Controversial role of neutrophilic granulocytes in the immunopathogenesis of COVID-19: correlation with imbalance of pro-inflammatory neutrophil-associated cytokines and interferon alpha deficiency.

Neutrophilic granulocytes (NG) are the main drivers of pathological inflammation in COVID-19. Objective. To specify the mechanisms of immunopathogenesis of COVID-19 based on a comparative immunological study of the number and phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets with an assessment of their effector functions against changing profile of NG-associated cytokines IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma. Patients and methods. In patients with moderate-to-severe and severe COVID-19, we determined IL-1beta, TNFalpha, IL-6, IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma (ELISA), the phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets, NF-kappaB-NG (CYTOMICS FC500), phagocytically active NG (%), neutrophil extracellular traps (NETs), NG in apoptosis, and the activity of NADPH oxidase. Results. In COVID-19 against the background of IFNalpha and IFNgamma production blockade and high levels of NG-associated IL-8, IL-18, IL-17A, VEGF-A, a reduction in the number of mature and functionally active CD16brightSD62LbrightCD11bbrightCD63-NG subsets was revealed, as well as an increase in the number of CD16dimSD62LdimSD11bbrightCD63-NG subsets with an immunosuppressive phenotype and CD16brightSD62LbrightSD11bbrightCD63bright-NG subsets with high cytotoxic activity and ability to form NETs, a decrease in the percentage of phagocytically active NG and an increase in the activity of NADPH oxidase, NETs, and NG in apoptosis. Conclusion. IFNalpha deficiency provokes a hyperergic response of NG-associated cytokines, which leads to the formation of uncontrolled immune inflammation involving NG subsets with an immunosuppressive and cytotoxic phenotype, exacerbating the course of COVID-19. The use of recombinant IFNalpha-2b with antioxidants (Viferon) in the early stages of the disease can help to restore immune homeostasis, normalize the level of NG-associated cytokines, reduce NERTs, and achieve good clinical efficacy.Copyright © 2022, Dynasty Publishing House. All rights reserved.

Exploration of potential mechanism of SARS-CoV-2 induced immune inflammatory response leading to progression of atherosclerosis and prediction of traditional Chinese medicine for preventing and treating based on bioinformatics.

Objective To explore the core targets and important pathways of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induced atherosclerosis (AS) progression from the perspective of immune inflammation, so as to predict the potential prevention and treatment of traditional Chinese medicine (TCM). Methods Microarray data were obtained from the Gene Expression Omnibus (GEO) database for coronavirus disease 2019 (COVID-19) patients and AS patients, and the "limmar" and "Venn" packages were used to screen out the common differentially expressed genes (DEGs) genes in both diseases. The gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were performed on the common DEGs to annotate their functions and important pathways. The two gene sets were scored for immune cells and immune function to assess the level of immune cell infiltration. The protein-protein interaction (PPI) network was constructed by STRING database, and the CytoHubba plug-in of Cytoscape was used to identify the hub genes. Two external validation datasets were introduced to validate the hub genes and obtain the core genes. Immuno-infiltration analysis and gene set enrichment analysis (GSEA) were performed on the core genes respectively. Finally the potential TCM regulating the core genes were predicted by Coremine Medical database. Results A total of 7898 genes related to COVID-19, 471 genes related to AS progression;And 51 common DEGs, including 32 highly expressed genes and 19 low expressed genes were obtained. GO and KEGG analysis showed that common DEGs, which were mainly localized in cypermethrin-encapsulated vesicles, platelet alpha particles, phagocytic vesicle membranes and vesicles, were involved in many biological processes such as myeloid differentiation factor 88 (MyD88)-dependent Toll-like receptor signaling pathway transduction, interleukin-8 (IL-8) production and positive regulation, IL-6 production and positive regulation to play a role in regulating nicotinamide adenine dinucleotide phosphate oxidase activity, Toll-like receptor binding and lipopeptide and glycosaminoglycan binding through many biological pathways, including Toll-like receptor signaling pathways, neutrophil extracellular trap formation, complement and coagulation cascade reactions. The results of immune infiltration analysis demonstrated the state of immune microenvironment of COVID-19 and AS. A total of 5 hub genes were obtained after screening, among which Toll-like receptor 2 (TLR2), cluster of differentiation 163 (CD163) and complement C1q subcomponent subunit B (C1QB) genes passed external validation as core genes. The core genes showed strong correlation with immune process and inflammatory response in both immune infiltration analysis and GSEA enrichment analysis. A total of 35 TCMs, including Chuanxiong (Chuanxiong Rhizoma), Taoren (Persicae Semen), Danggui (Angelicae Sinensis Radix), Huangqin (Scutellariae Radix), Pugongying (Taraxaci Herba), Taizishen (Pseudostellariae Radix), Huangjing (Polygonati Rhizoma), could be used as potential therapeutic agents. Conclusion TLR2, CD163 and C1QB were the core molecules of SARS-CoV-2-mediated immune inflammatory response promoting AS progression, and targeting predicted herbs were potential drugs to slow down AS progression in COVID-19 patients.Copyright © 2023 Editorial Office of Chinese Traditional and Herbal Drugs. All rights reserved.

