High Mortality Research Articles

Nicotinamide riboside restores nicotinamide adenine dinucleotide levels and alleviates brain injury by inhibiting oxidative stress and neuroinflammation in a mouse model of intracerebral hemorrhage.

Hemorrhagic stroke is a global health problem owing to its high morbidity and mortality rates. Nicotinamide riboside is an important precursor of nicotinamide adenine dinucleotide characterized by a high bioavailability, safety profile, and robust effects on many cellular signaling processes. This study aimed to investigate the protective effects of nicotinamide riboside against collagenase-induced hemorrhagic stroke and its underlying mechanisms of action. An intracerebral hemorrhage model was constructed by stereotactically injecting collagenase into the right striatum of adult male Institute for Cancer Research mice. After 30 minutes, nicotinamide riboside was administered via the tail vein. The mice were sacrificed at different time points for assessments. Nicotinamide riboside reduced collagenase-induced hemorrhagic area, significantly reduced cerebral water content and histopathological damage, promoted neurological function recovery, and suppressed reactive oxygen species production and neuroinflammation. Nicotinamide riboside exerts neuroprotective effects against collagenase-induced intracerebral hemorrhage by inhibiting neuroinflammation and oxidative stress.

Neuroinflammation in Glioblastoma: Progress and Perspectives

Glioblastoma is the most common and malignant primary brain tumor, with high morbidity and mortality. Despite an aggressive, multimodal treatment regimen, including surgical resection followed by chemotherapy and radiotherapy, the prognosis of glioblastoma patients remains poor. One formidable challenge to advancing glioblastoma therapy is the complexity of the tumor microenvironment. The tumor microenvironment of glioblastoma is a highly dynamic and heterogeneous system that consists of not only cancerous cells but also various resident or infiltrating inflammatory cells. These inflammatory cells not only provide a unique tumor environment for glioblastoma cells to develop and grow but also play important roles in regulating tumor aggressiveness and treatment resistance. Targeting the tumor microenvironment, especially neuroinflammation, has increasingly been recognized as a novel therapeutic approach in glioblastoma. In this review, we discuss the components of the tumor microenvironment in glioblastoma, focusing on neuroinflammation. We discuss the interactions between different tumor microenvironment components as well as their functions in regulating glioblastoma pathogenesis and progression. We will also discuss the anti-tumor microenvironment interventions that can be employed as potential therapeutic targets.

Bone and Joint Infections in Children With Sickle Cell Disease in French Guiana: A 13-year Retrospective Multicenter Review.

Sickle cell disease (SCD) is a genetic disorder with a high infectious morbidity and mortality and a heterogeneous distribution in France. One of the challenges is to differentiate a bone and joint infection (BJI) from a vaso-occlusive crisis. This challenge is particularly prevalent in French Guiana, an overseas territory with the highest incidence of SCD in France. The aim of this study was to describe the epidemiology of BJI in children with SCD in French Guiana. This was a retrospective multicentric descriptive study of SCD patients living in French Guiana aged under 18 and diagnosed with a BJI between 2010 and 2022. These BJI were divided into 2 groups: those with microbiological documentation (d-BJI) and those without microbiological identification (ud-BJI). A total of 53 episodes of BJI in 42 patients (mean age 7.2 years) were reported. Clinical symptoms on arrival were comparable between the d-BJI and ud-BJI groups. Patients in the d-BJI group had longer average hospital stays (40.4 days vs. 16.8 days, P = 0.01) and Salmonella spp. were the most identified bacteria (n = 8/13). White blood cell count was greater in the d-BJI group (30.3 G/L vs. 18.G/L, P = 0.01) and a collection was more frequently identified on imaging (11/13 vs. 16/40, P = 0.01) in this group. Initial in-hospital antibiotic therapy was longer in the d-BJI group (17.2 days vs. 12.8, P = 0.02), as were infection-related complications (9/13 vs. 12/40 P = 0.01). BJI in children with SCD is not sufficiently microbiologically documented. Progress must be made to improve the documentation of BJI.

