COVID-19 associated candidemia: From a shift in fungal epidemiology to a rise in azole drug resistance.

Our understanding of fungal epidemiology and the burden of antifungal drug resistance in COVID-19-associated candidemia (CAC) patients is limited. Therefore, we conducted a retrospective multicenter study in Iran to explore clinical and microbiological profiles of CAC patients. Yeast isolated from blood, were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and subjected to antifungal susceptibility testing (AFST) using the broth microdilution method M27-A3 protocol. A total of 0.6% of the COVID-19 patients acquired CAC (43/6174). Fluconazole was the most widely used antifungal, and 37% of patients were not treated. Contrary to historic candidemia patients, Candida albicans and C. tropicalis were the most common species. In vitro resistance was high and only noted for azoles; 50%, 20%, and 13.6% of patients were infected with azole-non-susceptible (ANS) C. tropicalis, C. parapsilosis, and C. albicans isolates, respectively. ERG11 mutations conferring azole resistance were detected for C. parapsilosis isolates (Y132F), recovered from an azole-naïve patient. Our study revealed an unprecedented rise in ANS Candida isolates, including the first C. parapsilosis isolate carrying Y132F, among CAC patients in Iran, which potentially threatens the efficacy of fluconazole, the most widely used drug in our centers. Considering the high mortality rate and 37% of untreated CAC cases, our study underscores the importance of infection control strategies and antifungal stewardship to minimize the emergence of ANS Candida isolates during COVID-19.

Identification of new variants in patients with mucopolysaccharidosis in consanguineous Iranian families.

Introduction: Mucopolysaccharidoses are a group of lysosomal storage disorders that include seven types that are classified based on the enzymes that are disrupted. Malfunction of these enzymes leads to the accumulation of glycosaminoglycans (GAGs) in various tissues. Due to genetic and clinical heterogeneity, diagnosing and distinguishing the different types is challenging. Genetic methods such as whole exome sequencing (WES) and Sanger sequencing are accurate methods for detecting pathogenic variants in patients. Methods: Thirty-two cases of mucopolysaccharidosis, predominantly from families with consanguineous marriages, were genetically examined. Out of these, fourteen cases underwent targeted sequencing, while the rest underwent WES. The results of WES were analyzed and the pathogenicity of the variants was examined using bioinformatics tools. In addition, a segregation analysis within families was carried out. Results: In most cases, a pathogenic or likely pathogenic variant was detected. Sixteen previously reported variants and six new variants were detected in the known IDS (c.458G>C, c.701del, c.920T>G), GNS (c.1430A>T), GALNS (c.1218_1221dup), and SGSH (c.149T>C) genes. Furthermore, we discovered a c.259G>C substitution in the NAGLU gene for the first time in three homozygous patients. This substitution was previously reported as heterozygous. Except for the variants related to the IDS gene, which were hemizygous, all the other variants were homozygous. Discussion: It appears that the high rate of consanguineous marriages in the families being studied has had a significant impact on the occurrence of this disease. Overall, these findings could expand the spectrum of pathogenic variants in mucopolysaccharidoses. Genetic methods, especially WES, are very accurate and can be used alone or in conjunction with other diagnostic methods for a more precise and rapid diagnosis of mucopolysaccharidoses. Additionally, they could be beneficial for family screening and disease prevention.

ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations.

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1,500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations, however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESC), including a knock-out and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and Western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR), and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-Seq analyses in Zscan10-/- mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry, and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10.

Low plasma vitamin D is associated with increased 28-day mortality and worse clinical outcomes in critically ill patients.

BACKGROUND & OBJECTIVE: Patients in the intensive care unit have a high prevalence of vitamin D deficiency (VDD). In the present study, clinical outcomes in the ICU were analyzed with vitamin D status. MATERIALS AND METHODS: In this prospective, multicenter study, sampling was conducted on seven ICUs in three hospitals. Within the first 24 h of ICU admission, patient's serum vitamin D levels were measured, and their disease severity was monitored using the scores of acute physiologic assessment and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), and the modified Nutrition Risk in Critically ill (mNUTRIC) score. RESULTS: A total of 236 patients were enrolled in this study, of which 163 (69.1%) had lower vitamin D levels than 20 ng/ml upon ICU admission. The patients with VDD had higher APACHE II scores)P = 0.02), SOFA scores (P < 0.001), and mNUTRIC scores (P = 0.01). Patients with sufficient levels of vitamin D (> 30 ng/ml) had a shorter stay at ICU (P < 0.001). VDD was independently associated with 28-day mortality (OR: 4.83; 95% CI: 1.63-14.27; P = 0.004). CONCLUSION: The data showed that VDD was common among the critically ill and was related to a more severe course of illness and a higher mortality rate.

