Analysis of Survival Modification by Furosemide Use in a Cohort of Hospitalized COVID-19 Patients with Severe or Critical Disease in Mexico: Due to Its Chemical Structure, Furosemide Is More than Just a Diuretic.

In the ongoing fight against Coronavirus Disease 2019 (COVID-19), researchers are exploring potential treatments to improve outcomes, especially in severe cases. This includes investigating the repurposing of existing medications, such as furosemide, which is widely available. This study aimed to evaluate the impact of furosemide on mortality rates among COVID-19 patients with severe or critical illness. We assessed a cohort of 515 hospitalized adults who experienced a high mortality rate of 43.9%. Using a multivariate analysis with adjusted risk ratios (AdRRs), factors like smoking (AdRR 2.48, 95% CI 1.53-4.01, p < 0.001), a high Pneumonia Severity Index (PSI) score (AdRR 7.89, 95% CI 5.82-10.70, p < 0.001), mechanical ventilation (AdRR 23.12, 95% CI 17.28-30.92, p < 0.001), neutrophilia (AdRR 2.12, 95% CI 1.52-2.95, p < 0.001), and an elevated neutrophil-to-lymphocyte ratio (NLR) (AdRR 2.39, 95% CI 1.72-3.32, p < 0.001) were found to increase mortality risk. In contrast, vaccination and furosemide use were associated with reduced mortality risk (AdRR 0.58, p = 0.001 and 0.60, p = 0.008; respectively). Furosemide showed a pronounced survival benefit in patients with less severe disease (PSI < 120) and those not on hemodialysis, with mortality rates significantly lower in furosemide users (3.7% vs. 25.7%). A Kaplan-Meier analysis confirmed longer survival and better oxygenation levels in patients treated with furosemide. Furthermore, a Structure-Activity Relationship analysis revealed that furosemide's sulfonamide groups may interact with cytokine sites such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), potentially explaining its beneficial effects in COVID-19 management. These findings suggest that furosemide could be a beneficial treatment option in certain COVID-19 patient groups, enhancing survival and improving oxygenation.

Time­dependent ROC curve analysis to determine the predictive capacity of seven clinical scales for mortality in patients with COVID­19: Study of a hospital cohort with very high mortality.

Clinical data from hospital admissions are typically utilized to determine the prognostic capacity of Coronavirus disease 2019 (COVID-19) indices. However, as disease status and severity markers evolve over time, time-dependent receiver operating characteristic (ROC) curve analysis becomes more appropriate. The present analysis assessed predictive power for death at various time points throughout patient hospitalization. In a cohort study involving 515 hospitalized patients (General Hospital Number 1 of Mexican Social Security Institute, Colima, Mexico from February 2021 to December 2022) with COVID-19, seven severity indices [Pneumonia Severity Index (PSI) PaO2/FiO2 arterial oxygen pressure/fraction of inspired oxygen (Kirby index), the Critical Illness Risk Score (COVID-GRAM), the National Early Warning Score 2 (NEWS-2), the quick Sequential Organ Failure Assessment score (qSOFA), the Fibrosis-4 index (FIB-4) and the Viral Pneumonia Mortality Score (MuLBSTA were evaluated using time-dependent ROC curves. Clinical data were collected at admission and at 2, 4, 6 and 8 days into hospitalization. The study calculated the area under the curve (AUC), sensitivity, specificity, and predictive values for each index at these time points. Mortality was 43.9%. Throughout all time points, NEWS-2 demonstrated the highest predictive power for mortality, as indicated by its AUC values. PSI and COVID-GRAM followed, with predictive power increasing as hospitalization duration progressed. Additionally, NEWS-2 exhibited the highest sensitivity (>96% in all periods) but showed low specificity, which increased from 22.9% at admission to 58.1% by day 8. PSI displayed good predictive capacity from admission to day 6 and excellent predictive power at day 8 and its sensitivity remained >80% throughout all periods, with moderate specificity (70.6-77.3%). COVID-GRAM demonstrated good predictive capacity across all periods, with high sensitivity (84.2-87.3%) but low-to-moderate specificity (61.5-67.6%). The qSOFA index initially had poor predictive power upon admission but improved after 4 days. FIB-4 had a statistically significant predictive capacity in all periods (P=0.001), but with limited clinical value (AUC, 0.639-0.698), and with low sensitivity and specificity. MuLBSTA and IKIRBY exhibited low predictive power at admission and no power after 6 days. In conclusion, in COVID-19 patients with high mortality rates, NEWS-2 and PSI consistently exhibited predictive power for death during hospital stay, with PSI demonstrating the best balance between sensitivity and specificity.

Differences in the Evolution of Clinical, Biochemical, and Hematological Indicators in Hospitalized Patients with COVID-19 According to Their Vaccination Scheme: A Cohort Study in One of the World's Highest Hospital Mortality Populations.