Integrating bioinformatics and multiple machine learning to identify mitophagy-related targets for the diagnosis and treatment of diabetic foot ulcers: evidence from transcriptome analysis and drug docking

BackgroundDiabetic foot ulcers are the most common and serious complication of diabetes mellitus, the high morbidity, mortality, and disability of which greatly diminish the quality of life of patients and impose a heavy socioeconomic burden. Thus, it is urgent to identify potential biomarkers and targeted drugs for diabetic foot ulcers.MethodsIn this study, we downloaded datasets related to diabetic foot ulcers from gene expression omnibus. Dysregulation of mitophagy-related genes was identified by differential analysis and weighted gene co-expression network analysis. Multiple machine algorithms were utilized to identify hub mitophagy-related genes, and a novel artificial neural network model for assisting in the diagnosis of diabetic foot ulcers was constructed based on their transcriptome expression patterns. Finally, potential drugs that can target hub mitophagy-related genes were identified using the Enrichr platform and molecular docking methods.ResultsIn this study, we identified 702 differentially expressed genes related to diabetic foot ulcers, and enrichment analysis showed that these genes were associated with mitochondria and energy metabolism. Subsequently, we identified hexokinase-2, small ribosomal subunit protein us3, and l-lactate dehydrogenase A chain as hub mitophagy-related genes of diabetic foot ulcers using multiple machine learning algorithms and validated their diagnostic performance in a validation cohort independent of the present study (The areas under roc curve of hexokinase-2, small ribosomal subunit protein us3, and l-lactate dehydrogenase A chain are 0.671, 0.870, and 0.739, respectively). Next, we constructed a novel artificial neural network model for the molecular diagnosis of diabetic foot ulcers, and the diagnostic performance of the training cohort and validation cohort was good, with areas under roc curve of 0.924 and 0.840, respectively. Finally, we identified retinoic acid and estradiol as promising anti-diabetic foot ulcers by targeting hexokinase-2 (−6.6 and −7.2 kcal/mol), small ribosomal subunit protein us3 (−7.5 and −8.3 kcal/mol), and l-lactate dehydrogenase A chain (−7.6 and −8.5 kcal/mol).ConclusionThe present study identified hexokinase-2, small ribosomal subunit protein us3 and l-lactate dehydrogenase A chain, and emphasized their critical roles in the diagnosis and treatment of diabetic foot ulcers through multiple dimensions, providing promising diagnostic biomarkers and targeted drugs for diabetic foot ulcers.

Neuroinflammation in Glioblastoma: Progress and Perspectives

Glioblastoma is the most common and malignant primary brain tumor, with high morbidity and mortality. Despite an aggressive, multimodal treatment regimen, including surgical resection followed by chemotherapy and radiotherapy, the prognosis of glioblastoma patients remains poor. One formidable challenge to advancing glioblastoma therapy is the complexity of the tumor microenvironment. The tumor microenvironment of glioblastoma is a highly dynamic and heterogeneous system that consists of not only cancerous cells but also various resident or infiltrating inflammatory cells. These inflammatory cells not only provide a unique tumor environment for glioblastoma cells to develop and grow but also play important roles in regulating tumor aggressiveness and treatment resistance. Targeting the tumor microenvironment, especially neuroinflammation, has increasingly been recognized as a novel therapeutic approach in glioblastoma. In this review, we discuss the components of the tumor microenvironment in glioblastoma, focusing on neuroinflammation. We discuss the interactions between different tumor microenvironment components as well as their functions in regulating glioblastoma pathogenesis and progression. We will also discuss the anti-tumor microenvironment interventions that can be employed as potential therapeutic targets.

Bone and Joint Infections in Children With Sickle Cell Disease in French Guiana: A 13-year Retrospective Multicenter Review.

