The genetic nature of aHUS was confirmed in 53.4% of cases. Pathogenic mutations were detected in 8.6% of cases, probably pathogenic in 42.8% and those with unclear clinical significance in 46.8%. The complement genes mutations were detected in 88.5% of cases and mutations of genes not related to the complement system (ADAMTS13, DGKE, INF2) in 11.5%. The most frequently identified mutations were in the CFH (17.1%), C3 (12.9%) and CD46 (12.9%) genes and less frequently in CFI (7.1%), THBD (5.7%), CFHR5 (5.7%) and CFB (1.4%). In children with CFH-Ab HUS, the CFHR1/CFHR3 deletion was detected in 87.8% of cases, including in 19.4% in combination with mutations of unknown clinical significance. Multiple organ failure syndrome had developed in 77.8% of cases in children with pathogenic/probably pathogenic mutations, in 85.3% in patients with mutations of unknown clinical significance, in 91.8% in patients without mutations and in 83.3% in patients with CFHR1/CFHR3 deletion. Chronic kidney disease (CKD) stages 3 to 5 in sporadic/familial aHUS, regardless of genetic profile, had counted for 14.5% and 16.7% in CFH-Ab HUS. Lethal outcome occurred in 4.3% of cases in the presence of mutations, in 4.9% in the absence of mutations and in 2.8% in cases of CFHR1/CFHR3 deletion. Relapses of aHUS prior to the Eculizumab treatment had developed more often in the presence of CFHR1/CFHR3 mutations and deletion in comparison with children without mutations (31.4% v. 13.1%, p=0.0313 and 44.4% v. 13.1%, p= 0.004). Relapse of aHUS after discontinuation of the Eculizumab therapy had developed in 16.4% of cases. Risk factors for the relapse of aHUS were as follows: patient’s age above 12 months old at the time of the development of aHUS, severe arterial hypertension in the acute period, the use of Eculizumab at the fourth week after the onset of the disease and/or later, recurrent course of aHUS and the presence of CKD prior to the start of the Eculizumab therapy. Conclusion: The genetic profile of patients does not determine the severity and outcome of aHUS though it does affect the relapse rate. The prognosis and survival of patients with aHUS are determined by the severity of the acute period and the timeliness of the complement blocking therapy management.

Alliin mitigates the acute kidney injury by suppressing ferroptosis via regulating the Nrf2/GPX4 axis.

Acute kidney injury (AKI) is a clinical syndrome that is characterized by a sudden loss of kidney function, leading to severe metabolic disorders, multiple organ failure, and even death. Recent studies have strengthened the evidence for ferroptosis in AKI development. Alliin, a sulfur-containing amino acid with multiple pharmacological functions, was claimed with promising antioxidant and anti-inflammation effects in protecting organ damages. Herein, Alliin's potential in AKI treatment was investigated by exploring its impact on ferroptosis, providing a new strategy for clinical AKI treatments. Cecal ligation and puncture (CLP) modeling was performed on rats, followed by treated with 7.5 and 15mg/kg/day of alliin for 6days. A declined survival rate, severe renal pathological changes, renal dysfunction, and enhanced inflammatory state were observed in CLP-treated rats, which were remarkably alleviated by alliin. Moreover, increased MDA levels, declined SOD activity, and downregulated Nrf2, GPX4, and xCT in CLP-treated rats were notably reversed by alliin. To explore potential mechanisms of alliin, NRK-52E cells were stimulated with 1μg/mL LPS for 24h, followed by culturing with 30 and 100μM of alliin for 24h. Reduced cell viability, enhanced apoptosis, increased ROS production, boosted MDA level, and declined SOD activity were observed in LPS-stimulated NRK-52E cells, accompanied by downregulated Nrf2, GPX4, and xCT, which were strikingly ameliorated by alliin. Additionally, the influence of alliin on cell viability, oxidative stress (OS), and ferroptosis in LPS-stimulated NRK-52E cells were markedly abolished by silencing Nrf2. Collectively, alliin mitigated AKI by suppressing ferroptosis via regulating the Nrf2/GPX4 axis.

