Abstract The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated. We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition. 

Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches.

Dolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART.We performed a PubMed search using the term "Dolutegravir", last updated 18 December 2023, to estimate the prevalence of VF with emergent INSTI DRMs in people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART.Of 2131 retrieved records, 43 clinical trials, 39 cohorts, and 6 cross-sectional studies provided data across 6 clinical scenarios based on ART history, virological status, and co-administered ARVs: (1) ART-naïve PLWH receiving DTG plus two NRTIs; (2) ART-naïve PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on a previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The median proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.5% for scenario 3 and 3.4% for scenario 6. In the remaining four trial scenarios, VF prevalence with emergent INSTI DRMs was ≤0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, whereas cross-sectional studies yielded prevalence data lacking denominator details.In clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess VF prevalence with emergent INSTI DRMs in PLWH receiving DTG in real-world settings. 

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are increasingly recognised as important complications in patients requiring intensive care for severe viral pneumonia. The diagnosis can typically be made in 10-20% of patients with severe influenza or COVID-19, but only when appropriate diagnostic tools are used. Bronchoalveolar lavage sampling for culture, galactomannan testing, and PCR forms the cornerstone of diagnosis, whereas visual examination of the tracheobronchial tract during bronchoscopy is required to detect invasive Aspergillus tracheobronchitis. Azoles are the first-choice antifungal drugs, with liposomal amphotericin B as an alternative in settings where azole resistance is prevalent. Despite antifungal therapy, IAPA and CAPA are associated with poor outcomes, with fatality rates often exceeding 50%. In this Review, we discuss the mechanistic and clinical aspects of IAPA and CAPA. Moreover, we identify crucial knowledge gaps and formulate directions for future research. 

Influenza-associated and COVID-19-associated pulmonary aspergillosis in critically ill patients

Abstract Coronavirus disease 2019 (COVID-19) can lead to severe acute respiratory syndrome, and while most individuals recover within weeks, approximately 30–40% experience persistent symptoms collectively known as Long COVID, post-COVID-19 syndrome, or post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC). These enduring symptoms, including fatigue, respiratory difficulties, body pain, short-term memory loss, concentration issues, and sleep disturbances, can persist for months. According to recent studies, SARS-CoV-2 infection causes prolonged disruptions in mitochondrial function, significantly altering cellular energy metabolism. Our research employed transmission electron microscopy to reveal distinct mitochondrial structural abnormalities in Long COVID patients, notably including significant swelling, disrupted cristae, and an overall irregular morphology, which collectively indicates severe mitochondrial distress. We noted increased levels of superoxide dismutase 1 which signals oxidative stress and elevated autophagy-related 4B cysteine peptidase levels, indicating disruptions in mitophagy. Importantly, our analysis also identified reduced levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in these patients, serving as a novel biomarker for the condition. These findings underscore the crucial role of persistent mitochondrial dysfunction in the pathogenesis of Long COVID. Further exploration of the cellular and molecular mechanisms underlying post-viral mitochondrial dysfunction is critical, particularly to understand the roles of autoimmune reactions and the reactivation of latent viruses in perpetuating these conditions. This comprehensive understanding could pave the way for targeted therapeutic interventions designed to alleviate the chronic impacts of Long COVID. By utilizing circulating ccf-mtDNA and other novel mitochondrial biomarkers, we can enhance our diagnostic capabilities and improve the management of this complex syndrome. 

Novel biomarkers of mitochondrial dysfunction in Long COVID patients

Background Sepsis is a life-threatening organ dysfunction caused by the host’s dysfunctional response to infection, which can cause acute gastrointestinal injury (AGI). The gut microbiota is dynamic and plays a role in the immune and metabolic. The aim of this study was to investigate the composition and function of gut microbiota in patients with sepsis, as well as the gut microbiome that may be involved in the occurrence of AGI. Methods A total of 23 stool samples from healthy control individuals and 41 stool samples from sepsis patients were collected. Patients with sepsis were followed up for one week to observe whether AGI has occurred. Finally, 41 patients included 21 sepsis complicated with AGI (referred to as Com-AGI) and 20 sepsis without complicated with AGI (referred to as No-AGI). The gut microbiota was analyzed by 16S rRNA gene sequencing, followed by composition analysis, difference analysis, correlation analysis, functional prediction analysis. Results The diversity and evenness of gut microbiota were decreased in patients with sepsis. Compared with No-AGI, the gut microbiota of Com-AGI has higher community diversity, richness, and phylogenetic diversity. Escherichia-Shigella, Blautia and Enterococcus may be important indicators of sepsis. The correlation analysis showed that aspartate aminotransferase (AST) and Barnesiella have the most significant positive correlation. Moreover, Clostridium_innocuum_group, Christensenellaceae_R-7_group and Eubacterium were all significantly correlated with LAC and DAO. Clostridium_innocuum_group, Barnesiella, Christensenellaceae_R-7_group and Eubacterium may play important roles in the occurrence of AGI in sepsis. PICRUSt analysis revealed multiple functional pathways involved in the relationship between gut microbiota and sepsis, including starch degradation V, glycogen degradation I (bacterial), Lipoic acid metabolism and Valine, leucine and isoleucine biosynthesis. BugBase analysis showed that the gut microbiota with Aerobic phenotype may play an important role in sepsis. Conclusion Dysfunction of gut microbiota was associated with sepsis and AGI in patients with sepsis.