Sickle cell disease (SCD) is a genetic disorder with a high infectious morbidity and mortality and a heterogeneous distribution in France. One of the challenges is to differentiate a bone and joint infection (BJI) from a vaso-occlusive crisis. This challenge is particularly prevalent in French Guiana, an overseas territory with the highest incidence of SCD in France. The aim of this study was to describe the epidemiology of BJI in children with SCD in French Guiana. This was a retrospective multicentric descriptive study of SCD patients living in French Guiana aged under 18 and diagnosed with a BJI between 2010 and 2022. These BJI were divided into 2 groups: those with microbiological documentation (d-BJI) and those without microbiological identification (ud-BJI). A total of 53 episodes of BJI in 42 patients (mean age 7.2 years) were reported. Clinical symptoms on arrival were comparable between the d-BJI and ud-BJI groups. Patients in the d-BJI group had longer average hospital stays (40.4 days vs. 16.8 days, P = 0.01) and Salmonella spp. were the most identified bacteria (n = 8/13). White blood cell count was greater in the d-BJI group (30.3 G/L vs. 18.G/L, P = 0.01) and a collection was more frequently identified on imaging (11/13 vs. 16/40, P = 0.01) in this group. Initial in-hospital antibiotic therapy was longer in the d-BJI group (17.2 days vs. 12.8, P = 0.02), as were infection-related complications (9/13 vs. 12/40 P = 0.01). BJI in children with SCD is not sufficiently microbiologically documented. Progress must be made to improve the documentation of BJI.

A fungal metabolic regulator underlies infectious synergism during Candida albicans-Staphylococcusaureus intra-abdominal co-infection

Candida albicans and Staphylococcus aureus are two commonly associated pathogens that cause nosocomial infections with high morbidity and mortality. Our prior and current work using a murine model of polymicrobial intra-abdominal infection (IAI) demonstrates that synergistic lethality is driven by Candida-induced upregulation of functional S. aureus α-toxin leading to polymicrobial sepsis and organ damage. In order to determine the candidal effector(s) mediating enhanced virulence, an unbiased screen of C. albicans transcription factor mutants was undertaken revealing that zcf13Δ/Δ fails to drive augmented α-toxin or lethal synergism during co-infection. A combination of transcriptional and phenotypic profiling approaches shows that ZCF13 regulates genes involved in pentose metabolism, including RBK1 and HGT7 that contribute to fungal ribose catabolism and uptake, respectively. Subsequent experiments reveal that ribose inhibits the staphylococcal agr quorum sensing system and concomitantly represses toxicity. Unlike wild-type C. albicans, zcf13Δ/Δ did not effectively utilize ribose during co-culture or co-infection leading to exogenous ribose accumulation and agr repression. Forced expression of RBK1 and HGT7 in the zcf13Δ/Δ mutant fully restores pathogenicity during co-infection. Collectively, our results detail the interwoven complexities of cross-kingdom interactions and highlight how intermicrobial metabolism impacts polymicrobial disease pathogenesis with devastating consequences for the host.

Integrating bioinformatics and multiple machine learning to identify mitophagy-related targets for the diagnosis and treatment of diabetic foot ulcers: evidence from transcriptome analysis and drug docking

BackgroundDiabetic foot ulcers are the most common and serious complication of diabetes mellitus, the high morbidity, mortality, and disability of which greatly diminish the quality of life of patients and impose a heavy socioeconomic burden. Thus, it is urgent to identify potential biomarkers and targeted drugs for diabetic foot ulcers.MethodsIn this study, we downloaded datasets related to diabetic foot ulcers from gene expression omnibus. Dysregulation of mitophagy-related genes was identified by differential analysis and weighted gene co-expression network analysis. Multiple machine algorithms were utilized to identify hub mitophagy-related genes, and a novel artificial neural network model for assisting in the diagnosis of diabetic foot ulcers was constructed based on their transcriptome expression patterns. Finally, potential drugs that can target hub mitophagy-related genes were identified using the Enrichr platform and molecular docking methods.ResultsIn this study, we identified 702 differentially expressed genes related to diabetic foot ulcers, and enrichment analysis showed that these genes were associated with mitochondria and energy metabolism. Subsequently, we identified hexokinase-2, small ribosomal subunit protein us3, and l-lactate dehydrogenase A chain as hub mitophagy-related genes of diabetic foot ulcers using multiple machine learning algorithms and validated their diagnostic performance in a validation cohort independent of the present study (The areas under roc curve of hexokinase-2, small ribosomal subunit protein us3, and l-lactate dehydrogenase A chain are 0.671, 0.870, and 0.739, respectively). Next, we constructed a novel artificial neural network model for the molecular diagnosis of diabetic foot ulcers, and the diagnostic performance of the training cohort and validation cohort was good, with areas under roc curve of 0.924 and 0.840, respectively. Finally, we identified retinoic acid and estradiol as promising anti-diabetic foot ulcers by targeting hexokinase-2 (−6.6 and −7.2 kcal/mol), small ribosomal subunit protein us3 (−7.5 and −8.3 kcal/mol), and l-lactate dehydrogenase A chain (−7.6 and −8.5 kcal/mol).ConclusionThe present study identified hexokinase-2, small ribosomal subunit protein us3 and l-lactate dehydrogenase A chain, and emphasized their critical roles in the diagnosis and treatment of diabetic foot ulcers through multiple dimensions, providing promising diagnostic biomarkers and targeted drugs for diabetic foot ulcers.