Circulating inflammatory cytokines and the risk of sepsis: a bidirectional mendelian randomization analysis

BackgroundSepsis is a life-threatening condition that is characterized by multiorgan dysfunction and caused by dysregulated cytokine networks, which are closely associated with sepsis progression and outcomes. However, currently available treatment strategies that target cytokines have failed. Thus, this study aimed to investigate the interplay between genetically predicted circulating concentrations of cytokines and the outcomes of sepsis and to identify potential targets for sepsis treatment.MethodsData related to 35 circulating cytokines in 31,112 individuals (including 11,643 patients with sepsis) were included in genome-wide association studies (GWASs) from the UK Biobank and FinnGen consortia. A bidirectional two-sample Mendelian randomization (MR) analysis was performed using single nucleotide polymorphisms (SNPs) to evaluate the causal effects of circulating cytokines on sepsis outcomes and other cytokines.ResultsA total of 35 inflammatory cytokine genes were identified in the GWASs, and 11 cytokines, including Interleukin-1 receptor antagonist (IL-1ra), macrophage inflammatory protein 1 (MIP1α), IL-16, et al., were associated with sepsis outcome pairs according to the selection criteria of the cis-pQTL instrument. Multiple MR methods verified that genetically predicted high circulating levels of IL-1ra or MIP1α were negatively correlated with genetic susceptibility to risk of sepsis, including sepsis (28-day mortality), septicaemia, streptococcal and pneumonia-derived septicaemia (P ≤ 0.01). Furthermore, genetic susceptibility of sepsis outcomes except sepsis (28-day mortality) markedly associated with the circulating levels of five cytokines, including active plasminogen activator inhibitor (PAI), interleukin 7 (IL-7), tumour necrosis factor alpha (TNF-α), beta nerve growth factor (NGF-β), hepatic growth factor (HGF) (P < 0.05). Finally, we observed that the causal interaction network between MIP1α or IL-1ra and other cytokines (P < 0.05).ConclusionsThis comprehensive MR analysis provides insights into the potential causal mechanisms that link key cytokines, particularly MIP1α, with risk of sepsis, and the findings suggest that targeting MIP1α may be a potential strategy for preventing sepsis.

Thrombocytopenia in Plasmodium vivax Malaria: A Report from a Sub-zonal Hospital in Western Rajasthan

Abstract Background: Malaria continues to be a major public health problem in India. Vivax malaria is being increasingly seen with thrombocytopenia. The reported prevalence of the same has been extremely variable and its significance is not well established. This study was conducted to ascertain the prevalence and severity of thrombocytopenia in vivax malaria and assess the outcome of cases with severe thrombocytopenia. A secondary objective was to compare the clinical and laboratory profile of cases of vivax malaria with falciparum malaria and mixed infection. Materials and Methods: This hospital-based prospective study was carried out in the department of general medicine at a sub-zonal hospital in Western Rajasthan in the year 2022. Consecutive febrile patients with a diagnosis of malaria were included in the study after ruling out coexistent alternate infections. Results: A total of 396 cases were enrolled. Ninety-nine percent of patients were male. The mean age of the study group was 32.1 years. A total of 328 (90.8%) out of 361 vivax malaria cases had thrombocytopenia (platelet count &lt;150 × 103 μL) with 26.5% having severe thrombocytopenia (platelet count &lt;50 × 103 μL). The mean defervescence duration was 44.4 h in vivax malaria. 3.4% of severe vivax malaria cases required intensive care unit care due to hypotension, respiratory distress, and multiorgan dysfunction, and none of them had any bleeding manifestations. All cases recovered well after standard treatment. There was a significant statistical difference between the mean platelet count among the three types of malaria: vivax, falciparum, and mixed (vivax + falciparum infections) (P = 0.03). Similarly, on applying Chi-square test, there was a significant difference in severe thrombocytopenia across the groups (P = 0.01). Conclusion: There is a high prevalence of thrombocytopenia in vivax malaria including severe thrombocytopenia. In the majority of cases, this thrombocytopenia does not result in any adverse event, and cases respond well to conventional treatment. Clinicians need to be aware of the extent and severity of thrombocytopenia in vivax malaria and rule out this treatable condition in endemic areas with a high prevalence of other coexistent infections causing thrombocytopenia.

The foremost and greatest barrier to end-stage heart failure treatment: the impact of caregiver shortage.