COVID-19 vaccines primarily prevent severe illnesses or hospitalization, but there is limited data on their impact during hospitalization for seriously ill patients. In a Mexican cohort with high COVID-19 mortality, a study assessed vaccination's effects. From 2021 to 2022, 462 patients with 4455 hospital days were analyzed. The generalized multivariate linear mixed model (GENLINMIXED) with binary logistic regression link, survival analysis and ROC curves were used to identify risk factors for death. The results showed that the vaccinated individuals were almost half as likely to die (adRR = 0.54, 95% CI = 0.30-0.97, p = 0.041). When stratifying by vaccine, the Pfizer group (BNT162b2) had a 2.4-times lower risk of death (adRR = 0.41, 95% CI = 0.2-0.8, p = 0.008), while the AstraZeneca group (ChAdOx1-S) group did not significantly differ from the non-vaccinated (adRR = 1.04, 95% CI = 0.5-2.3, p = 0.915). The Pfizer group exhibited a higher survival, the unvaccinated showed increasing mortality, and the AstraZeneca group remained intermediate (p = 0.003, multigroup log-rank test). Additionally, BNT162b2-vaccinated individuals had lower values for markers, such as ferritin and D-dimer. Biochemical and hematological indicators suggested a protective effect of both types of vaccines, possibly linked to higher lymphocyte counts and lower platelet-to-lymphocyte ratio (PLR). It is imperative to highlight that these results reinforce the efficacy of COVID-19 vaccines. However, further studies are warranted for a comprehensive understanding of these findings.

Potassium permanganate use in the management of a wound induced by contact with Paederus: A case report.

Pederin is a vesicant toxic amide, found in the hemolymph of the beetle genus, Paederus. Physical contact with these insects produces a type of irritant dermatitis with variable clinical symptoms. It has been identified that Pederin (a vesicant toxic amide responsible for the ulcerative lesion) is produced by Gram-negative endosymbiotic bacteria of the Pseudomonas genus. The present study describes the case of a patient who had come into contact with the insect Paederus sp. and developed an ulcerative lesion. He was first treated with topical steroids, as part of the conventional management, and following no response to treatment, he was treated locally with a 5% potassium permanganate solution, in conjunction with systemic antibiotic therapy, obtaining a good response in the healing process. On the whole, the present study demonstrates that potassium permanganate solutions, in conjunction with antibiotics and anti-inflammatories, may be beneficial in the treatment of dermatitis or ulcerative lesions caused by insects of the Paederus genus. However, further research is required to fully determine the complete benefits and any side-effects.

Doxycycline Prevents Preclinical Atherosclerosis, Pancreatic Islet Loss and Improves Insulin Secretion after Glycemic Stimulation: Preclinical Study in Individuals with a High-Fat Diet.

Doxycycline (Doxy) is an antibiotic, which has exhibited anti-inflammatory activity and glucose metabolism improvement. The present study was proposed to evaluate its effects on glucose metabolism and other associated processes, such as lipemia and adipogenesis, as well as, to evaluate its effects on the liver, pancreas, and aorta in subjects fed with an occidental high-fat diet (HFD). The trial followed three groups of BALB/c mice for 6 months: (1) Standard diet (SD); (2) HFD-placebo (saline solution); and (3) HFD-Doxy (10 mg/kg/day). Intrahepatic fat accumulation (steatohepatosis) and the epididymal fat pad, as well as the hepatic inflammatory infiltrate and ALT serum levels were higher in both groups with the HFD (with/without doxycycline) in comparison with the SD group. The thickness of the aorta (preclinic atherosclerosis) was significantly elevated in the HFD group with respect to the HFD + Doxy and SD group, these two being similar groups to each other. The HFD-Doxy group had pancreatic morphological parameters very similar to those of the SD group; on the contrary, the HFD group reduced the number of pancreatic islets and the number of ß cells per mm2, in addition to losing large islets. The index of ß cell function (∆Insulin0-30/∆Glucose0-30 ratio) was significantly higher in the HFD + Doxy group, compared to the rest of the groups.

Clinical Characteristics in the Acute Phase of COVID-19 That Predict Long COVID: Tachycardia, Myalgias, Severity, and Use of Antibiotics as Main Risk Factors, While Education and Blood Group B Are Protective.