Protective effects of DcR3-SUMO on lipopolysaccharide-induced inflammatory cells and septic mice

Despite the high mortality rate associated with sepsis, no specific drugs are available.Decoy receptor 3 (DcR3) is now considered a valuable biomarker and therapeutic target for managing inflammatory conditions. DcR3-SUMO, an analog of DcR3, has a simple production process and high yield. However, its precise underlying mechanisms in sepsis remain unclear. This study investigated the protective effects of DcR3-SUMO on lipopolysaccharide (LPS)-induced inflammatory cells and septic mice. We evaluated the effects of DcR3 intervention and overexpression on intracellular inflammatory cytokine levels in vitro. DcR3-SUMO significantly reduced cytokine levels within inflammatory cells, and notably increased DcR3 protein and mRNA levels in LPS-induced septic mice, confirming its anti-inflammatory efficacy. Our in vitro and in vivo results demonstrated comparable anti-inflammatory effects between DcR3-SUMO and native DcR3. DcR3-SUMO protein administration in septic mice notably enhanced tissue morphology, decreased sepsis scores, and elevated survival rates. Furthermore, DcR3-SUMO treatment effectively lowered inflammatory cytokine levels in the serum, liver, and lung tissues, and mitigated the extent of tissue damage. AlphaFold3 structural predictions indicated that DcR3-SUMO, similar to DcR3, effectively interacts with the three pro-apoptotic ligands, namely TL1A, LIGHT, and FasL. Collectively, DcR3-SUMO and DcR3 exhibit comparable anti-inflammatory effects, making DcR3-SUMO a promising therapeutic agent for sepsis.

Clinical characteristics and risk factors for mortality in pneumonia-associated acute respiratory distress syndrome patients: a single center retrospective cohort study

BackgroundPathogenic diversity may have contributed to the high mortality of pneumonia-associated acute respiratory distress syndrome (p-ARDS). Metagenomics next-generation sequencing (mNGS) serves as a valuable diagnostic tool for early pathogen identification. However, its clinical utility in p-ARDS remains understudied. There are still limited researches on the etiology, clinical characteristics and risk factors for 28-day mortality in p-ARDS patients.MethodsA single center retrospective cohort study of 75 p-ARDS patients was conducted. Patients were categorized into survival and deceased groups based on their 28-day outcomes. A comprehensive clinical evaluation was conducted, including baseline characteristics, laboratory indicators, outcomes and pathogen identification by mNGS and traditional microbiological testing. We then evaluated the diagnostic value of mNGS and identified clinical characteristics and risk factors for 28-day mortality in p-ARDS.ResultThe overall ICU mortality was 26.67%, and the 28-day mortality was 57.33%, with 32 cases (42.67%) in the survival group, and 43 cases (57.33%) in the deceased group. Patients in the deceased group were older than those in the survival group (68(59,73) years vs. 59(44,67) years, P=0.04). The average lengths of ICU and hospital stay were 9(5,13) days and 14(7,21) days, respectively. The survival group had longer lengths of ICU and hospital stay (ICU: 11(7,17) days and hospital: 17(9,27) days) compared to the deceased group (ICU: 8(4,11) days and hospital: 12(6,19) days) (P<0.05). Survival patients exhibited lower Acute Physiology and Chronic Health Evaluation (APACHE) II score on the 3rd and 7th days, higher lymphocyte counts, higher CD3+ and CD8+ T cell counts compared to deceased patients (P<0.05). Multivariate logistic regression analysis identified age, APACHE II scores on 3rd and 7th days, CD8+ T cell count and length of ICU as independent risk factors for 28-day mortality in p-ARDS patients. mNGS demonstrated a significantly higher overall pathogen detection rate (70/75, 93.33%) compared to the traditional method (50/75, 66.67%, P=0.022). The average turnaround time (TAT) for mNGS was significantly shorter at 1(1,1) day compared to 4(3,5) days for the traditional method (P<0.001).ConclusionMetagenome next-generation sequencing can be used as a valuable tool for identifying pathogens in p-ARDS, reducing diagnostic time and improving accuracy. Early application of mNGS alongside traditional methods is recommended for p-ARDS. Furthermore, older age, higher APACHE II scores, lower lymphocyte counts and lymphocyte subset counts were associated with increased mortality in p-ARDS patients, highlighting the importance of timely assessment of immune status and disease severity, especially in elderly.

