Objectives The study aimed to clinically assess the association between periodontitis and COVID-19-related outcomes. Material and methods Data pertaining to patient demographics, medical history, blood parameters, periodontal clinical examination and aMMP-8 point-of-care diagnostics (both site-level and patient-level) was recorded for eighty-two COVID-19positive patients. COVID-19-related outcomes such as COVID-19 pneumonia, death/survival, types of hospital admission and need of assisted ventilation were also assessed. Results Males were predominantly afflicted with COVID-19, with advanced age exhibiting a greater association with the presence of periodontitis. Higher severity of periodontitis led to 7.45 odds of requiring assisted ventilation, 36.52 odds of hospital admission, 14.58 odds of being deceased and 4.42 odds of COVID-19-related pneumonia. The aMMP-8 mouthrinse kit was slightly more sensitive but less specific than aMMP-8 site-specific tests. Conclusions Based on the findings of the present study, periodontitis seems to be related to poorer COVID-19-related outcomes. However, within the constraints of this work, a direct causality may not be established. Periodontitis, by means of skewing the systemic condition for a number of comorbidities, may eventually influence COVID-19 outcomes in an indirect manner. Clinical relevanceThe study is the first to clinically, and by means of a validated point-of-care diagnostic methodology, assess the association between periodontal health and COVID-19-related outcomes. Assessment of the periodontal status of individuals can aid in the identification of risk groups during the pandemic along with reinforcing the need to maintain oral hygiene and seeking periodontal care.
Purpose: Methoxyamine has been shown to potentiate the cytotoxic effect of temozolomide both in vitro and in human tumor xenograft models.We postulate that the enhanced cytotoxicity is mediated by methoxyamine-bound apurininc/pyrimidinic (MX-AP) site, a key lesion formed by the combination of temozolomide and methoxyamine. When located within topoisomerase IIa (topo II) cleavage sites in DNA, MX-AP sites act as dual lethal targets, not only functionally disrupting the base excision repair (BER) pathway but also potentially poisoning topo II. Experimental Design: Using oligonucleotide substrates, in which a position-specific MX-AP site is located within topo II cleavage sites, we examined the effect of MX-AP site on both AP endonuclease^and topo II^mediated DNA cleavage in vitro. Results: MX-AP sites were refractory to the catalytic activity of AP endonuclease, indicating their ability to block BER. However, they were cleaved by either purified topo II or nuclear extracts from tumor cells expressing high levels of topo II, suggesting that MX-AP sites stimulate topo II^mediated DNA cleavages. In cells, treatment with temozolomide and methoxyamine increased the expression of topo II and enriched the formation of gH2AX foci, which were colocalized with up-regulated topo II, confirming that DNA double-strand breaks marked by gH2AX foci are associated with topo II in cells. Conclusions: Our findings identify a molecular mechanism of cell death whereby MX-AP sites that cumulated in cells due to resistance to BER potentially convert topo II into biotoxins, resulting in enzyme-mediated DNA scission and cell death.Topoisomerase IIa (topo II) is an essential enzyme that plays a critical role in many DNA processes, including DNA replication/recombination and chromosome segregation. To carry out its important physiologic functions, topo II alters DNA topology by passing an intact double helix through a transient double-stranded break in the genetic material. Thus, whereas the enzyme is necessary for cell survival, it also has the capacity to fragment the genome (1 -3). During the double-stranded DNA passage reaction, topo II has preferential cleavage sites in the DNA. Its two active sites (tyrosyl residues) covalently bind to a 5 ¶-phosphoryl group on each DNA strand, forming a topo II -cleavable DNA complex (4). Normally, these cleavage complexes are present at low levels and can be tolerated by cells. However, conditions that significantly increase the physiologic concentration of this cleavage complex, such as the action of topo II poisons, will convert this physiologic process to a lethal toxicity (5, 6). Therefore, topo II has been identified as the molecular target for a variety of toxic agents that have proved lethal by enhancing topo II -mediated DNA strand breaks (7,8). Recent evidence indicates that many DNA lesions, such as abasic sites [apurininc/pyrimidinic (AP) sites], nicks, or smaller adducts, also act as topo II poisons. Of the lesions examined to date, AP sites seem to be the most active (9 -13). W...