We examined the number of patients abandoning cardiac replacement therapy due to the inability to secure a designated caregiver. At Osaka University Hospital Heart Center, when we receive a consultation for a patient with severe heart failure from another hospital, a heart failure team makes a visit to the referring hospital as soon as possible. We retrospectively analyzed this hospital-visit database. We received 199 severe heart failure consultations from 2016-2023. Issues identified during hospital visits included age ≥ 65years (8%), inability to confirm the patient's intention (8.5%), and explicit refusal of therapy (2.5%). Medical problems included multiple organ failure (18.1%), obesity (13.1%), diabetes (9.5%), malignancy (5.5%), chronic dialysis (1.0%), and other systemic diseases (12.6%). Adherence problems included poor medication compliance (3.5%), history of heavy drinking (2.5%), and smoking (2.0%). Social problems included inadequate family support in 16.1% of patients. Of the 199 patients, 95 (48.0%) proceeded to a heart transplant and LVAD indication review meeting at Osaka University Hospital. The remaining 104 patients (52.0%) did not proceed to the meeting. Reasons included improvement of heart failure with conservative treatment in 37 cases (35.6%), death before discussion in 21 cases (20.2%), medical contraindications in 18 cases (18.3%), lack of caregivers in 18 cases (18.3%; 9.5% of 199 cases), and patient refusal in 5 cases (4.8%). Approximately 10% of patients consulted at Osaka University Hospital Heart Center for severe heart failure abandoned cardiac replacement therapy due to the lack of caregivers.

39 Safety profile of belzutifan monotherapy in patients with renal cell carcinoma: A pooled analysis of 4 clinical trials

Abstract Background The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, is indicated in the United States for the treatment of certain patients with von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery and for patients with advanced RCC previously treated with a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. Due to its unique mechanism of action, belzutifan has a distinct safety profile. We characterized the safety profile of belzutifan monotherapy in a post hoc pooled analysis of patients with previously treated advanced clear cell RCC in the phase 1 LITESPARK-001 (NCT02974738), phase 3 LITESPARK-005 (NCT04195750), and phase 2 LITESPARK-013 (NCT04489771) studies and patients with RCC associated with VHL disease in the phase 2 LITESPARK-004 study (NCT03401788). Methods All patients who received ≥1 dose of belzutifan 120 mg orally once daily across the 4 studies were included. Severity of adverse events (AEs) were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 or 5.0, and were descriptively summarized. Results A total of 576 patients were included (n = 58 [including 3 patients with advanced solid tumors other than RCC], LITESPARK-001; n = 381, LITESPARK-005; n = 76, LITESPARK-013; and n = 61, LITESPARK-004). Overall, 572 patients (99.3%) had ≥1 all-cause AE and 355 patients (61.6%) had ≥1 grade 3-5 AE. AEs led to dose modification (reduction, interruption, or discontinuation) in 288 patients (50.0%), although treatment discontinuation for AEs occurred in 37 patients (6.4%). The most common all-grade AEs were anemia (including patients with decreased hemoglobin; n = 485 [84.2%]; grade 3 or 4, n = 166 [28.8%]), fatigue (n = 246 [42.7%]; grade 3, n = 16 [2.8%]), nausea (n = 139 [24.1%]; grade 3, n = 5 [0.9%]), and dyspnea (n = 123 [21.4%]; grade 3 or 4, n = 10 [1.7%]). Hypoxia was reported in 94 patients (16.3%); grade 3 or 4 hypoxia occurred in 57 patients (9.9%). Summary and time to first onset of adverse drug reactions (AEs considered associated with belzutifan), including anemia and hypoxia, are reported in the table. Among 485 patients with anemia or decreased hemoglobin, 111 (22.9%) were treated with erythropoiesis-stimulating agent (ESA) only, 85 (17.5%) were treated with blood transfusions only, and 62 (12.8%) were treated with ESA and blood transfusions. Among 94 patients with hypoxia, 66 (70.2%) were treated with oxygen therapy. Treatment-related AEs occurred in 526 patients (91.3%) and 217 (37.7%) experienced a grade 3-5 treatment-related AE. One grade 5 adverse event (multiple organ dysfunction syndrome) was considered related to treatment. Conclusions To date, this is the largest pooled safety dataset for belzutifan monotherapy in patients with RCC. The results provide an in-depth characterization of the safety profile for belzutifan and the associated AE management strategies.

Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature.