Endovascular Therapy for Isolated Cervical Internal Carotid Artery Occlusion

BACKGROUND Guidelines on endovascular therapy for acute ischemic stroke do not include isolated cervical internal carotid artery (cICA) occlusions. The effect of treating these lesions remains unclear. This study aimed to compare the baseline characteristics and treatment outcomes between patients with isolated cICA occlusions to patients who underwent endovascular therapy due to a level of occlusion supported by guidelines. METHODS A retrospective cohort study was conducted on 1162 patients who underwent endovascular therapy. Of these, 115 had an isolated cICA occlusion. Univariate analysis of baseline characteristics and outcome measured by the modified Rankin scale 90 days after endovascular therapy were compared between patients with isolated cICA occlusion, those with tandem occlusions, and those with occlusions of the middle cerebral artery/top of the internal carotid artery (first segment of the middle cerebral artery/intracranial internal carotid artery). To adjust for confounders, an inverse probability of treatment weighting was performed. RESULTS Patients with isolated cICA occlusions were more likely men (67.8% versus 50.9%; P <0.001) and active smokers (42.2% versus 26.4%; P = 0.002) compared with patients with first segment of the middle cerebral artery/intracranial internal carotid artery occlusions where atrial fibrillation was more common (35.5% versus 23.5%; P = 0.02). Patients with an isolated cICA had a lower chance of achieving a modified Rankin scale score of 0 to 2 at 90 days (adjusted relative risk, 0.71 [95% CI, 0.54–0.92]) and a higher mortality rate (adjusted relative risk, 1.97 [95% CI, 1.36–2.87]) compared with patients with first segment of the middle cerebral artery/intracranial internal carotid artery occlusions. CONCLUSION Patients with isolated cICA occlusions and first segment of the middle cerebral artery/intracranial internal carotid artery occlusions differ in sex, smoking status, and rate of atrial fibrillation. Patients with isolated cICA occlusions have lower reperfusion rates, worse outcome, and a higher mortality rate.

Bioengineered Abiotic Nanomaterials Through Cell Membrane-Camouflaging: Advancements and Challenges in Lung Cancer.

Lung cancer remains a major global health concern with high mortality rates and poor prognosis. Bridging the gap between the chemical and cellular understanding of cell-decorated biomimetic nanocomposites and their clinical translation is crucial for developing effective therapies. Nanocomposites show promise in targeted drug delivery and diagnostics, but their clinical application is hindered by biocompatibility and clearance issues. To overcome these challenges, biomimetic approaches utilizing cell membrane-coated nanomaterials emerge. By camouflaging nanomaterials with cell membranes, the biointerfaces are enhanced, and the inherent properties of the donor cell membranes are acquired. This review provides an overview of recent advancements on cell membrane-coated nanocomposites for lung cancer diagnosis and treatment. It discusses fabrication techniques, biomedical applications, challenges, and future prospects. The incorporation of cell membranes into nanocomposites holds potential for improved lung cancer therapy, but further development and refinement are needed for precise tumor targeting. Addressing the identified challenges will pave the way for clinical translation of these biomimetic nanoplatforms and advance lung cancer diagnosis and treatment.

The efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of hemophagocytic lymphohistiocytosis in adult patients: an open-label, single-center study

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by hyperinflammation and organ failure, with a high mortality rate. Current first-line treatments for adult patients have limited efficacy and significant toxicity. The novel selective histone deacetylase inhibitor (HDACi), chidamide, has shown promise in preclinical studies for the potential treatment of HLH.MethodsAn open-label, single-center study was conducted to evaluate the efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of HLH in adult patients. Seventeen patients who fulfilled at least five of the eight HLH-2004 criteria were enrolled and treated with the combination therapy. The primary outcome was overall response rate (ORR), and secondary outcomes included survival, safety and tolerability, and changes in laboratory indicators.ResultsA total of 17 HLH patients who met the inclusion criteria were enrolled in this study, with a male to female ratio of 1.8:1. The age range at enrollment was 31 to 71 years old, with a median age of 52 years old. The ORR was 76.5% (13/17 patients), with a complete response (CR) rate of 17.6% (3/17 patients) and a partial response (PR) rate of 58.8% (10/17 patients). The median overall survival (OS) was not achieved, with OS at 6 months and 12 months being 81% and 65%, respectively. The median progression free survival (PFS) was not achieved, with PFS at 6 months and 12 months being 68% and 55%, respectively. Hematologic toxicities is the most common. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. The results showed that the levels of sCD25, platelets, aspartate aminotransferase, lactate dehydrogenase, and albumin in these patients were significantly improved 3 weeks after treatment.ConclusionThe addition of chidamide to etoposide and glucocorticoids may be a promising new treatment option for patients with HLH, with a high ORR, manageable safety profile, and significant improvement in laboratory indicators. Further research is needed to confirm these findings and determine the optimal dosing and duration of therapy.

Psychiatric Morbidity Among Patients Recovered from COVID-19 Pneumonia: A Cross Sectional Telephonic Survey

Background: Mental health issues among COVID-19 survivors can have broader public health implications, including decreased quality of life, impaired functional recovery, increased healthcare utilization, and higher mortality rates. Aims and Objectives: The aim of this study was to evaluate the psychiatric morbidities among the persons treated and recovered from COVID-19. Materials and Methods: A cross sectional telephonic survey was undertaken in hundred patients infected with COVID-19 pneumonia, treated and discharged from a tertiary care centre. Depression, anxiety, PTSD symptoms were assessed using PHQ-2, GAD-2, PTSD screen for DSM-5 respectively. Sleep quality was assessed using single item sleep quality scale. Overall quality of life and health satisfaction was assessed using WHOQOL-BREF. Results: Mean age of study participants is 46.15 years and study sample included 62% of males. Admitted patients had mean CT severity score of 40% lung involvement. On the measures of sleep quality, twelve were having fair range and two participants had poor sleep quality. 24% and 31% of participants had anxiety and depressive symptoms respectively while 14% had symptoms of PTSD. Conclusion: Post covid sequelae is an important concern to be addressed, larger studies are required to assess the psychiatry morbidity accurately. Further sequential assessments would help to delineate the natural course of post covid psychiatric sequalae.

Psychiatric Morbidity Among Patients Recovered from COVID-19 Pneumonia: A Cross Sectional Telephonic Survey

Background: Mental health issues among COVID-19 survivors can have broader public health implications, including decreased quality of life, impaired functional recovery, increased healthcare utilization, and higher mortality rates. Aims and Objectives: The aim of this study was to evaluate the psychiatric morbidities among the persons treated and recovered from COVID-19. Materials and Methods: A cross sectional telephonic survey was undertaken in hundred patients infected with COVID-19 pneumonia, treated and discharged from a tertiary care centre. Depression, anxiety, PTSD symptoms were assessed using PHQ-2, GAD-2, PTSD screen for DSM-5 respectively. Sleep quality was assessed using single item sleep quality scale. Overall quality of life and health satisfaction was assessed using WHOQOL-BREF. Results: Mean age of study participants is 46.15 years and study sample included 62% of males. Admitted patients had mean CT severity score of 40% lung involvement. On the measures of sleep quality, twelve were having fair range and two participants had poor sleep quality. 24% and 31% of participants had anxiety and depressive symptoms respectively while 14% had symptoms of PTSD. Conclusion: Post covid sequelae is an important concern to be addressed, larger studies are required to assess the psychiatry morbidity accurately. Further sequential assessments would help to delineate the natural course of post covid psychiatric sequalae.