Genotypic variants of the tetrahydrobiopterin (BH4) biosynthesis genes in patients with hyperphenylalaninemia from different regions of Iran.

BACKGROUND: Hyperphenylalaninemia (HPA) is a metabolic disorder classified into phenylalanine-4-hydroxylase (PAH) and non-PAH deficiency. The latter is produced by mutations in genes involved in the tetrahydrobiopterin (BH4) biosynthesis pathway and DNAJC12 pathogenetic variants. The BH4 metabolism, including de novo biosynthesis involved genes (i.e., guanosine 5'-triphosphate cyclohydrolase I (GTPCH/GCH1), sepiapterin reductase (SR/SPR), 6-pyruvoyl-tetrahydropterin synthase (PTPS/PTS)), and two genes that play roles in cofactor regeneration pathway (i.e., dihydropteridine reductase (DHPR/QDPR) and pterin-4α-carbinolamine dehydratase (PCD/PCBD1)). The subsequent systemic hyperphenylalaninemia and monoamine neurotransmitter deficiency lead to neurological consequences. The high rate of consanguineous marriages in Iran substantially increases the incidence of BH4 deficiency. METHODS: We utilized the Sanger sequencing technique in this study to investigate 14 Iranian patients with non-PAH deficiency. All affected subjects in this study had HPA and no mutation was detected in their PAH gene. RESULTS: We successfully identified six mutant alleles in BH4-deficiency-associated genes, including three novel mutations: one in QDPR, one in PTS, and one in the PCBD1 gene, thus giving a definite diagnosis to these patients. CONCLUSION: In this light, appropriate patient management may follow. The clinical effect of reported variants is essential for genetic counseling and prenatal diagnosis in the patients' families and significant for the improvement of precision medicine.

Basal complex: a smart wing component for automatic shape morphing.

Insect wings are adaptive structures that automatically respond to flight forces, surpassing even cutting-edge engineering shape-morphing systems. A widely accepted but not yet explicitly tested hypothesis is that a 3D component in the wing's proximal region, known as basal complex, determines the quality of wing shape changes in flight. Through our study, we validate this hypothesis, demonstrating that the basal complex plays a crucial role in both the quality and quantity of wing deformations. Systematic variations of geometric parameters of the basal complex in a set of numerical models suggest that the wings have undergone adaptations to reach maximum camber under loading. Inspired by the design of the basal complex, we develop a shape-morphing mechanism that can facilitate the shape change of morphing blades for wind turbines. This research enhances our understanding of insect wing biomechanics and provides insights for the development of simplified engineering shape-morphing systems.

The effects of adjunctive treatment with L-carnitine on monitoring laboratory variables in ICU patients: a double-blinded randomized controlled clinical trial.

BACKGROUND: Critically ill patients must be monitored constantly in intensive care units (ICUs). Among many laboratory variables, nutritional status indicators are a key role in the prognosis of diseases. We investigated the effects of L-carnitine adjunctive therapy on monitoring variables in critical illness. METHOD: A prospective, double-blind, randomized controlled trial was implemented in a medical ICU. Participants were 54 patients, aged > 18 years, with multiple conditions, randomly assigned to receive 3 g L-carnitine per day or placebo, along with enteral feeding, for 1 week. Primary outcomes included monitoring variables related to nutritional status. RESULT: Of 54 patients randomly assigned, 51 completed the trial. Serum albumin (Alb) (P-value: 0.001), total protein (P-value: 0.003), and calcium (Ca) (0.044) significantly increased in the intervention vs. control group. Alanine transaminase (ALT) (0.022), lactate (<0.001), creatinine (Cr) (0.005), and international normalized ratio (INR) (0.049) decreased meaningfully in the intervention vs. control group. CONCLUSION: L-Carnitine supplementation in critically ill patients can improve several parameters including INR, Cr, ALT, lactate, Ca, Alb, and total protein. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT 20151108024938N2. This trial was approved by the Research Ethics Committee of Mashhad University of Medical Sciences (registration code: IR.MUMS.fm.REC.1396.671) (available at https://en.irct.ir/trial/30748 , May 2018).