Cool Your Jets Bro

History: Twenty-two year old male basic trainee was brought to the ED after collapsing during a routine ruck march. At mile 8/12, soldier was noted to develop an unsteady gate and had witnessed loss of consciousness. A rectal core temperature was obtained and noted to be >107degreeF. Cooling initiated with ice sheets and EMS was activated. On arrival to the ED, patient demonstrated confusion and persistently elevated core temperatures despite ice sheeting, chilled saline and cold water bladder lavage. Cooling measures were discontinued after patient achieved euthermia in the ED;however, his temperatures subsequently spiked>103degreeF. Given rebound hyperthermia, an endovascular cooling (EVC) device was placed in the right femoral vein and patient was transferred to the ICU. Multiple attempts to place EVC device on standby were unsuccessful with subsequent rebound hyperthermia. Prolonged cooling was required. Physical Exam: VS: HR 121, BP 85/68, RR 22 SpO2 100% RA, Temp 102.4degreeF Gen: young adult male, NAD, shivering, A&Ox2 (person and place only) HEENT: Scleral anicteric, conjunctiva non-injected, moist mucus membranes Neck: Supple, no LAD Chest: CTAB, no wheezes/rales/rhonchi CV: tachycardia, regular rhythm, normal S1, S2 without murmurs, rubs, gallops ABD: NABS, soft/non-distended, no guarding or rebound EXT: No LE edema, tenderness SKIN: blisters with broad erythematous bases on bilateral heels Neuro: CN II-XII grossly intact, 5/5 strength in all extremities. Differential Diagnosis: 216. Septic Shock 217. Hypothalamic Stroke 218. Exertional Heat Stroke (EHS) 219. Neuroleptic Malignant Syndrome 220. Thyroid Storm Test Results: CBC: 18.2>14.5/40.6<167 CMP: 128/3.5 88/1831/2.7<104, AST 264, ALT 80, Ca 8.8 Lactate: 7.1 CK: 11 460 Myoglobin: 18 017 TSH: 3.16 CXR: No acute cardiopulmonary process Blood Cx: negative x2 CSF Cx: Negative COVID/Influenza/EBV: Negative Brain MRI: wnl. Final Diagnosis: Exertional Heat Stroke. Discussion(s): No EVC protocols exist for the management of EHS or rebound/refractory hyperthermia. As a result, the protocol used for this patient was adapted from post-cardiac arrest cooling protocols. It is unclear if this adapted protocol contributed to his delayed cooling and rebound hyperthermia as it was not intended for this patient demographic/ pathophysiology. Furthermore, despite initiating empiric antibiotics upon admission, delayed recognition and tailored therapy for his bilateral ankle cellulitis may have contributed to the difficulty in achieving euthermia. In summary, more research needs to be done to evaluate and develop an EVC protocol for EHS. Outcome(s): Euthermia was achieved and maintained after 36 hours of continuous EVC, at which point it was discontinued. His CK, AST/ALT, creatinine and sodium down-trended after discontinuation of EVC. Patient's antibiotics were transitioned to an oral formulation for treatment of ankle cellulitis and he was prepared for discharge. He was discharged with regular follow-up with the Fort Benning Heat Clinic. Follow-Up: After discharge, patient had regularly scheduled visits with the Fort Benning Heat Clinic. His typical lab markers for exertional heat stroke were regularly monitored. He had continued resolution of his Rhabdomyolysis, acute kidney injury and hyponatremia with typical treatment. Soldier returned to duty after 10 weeks of close monitoring and rehabilitation.

Controversial role of neutrophilic granulocytes in the immunopathogenesis of COVID-19: correlation with imbalance of pro-inflammatory neutrophil-associated cytokines and interferon alpha deficiency.