In vivo functional analysis of the cotton bollworm Helicoverpa armigera 24-dehydrocholesterol reductase (HaDHCR24) in phytosterol metabolism.

Insects have to obtain sterols from food due to the inability to synthesize this essential nutrient de novo. For lepidopteran insects, they can convert a variety of phytosterols into cholesterol to meet their growth needs. The final step of the cholesterol biosynthesis is the metabolism of desmosterol catalyzed by 24-dehydrocholesterol reductase (DHCR24). In this study, we identified a DHCR24 homolog in the cotton bollworm Helicoverpa armigera, designated as H. armigera 24-dehydrocholesterol reductase (HaDHCR24)-1. The quantitative expression analyses indicated that HaDHCR24-1 was highly enriched in the midgut where dietary sterol uptake occurs. Compared to the control, the DHCR24-1 mutant larvae generated by clustered regularly interspaced palindromic repeats (CRISPR) / CRISPR-associated nuclease 9 technology accumulated more desmosterol in the gut, while the content of cholesterol was significantly reduced. A similar phenomenon was observed when the DHCR24 inhibitor, amiodarone, was applied to the insects. Moreover, DHCR24-1 played an important role for the usage of β-sitosterol, a major sterol in plants, in H. armigera, and loss of function of DHCR24-1 resulted in higher mortality on β-sitosterol. However, the DHCR24 homolog does not necessarily exist in the genomes of all insects. The loss of this gene occurred more frequently in the insects feeding on animals, which further support the role of DHCR24-1 in using phytosterols. This gene may have important potential in developing new strategies to control herbivory pests in Lepidoptera and other insect orders.

In vivo functional analysis of the cotton bollworm Helicoverpa armigera 24-dehydrocholesterol reductase (HaDHCR24) in phytosterol metabolism.

Insects have to obtain sterols from food due to the inability to synthesize this essential nutrient de novo. For lepidopteran insects, they can convert a variety of phytosterols into cholesterol to meet their growth needs. The final step of the cholesterol biosynthesis is the metabolism of desmosterol catalyzed by 24-dehydrocholesterol reductase (DHCR24). In this study, we identified a DHCR24 homolog in the cotton bollworm Helicoverpa armigera, designated as H. armigera 24-dehydrocholesterol reductase (HaDHCR24)-1. The quantitative expression analyses indicated that HaDHCR24-1 was highly enriched in the midgut where dietary sterol uptake occurs. Compared to the control, the DHCR24-1 mutant larvae generated by clustered regularly interspaced palindromic repeats (CRISPR) / CRISPR-associated nuclease 9 technology accumulated more desmosterol in the gut, while the content of cholesterol was significantly reduced. A similar phenomenon was observed when the DHCR24 inhibitor, amiodarone, was applied to the insects. Moreover, DHCR24-1 played an important role for the usage of β-sitosterol, a major sterol in plants, in H. armigera, and loss of function of DHCR24-1 resulted in higher mortality on β-sitosterol. However, the DHCR24 homolog does not necessarily exist in the genomes of all insects. The loss of this gene occurred more frequently in the insects feeding on animals, which further support the role of DHCR24-1 in using phytosterols. This gene may have important potential in developing new strategies to control herbivory pests in Lepidoptera and other insect orders.

Plasma as endothelial rescue in septic shock: A randomized, phase 2a pilot trial.

