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Medical Mycology Jun 2024The emergence of COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), triggered a global pandemic. Concurrently, reports of mucormycosis...
The emergence of COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), triggered a global pandemic. Concurrently, reports of mucormycosis cases surged, particularly during the second wave in India. This study aims to investigate mortality factors in COVID-19-associated mucormycosis (CAM) cases, exploring clinical, demographic, and therapeutic variables across mostly Asian and partly African countries. A retrospective, cross-sectional analysis of CAM patients from 22 medical centers across eight countries was conducted, focusing on the first three months post-COVID-19 diagnosis. Data collected through the IDI-IR included demographics, comorbidities, treatments, and outcomes. A total of 162 CAM patients were included. The mean age was 54.29±13.04 years, with 54% male. Diabetes mellitus (85%) was prevalent, and 91% had rhino-orbital-cerebral mucormycosis (ROCM). Surgical debridement was performed in 84% of the cases. Mortality was 39%, with advanced age [Hazard Ratio (HR)=1.06, (p<0.001)], rituximab use (HR=21.2, p=0.05), diabetic ketoacidosis (HR=3.58, p=0.009) identified as risk factors. The mortality risk increases by approximately 5.6% for each additional year of age. Surgical debridement based on organ involvement correlated with higher survival (HR=8.81, p<0.001). The utilization of rituximab and diabetic ketoacidosis along with advancing age, has been associated with an increased risk of mortality in CAM patients. A combination of antifungal treatment and surgical intervention has demonstrated a substantial improvement in survival outcomes.
PubMed: 38914466
DOI: 10.1093/mmy/myae064 -
Journal of Neurointerventional Surgery Jun 2024The first-pass effect (FPE) is linked to better safety and efficacy prognosis in patients with small- to- moderate sized ischemic infarctions. We evaluated the...
BACKGROUND
The first-pass effect (FPE) is linked to better safety and efficacy prognosis in patients with small- to- moderate sized ischemic infarctions. We evaluated the incidence, prognosis, and predictors of FPE in patients with large core infarctions (LCIs).
METHODS
We conducted a post-hoc analysis of data from the Trial of Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients with a Large Infarct Core (ANGEL-ASPECT). The FPE was defined as a successful recanalization (expanded Thrombolysis in Cerebral Infarction (eTICI) 2 c/3, and eTICI 2b-3 as modified FPE (mFPE)) after one pass. The primary outcome was clinical functional independence, and the secondary outcomes were independent ambulation, assessed by the modified Rankin Scale (mRS) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage (sICH) defined by the Heidelberg bleeding classification, any intracranial hemorrhage (ICH), and death within 90 days of stroke onset.
RESULTS
Of the 226 patients in the study, FPE and mFPE were achieved in 33 (14.6%) and 82 (36.3%) patients, respectively. Patients with FPE exhibited shorter onset-to-puncture times (adjusted odds ratio [OR] 0.915; 95% confidence interval [CI]: 0.84 to 0.996), and patients with mFPE were older (OR 1.039; 95% CI: 1.005 to 1.075). mFPE was significantly associated with favorable outcomes (modified Rankin score [mRS] 0-2: OR 2.64; 95% CI: 1.37 to 5.07; mRS 0-3: OR 3.31; 95% CI: 1.73 to 6.33). FPE tended to improve outcomes (mRS 0-3: OR 2.24; 95% CI: 0.92 to 4.97; p=0.08). ICH rates (OR 0.60; 95% CI: 0.34 to 1.05; p=0.07) and 90-day deaths (OR 0.57; 95% CI: 0.30 to 1.09; p=0.09) tended to decrease in patients who achieved mFPE but not in patients who achieved FPE.
CONCLUSIONS
In the ANGEL-ASPECT trial, patients who achieved mFPE had a higher rate of independent ambulation and functional independence, and the rates of any ICH and 90-day death tended to decrease.
PubMed: 38914460
DOI: 10.1136/jnis-2024-021728 -
ESMO Open Jun 2024Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a...