Neutrophilic granulocytes (NG) are the main drivers of pathological inflammation in COVID-19. Objective. To specify the mechanisms of immunopathogenesis of COVID-19 based on a comparative immunological study of the number and phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets with an assessment of their effector functions against changing profile of NG-associated cytokines IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma. Patients and methods. In patients with moderate-to-severe and severe COVID-19, we determined IL-1beta, TNFalpha, IL-6, IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma (ELISA), the phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets, NF-kappaB-NG (CYTOMICS FC500), phagocytically active NG (%), neutrophil extracellular traps (NETs), NG in apoptosis, and the activity of NADPH oxidase. Results. In COVID-19 against the background of IFNalpha and IFNgamma production blockade and high levels of NG-associated IL-8, IL-18, IL-17A, VEGF-A, a reduction in the number of mature and functionally active CD16brightSD62LbrightCD11bbrightCD63-NG subsets was revealed, as well as an increase in the number of CD16dimSD62LdimSD11bbrightCD63-NG subsets with an immunosuppressive phenotype and CD16brightSD62LbrightSD11bbrightCD63bright-NG subsets with high cytotoxic activity and ability to form NETs, a decrease in the percentage of phagocytically active NG and an increase in the activity of NADPH oxidase, NETs, and NG in apoptosis. Conclusion. IFNalpha deficiency provokes a hyperergic response of NG-associated cytokines, which leads to the formation of uncontrolled immune inflammation involving NG subsets with an immunosuppressive and cytotoxic phenotype, exacerbating the course of COVID-19. The use of recombinant IFNalpha-2b with antioxidants (Viferon) in the early stages of the disease can help to restore immune homeostasis, normalize the level of NG-associated cytokines, reduce NERTs, and achieve good clinical efficacy.Copyright © 2022, Dynasty Publishing House. All rights reserved.

Adipose tissue, systematic inflammation, and neurodegenerative diseases

Obesity is associated with several diseases, including mental health. Adipose tissue is distributed around the internal organs, acting in the regulation of metabolism by storing and releasing fatty acids and adipokine in the tissues. Excessive nutritional intake results in hypertrophy and proliferation of adipocytes, leading to local hypoxia in adipose tissue and changes in these adipokine releases. This leads to the recruitment of immune cells to adipose tissue and the release of pro-inflammatory cytokines. The presence of high levels of free fatty acids and inflammatory molecules interfere with intracellular insulin signaling, which can generate a neuroinflammatory process. In this review, we provide an up-to-date discussion of how excessive obesity can lead to possible cognitive dysfunction. We also address the idea that obesity-associated systemic inflammation leads to neuroinflammation in the brain, particularly the hypothalamus and hippocampus, and that this is partially responsible for these negative cognitive outcomes. In addition, we discuss some clinical models and animal studies for obesity and clarify the mechanism of action of anti-obesity drugs in the central nervous system.Copyright © 2023 Wolters Kluwer Medknow Publications. All rights reserved.

NAD+ metabolism-based immunoregulation and therapeutic potential.

Nicotinamide adenine dinucleotide (NAD+) is a critical metabolite that acts as a cofactor in energy metabolism, and serves as a cosubstrate for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ metabolism can regulate functionality attributes of innate and adaptive immune cells and contribute to inflammatory responses. Thus, the manipulation of NAD+ bioavailability can reshape the courses of immunological diseases. Here, we review the basics of NAD+ biochemistry and its roles in the immune response, and discuss current challenges and the future translational potential of NAD+ research in the development of therapeutics for inflammatory diseases, such as COVID-19.

Adjunctive therapy with lipid-lowering agents in COVID-19: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Many commonly used drugs were evaluated as repurposed treatment options since the emergence of the COVID-19 pandemic. The benefit of lipid-lowering agents has been controversial in this regard. In this systematic review, we assessed the effect of these medications as adjunctive therapy in COVID-19 by the inclusion of randomized controlled trials (RCTs). METHODS: We searched four international databases including PubMed, the Web of Science, Scopus, and Embase for RCTs in April 2023. The primary outcome was mortality, while other efficacy indices were considered secondary outcomes. In order to estimate the pooled effect size of the outcomes, considering the odds ratio (OR) or standardized mean difference (SMD) and 95% confidence interval (CI), random-effect meta-analyses was conducted. RESULTS: Ten studies involving 2,167 COVID-19 patients using statins, omega-3 fatty acids, fenofibrate, PCSK9 inhibitors, and nicotinamide as intervention compared to control or placebo, were included. No significant difference was found in terms of mortality (OR 0.96, 95% CI 0.58 to 1.59, p-value = 0.86, I2 = 20.4%) or length of hospital stay (SMD -0.10, 95% CI -0.78 to 0.59, p-value = 0.78, I2 = 92.4%) by adding a statin to the standard of care. The trend was similar for fenofibrate and nicotinamide. PCSK9 inhibition, however, led to decreased mortality and an overall better prognosis. Omega-3 supplementation showed contradicting results in two trials, suggesting the need for further evaluation. CONCLUSION: Although some observational studies found improved outcomes in patients using lipid-lowering agents, our study found no benefit in adding statins, fenofibrate, or nicotinamide to COVID-19 treatment. On the other hand, PCSK9 inhibitors can be a good candidate for further assessment. Finally, there are major limitations in the use of omega-3 supplements in treating COVID-19 and more trials are warranted to evaluate this efficacy.