Human granulocytotropic anaplasmosis (HGA) is a zoonotic tick-borne bacterial infection caused by Anaplasma phagocytophilum. While most cases are reported from North America, HGA has been recognized as an emerging disease in several regions of the world in recent decades. Most available data comes from case reports, case series and retrospective studies, while prospective studies and clinical trials are largely lacking. To obtain a clearer picture of the currently known epidemiologic distribution, clinical and paraclinical presentation, diagnostic aspects, complications, therapeutic aspects, and outcomes of HGA, we systematically reviewed the literature and analyzed and summarized the data. Cases of HGA are reported from all continents except from Antarctica. HGA primarily presents as an unspecific febrile illness (88.5% of the cases) often accompanied by thrombocytopenia (71.8% of the cases), abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8% of the cases). Although we found complications reported in a total of 40.5% of the reviewed cases and severe and even life-threatening complications are not infrequent (e.g. acute renal failure 9.8%, multi organ failure 7.5%, ARDS 6.3%, a.o.), sequelae are rare (2.1% of the cases) and lethality is low (3.0% of the cases). Treatment with doxycycline shows a rapid response, with the fever subsiding in the majority of patients within one day of starting treatment. Unlike in human monocytotropic ehrlichiosis (HME), reports of opportunistic infections complicating HGA are rare. HGA during pregnancy does not appear to be associated with unfavorable outcomes. In addition, our analysis provides some evidence that HGA may differ in clinical aspects and laboratory characteristics in different regions of the world. Overall, the data analyzed indicates a non-negligible bias in reporting/publication, so a certain degree of caution is required when generalizing the data.

Takotsubo cardiomyopathy associated with free wall rupture and ventricular septal defect: a case report.

Takotsubo cardiomyopathy is a rare cardiac presentation. It can be associated with severe complications such as hemodynamically significant ventricular septal defect and cardiac free wall rupture. In cases of mechanical complications, surgical repair is often indicated. Despite best medical and surgical efforts, patients with Takotsubo cardiomyopathy and mechanical complications carry significant mortality risk. Herein, we present an unusual presentation of Takotsubo cardiomyopathy that was associated with a mechanical complication. Although the patient underwent a successful surgical repair, she passed away from multiorgan failure during the postoperative period.

Neuroinflammatory Approach to Surgical Trauma: Biomarkers and Mechanisms of Immune and Neuroendocrine Responses

The severity and invasiveness of clinical outcomes from organic responses to trauma are influenced by individual, surgical, and anesthetic factors. A stress response elicits neuroendocrine and immune reactions that may lead to multi-organ dysfunction. The degree of neuroinflammatory reflex activation from trauma can increase pro-inflammatory cytokine production, leading to endothelial dysfunction, glycocalyx damage, neutrophil activation, and multisystem tissue destruction. A shift in patient treatment towards a neuroinflammatory perspective has prompted a new evaluation protocol for surgical patients, required to understand surgical pathogenesis and its link to chosen anesthetic–surgical methods. The goal of this study is to summarize and disseminate the present knowledge about the mechanisms involved in immune and neuroendocrine responses, focusing on video laparoscopic surgeries. This article outlines various measures cited in the literature aimed at reducing the burden of surgical trauma. It reviews anesthetic drugs, anesthetic techniques, and intensive care procedures that are known to have immunomodulatory effects. The results show a preference for more sensitive inflammatory mediators to tissue trauma serving as care tools, indicators for prognosis, and therapeutic outcomes.

Visceral adipose tissue for predicting severe acute pancreatitis

Background &amp; objectives Acute pancreatitis (AP) is a well known gastrointestinal cause of hospital admissions. There is a proven association between the severity of AP and obesity due to increased rates of local complications, multiple organ failure and mortality. Increased visceral adiposity is reported to be a better predictor of severe pancreatitis than body mass index (BMI) in many studies. This study aimed to assess the relationship between visceral adiposity and the severity of AP by measuring the visceral adipose tissue (VAT) area. Methods This single-centre, prospective study was conducted on consecutive individuals admitted with AP. The severity of AP was correlated with the VAT area, as estimated between 48 and 72 h of admission. Results Seventy-four individuals with AP were recruited during the study period. The overall study cohort’s mean±SD for VAT area was 128.06±34.22 cm2. The VAT area was significantly larger in individuals with severe pancreatitis (141.01±33.75cm2) than in those with mild or moderate pancreatitis (115.11±29.85 cm2). The sensitivity, specificity and area under the receiver operating characteristics (AUROC) of VAT were 78.4 per cent, 54.1 per cent and 0.722 in predicting severe AP, respectively. Interpretation &amp; conclusions There is a significant association between severe AP and VAT. With the worldwide increase in obesity incidences, incorporating VAT into one of the prognostic indices for AP needs to be further explored.