Whole exome sequencing reveals several novel variants in congenital disorders of glycosylation and glycogen storage diseases in seven patients from Iran.

BACKGROUND: Congenital disorder of glycosylation (CDG) and Glycogen storage diseases (GSDs) are inborn metabolic disorders caused by defects in some metabolic pathways. These disorders are a heterogeneous group of diseases caused by impaired O- as well as N-glycosylation pathways. CDG patients show a broad spectrum of clinical presentations; many GSD types (PGM1-CDG) have muscle involvement and hypoglycemia. METHODS: We applied WES for all seven patients presenting GSD and CDG symptoms. Then we analyzed the data using various tools to predict pathogenic variants in genes related to the patients' diseases. RESULTS: In the present study, we identified pathogenic variants in Iranian patients suffering from GSD and CDG, which can be helpful for patient management, and family counseling. We detected seven pathogenic variants using whole exome sequencing (WES) in known AGL (c.1998A>G, c.3635T>C, c.3682C>T), PGM1 (c.779G>A), DPM1 (c.742T>C), RFT1 (c.127A>G), and GAA (c.1314C>A) genes. CONCLUSION: The suspected clinical diagnosis of CDG and GSD patients was confirmed by identifying missense and or nonsense mutations in PGM1, DPM1, RFT1, GAA, and AGL genes by WES of all 7 cases. This study helps us understand the scenario of the disorder causes and consider the variants for quick disease diagnosis.

Effect of Helicobacter pylori eradication on metabolic profile: an international, multicenter, case-control study.

BACKGROUND: As a gram-negative and microaerophilic bacterium, Helicobacter pylori (HP) is the main cause of chronic gastritis. Therefore, considering the high prevalence of HP infection worldwide, as well as the increasing prevalence of metabolic disorders, the present study aimed to investigate the relationship between HP infection eradication and metabolic profile. METHODS: This prospective case-control study was performed on patients with HP infection whom referred to 7 medical centers in 3 countries (Iran, Egypt, and Vietnam) in 2020-2021. The metabolic profile of all of the participants evaluated before starting of treatment for HP eradication and 3 months after the treatment. Then changes of metabolic profile compared between those with successful HP eradication (group A) and subjects who failed to eradicate (group B). RESULTS: Overall, 199 patients, including 93 male (46.7%) with the mean age of 44.5 years (18-93 years) included. Based on response to treatment, the participants allocate into group A (those who respond to HP eradication): 164 cases (82.42%); or group B as those who failed to achieve eradication (35 cases, 17.58%). Racially 86.9% of participants were Caucasian and 89% diagnosed as non-ulcer dyspepsia (NUD). The most prevalent comorbidity include hypertension (11.5%) and hyperlipidemia (10%) which were more prevalent in group B (P = 0.002). Three months after therapy, average weight of participants among those who achieved eradication (group A) decreased from 73.1 to 71.4 kg (P = 0.01), but in comparison with group B, was non-significant (P = 0.171). The BMI of patients before and after treatment did not show any significant differences. The biochemical parameters of patients before and after treatment were not significantly different regardless of treatment success (P > 0.05). The levels of total cholesterol and VLDL cholesterol after treatment were not significantly different from baseline values in two groups. HDL and LDL cholesterol levels before and after treatment in the resistant group were significantly higher than the responding group. Average serum TG level decreased significantly after treatment in the group A (P < 0.0001), in contrast to the resistant group (P = 0.356). The liver transaminases (AST and ALT) before and after treatment were not significantly different between the two groups (P > 0.05). The results of logistic regression showed that the eradication of infection has no significant affect any of the metabolic profile parameters. CONCLUSION: HP infection treatment in individuals without significant metabolic disorders does not affect metabolic parameters up to 3 months after eradication. HP eradication among subjects with several comorbidities mandates eradication protocol intensification to avoid treatment failure.

The effects of synbiotic supplementation on enteral feeding tolerance, protein homeostasis, and muscle wasting of critically ill adult patients: a randomized controlled trial.