Investigation of Gut Microbiota Disorders in Sepsis and Sepsis Complicated with Acute Gastrointestinal Injury Based on 16S rRNA Genes Illumina Sequencing

During the novel coronavirus disease-2019 pandemic, a considerable number of pneumothorax (PNX)/pneumomediastinum (PNM) associated with COVID-19 have been reported, and the incidence is higher in critically ill patients. Despite using a protective ventilation strategy, PNX/PNM still occurs in patients on invasive mechanical ventilation (IMV). This matched case-control study aims to identify the risk factors and clinical characteristics of PNX/PNM in COVID-19.This retrospective study enrolled adult patients with COVID-19, admitted to a critical care unit from March 1, 2020, to January 31, 2022. COVID-19 patients with PNX/PNM were compared, in a 1-2 ratio, to COVID-19 patients without PNX/PNM, matched for age, gender, and worst National Institute of Allergy and Infectious Diseases ordinal scale. Conditional logistic regression analysis was performed to assess the risk factors for PNX/PNM in COVID-19.427 patients with COVID-19 were admitted during the period, and 24 patients were diagnosed with PNX/PNM. Body mass index (BMI) was significantly lower in the case group (22.8 kg/m2 and 24.7 kg/m2; P = 0.048). BMI was statistically significant risk factor for PNX/PNM in univariate conditional logistic regression analysis [odds ratio (OR), 0.85; confidence interval (CI), 0.72-0.996; P = 0.044]. For patients on IMV support, univariate conditional logistic regression analysis showed the statistical significance of the duration from symptom onset to intubation (OR, 1.14; CI, 1.006-1.293; P = 0.041).Higher BMI tended to show a protective effect against PNX/PNM due to COVID-19 and delayed application of IMV might be a contributive factor for this complication. 

/pdf/risk-factors-of-pneumothorax-and-pneumomediastinum-in-covid-d5t52l5d.pdf

Risk factors of pneumothorax and pneumomediastinum in COVID-19: a matched case–control study

Abstract Progressive multifocal leukoencephalopathy (PML) is a rare but fatal opportunistic infection and mainly occurs in patients with immunosuppressive conditions. Despite the increasing number of patients receiving immunosuppressive treatments, studies on PML are still lacking due to its low prevalence and incidence. We retrospectively reviewed patients diagnosed with PML in two tertiary hospitals in South Korea from 1999 to 2021. Total of 47 PML patients were included. Of 27 patients (57.4%) were diagnosed with human immunodeficiency virus (HIV). Median last follow-up modified Rankin Scale (mRS) score was higher in the non-HIV PML group than that in the HIV group (5 vs. 4, p = 0.020). Median survival duration was lower in the non-HIV group (184 vs. 1,564 days). The 1-year and overall mortality rates of PML patients were significantly higher in the non-HIV group than that in HIV group (60.0% vs. 25.9%, p = 0.019; 80.0% vs. 40.7%, p = 0.007). Initial mRS score (HR 1.685, p = 0.038) and highly active antiretroviral therapy (HAART) in HIV patients (HR 0.374, p = 0.013) had a significant effect on overall mortality. Our findings suggest that early detection of PML with low mRS score and early initiation of HAART in patients with HIV may improve prognosis. 

Long-term prognosis and overall mortality in patients with progressive multifocal leukoencephalopathy

PURPOSE
As ophthalmic side effects of messenger RNA (mRNA)-based COVID-19 vaccination are not well understood, it is crucial to document and report such instances should they occur.


METHODS
In this observational case series, we report nine patients (55.6% male, mean age 58.9) who received either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) COVID-19 vaccinations from January to June of 2021, and presented with symptoms of keratitis within 14 days. All patients underwent slit-lamp examination and histories were taken.


RESULTS
Most subjects (66.7%) had a history of corneal inflammatory diseases and resolved under antiviral and/or steroidal treatment. Patients who reported symptoms after their second vaccine dose presented earlier than those who reported symptoms after the first dose (mean 4.4 days vs 10.5 days, respectively).


CONCLUSIONS
The immunological reaction following mRNA-based COVID-19 vaccinations may trigger new-onset or reactivation of keratitis, though causality cannot be proven. Despite its rarity, clinicians should be aware of this possible complication and be prepared to treat.

Reports of New and Recurrent Keratitis following mRNA-based COVID-19 Vaccination.

INTRODUCTION
Gut microbiota dysbiosis is associated with susceptibility to sepsis and poor outcomes. However, changes to the intestinal microbiota during sepsis and their value as biomarkers are unclear. In this study, we compared the intestinal microbiota of patients with sepsis and healthy controls.


METHODS
Stool was collected from patients with sepsis (subdivided according to mortality) and controls. Microbiome diversity and composition were analyzed by 16S rRNA gene pyrosequencing. The α-diversity of the intestinal microbiome was determined using operational taxonomic unit (OTU) counts and the Chao1, Shannon, and ACE indices. Adjusted Cox regression analyses assessed 6-month mortality risk factors.


RESULTS
Fifty-nine patients (14 in-hospital deaths) and 29 healthy controls were enrolled. OTU counts and Chao1 and ACE indices were lower in the non-survivor than in the other groups. The controls showed a higher Shannon and lower Simpson index than did the sepsis group. The genus Blautia was more abundant in controls than in the sepsis group, and Faecalibacterium less abundant in the non-survivor than in the other groups. Regression analysis associated low Shannon index with 6-month mortality.


CONCLUSIONS
Survivors of sepsis, non-survivors, and healthy controls have different gut microbiomes, and a low Shannon index is a risk factor for 6-month mortality.

Deciphering gut microbiota in patients with severe sepsis and septic shock.

The obesity paradox in younger adult patients with sepsis: analysis of the MIMIC-IV database.

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