COVID-19-Associated Sepsis: Potential Role of Phytochemicals as Functional Foods and Nutraceuticals

The acute manifestations of coronavirus disease 2019 (COVID-19) exhibit the hallmarks of sepsis-associated complications that reflect multiple organ failure. The inflammatory cytokine storm accompanied by an imbalance in the pro-inflammatory and anti-inflammatory host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to severe and critical septic shock. The sepsis signature in severely afflicted COVID-19 patients includes cellular reprogramming and organ dysfunction that leads to high mortality rates, emphasizing the importance of improved clinical care and advanced therapeutic interventions for sepsis associated with COVID-19. Phytochemicals of functional foods and nutraceutical importance have an incredible impact on the healthcare system, which includes the prevention and/or treatment of chronic diseases. Hence, in the present review, we aim to explore the pathogenesis of sepsis associated with COVID-19 that disrupts the physiological homeostasis of the body, resulting in severe organ damage. Furthermore, we have summarized the diverse pharmacological properties of some potent phytochemicals, which can be used as functional foods as well as nutraceuticals against sepsis-associated complications of SARS-CoV-2 infection. The phytochemicals explored in this article include quercetin, curcumin, luteolin, apigenin, resveratrol, and naringenin, which are the major phytoconstituents of our daily food intake. We have compiled the findings from various studies, including clinical trials in humans, to explore more into the therapeutic potential of each phytochemical against sepsis and COVID-19, which highlights their possible importance in sepsis-associated COVID-19 pathogenesis. We conclude that our review will open a new research avenue for exploring phytochemical-derived therapeutic agents for preventing or treating the life-threatening complications of sepsis associated with COVID-19.

Effect of Continuous Infusion Therapy With Low-dose Terlipressin Combined With Norepinephrine on Hemodynamics, Inflammatory Markers, and Prognosis in Patients With Severe Septic Shock.

The present study investigated the impact of continuous infusion therapy with low-dose terlipressin (TP) combined with norepinephrine on hemodynamics, inflammatory markers, and prognosis in patients with severe septic shock. Seventy-four patients with severe septic shock were randomly assigned to either a control group (n = 37) or an observation group (n = 37). Patients in the control group received norepinephrine alone, while those in the observation group received a continuous infusion of low-dose TP in addition to norepinephrine. To assess the effect of treatment, a set of clinical parameters was evaluated in both groups before and after treatment. These parameters included hemodynamic indicators (heart rate [HR], mean arterial pressure [MAP], central venous pressure [CVP], cardiac index [CI], and systemic vascular resistance index [SVRI]), levels of serum inflammatory markers (interleukin-8 [IL-8], tumor necrosis factor-α [TNF-α], and hypersensitivity C-reactive protein [hs-CRP]), renal function indicators (blood urea nitrogen [BUN], serum creatinine [SCr], and cystatin C [Cys-C]), serum procalcitonin (PCT), and lactate, as well as lactate clearance rate (LCR). Additionally, the acute physiology and chronic health evaluation II (APACHE II) score, 28-day mortality rate, multiple organ dysfunction syndrome (MODS) incidence rate, and adverse reaction incidence were also determined. Compared to baseline values, MAP, CVP, CI, SVRI, and LCR increased in both groups after treatment, while HR, levels of IL-8, TNF-α, hs-CRP, BUN, SCr, PCT, and lactate all decreased. Additionally, APACHE II scores also decreased. Furthermore, the observation group exhibited higher MAP, CVP, CI, SVRI, and LCR, along with lower HR, levels of IL-8, TNF-α, hs-CRP, BUN, SCr, PCT, and lactate than the control group after treatment. The observation group also had lower APACHE II score, 28-day mortality rate, MODS incidence rate, and adverse reaction incidence than the control group after treatment (P < .05). Continuous infusion therapy with low-dose TP combined with norepinephrine was effective in treating patients with severe septic shock, improving hemodynamic parameters, reducing the levels of inflammatory markers, promoting renal function recovery, and reducing the mortality rate.