BACKGROUND: Enteral feeding intolerance, energy-protein malnutrition, and muscle wasting are common conditions in the critical care setting. The primary aim of this study was to investigate the effect of synbiotic supplementation on enteral feed volume, energy and protein homeostasis, and muscle mass maintenance in critically ill adult patients. METHODS: A consecutive of 42 patients admitted to the Edalatian Medical ICU, requiring enteral nutrition (EN), were prospectively randomized to receive the synbiotic capsule (containing a combination of Lactobacillus, Bifidobacterium, Streptococcus, and fructooligosaccharides) or placebo (21 patients in each group) for a maximum of 14 days. Enteral intolerance and energy homeostasis were evaluated on a daily basis. Nitrogen balance and 24-h urine creatinine excretion were recorded on days 1 and 14. Mid-arm circumference was recorded every 3 days. RESULTS: Mean EN volume, energy, and protein intake per day were 962.5 ± 533.82 ml, 770 ± 427.05 kcal, and 38.5 ± 21.35 g (fourth day) vs. 590 ± 321.1 ml, 472 ± 256.81 kcal, and 23.6 ± 12.84 g (first day) in the synbiotic group (p < 0.05). Changes in the placebo group were not statistically significant. On day 1, nitrogen balance (NB) was - 19.84 ± 8.03 in the synbiotic vs. - 10.99 ± 9.12 in the placebo group (p = 0.003). On day 14, NB was - 14.18 ± 13.05 in the synbiotic and - 9.59 ± 7.71 in the placebo group (p = 0.41). Mid-arm circumference (MAC), 24-h urine creatinine, and creatinine-height index were almost steady in the synbiotic group, while they decreased in the placebo group. CONCLUSION: Overall, it can be concluded that enteral nutrition supplemented with synbiotics has no statistically significant effect on energy and protein homeostasis and muscle mass maintenance of critically ill patients on day 14, but it can increase enteral feed volume and energy and protein intake during the first 4 days of ICU admission. TRIAL REGISTRATION: The trial protocol has been approved in Iranian Registry of Clinical Trials on March 17, 2019. The registration reference is IRCT20190227042857N1.

A Review of Routine Laboratory Biomarkers for the Detection of Severe COVID-19 Disease.

As the COVID-19 pandemic continues, there is an urgent need to identify clinical and laboratory predictors of disease severity and prognosis. Once the coronavirus enters the cell, it triggers additional events via different signaling pathways. Cellular and molecular deregulation evoked by coronavirus infection can manifest as changes in laboratory findings. Understanding the relationship between laboratory biomarkers and COVID-19 outcomes would help in developing a risk-stratified approach to the treatment of patients with this disease. The purpose of this review is to investigate the role of hematological (white blood cell (WBC), lymphocyte, and neutrophil count, neutrophil-to-lymphocyte ratio (NLR), platelet, and red blood cell (RBC) count), inflammatory (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and lactate dehydrogenase (LDH)), and biochemical (Albumin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, D-dimer, total Cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)) biomarkers in the pathogenesis of COVID-19 disease and how their levels vary according to disease severity.

Phenotypic continuum of NFU1-related disorders.

Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum.

Hb Narges Lab, a Novel Hemoglobin Variant of the ß-Globin Gene.

In this study, we describe a new missense variant on the ß-globin gene in a heterozygous form in a female individual. Standard methods were used to determine red blood cell indices and perform hemoglobin analyses. Molecular studies were performed on the genomic DNA isolated from peripheral blood cells. Beta-globin genes were amplified and sequenced. We report a novel mutation on the ß-globin gene (HBB), c.134 C>T; p.S44F variant, in the heterozygote state which was detected in a female of Persian ethnic origin in the Khuzestan province, southern Iran, that we named Hb Narges Lab (HbNL) variant. This mutation was predicted to be disease-causing in all except one in silico prediction tools. This variant was reported for the first time worldwide, had no shown hematological abnormalities but should be considered when inherited in the compound heterozygous form with ß- thalassemia (ß0-thal) carrier, which might result in the phenotype of thalassemia intermedia.

TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.

The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into 'pure HSP' in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and 'complex HSP' when these features are accompanied by other neurological (or non-neurological) clinical signs. Here, we identified biallelic variants in the transmembrane protein 63C (TMEM63C) gene, encoding a predicted osmosensitive calcium-permeable cation channel, in individuals with hereditary spastic paraplegias associated with mild intellectual disability in some, but not all cases. Biochemical and microscopy analyses revealed that TMEM63C is an endoplasmic reticulum-localized protein, which is particularly enriched at mitochondria-endoplasmic reticulum contact sites. Functional in cellula studies indicate a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Together, these findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases.