BACKGROUND
Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.
PATIENTS AND METHODS
Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.
RESULTS
Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.
CONCLUSIONS
The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
Topics: Humans; Paclitaxel; Female; Middle Aged; Aged; Neoplasms; Male; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Taxoids; Maximum Tolerated Dose; Syk Kinase
PubMed: 38914452
DOI: 10.1016/j.esmoop.2024.103486 -
Archives of Disease in Childhood.... Jun 2024Major trauma is a principal cause of morbidity and mortality in children. Severe haemorrhage is the second-leading cause of death in paediatric trauma, preceded by...
Major trauma is a principal cause of morbidity and mortality in children. Severe haemorrhage is the second-leading cause of death in paediatric trauma, preceded by traumatic brain injury. Major haemorrhage protocols (MHPs), also known as 'code red' and 'massive transfusion protocols', are used to make large volumes of blood products rapidly available. Most recommendations for paediatric MHPs are extrapolated from adult data because of a lack of large, high-quality, prospective paediatric studies. However, applying adult data in a paediatric context requires caution due to differences in injury mechanisms and physiological responses between adults and children. Since major haemorrhage is a high-acuity low-occurrence event, MHP requires effective training, collaboration and communication among a large multidisciplinary team.In this 15-minute consultation, we provide an evidence-based synthesis of the management principles of paediatric major haemorrhage.
PubMed: 38914447
DOI: 10.1136/archdischild-2024-327224 -
The American Journal of Cardiology Jun 2024Mitral annular calcification (MAC) may be a potential marker of biological aging. However, the association of MAC with non-cardiovascular measures, including bone...
Mitral annular calcification (MAC) may be a potential marker of biological aging. However, the association of MAC with non-cardiovascular measures, including bone mineral density (BMD), incident renal failure, dementia, and non-cardiovascular mortality, is not well studied in a multiracial cohort. We used data from 6,814 participants (mean age:62.2±10.2 years; 52.9%-females) without cardiovascular disease at baseline in the Multi-Ethnic Study of Atherosclerosis. MAC was assessed with non-contrast cardiac computed tomography at study baseline. Using multivariable-adjusted linear and logistic regression, we assessed cross-sectional association of MAC with BMD and walking pace. Also, using Cox proportional hazards, we evaluated the association of MAC with incident renal failure, dementia, and all-cause mortality. Additionally, we assessed the association of MAC with cardiovascular and non-cardiovascular mortality using competing risks regression. The prevalence of MAC was 9.5% and was higher in women (10.7%) than in men (8.0%). MAC was associated with low BMD (coefficient: -0.04; 95%CI: -0.06 - -0.02) with significant interaction by sex (p-interaction:0.035). MAC was, however, not associated with impaired walking pace (odds ratio:1.09; 95%CI:0.89-1.33). Compared to individuals without MAC, those with MAC had an increased risk of incident renal failure albeit nonsignificant (hazard ratio [HR]:1.18; 95%CI:0.95-1.45) but a significantly higher hazards of dementia (HR:1.36; 95%CI:1.10-1.70). Additionally, persons with MAC had a substantially higher risk of all-cause (HR:1.47; 95%CI:1.29-1.69), cardiovascular (sub-distribution HR:1.39; 95%CI:1.04-1.87), and non-cardiovascular mortality (sub-distribution HR:1.35; 95%CI:1.14-1.60), compared to those without MAC. MAC≥100 vs <100 was significantly associated with reduced BMD, incident renal failure, dementia, all-cause, cardiovascular, and non-cardiovascular mortality. In conclusion, MAC was associated with reduced BMD and dementia, as well as all-cause, cardiovascular, and non-cardiovascular mortality in this multiracial cohort. Thus, MAC may be a marker not only for atherosclerotic burden but also for other metabolic and inflammatory factors that increase the risk of non-cardiovascular outcomes and death from other causes.