Human monocytotropic ehrlichiosis-A systematic review and analysis of the literature.

Human monocytotropic ehrlichiosis (HME) is a tick-borne bacterial infection caused by Ehrlichia chaffeensis. Most available data come from case reports, case series and retrospective studies, while prospective studies and clinical trials are largely lacking. To obtain a clearer picture of the currently known epidemiologic distribution, clinical and paraclinical presentation, diagnostic aspects, complications, therapeutic aspects, and outcomes of HME, we systematically reviewed the literature and analyzed and summarized the data. Cases of HME are almost exclusively reported from North America. Human infections due to other (non-chaffeensis) Ehrlichia spp. are rare. HME primarily presents as an unspecific febrile illness (95% of the cases), often accompanied by thrombocytopenia (79.1% of the cases), leukopenia (57.8% of the cases), and abnormal liver function tests (68.1% of the cases). Immunocompromized patients are overrepresented among reviewed HME cases (26.7%), which indicates the role of HME as an opportunistic infection. The incidence of complications is higher in immunocompromized compared to immunocompetent cases, with ARDS (34% vs 19.8%), acute renal failure (34% vs 15.8%), multi organ failure (26% vs 14.9%), and secondary hemophagocytic lymphohistiocytosis (26% vs 14.9%) being the most frequent reported. The overall case fatality is 11.6%, with a significant difference between immunocompetent (9.9%) and immunocompromized (16.3%) cases, and sequelae are rare (4.2% in immunocompetent cases, 2.5% in immunocompromised cases).

Whole-exome sequencing revealed a novel mutation of the ALMS1 gene in a Chinese family with Alström syndrome: a case report

BackgroundAlström syndrome (AS) is a rare autosomal recessive disorder that leads to multiple organ fibrosis and failure. Precise diagnosis from the clinical symptoms is challenging due to its highly variabilities and its frequent confusion with other ciliopathies and genetic diseases. Currently, mutations in the ALMS1 gene have been reported as a major cause of AS, thus, it is crucial to focus on the detection and discovery of ALMS1 mutations.Case presentationWe present a case of a 13-year-old Chinese boy weighing 70 kg and standing 168 cm tall. He has two younger brothers. Their parents hail from different ancestral homes in eastern and northern China. The patient’s primary clinical findings included visual impairment at the age of four and progressive hearing loss starting at the age of ten. Subsequently, at the age of twelve, the patient developed hyperlipidaemia and hyperinsulinemia. Ultrasonographic findings indicated the presence of gallstones and mild fatty liver. His Body Mass Index (BMI) significantly increased to 25 kg/m2 (ref: 18.5–23.9 kg/m2). Additionally, echocardiography revealed mild mitral and tricuspid regurgitation. Ultimately, Whole Exome Sequencing (WES) identified a new missense mutation in the ALMS1 gene (NG_011690.1 (NM_015120): c.9536G > A (p.R3179Q)). This missense mutation generated an aberrant splicer and disrupted the stability and hydrophobicity of proteins, which preliminarily determined as “ likely pathogenic”. Therefore, considering all the above symptoms and molecular analysis, we deduced that the patient was diagnosed with AS according to the guidelines. We recommended that he continue wearing glasses and undergo an annual physical examination.ConclusionIn this case report, we report a novel homozygous ALMS1 mutation associated with AS in the Chinese population, which expands the mutation spectrum of ALMS1. Genetic testing indeed should be incorporated into the diagnosis of syndromic deafness, as it can help avoid misdiagnoses of AS. While there is no specific treatment for AS, early diagnosis and intervention can alleviate the progression of some symptoms and improve patients’ quality of life.

Dysglycaemia in Ebola virus disease: a retrospective analysis from the 2018 to 2020 outbreak