Benefit from BCON? The unmet need of bladder cancer patients unsuitable for chemoradiation treated with radical radiotherapy alone: A single institution retrospective case note review

Introduction & Objectives: Bladder preservation is routinely used as an alternative to radical cystectomy in the UK and is becoming more accepted elsewhere globally. The gold standard is for patients to receive radiotherapy with a radiosensitiser most commonly concurrent chemotherapy e.g. 5FU/mitomycin C, gemcitabine or cisplatin. Patients with poor performance status or comorbidities may be unable to be offered concurrent treatment with chemotherapy but alternative treatment with concurrent carbogen +/- nicotinamide as a hypoxic modifier may be of benefit. Our aim therefore was to retrospectively review patients with bladder TCC treated with radical radiotherapy alone in the last 5 years who may have benefited from carbogen +/- nicotinamide radiosensitisation at a large cancer centre in the north of England. Material(s) and Method(s): In this single institution retrospective case note review, electronic records were reviewed for 175 patients who had received radiotherapy to the bladder for TCC between 2017-2022. Patients who had radical radiotherapy (RT) alone without radiosensitisation were scrutinised to ascertain whether they would have been candidates for carbogen and nicotinamide using the inclusion/exclusion criteria previously defined in the Bladder Carbogen Nicotinamide (BCON) Randomised Phase 3 trial. Result(s): We analysed 175 patients. Of these, 133 received had radical RT without radiosensitisation. The most common reason for not offering radiosensitisation was the presence of co-morbidities (27.8%). Of interest, the proportion of patients having chemotherapy radiosensitisation did not change after COVID19 in March 2020 (21.5% pre- vs 27.5% post;p=0.32 chi2). Conversely, the proportion of patients receiving neo-adjuvant chemotherapy reduced though failed to reach significance (12.6% pre- vs 5% post;p=0.08 chi2). After review of the notes and criteria from the original BCON trial, 106 patients (79.6%) could have benefited from carbogen +/- nicotinamide. Of these, 14 patients (13.2%) could have been offered carbogen alone due to poor renal function. The most common reason for not being eligible for BCON was respiratory disease with reduced respiratory drive (44%). Conclusion(s): The National Institute for Health and Care Excellence (NICE) state that all radical RT for bladder TCC should be with a radiosensitiser. Due to logistical and departmental issues, the BCON regimen is not currently offered as a standard alternative to radiosensitisation with chemotherapy. BCON has been demonstrated to be tolerable and, whilst updated follow-up data failed to demonstrate statistical significance for overall survival (OS), meta-analysis of hypoxia modification has shown significant improvement in OS compared to RT alone. Hypoxia modification with carbogen +/- nicotinamide should be considered for all patients unsuitable for chemotherapy radiosensitisation.Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Functional Role of Natural Antioxidants in Controlling Oxidative Stress Associated with SARS-CoV-2 Infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogenic coronavirus that emerged in late 2019, resulting in coronavirus disease (COVID-19). COVID-19 can be potentially fatal among a certain group of patients. Older age and underlying medical illness are the major risk factors for COVID-19-related fatal respiratory dysfunction. The reason for the pathogenicity of COVID-19 in the older age group remains unclear. Factors, such as coagulopathy, cytokine storm, metabolic disrup-tion, and impaired T cell function, may worsen the symptoms of the disease. Recent literature has indicat-ed that viral infections are particularly associated with a high degree of oxidative stress and an imbalance of antioxidant response. Although pharmacological management has taken its place in reducing the severity of COVID-19, the antioxidants can serve as an adjunct therapy to protect an individual from oxidative damage triggered by SARS-CoV-2 infection. In general, antioxidant enzymes counteract free radicals and prevent their formation. The exact functional role of antioxidant supplements in reducing disease symptoms of SARS-CoV-2 infection remains mostly unknown. In this review, the functional role of natural antioxidants in SARS-CoV-2 infection management is discussed in brief.Copyright © 2022 Bentham Science Publishers.