PubMed: 38914415
DOI: 10.1016/j.amjcard.2024.06.017 -
International Journal of Biological... Jun 2024Acquiring rapid and effective hemostasis remains a critical clinical challenge. Current researches focus on concentrating blood components to speed up the hemostatic...
Acquiring rapid and effective hemostasis remains a critical clinical challenge. Current researches focus on concentrating blood components to speed up the hemostatic while ignore the effect of anti-fibrinolysis in promoting blood coagulation. Herein, we designed a novel tranexamic acid (TA)-loaded physicochemical double cross-linked multifunctional catechol-modified hyaluronic acid-dopamine/carboxymethyl chitosan porous gel micropowders (TA&Fe@HA-DA/CMCS PGMs) for rapid hemostasis and wound healing. TA&Fe@HA-DA/CMCS PGMs exhibited high water absorption rate (505.9 ± 62.1 %) and rapid hemostasis (79 ± 4 s) in vivo. Catechol groups, Fe and the protonated amino groups of CMCS induced bacterial death. Moreover, TA&Fe@HA-DA/CMCS PGMs displayed sufficient adhesion to a variety of wet rat tissues. TA&Fe@HA-DA/CMCS PGMs on various bleeding wounds, including rat liver injury and tail severed models showed excellent hemostasis performance. The TA&Fe@HA-DA/CMCS PGMs could promote the healing of full-thickness skin wounds on the backs of rats. The advantages of TA&Fe@HA-DA/CMCS PGMs including rapid hemostasis, effective wound healing, good tissue adhesion, antibacterial properties and ease of use make it potentially valuable in clinical application.
PubMed: 38914405
DOI: 10.1016/j.ijbiomac.2024.133363 -
International Journal of Biological... Jun 2024Cytochrome C (cyt C), the protein involved in oxidative phosphorylation, plays several other crucial roles necessary for both cell life and death. Studying natural...
Cytochrome C (cyt C), the protein involved in oxidative phosphorylation, plays several other crucial roles necessary for both cell life and death. Studying natural variants of cyt C offers the possibility to better characterize the structure-to-function relationship that modulates the different activities of this protein. Naturally occurring mutations in human cyt C (G41S and Y48H) occur in the protein central Ω-loop and cause thrombocytopenia 4. In this study, we have investigated the binding of such variants and of wild type (wt) cyt C to synthetic cardiolipin-containing vesicles. The mutants have a lower propensity in membrane binding, displaying higher dissociation constants with respect to the wt protein. Compressibility measurements reveal that both variants are more flexible than the wt, suggesting that the native central Ω-loop is important for the interaction with membranes. Such hypothesis is supported by molecular dynamics simulations. A minimal distance analysis indicates that in the presence of cardiolipin the central Ω-loop of the mutants is no more in contact with the membrane, as it happens instead in the case of wt cyt C. Such finding might provide a hint for the reduced membrane binding capacity of the variants and their enhanced peroxidase activity in vivo.
PubMed: 38914400
DOI: 10.1016/j.ijbiomac.2024.133371 -
Journal of Stroke and Cerebrovascular... Jun 2024Stroke is a leading cause of death and disability in Nigeria. Effective stroke management is essential to reduce morbidity and mortality. Few trained neurologists in...
BACKGROUND
Stroke is a leading cause of death and disability in Nigeria. Effective stroke management is essential to reduce morbidity and mortality. Few trained neurologists in Nigeria are mostly concentrated in the cities, making non-specialists the backbone of acute stroke management in Nigeria. Physicians-related factors have been identified as one of the factors leading to sub-optimal stroke care. This study aimed to describe the knowledge of medical doctors in acute stroke care and the factors responsible for the disparity in their skills.
METHODS
A descriptive cross-sectional survey was conducted among 404 medical doctors across all the six geo-political zones in Nigeria using the Acute Stroke Management Questionnaire (ASMaQ). Data were analysed using descriptive statistics and simple logistics regression to predict the relationship between independent variables and the outcome variable (good knowledge vs poor knowledge).