BackgroundEbola virus disease (EVD) is associated with multisystem organ failure and high mortality. Severe hypoglycaemia is common, life-threatening, and correctable in critically ill patients, but glucose monitoring may be limited in EVD treatment units. MethodsWe conducted a retrospective review of patients admitted to EVD treatment units in Butembo and Katwa, Eastern DRC. Glucose measurements were done using a handheld glucometer at the bedside or using the Piccolo xpress Chemistry Analyzer on venous samples. Findings384 patients (median age 30 years (interquartile range, IQR, 20-45), 57% female) and 6,422 glucose measurements (median 11 per patient, IQR 4 to 22) were included in the analysis. Severe hypoglycaemia (≤2.2mmol/L) and hyperglycaemia (>10mmol/L) were recorded at least once during the ETU admission in 97 (25%) and 225 (59%) patients, respectively. A total of 2,004 infusions of glucose-containing intravenous solutions were administered to 302 patients (79%) with a median cumulative dose of 175g (IQR 100 to 411). The overall case fatality rate was 157/384 (41%) and was 2.2-fold higher (95%CI 1.3 to 3.8) in patients with severe hypoglycaemia than those without hypoglycaemia (p=0.0042). In a multivariable Cox proportional hazards model, periods of severe hypoglycaemia (adjusted hazard ratio (aHR) 6.2, 95%CI 3.2-12, p<0.0001) and moderate hypoglycaemia (aHR 3.0, 95%CI 1.9-4.8, p<0.0001) were associated with elevated mortality. InterpretationHypoglycaemia is common in EVD, requires repeated correction with intravenous dextrose solutions, and is associated with mortality. FundingThis study was not supported by any specific funding.

A comparison between direct true lumen versus conventional cannulation for management of acute type- aortic dissection patients.

Objective: To compare the postoperative outcomes while using direct true lumen approach versus conventional cannulation approach in management of acute type-A aortic dissection patients. Study Design: Randomized Clinical Trial. Setting: Department of Vascular Surgery, Combined Military Hospital, Rawalpindi. Period: 1st June 2022 to 31st December 2022. Methods: A total of 22 patients age more than 18 years who presented in CMH Emergency Department with acute type A aortic dissection were included in this study. In group A (11 patients) were managed with direct true lumen cannulation while in group B (11 patients) were managed with conventional (axillary/femoral) cannulation. In both groups intra-operative parameters like procedure time, mean time of cardiopulmonary bypass, cross clamp and circulatory arrest time were measured. In both groups, outcome was measured in terms of occurrence of multi-organ failure, acute kidney injury, arrhythmias on ECG and in-hospital mortality. Data was analyzed using SPSS 26. Results: Mean age of our patients were 43.36±2.16yrs in group A while 43.36±2.94yrs in group B. Male gender predominates in both groups (gp A- 81.8% &amp; gp B-90.9%). We found no difference of statistical significance between two groups in terms of various intra-operative parameters like mean duration of procedure in group A was 428.15min and in group B was 427.36 min. Similarly mean circulatory arrest time was 31 min in group A and 29.09 min in group B. Patients in “direct true lumen cannulation” group had significantly shorter duration of intubation. In terms of post-operative outcomes, multi-organ failure occurred in 1 (9.09%) patient in group A while it occurred in 3(27.27%) patients in group B. In hospital mortality occurred in 2(18%) patients in group A as compared to 4(36%) in group B. So better results were observed in “direct true lumen cannulation” group as compared to “conventional (axillary/femoral) cannulation” group. Conclusion: In our study, acute type-A aortic dissection patients who had undergone direct true lumen cannulation during operative management showed better post-operative outcomes.

Breaking the Chain in Organ Failure: Role of Umbilical Cord and Bone Marrow Derived Mesenchymal Stem Cells in Treatment of Severe Acute Pancreatitis

BackgroundPrevious studies showed that MSCs could mitigate damage in the pancreas during acute pancreatitis (AP). However, acute mortality associated with AP was more often a result of persistent failure of remote organs, rather than local damage, especially in severe acute pancreatitis (SAP), and the effect of MSCs may vary depending on their origin. MethodsAn SAP model was induced in 8-week C57BL/6J male mice by retrograde injection of 5% sodium taurocholate solution through the bile duct. SAP mice were divided into the SAP group, UC-MSCs group, and BMSCs group, which were treated with saline, 1×106 UC-MSCs, and 1×106 BMSCs respectively, through the tail vein. After treatment, serum markers, inflammation, and morphology were assessed in the pancreas, kidneys, lungs, and hearts. ResultsMSCs infusion ameliorated the systemic inflammatory response in SAP mice. In the MSCs-treated SAP mice, local tissue injury and inflammation response in the pancreas were alleviated. But more importantly, the renal and lung injury were all significantly and drastically mitigated, and the levels of pro-inflammatory factors such as IL-6, MCP-1, IL-1β, and TNF-α in the kidney, lung and heart were sharply decreased. In terms of origin, UC-MSCs exhibited superior efficacy compared with BMSCs. Furthermore, compared to the normal control mice, UC-MSCs showed an earlier appearance, higher distribution densities, and longer duration of presence in the injured tissue. ConclusionsThis study provides compelling evidence supporting the therapeutic potential of MSCs in SAP treatment and particularly their ability to mitigate multi-organ failure. Our results also suggested that UC-MSCs may offer greater advantages over BMSCs in SAP therapy.