BACKGROUND: Risk factors for developing long COVID are not clearly established. The present study was designed to determine if any sign, symptom, or treatment of the acute phase, or personal characteristics of the patient, is associated with the development of long COVID. METHODS: A cohort study was carried out, randomly selecting symptomatic COVID-19 patients and not vaccinated. The severity of the acute illness was assessed through the number of compatible COVID-19 symptoms, hospitalizations, and the symptom severity score using a 10-point visual analog scale. RESULTS: After multivariate analysis, a severity score ≥8 (RR 2.0, 95%CI 1.1-3.5, p = 0.022), hospitalization (RR 2.1, 95%CI 1.0-4.4, p = 0.039), myalgia (RR 1.9, 95%CI 1.08-3.6, p = 0.027), tachycardia (RR 10.4, 95%CI 2.2-47.7, p = 0.003), and use of antibiotics (RR 2.0, 95%CI 1.1-3.5, p = 0.022), was positively associated with the risk of having long COVID. Higher levels of education (RR 0.6, 95%CI 0.4-0.9, p = 0.029) and type positive B blood group (B + AB, RR 0.44, 95%CI 0.2-0.9, p = 0.044) were protective factors. The most important population attributable fractions (PAFs) for long COVID were myalgia (37%), severity score ≥8 (31%), and use of antibiotics (27%). CONCLUSIONS: Further studies in diverse populations over time are needed to expand the knowledge that could lead us to prevent and/or treat long COVID.

Improve cognitive impairment using mefenamic acid non-steroidal anti-inflammatory therapy: additional beneficial effect found in a controlled clinical trial for prostate cancer therapy.

Inflammation is an essential component of prostate cancer (PCa), and mefenamic acid has been reported to decrease its biochemical progression. The current standard therapy for PCa is androgen deprivation therapy (ADT), which has side effects such as cognitive dysfunction, risk of Alzheimer's disease, and dementia. Published results of in vitro tests and animal models studies have shown that mefenamic acid could be used as a neuroprotector. Objective: Examine the therapeutic potential of mefenamic acid in cognitive impairment used in a controlled clinical trial. Clinical trial phase II was conducted on patients undergoing ADT for PCa. Two groups of 14 patients were included. One was treated with a placebo, while the other received mefenamic acid 500 mg PO every 12hrs for six months. The outcome was evaluated through the Mini-Mental State Examination (MMSE) score at six months. At the beginning of the study, both groups had similar MMSE scores (mefenamic acid vs. placebo: 26.0±2.5 vs. 27.0±2.6, P=0.282). The mefenamic acid group improved its MMSE score after six months compared with the placebo group (27.7±1.8 vs. 25.5±4.2, P=0.037). Treatment with mefenamic acid significantly increases the probability of maintained or raised cognitive function compared to placebo (92% vs. 42.9%, RR=2.2, 95% CI: 1.16-4.03, NNT=2.0, 95% CI: 1.26-4.81, P=0.014). Furthermore, 42.9% of the placebo group patients had relevant cognitive decline (a 2-point decrease in the MMSE score), while in patients treated with mefenamic acid, cognitive impairment was not present. This study is the first conducted on humans that suggests that mefenamic acid protects against cognitive decline.

Decreased biochemical progression in patients with castration-resistant prostate cancer using a novel mefenamic acid anti-inflammatory therapy: A randomized controlled trial.

Prostate cancer (PCa) is the second most common non-dermatological cancer in men and is a growing public health problem. Castration-resistant disease (CRD) is the most advanced stage of the disease and is difficult to control. Patients with CRD may no longer accept conventional therapies as they are not in appropriate clinical conditions or they refuse to receive it. Given that inflammation is an essential component of CRD origin and progression, anti-inflammatory agents could be a therapeutic option with fenamates as one of the proposed choices. A prospective, randomized, double-blinded, 2-arm, parallel group, phase II-III clinical trial was performed involving 20 patients with CRD-PCa (with a prostate specific antigen level <100 ng/ml) that were undergoing androgen deprivation therapy (ADT) and did not accept any established treatment for that disease stage. In addition to ADT, 10 patients received placebo and 10 received mefenamic acid (500 mg orally every 12 h) for 6 months. The primary endpoint was the change in serum prostate-specific antigen (PSA) at 6 months. The PSA levels decreased significantly with mefenamic acid (an average 42% decrease), whereas there was an average 55% increase in the placebo group (P=0.024). In the patients treated with the placebo, 70% had biochemical disease progression (an increase of ≥25% in PSA levels), which did not occur in any of the patients treated with mefenamic acid (relative risk=0.12; 95% confidence interval, 0.01-0.85; P=0.033). There was a significant increase in quality of life (EQ-5D-5L score) and body mass index (BMI) with the experimental treatment. In conclusion, mefenamic acid administration decreased biochemical progression in patients with castration resistant PCa, improved their quality of life and increased their BMI. Future studies are required in order to strengthen the findings of the present clinical trial. Trial registration, Cuban Public Registry of Clinical Trials Database RPCEC00000248, August 2017.

Patient-reported health outcomes for severe knee osteoarthritis after conservative treatment with an intra-articular cell-free formulation for articular cartilage regeneration combined with usual medical care vs. usual medical care alone: A randomized controlled trial.