RESULTS
67% (95% CI =63% - 72%) of respondents had good overall knowledge of stroke management. Most respondents [88.6%, 95% CI =85% - 92%] had good knowledge of General Stroke Knowledge (GSK) followed by Hyperacute Stroke Management (HSM) [52.5%, 95% CI=47.3% - 57.7%] and Advanced Stroke Management (ASM) [49.5%, 95%CI= 49.5% -54.4%]. Working in a primary healthcare center (PHCs) and government hospital were significant predictor of overall poor knowledge of stroke. Physicians at PHCs had 2.29 times the odds of poor knowledge compared to those in tertiary hospital CONCLUSIONS: It is essential to retrain doctors on stroke management regularly, as part of their professional development.
PubMed: 38914357
DOI: 10.1016/j.jstrokecerebrovasdis.2024.107832 -
The Science of the Total Environment Jun 2024The 2022 wildfires in New Mexico, United States, were unparalleled compared to past wildfires in the state in both their scale and intensity, resulting in poor air...
The 2022 wildfires in New Mexico, United States, were unparalleled compared to past wildfires in the state in both their scale and intensity, resulting in poor air quality and a catastrophic loss of habitat and livelihood. Among all wildfires in New Mexico in 2022, six wildfires were selected for our study based on the size of the burn area and their proximity to populated areas. These fires accounted for approximately 90 % of the total burn area in New Mexico in 2022. We used a regional chemical transport model and data-fusion technique to quantify the contribution of these six wildfires (April 6 to August 22) on particulate matter (PM: diameter ≤ 2.5 μm) and ozone (O) concentrations, as well as the associated health impacts from short-term exposure. We estimated that these six wildfires emitted 152 thousand tons of PM and 287 thousand tons of volatile organic compounds to the atmosphere. We estimated that the average daily wildfire smoke PM across New Mexico was 0.3 μg/m, though 1 h maximum exceeded 120 μg/m near Santa Fe. Average wildfire smoke maximum daily average 8-h O (MDA8-O) contribution was 0.2 ppb during the study period over New Mexico. However, over the state 1 h maximum smoke O exceeded 60 ppb in some locations near Santa Fe. Estimated all-cause excess mortality attributable to short term exposure to wildfire PM and MDA8-O from these six wildfires were 18 (95 % Confidence Interval (CI), 15-21) and 4 (95 % CI: 3-6) deaths. Additionally, we estimate that wildfire PM was responsible for 171 (95 %: 124-217) excess cases of asthma emergency department visits. Our findings underscore the impact of wildfires on air quality and human health risks, which are anticipated to intensify with global warming, even as local anthropogenic emissions decline.
PubMed: 38914336
DOI: 10.1016/j.scitotenv.2024.174197 -
Cancer Letters Jun 2024Metastasis is the leading cause of death in ovarian cancer (OC), with anoikis resistance being a crucial step for detached OC cells survival. Despite extensive research,...
Metastasis is the leading cause of death in ovarian cancer (OC), with anoikis resistance being a crucial step for detached OC cells survival. Despite extensive research, targeting anoikis resistance remians a challenge. Here, we identify argininosuccinate synthase 1 (ASS1), a key enzyme in urea cycle, is markedly upregulated in OC cells in detached culture and is associated with increased anoikis resistance and metastasis. Disruption of the AMP/ATP balance by elevated ASS1 activates AMPK and its downstream factor, CPT1A. Then, ASS1 enhances FAO, leading to higher ATP generation and lipid utilization. Inhibition of CPT1A reverses ASS1-induced FAO. Our study gives some new functional insights into OC metabolism and represents a shift from traditional views, expanding ASS1's relevance beyond nitrogen metabolism to fatty acid metabolism. It uncovers how ASS1-induced FAO disrupts the AMP/ATP balance, leading to AMPK activation. By identifying the ASS1/AMPK/CPT1A axis as crucial for OC anoikis resistance and metastasis, our study opens up new avenues for therapeutic interventions.
PubMed: 38914306
DOI: 10.1016/j.canlet.2024.217082