PREDICTIVE VALUE OF SHOCK INDEX, MODIFIED SHOCK INDEX, AND AGE SHOCK INDEX FOR OUTCOMES IN PATIENTS ADMITTED WITH SEPSIS TO THE INTENSIVE CARE UNIT

Sepsis is a life-threatening multi-organ dysfunction resulting in multiple organ failure. Various indices have been developed to predict outcomes in sepsis. Objective: The objective of this study is to evaluate the predictive value of the Shock Index (SI), Modified Shock Index (MSI), and Age Shock Index (ASI) for determining outcomes in patients admitted to ICU with sepsis. Methods: It is a retrospective observational study conducted at the intensive care unit of Shifa International Hospital Islamabad from January 2024 to June 2024. The data was collected from hospital medical records. After screening, 162 patients were included in this study. Demographic data and Clinical data such as vital signs, laboratory results, and clinical diagnosis were collected at admission in the ICU. Data was analyzed using SPSS v25.0. The p-value ≤0.05 was considered significant. Result: The result of the study has shown that 77 patients (47.53%) were male, 85 (52.47%) were female, and 82 (50.62%) had critical outcomes. For critical outcomes, an SI &gt; 0.7 had a sensitivity of 53.9% and a high specificity of 94.3% but a low positive predictive value (PPV). MSI &gt; 1.3 showed a sensitivity of 19.6% and a specificity of 98.1%, with a PPV of 1.6%. ASI &gt; 0.7 had a sensitivity of 15.9% and a specificity of 93.2%, with a PPV of 0.9%. Conclusion: The Shock Index (SI), Modified Shock Index (MSI), and Age Shock Index (ASI) are more effective at ruling out critical outcomes than predicting them.

Immunopathogenesis of Lung in Fatal COVID-19 Cases in Erbil, Iraq

Coronavirus disease 2019 (COVID-19) infection is caused by severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2). It is characterized by respiratory distress, multiorgan dysfunction and death in some cases. The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestation. However the pathological mechanism underling the disease has not been fully defined. Lung autopsy samples from 3 patients with fatal COVID-19 were evaluated using hematoxylin and eosin stain to analyze the histopathological changes. While immunohistochemical (IHC) staining was performed for detecting CD4 in helper T-cells, CD8 in cytotoxic T-cells, CD56 in NK-cells and CD45RO in memory T-cells. Histopathological examination revealed features of diffuse alveolar damage (DAD) with exudate in alveolar space and infiltration of inflammatory cells. Immunohistochemistry staining for CD4 showed weak to positive staining, CD8 showed weak positive staining, CD56 showed negative staining, while CD45RO showed a positive staining. It can be concluded that SARS-CoV-2 virus impaired innate immune response through a decrease in NK cells and adaptive immune response through a decrease in CD8 T cells which is one of the explanations of the destructive nature of SARS-CoV-2 virus.

Multiple infections secondary to immunosuppression after Chlamydia psittaci infection: a case report

This study presents the clinical profile of a 74-year-old male patient admitted to the hospital due to a 20-day history of coughing, chest tightness, and dyspnea. Upon admission, the patient presented with fever, tachycardia, and tachypnea. Clinical examination revealed evidence of lung infection, sepsis, and multi-organ dysfunction, alongside abnormal blood gas analysis and elevated C-reactive protein (CRP) levels. Pathogen testing confirmed Chlamydia psittaci (C. psittaci), infection. Throughout the treatment course, the patient developed concurrent fungal and viral infections, necessitating a comprehensive approach involving combined antibiotic and antifungal therapy. Despite encountering treatment-related complications, the patient demonstrated clinical improvement with aggressive management. This case underscores the importance of recognizing immune suppression subsequent to Chlamydia infection, emphasizing the critical role of early diagnosis, intervention, and standardized treatment protocols in enhancing patient prognosis.