Proteomic determinants of disease, mortality and sequelae in COVID-19 patients requiring invasive mechanical ventilation

Introduction: The molecular mechanisms linked to the pathology of severe COVID-19 and its outcomes are poorly described. Aim(s): To analyze the proteomic profile of bronchial aspirates (BAS) samples from critically ill COVID-19 patients in order to identify factors associated with the disease and its prognosis. Method(s): Multicenter study including 74 critically ill non-COVID-19 and COVID-19 patients. BAS was obtained by bronchoaspiration after invasive mechanical ventilation (IMV) initiation. Proximity extension assay (PEA) technology was used for proteomic profiling. Random forest (RF) statistical models were used to predict the variable importance. Result(s): After adjusting for confounding factors, CST5, NADK, SRPK2 and TGF-alpha showed differences between COVID-19 and non-COVID-19 patients. Reduced levels of ENTPD2 and PTN were observed in non-survivors, even after adjustment. AGR2, NQO2, IL-1alpha, OSM and TRAIL, were the top five strongest predictors for ICU mortality and were used to build a prediction model. PTN (HR=4.00) ENTPD2 (HR=2.14) and the prediction model (HR=6.25) were associated with higher risk of death. In survivors, FCRL1, NTF4 and THOP1 correlated with lung function (DLCO levels) 3-months after hospital discharge. Similar findings were observed for Flt3L and THOP1 and radiological features (TSS). The proteins identified are expressed in immune and non-immune lung cells. A poor control of viral infectivity and an inappropriate reparative response seems to be linked to the disease and fatal outcomes, respectively. Conclusion(s): In critically ill COVID-19 patients, specific proteomic profiles are associated with the pathology, mortality and lung sequelae.

Severe Prps1 Deficiency and Response to S-Adenosylmethionine and Nicotinamide Riboside Supplementation

Background: PRPS1 deficiency spectrum is an X-linked condition caused by pathogenic variants in PRPS1, which encodes for the PRPP enzyme involved in the purine synthesis pathway, among other metabolic pathways. Severely affected individuals, also known as Arts syndrome, have congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections. Infections often precipitate worsening of symptoms and many individuals pass away in childhood. Mildly to moderately affected individuals can have isolated hearing loss, also known as DFNX1, or hearing loss with later onset ataxia and optic neuropathy concerns, also known as CMTX5. Given the importance of PRPP in the role of purine synthesis as well as other cellular processes, including formation of NAD(P), supplementation of these pathways is a logical approach for these patients. 2 Arts syndrome patients were previously supplemented with S-adenosylmethionine, starting in mid-childhood, with improvement in infection severity and frequency, as well as stabilization of other symptoms. Recently another Arts syndrome patient was supplemented with S-adenosylmethionine and nicotinamide riboside, starting in early childhood, with improvement in infection frequency and developmental gains. Here we present a now 23 month old male patient with severe PRPS1 deficiency spectrum symptoms, who was started on S-adenosylmethionine and nicotinamide riboside supplementation. Result(s): This is a 23 month old male with developmental delay, retinal dystrophy, congenital bilateral sensorineural hearing loss, and hypotonia with a PRPS1 c.383A > T / p.Asp128Val likely pathogenic variant. He does not have a history of recurrent infections, however family reports relative isolation due to the Covid-19 pandemic. He sat unsupported at 10 months, crawled at 14 months, pulled to stand at 18 months, and is nonverbal. His uric acid testing was in the low range of normal. He had normal purine testing with low normal xanthine and hypoxanthine levels. At 19 months the patient started 20 mg/kg/d S-adenosylmethionine supplementation. At 20 months this was increased to 40 mg/kg/d S-adenosylmethionine and he started on 30 mg/kg/d nicotinamide riboside supplementation. Parents reported subjective improvement in strength and endurance with supplementation. He made significant developmental gains including walking with a walker. He had done well with occasional upper respiratory infections without regression in skills, worsening hypotonia, or increased respiratory needs. Unfortunately, very recently he had a cardiac arrest secondary to respiratory failure from rhinovirus/enterovirus and H. influzenzae pneumonia, for which he remains hospitalized at this time. Conclusion(s): This is the 4th reported patient with severe PRPS1 deficiency treated with S-adenosylmethionine supplementation and the 2nd reported patient treated with nicotinamide riboside supplementation. Both supplements have a limited side effect profile and have a biochemical basis for consideration in PRPS1 deficiency. He initially did well on supplementation with improvements in strength and endurance, as well as developmental gains, however his current trajectory remains to be seen. Unfortunately, NAD/NADP, ADP/ATP, and similar markers were unavailable to us and we plan to continue clinical monitoring on supplementation. Further studies are needed to evaluate the effectiveness of S-adenosylmethionine and nicotinamide riboside supplementation in these patients.Copyright © 2023