Mesenchymal stromal cell therapy for COVID-19-induced ARDS patients: a successful phase 1, control-placebo group, clinical trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is the devastating complication of the new COVID-19 pandemic, directly correlated with releasing large amounts of inflammatory cytokines. Due to their immunoregulatory features, mesenchymal stromal cells (MSCs) provide a promising approach against this disease. In this regard, this study was designed as a single-center, open-label, phase 1 clinical trial with a control group to examine the safety and explore the possible potency of three injections of umbilical cord-derived MSCs (UC-MSCs) in mild-moderate COVID-19-induced ARDS patients. METHODS: Twenty confirmed COVID-19 patients with mild-to-moderate ARDS degree entered the study and were divided into two groups: control group (standard care) and intervention group (standard care + UC-MSCs). The patients received three intravenous infusions of UC-MSCs (1 × [Formula: see text] cells/kg BW per injection) every other day. Respiratory markers, CRP levels and specific serum cytokines were assessed four times (days of 0, 5, 10 and 17) during the 17-day follow-up period. RESULTS: During the study, there were no serious adverse effects after cell transplantations. Besides, significant improvement in SPO2/FIO2 ratio and serum CRP levels was observed. On the other hand, a significant decrease (P < 0.05) in serum cytokine levels of IL-6, IFN-g, TNF-α, IL-17 A and a significant increase in serum cytokine levels of TGF-B, IL-1B and IL-10 were observed. Also, no significant changes were observed in CT scan images of patients during the study period. CONCLUSION: Our obtained results demonstrated that multiple intravenous transplantations of allogenic UC-MSCs in non-severe COVID-19-induced ARDS patients are a safe procedure. In addition, this intervention is a hopeful approach to decline cytokine storm and recover respiratory functions. Indeed, more clinical trials with larger sample sizes are required to confirm these results. Trial registration This clinical trial was registered with the Iranian Registry of Clinical Trials (ID: IRCT20160809029275N1 at 2020.05.30).

Whole-exome sequencing deciphers the genetic profile of visual impairments in patients from Southwest Iran.

Genetic ocular diseases are heterogeneous disorders. Recent advances have led to a paradigm shift in the discovery of eye disease-associated genetic variants from linkage and genome-wide association studies to next-generation sequencing-based genome studies. The aim of the current study was to investigate the spectrum of possible vision impairment-related variants in 66 Iranian patients. Whole-exome sequencing (WES) technology followed by bioinformatics analysis, Sanger validation, and co-segregation study were done to find eye disease-causing variants in the patients with vision impairments from Southwest Iran. WES revealed disease-causing variants in 82% of the enrolled cases. WES of understudied cohorts presented an effective strategy for determining pathogenic variants in heterogeneous eye diseases and demonstrated the distribution of causative genetic mutations in Iranian patients. The present data could provide the potential to accelerate genetic screening and a reference for treatment modalities for patients with different types of eye disorders from Southwest Iran.

The effects of l-Carnitine supplementation on inflammatory markers, clinical status, and 28 days mortality in critically ill patients: A double-blind, randomized, placebo-controlled trial.

AIM: Critical ill patients experience catabolic stress, which results in a systemic inflammatory response. The inflammatory response is associated with increased complications, including infection, multi-organ dysfunction, increased length of ICU stays, and mortality. l-Carnitine supplementation may play an important role in these patients by regulating inflammatory cell function. The purpose of the present study was to investigate the effect of l-Carnitine supplementation on clinical status, inflammatory markers, and mortality rate in critically ill patients admitted to the intensive care unit (ICU). METHODS: This randomized, double-blind, placebo-controlled trial was performed on critically ill patients. Subjects were randomly assigned into placebo (n = 27) and l-Carnitine (n = 27) groups. l-Carnitine (3000 mg/day) was administered via nasogastric tube for the intervention group for 7 days, while the other group received a placebo for the same duration. Serum levels of inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6) were measured. Nutritional status and the acute physiology and chronic health evaluation (APACHE) score, sequential organ failure assessment (SOFA) score, and 28-day mortality were also recorded. RESULTS: Fifty-one critically ill patients completed the study. l-Carnitine supplementation significantly reduced the levels of CRP (mean change ± SE: -34.9 ± 6.5) and IL-6 (mean change ± SE: -10.64 ± 2.16) compared to the baseline, which is both statistically significant compared with the control group (p < 0.05). The SOFA and APACHE scores were significantly reduced in the l-Carnitine group compared with the placebo group (p = 0.02 and p < 0.001, respectively). CONCLUSIONS: l-Carnitine supplementation showed beneficial effects on inflammatory and clinical outcomes of critically ill patients. TRIAL REGISTRATION DETAILS: Trial registration: IRCT, Registered 30 May 2018, https://www.irct.ir/trial/30748.