IntroductionEvidence on new-onset endocrine dysfunction and identifying whether the degree of this dysfunction is associated with the severity of disease in patients with COVID-19 is scarce.Patients and MethodsConsecutive patients enrolled at PGIMER Chandigarh were stratified on the basis of disease severity as group I (moderate-to-severe disease including oxygen saturation <94% on room air or those with comorbidities) (n= 35) and group II (mild disease, with oxygen saturation >94% and without comorbidities) (n=49). Hypothalamo-pituitary-adrenal, thyroid, gonadal axes, and lactotroph function were evaluated. Inflammatory and cell-injury markers were also analysed.ResultsPatients in group I had higher prevalence of hypocortisolism (38.5 vs 6.8%, p=0.012), lower ACTH (16.3 vs 32.1pg/ml, p=0.234) and DHEAS (86.29 vs 117.8µg/dl, p= 0.086) as compared to group II. Low T3 syndrome was a universal finding, irrespective of disease severity. Sick euthyroid syndrome (apart from low T3 syndrome) (80.9 vs 73.1%, p= 0.046) and atypical thyroiditis (low T3, high T4, low or normal TSH) (14.3 vs 2.4%, p= 0.046) were more frequent in group I than group II. Male hypogonadism was also more prevalent in group I (75.6% vs 20.6%, p=0.006) than group II, with higher prevalence of both secondary (56.8 vs 15.3%, p=0.006) and primary (18.8 vs 5.3%, p=0.006) hypogonadism. Hyperprolactinemia was observed in 42.4% of patients without significant difference between both groups.ConclusionCOVID-19 can involve multiple endocrine organs and axes, with a greater prevalence and degree of endocrine dysfunction in those with more severe disease.
Background and objectivesRecent randomized controlled trials (RCTs) have indicated potential therapeutic benefits with high-dose dexamethasone (HDD) or tocilizumab (TCZ) plus standard care in moderate to severe coronavirus disease 2019 (COVID-19) with acute respiratory distress syndrome (ARDS). No study has compared these two against each other. We aimed to compare the efficacy and safety of HDD against TCZ in moderate to severe COVID-ARDS. MethodsPatients admitted with moderate to severe COVID-19 ARDS with clinical worsening within 48 hours of standard care were randomly assigned to receive either HDD or TCZ plus standard care. The primary outcome was ventilator-free days (VFDs) at 28 days. The main secondary outcomes were 28-day all-cause mortality and the incidence of adverse events. Our initial plan was to perform an interim analysis of the first 42 patients. ResultsVFDs were significantly lower in the HDD arm (median difference: 28 days; 95% confidence interval (CI): 19.35-36.65; Cohen's d = 1.14; p < 0.001). We stopped the trial at the first interim analysis due to high 28-day mortality in the HDD arm (relative risk (RR) of death: 6.5; p = 0.007; NNT (harm) = 1.91). The incidence of secondary infections was also significantly high in the HDD arm (RR: 5.5; p = 0.015; NNT (harm) = 2.33). ConclusionsIn our study population, HDD was associated with a very high rate of mortality and adverse events. We would not recommend HDD to mitigate the cytokine storm in moderate to severe COVID-19 ARDS. TCZ appears to be a much better and safer alternative.
BackgroundSurvivors of COVID-19 pneumonia may have residual lung injury and poor physical and mental health even after discharge. We hypothesized that COVID-19 severe acute respiratory distress syndrome (ARDS) patients needing mechanical ventilation may be at a greater risk of deterioration in pulmonary function, mental health, and quality of life (QOL). This study analyses the differences in pulmonary function, mental health, and QOL after recovery, in patients having received non-invasive oxygen therapy versus invasive mechanical ventilation during ICU stay. MethodsPatients aged >18 years, who had completed 3 months post ICU discharge, with moderate to severe COVID-19 ARDS, were consecutively enrolled from May 1 to July 31, 2021. Patients were allocated into Group Ahaving required high flow nasal cannula (HFNC)/non-invasive ventilation (NIV) and Group B -having received invasive mechanical ventilation. Pulmonary function tests, 6-minute walk test (6-MWT), and health-related quality of life were compared. ResultsOf the 145 eligible patients, 31 were lost to follow-up and 21 died. Seventy-four patients were allocated into Groups A (57 patients) and B (17 patients). In Group A, abnormal forced expiratory volume in first second (FEV 1 ), forced vital capacity (FVC), forced expiratory flow in mid-half of FVC (FEF 25-75 ), and peak expiratory flow rate (PEFR) values were obtained in 27 (47.37%), 43 (75.44%), 11 (19.3%), and 25 (43.86%) patients, and in Group B, in 13 (76.47%), 17 (100%), 1 (5.88%), and 8 (47%) patients, respectively. No patient had abnormal FEV 1 /FVC. All Group B patients had a restrictive pattern in spirometry as compared to 77% in Group A. Group B had a lower arterial partial pressure of oxygen (PaO 2 ) (p=0.0019), % predicted FVC (p<0.0001), % predicted FEV 1 (p=0.001), and 6-MWT distance (p<0.001). The physical component score in the short-form survey 12 questionnaire was higher in group A, p<0.001, whereas the mental component score was comparable. ConclusionsPatients requiring invasive mechanical ventilation (MV) have a greater risk of impaired pulmonary function and reduced QOL post-ICU discharge. This warrants a greater need for following these patients for better rehabilitation.
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