Covid-19 Fatigue: Diagnosis and Treatment for the Osteopathic Physician

The novel coronavirus disease 2019 (COVID-19) has given rise to a global pandemic, as well as a multitude of long-term sequelae that continue to perplex physicians around the world, including in the United States. Among the most common and impactful long-haul symptoms experienced by survivors is COVID-19 fatigue. This review will use long COVID-19, post-acute COVID-19 syndrome (PCS), and PostAcute Sequelae of COVID-19 (PASC) as synonymous terms to refer to the chronic symptomatology;chronic fatigue associated with PASC will be referred to as COVID-19 fatigue. While the knowledge and research on the exact pathophysiological mechanisms involved in the disease is still limited, parallels have been drawn between fatigue as a component of long COVID-19 and myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). Current studies suggest applying principles of pathophysiology, diagnosis, and treatment similar to those for ME/CFS in order to aid in managing chronic fatigue in COVID-19 survivors, particularly in the primary care setting. The osteopathic family physician can use the proposed pharmacologic agents, along with osteopathic manipulative treatment (OMT), as therapeutic modalities that can be tailored to each patient's unique case. Nevertheless, research on proven successful treatments is still scarce. For that reason, it is essential that COVID-19 fatigue is recognized early, especially since its longitudinal impacts may be debilitating for many. This review of the available literature on COVID-19 fatigue aims to help provide quality care and lessen the disease burden experienced by patients.Copyright © 2023 by the American College of Osteopathic Family Physicians. All rights reserved.

Vitamin B Complex in Patients with Acute Kidney Injury the Vibaki Trial

Introduction: Acute kidney injury (AKI) is associated with a very high mortality and an increased risk for progression to chronic kidney disease (CKD). Preclinical studies have identified that NAD+ augmentation as a potential strategy for the prevention and treatment of AKI. NAD+ is the final metabolized form of vitamin B3. A recent clinical study found that COVID-19 related AKI was associated with NAD+ biosynthetic impairment arising in the context of ischemic, inflammatory, or toxic kidney injury. Since there is no availability of vitamin B3 in the country, we tested if I.V. vitamin B complex (vitamin B1, B6 and B12) could improve renal recovery in patients with AKI. By oxidation, vitamin B6 through the pathway of pentose phosphate leads to the formation of NADPH (nicotamide adenine phosphate dinucleotide) an analog of NAD+. Method(s): We conducted randomized, blind, placebo-controlled study in hospitalized patients with AKI (NCT04893733). During the study I.V. vitamin B complex or placebo was given twice a day for 5 consecutive days. In each patient, a protocol-based treatment approach for AKI was used (STOP AKI protocol from the ISN 0by25 trial https://doi.org/10.1371/journal.pmed.1003408). Serum creatinine (sCr) was measured using a point of care device (NOVA Biomedical Xpress CREA) at enrollment and every 24 hours for 7 days, and then at day 30, and day 90. We evaluated if vitamin B complex could improve renal recovery in patients with AKI, reduce the risk of De Novo CKD or CKD progression, and improve survival. Result(s): From September 2020 to September 2021, 260 patients were enrolled. Baseline characteristics are shown on table 1. The drop in sCr values by day 7 was higher in the vitamin B complex group (1.04 vs. 0.33 mg/dl;p < 0.001). Complete recovery was higher in patients randomized to vitamin B complex (59.2% vs. 34.6%;p=0.001), no difference was found in terms of partial recovery (26.2% vs. 27.7%;p=0.888). Non-recovery was lower in patients who received vitamin B complex as compared to placebo (16.6% vs. 37.7%;p < 0.001). At 3 months, the incidence of de novo CKD was lower in patients who received vitamin B complex (19.2% vs. 26.9%;p=0.043) in patients with CKD the progression of the disease was lower in patients who received vitamin B complex (13.1% vs. 20.8%;p=0.023). No differences were found in terms of 90-day mortality (Vitamin B complex 74.3% vs. Placebo 80.1%;0.554). The relative risk of Vitamin B complex for renal recovery was 0.37 (95% CI 0.242 - 0.593;p<0,0001) with a NNT of 3.1 patients with a relative risk for CKD progression or De Novo CKD of 0.47 (95% CI 0.28 - 0.79;p = 0.005) with a NNT of 4.8 patients. Conclusion(s): Vitamin B complex could accelerate renal recovery in patients with AKI;reduce the incidence of De Novo CKD and CKD progression. Our results support ongoing studies investigating the therapeutic potential of NAD+ augmentation as a means to mitigate kidney injury. Conflict of interest Potential conflict of interest: Nova Biomedical MedtronicCopyright © 2023