Osteoarthritis (OA) is a major public health problem characterized by joint pain, fatigue, functional limitation and decreased quality of life of the patient, which results in increased use of healthcare services and high economical costs. A promising novel bioactive cell-free formulation (BIOF2) for cartilage regeneration has recently been tested in pre-clinical and clinical trials, and has demonstrated a success rate similar to that of total joint arthroplasty for the treatment of severe knee OA. The present study evaluated the efficacy of treatment with BIOF2, by including it within a conservative regimen of 'usual medical care' of knee OA, and whether its efficacy was affected in subgroups of patients presenting with comorbidities that exacerbate OA. A prospective, randomized, 2-arm parallel group phase III clinical trial was conducted, which included 105 patients in the 'usual medical care' group (paracetamol/NSAIDs and general care provided by the family physician) and 107 patients in the BIOF2 group (usual medical care + intra-articular BIOF2 application at 0, 1 and 2 months). Two aspects were evaluated at 0, 6 and 12 months: i) Minimal clinically important improvement (MCII), based on 30% improvement of pain from the baseline; and ii) the Patient Acceptable Symptom State (PASS), a questionnaire that determines patient well-being thresholds for articular pain and function. Adverse effects and regular NSAID use were registered. At 12 months, BIOF-2 treatment produced MCII in 70% of the patients and >50% achieved PASS. Excluding the patients with class 2 obesity or malalignment conditions (genu varum or genu valgum >20 degrees), the experimental treatment produced MCII and PASS in 100 and 92% of patients, respectively, compared with 25 and 8% in the group of usual medical care (P<0.001). No patient with malalignment and treatment with BIOF2 achieved PASS. Notably, there were no serious adverse effects. To conclude, BIOF2 is a safe therapeutic alternative that is easy to implement together with usual medical care for knee OA. Trial registration: Cuban Public Registry of Clinical Trials (RPCEC) Database RPCEC00000277. Retrospectively registered June, 2018.

A phase I-II controlled randomized trial using a promising novel cell-free formulation for articular cartilage regeneration as treatment of severe osteoarthritis of the knee.

BACKGROUND: A promising novel cell-free bioactive formulation for articular cartilage regeneration, called BIOF2, has recently been tested in pre-clinical trials. The aim of the present study was to evaluate the efficacy and safety of BIOF2 for intra-articular application in patients with severe osteoarthritis of the knee. METHODS: A prospective, randomized, 3-arm, parallel group clinical trial was conducted. It included 24 patients with severe osteoarthritis of the knee (WOMAC score 65.9 ± 17). Before they entered the study, all the patients were under osteoarthritis control through the standard treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), prescribed by their family physician. Patients were distributed into three groups of 8 patients each (intra-articular BIOF2, total joint arthroplasty, or conservative treatment with NSAIDs alone). The WOMAC score, RAPID3 score, and Rasmussen clinical score were evaluated before treatment and at months 3, 6, and 12. BIOF2 was applied at months 0, 3, and 6. Complete blood count and blood chemistry parameters were determined in the BIOF2 group before treatment, at 72 h, and at months 1, 3, 6, and 12. In addition, articular cartilage volume was evaluated (according to MRI) at the beginning of the study and at month 12. RESULTS: The NSAID group showed no improvement at follow-up. Arthroplasty and BIOF2 treatments showed significant improvement in all the scoring scales starting at month 3. There were no statistically significant differences between the BIOF2 group and the arthroplasty group at month 6 (WOMAC score: 19.3 ± 18 vs 4.3 ± 5; P = 0.24) or month 12 (WOMAC score: 15.6 ± 15 vs 15.7 ± 17; P = 1.0). Arthroplasty and BIOF2 were successful at month 12 (according to a WOMAC score: ≤ 16) in 75% of the patients and the daily use of NSAIDs was reduced, compared with the group treated exclusively with NSAIDs (RR = 0.33, 95% CI 0.12-0.87, P = 0.02. This result was the same for BIOF2 vs NSAIDs and arthroplasty vs NSAIDs). BIOF2 significantly increased the articular cartilage by 22% (26.1 ± 10 vs 31.9 ± 10 cm2, P < 0.001) and produced a significant reduction in serum lipids. BIOF2 was well tolerated, causing slight-to-moderate pain only upon application. CONCLUSIONS: The intra-articular application of the new bioactive cell-free formulation (BIOF2) was well tolerated and showed no significative differences with arthroplasty for the treatment of severe osteoarthritis of the knee. BIOF2 can regenerate articular cartilage and is an easily implemented alternative therapy for the treatment of osteoarthritis. Trial registration Cuban Public Registry of Clinical Trials (RPCEC) Database RPCEC00000250. Registered 08/15/2017-Retrospectively registered, http://rpcec.sld.cu/en/trials/RPCEC00000250-En .