Septic shock is associated with high morbidity and mortality, the endothelium plays an important role. Crystalloids is standard of care to maintain intravascular volume. Plasma is associated with improved endothelial integrity and restoration of the glycocalyx layer. We evaluated the efficacy and safety aspects of cell-free and pathogen inactivated pooled plasma (OctaplasLG®) as resuscitation in septic shock patients. This randomized, investigator-initiated phase IIa trial ran at a Danish single center intensive care unit, from 2017 to 2019. Patients were 18 years of age or older with septic shock and randomized to fluid optimization with OctaplasLG® or Ringer-acetate in the first 24 h. The primary endpoints were changes in biomarkers indicative of endothelial activation, damage, and microvascular perfusion from baseline to 24 h. Safety events and mortality were assessed during 90 days. Forty-four patients were randomized, 20 to OctaplasLG versus 24 to Ringer-acetate. The median age was 69, and 55% were men. Median Sequential Organ Failure Assessment score was 13. Baseline differences favoring the Ringer-acetate group were observed. The OctaplasLG® group was resuscitated with 740 mL plasma and the Ringer-acetate group with 841 mL crystalloids. There was no significant change in the microvascular perfusion or five biomarkers except VEGFR1 change, which was higher in patients receiving OctaplasLG® 0.12(SD 0.37) versus Ringer-acetate -0.24 (SD 0.39), with mean difference 0.36 (95% CI, 0.13-0.59, p = .003) in favor of Ringer-acetate. This study found that fluid resuscitation with OctaplasLG® in critically ill septic shock patients is feasible. Baseline confounding prevented assessment of the potential effect of OctaplasLG®.

Education of postpartum hemorrhage management clinical skills among midwifery students in Malawi: A qualitative study

BackgroundUnskilled health professionals in healthcare systems are contributing to the high numbers of maternal mortality in Malawi. It is therefore essential that midwifery students acquire postpartum hemorrhage management clinical skills, especially in view of high maternal mortality, with postpartum hemorrhage being the leading cause. However, there is limited evidence on how the teaching is conducted with regard to students’ learning of postpartum hemorrhage management clinical skills. PurposeThis study aimed to describe the current teaching of postpartum hemorrhage management clinical skills in undergraduate nursing and midwifery program in Malawi. MethodsThe study applied a qualitative exploratory descriptive design. Data were collected through ten individual interviews with lecturers and three focus group discussions with twenty-four students in a midwifery education program in Malawi. The data were analyzed using thematic analysis. ResultsTwo themes emerged from the data analysis: (1) there are various teaching and learning approaches for postpartum hemorrhage management in use and (2) unpreparedness of midwifery students in postpartum hemorrhage management for patient care. ConclusionThe present study demonstrated that teaching of postpartum hemorrhage management clinical skills in an undergraduate nursing and midwifery programme in Malawi focuses on theoretical knowledge rather than practical skills, leaving midwifery students unprepared for postpartum hemorrhage management during clinical practice. The findings from the present study may provide knowledge guiding revision of the curriculum for the undergraduate nursing and midwifery programme in Malawi to consider global standards of midwifery education; enhance the lecturer to student ratio to provide the students with appropriate supervision; and to employ innovative teaching and learning strategies that promote peer education and skills practice among midwifery students. In addition, to conduct more research related to various teaching approaches in nursing and midwifery educational programs and among qualified midwives in Malawi. Statement of significancePostpartum hemorrhage management education in undergraduate nursing and midwifery programme in Malawi focuses more on theory than clinical skills. Improving midwifery students' acquisition of postpartum hemorrhage management clinical skills is needed to ultimately help lower Malawi's maternal mortality ratio.

Multifocal Cryptococcus Neoformans Osteomyelitis in a Kidney Transplant Recipient

Cryptococcal infections are notoriously difficult to diagnose and have been associated with high morbidity and mortality. Cryptococcus neoformans presenting as osteomyelitis is an unexpected clinical scenario in the transplant ward. A young male who underwent spousal kidney donor transplantation 16 months ago presented with painful and ulcerated soft tissue in upper and lower limbs which were diagnosed as cryptococcus osteomyelitis. He was managed with surgical debridement, liposomal amphotericin B, flucytosine and reduction in maintenance immunosuppression (IS). To our knowledge this is the first reported case of multifocal cryptococcus osteomyelitis in a kidney transplant recipient.