New horizons for e-Learning in nephrology: The ISN Video Abstracts Series initiative

Introduction: Triggered by the recent revolution posed by the digital era, medical education has evolved enormously over the last decade. Much of this transformation was further accelerated by the COVID-19 pandemic. Video Abstracts are an innovative tool in science communication allowing a quick overview of a scientific paper. It can be used to build capacity by connecting patients and healthcare professionals to education and research, fostering critical thinking, and filling gaps in education. The Video Abstracts Series is an initiative that was envisioned by the ISN Education Working Group in association with the DOPPS collaboration and put into action by the ISN Education Social Media Team. Starting in Dec 2021, the International Society of Nephrology (ISN) Video Abstracts Series has integrated the ISN global education strategy. The videos are allowed a maximum length of 2:20 min to fit the Twitter limits. It constitutes a video narrative of a study's principal characteristics and findings. The project was fully developed based on voluntary work, from conception to video production. Method(s): This study aimed to assess quantitatively the impact of the ISN Video Abstracts Series initiative. From Dec 2021 to Sept 2022, video impressions, engagements, and video views from Twitter, Facebook, LinkedIn, Instagram, and the Academy were analyzed. Result(s): The ISN Video Abstracts Series highlighted studies published in the Kidney International Reports (KIR, n=12);Kidney International (KI, n=12);and the ISN-DOPPS initiative (n=1). In combination, the 25 Video Abstracts, resulted in 139,402 impressions;3,434 engagements;and 25,041 video views. Most of the interactions occurred on Twitter (79.8%). In this digital platform, on average videos had 5,300 impressions and 790 views. The videos redirected the user to the journal publication in 435 instances. The ISN Video Abstracts Series addressing the KIR publication "Nicotinamide Adenine Dinucleotide Biosynthetic Impairment and Urinary Metabolomic Alterations Observed in Hospitalized Adults With COVID19-Related AKI", had the most views (n=2,125). Conclusion(s): The future of continuing medical education relies on new strategies and media to build capacity and bridge the gaps. The ISN offers a wide variety of educational and interactive resources through Social Media and the ISN Academy, its official e-Learning portal. The Video Abstracts Series is an innovative, inclusive, and resourceful tool. It combines sharp and concise information with an entertaining format that captures and retains the user's attention, opening new perspectives in the ISN strategy to boost continuing medical education in nephrology globally. No conflict of interestCopyright © 2023

Effects of TND1128 (a 5-deazaflavin derivative), with self-redox ability, as a mitochondria activator on the mouse brain slice and its comparison with ß-NMN.

We have no definitive treatment for dementia characterized by prolonged neuronal death due to the enormous accumulation of foreign matter, such as ß-amyloid. Since Alzheimer's type dementia develops slowly, we may be able to delay the onset and improve neuronal dysfunction by enhancing the energy metabolism of individual neurons. TND1128, a derivative of 5-deazaflavin, is a chemical known to have an efficient self-redox ability. We expected TND1128 as an activator for mitochondrial energy synthesis. We used brain slices prepared from mice 22 ± 2 h pretreated with TND1128 or ß-NMN. We measured Ca2+ concentrations in the cytoplasm ([Ca2+]cyt) and mitochondria ([Ca2+]mit) by using fluorescence Ca2+ indicators, Fura-4F, and X-Rhod-1, respectively, and examined the protective effects of drugs on [Ca2+]cyt and [Ca2+]mit overloading by repeating 80K exposure. TND1128 (0.01, 0.1, and 1 mg/kg s.c.) mitigates the dynamics of both [Ca2+]cyt and [Ca2+]mit in a dose-dependent manner. ß-NMN (10, 30, and 100 mg/kg s.c.) also showed significant dose-dependent mitigating effects on [Ca2+]cyt, but the effect on the [Ca2+]mit dynamics was insignificant. We confirmed the mitochondria-activating potential of TND1128 in the present study. We expect TND1128 as a drug that rescues deteriorating neurons with aging or disease.