Genotype-phenotype correlation in patients with deletional and nondeletional mutations of Hb H disease in Southwest of Iran.

We studied the alpha-globin gene genotypes, hematologic values, and transfusion-dependence of patients with Hb H disease. Molecular characterization of alpha-thalassemia was performed. We identified 120 patients with Hb H disease. Of these patients, 35 (29.16%) had deletional form of Hb H disease, and 85 (70.83%) had different form of non-deletional Hb H disease. The most frequently observed Hb H genotypes were --Med/-α3.7 in 33 patients (27.5%), αCD19(-G) α/αCD19(-G) α in 25 cases (20.83%), αpolyA2α/αpolyA2α in 15 (12.5%), and αpolyA1α/αpolyA1α in 13 (10.83%) respectively. The probability of receiving at least one transfusion blood in deletional form was observed in 3 of 35 (8.57%) patients which just seen in 3 of 33 (9%) patients with --Med/-α3.7 genotype. This form was also observed in 8 of 85 (9.4%) patients in non-deletional Hb H diseases which five of them had Med deletion in compound with alpha globin point mutations. Nondeletional Hb H disease was more severe than deletional Hb H disease requiring more blood transfusions. We can recommend that Med deletion in compound with alpha-globin point mutations, polyA1 and constant spring in homozygous form needs to be taken into consideration when offering counseling to high-risk couples.

Effects of Melatonin and Propolis Supplementation on Inflammation, Oxidative Stress, and Clinical Outcomes in Patients with Primary Pneumosepsis: A Randomized Controlled Clinical Trial.

BACKGROUND AND OBJECTIVE: The present study aimed to investigate the effects of propolis and melatonin supplementation on inflammation, clinical outcomes, and oxidative stress markers in patients with primary pneumosepsis. MATERIALS AND METHODS: This pilot randomized controlled trial was conducted on 55 patients with primary pneumosepsis who were randomly assigned to the intervention and control groups. In the three intervention groups, the patients received propolis alone (1,000 mg/day), propolis (1,000 mg/day) plus melatonin (20 mg/day), and melatonin alone (20 mg/day). The control group received placebo. The inflammatory and oxidative stress markers as well as clinical outcomes were evaluated before and after the intervention, and the 28-day survival rate was also recorded. RESULTS: After the intervention, the combination of propolis and melatonin significantly reduced interleukin-6 (-55.282 pg/mL) and C-reactive protein (-21.656 mg/L) levels, while increasing gavage intake (326.680 mL/day) and improving some clinical outcomes (APACHE II, SOFA, and NUTRIC scores) compared to the control group. However, no significant difference was observed between the groups in terms of oxidative stress and hematological indices. In addition, there was no significant difference in the 28-day survival rate between the groups (p = 0.07). CONCLUSION: Supplementation with propolis and melatonin may improve clinical outcomes by reducing inflammation. Further investigations are required to confirm these findings.

Comparative effectiveness of pharmacological interventions on mortality and the average length of hospital stay of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Up to now, numerous randomized controlled trials (RCTs) have examined various drugs as possible treatments for Coronavirus Disease 2019 (COVID-19), but the results were diverse and occasionally even inconsistent with each other. To this point,we performed a systematic review and meta-analysis to assess the comparative effectiveness of pharmacological agents in published RCTs. AREAS COVERED: A literature search was performed using PubMed, SCOPUS, EMBASE, and Web of Science databases. RCTs evaluating mortality and the average length of hospital stay to standard of care (SOC)/placebo/control were included. RCTs mainly were classified into five categories of drugs, including anti-inflammatory, antiviral, antiparasitic, antibody and antibiotics. Meta-analysis was done on 5 drugs classes and sub-group meta-analysis was done on single drugs and moderate or severe stage of disease. EXPERT OPINION: Mortality and the average length of hospital stay of COVID-19 patients were significantly reduced with anti-inflammatory drugs (odds ratio [OR]: 0.77, 95% confidence interval [CI]: 0.69 to 0.85, P<0.00001, and mean difference [MD]: -1.41, CI:-1.75 to -1.07, P<0.00001, respectively) compared to SOC/control/placebo. Furthermore, antiparasitic was associated with reduced length of hospital stay (MD: -0.65, CI: -1.26 to -0.03, P<0.05) in comparison to SOC/placebo/control. However, no effectiveness was found in other pharmacological interventions.