An occurrence of immune-mediated necrotizing myopathy following treatment of polymyositis in a Filipino female: A case report

Background: Necrotizing myopathy has been previously described but was not included in the Peter and Bohan criteria until 2004, when immune-mediated necrotizing myopathy (IMNM) was distinguished from polymyositis (PM) based on immunologic and histopathologic differences. IMNM is currently a well-recognized autoimmune myopathy and represents up to 20% of these cases. Case: A 60-year- old female with biopsy-proven PM achieved sustained clinical remission with Rituximab. Her co-morbid conditions include hypertension, diabetes mellitus, and dyslipidemia. The patient noted a recurrence of gradual progressive, proximal muscle weakness and easy fatigability after receiving her first mRNA Covid-19 vaccine. Four months after onset of symptoms, CK Total was 9600 U/L. Rituximab was administered and muscle weakness and total CK levels (1247 U/L) improved within 10 days. She was prescribed rosuvastatin and fenofibrate for dyslipidemia within 7 days of completing the rituximab course. Two weeks later, proximal muscle weakness recurred. She became wheelchair-bound and experienced dysphonia. MMT score was 2/5 in proximal muscles and total CK total increased to 19,935 U/L. The patient received Methylprednisolone 500 mg IV once a day for 3 days. She had a good response with resolution of dysphonia and improvement of MMT to 4/5 on shoulder abduction and hip flexion on the 6th hospital day. She was discharged on oral methylprednisolone at 1 mg/kg/day. Muscle biopsy was consistent with an immune-mediated necrotizing myopathy, revealing necrotic fibers, intracellular macrophages, fatty infiltrates, irregular staining patterns on NADH stain with no evidence of endomysial inflammation, perifascicular atrophy, ragged red fibers, or rimmed vacuoles. Antibodiy against 3-hydoxy- 3- methylglutarylcoenzymeA reductase (HMGCR) result is pending but the other myositis-specific antibodies are negative.(including anti-SRP). Conclusion(s): IMNM is an autoimmune myopathy associated with anti-HMGCR and anti-SRP antibodies that clinically present similarly to polymyositis. The temporal occurrence of worsening muscle weakness with initiation of statin therapy make statin toxic myopathy or immune mediated necrotizing myopathy as diagnostic considerations. This case emphasizes the need to re-evaluate the etiology of new onset muscle weakness in patients with idiopathic inflammatory myopathy and highlights the role of myositis-specific antibodies and muscle biopsy in confirming the diagnosis.

Topical niacinamide (Nicotinamide) treatment for discoid lupus erythematosus (DLE): A prospective pilot study.

BACKGROUND: Cutaneous lupus erythematosus is an umbrella term for a group of autoimmune connective tissue disorders affecting the skin. Discoid lupus erythematosus (DLE) is the chronic condition and most common form of cutaneous lupus erythematosus. AIMS: Current therapies of DLE are challenging and not completely satisfactory, highly expensive, off-label, or poorly available (like antimalarials due to COVID-19 outbreaks). Nicotinamide, also called niacinamide, is a water-soluble form of vitamin B3 (niacin). Its multiple effects let us think that nicotinamide could be a therapy for lupus-associated skin lesions. METHODS: We performed a prospective randomized double-blind clinical trial on 60 subjects diagnosed with Discoid lupus erythematosus using topical Nicotinamide 2% and 4% preparations in form of cream and gel on skin and scalp lesions. Control group was included using only cream/gel base as placebo control. RESULTS: Obtained data showed that topical Nicotinamide can be used for the treatment of DLE as adjuvant to other treatment regimens with good cosmetic results and minimal side effects. Topical 4% Nicotinamide is superior to 2% preparation in response but associated with a higher incidence of irritation. CONCLUSION: Topical Nicotinamide can be used for the treatment of DLE as an adjuvant to other treatment regimens with good cosmetic results and minimal side effects. Further trials with long-term therapy, follow-up period, and bigger sample sizes are required.

Nicotinamide n-Oxide Attenuates HSV-1-Induced Microglial Inflammation through Sirtuin-1/NF-κB Signaling.

HSV-1 is a typical neurotropic virus that infects the brain and causes keratitis, cold sores, and occasionally, acute herpes simplex encephalitis (HSE). The large amount of proinflammatory cytokines induced by HSV-1 infection is an important cause of neurotoxicity in the central nervous system (CNS). Microglia, as resident macrophages in CNS, are the first line of defense against neurotropic virus infection. Inhibiting the excessive production of inflammatory cytokines in overactivated microglia is a crucial strategy for the treatment of HSE. In the present study, we investigated the effect of nicotinamide n-oxide (NAMO), a metabolite mainly produced by gut microbe, on HSV-1-induced microglial inflammation and HSE. We found that NAMO significantly inhibits the production of cytokines induced by HSV-1 infection of microglia, such as IL-1ß, IL-6, and TNF-α. In addition, NAMO promotes the transition of microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. More detailed studies revealed that NAMO enhances the expression of Sirtuin-1 and its deacetylase enzymatic activity, which in turn deacetylates the p65 subunit to inhibit NF-κB signaling, resulting in reduced inflammatory response and ameliorated HSE pathology. Therefore, Sirtuin-1/NF-κB axis may be promising therapeutic targets against HSV-1 infection-related diseases including HSE.