Acute Treatment Research Articles

Persistent intracranial steno-occlusion from calcified embolism: a treatment challenge.

Calcified arterial cerebral embolism is a rare occurrence among large and medium vessel occlusions causing ischemic stroke and its diagnosis and treatment is a challenge. The sources of calcified embolism might be a calcific atheroma from the aortic arch and carotid artery, but also heart valve disease has been reported in the literature. Calcified embolism is frequently simultaneous on multiple vascular territories. The prognosis of patients is usually poor, including patients treated by using endovascular thrombectomy (EVT) and this diagnosis could be easily missed in the acute phase. In addition, the optimal secondary prevention has not been yet fully stated. We are presenting two cases of acute stroke due to calcified embolism in the middle cerebral artery (MCA) coming from a complicated carotid atheroma, non-stenosing in the first case (a 49years old man) and stenosing in the second case (a 71years old man) without clinical indications to intravenous thrombolysis and/or EVT, extensively investigated in the acute phase and followed-up for over 12months with a favorable clinical course and the persisting steno-occlusion in the involved MCA. In both cases, antiplatelet treatment and targeting of vascular risk factors were done without recurrences in the follow-up period. Cerebral calcified embolism has been reported in 5.9% of cases of acute ischemic stroke in a single center series and only in 1.2% of a large retrospective cohort of EVT-treated patients. In both series the prognosis was poor and only one third of EVT-treated patients had functional independence at 3-months follow-up. The natural history of these subtype of ischemic stroke is relatively poorly understood and both etiological diagnosis and treatment have not yet defined. It is possible that some cases might be underdiagnosed and underreported. Calcified cerebral embolism is a rare cause of stroke, but it is largely underreported and both acute phase and secondary preventive treatment have to be defined.

Efficacy and Safety of Direct Oral Anticoagulants for Acute Treatment of Venous Thromboembolism in Older Adults: A Network Meta-Analysis of Randomised Controlled Trials.

This systematic review and network meta-analysis aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in adults aged 75 and over undergoing acute venous thromboembolism (VTE) treatment. PubMed, Embase and the CENTRAL were searched up to 25 December 2023. The incidence of VTE recurrence and bleeding events was assessed. Employing a frequentist network meta-analysis approach, interventions not directly compared could be indirectly assessed through the 95% confidence interval (CI), enhancing the interpretability of the search results. The surface under the cumulative ranking curves (SUCRA) was utilized to generate the relative ranking probabilities for each group. Our study, analysing 6 randomised controlled trials with 3665 patients, compares direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in adults aged 75 and over with acute venous thromboembolism. Edoxaban reduces VTE recurrence risk compared with VKAs (risk ratio [RR] .50, 95% CI 0.27 - .95), while apixaban significantly decreases bleeding risk compared with VKAs (RR .23, 95% CI 0.08 - .69), edoxaban (RR .28, 95% CI 0.09 - .86) and rivaroxaban (RR .28, 95% CI 0.09 - .86). Despite low overall evidence quality, apixaban consistently ranks highest for both efficacy and safety. Findings underscore the nuanced efficacy-safety balance in this population, emphasizing cautious interpretation due to evidence limitations. Apixaban emerges as a favourable choice for acute VTE treatment in the elderly, displaying reduced bleeding risk compared to other treatments while maintaining comparable efficacy. Future studies should explore diverse anticoagulants efficacy and safety in older populations. Additionally, clinical prediction models tailored to geriatric cohorts are crucial for guiding treatment duration decisions.

Characterizing gaps in the preventive pharmacologic treatment of migraine: Multi-country results from the CaMEO-I study.

To analyze data from the Chronic Migraine Epidemiology and Outcomes-International (CaMEO-I) Study in order to characterize preventive medication use and identify preventive usage gaps among people with migraine across multiple countries. Guidelines for the preventive treatment of migraine are available from scientific organizations in various countries. Although these guidelines differ among countries, eligibility for preventive treatment is generally based on monthly headache day (MHD) frequency and associated disability. The overwhelming majority of people with migraine who are eligible for preventive treatment do not receive it. The CaMEO-I Study was a cross-sectional, observational, web-based panel survey study performed in six countries: Canada, France, Germany, Japan, the United Kingdom, and the United States. People were invited to complete an online survey in their national language(s) to identify those with migraine according to modified International Classification of Headache Disorders, 3rd edition, criteria. People classified with migraine answered questions about current and ever use of both acute and preventive treatments for migraine. Available preventive medications for migraine differed by country. MHD frequency and associated disability data were collected. The American Headache Society (AHS) 2021 Consensus Statement algorithm was used to determine candidacy for preventive treatment (i.e., ≥3 monthly MHDs with severe disability, ≥4 MHDs with some disability, or ≥6 MHDs regardless of level of disability). Among 90,613 valid completers of the screening survey, 14,492 met criteria for migraine and completed the full survey, with approximately 2400 respondents from each country. Based on the AHS consensus statement preventive treatment candidacy algorithm, averaging across countries, 36.2% (5246/14,492) of respondents with migraine qualified for preventive treatment. Most respondents (84.5% [4431/5246]) who met criteria for preventive treatment according to the AHS consensus statement were not using a preventive medication at the time of the survey. Moreover, 19.3% (2799/14,492) of respondents had ever used preventive medication (ever users); 58.1% (1625/2799) of respondents who reported ever using a preventive medication for migraine were still taking it. Of the respondents who were currently using a preventive medication, 50.2% (815/1625) still met the criteria for needing preventive treatment based on the AHS consensus statement. Most people with migraine who qualify for preventive treatment are not currently taking it. Additionally, many people currently taking preventive pharmacologic treatment still meet the algorithm criteria for needing preventive treatment, suggesting inadequate benefit from their current regimen.

ELECT: prospective, randomized trial comparing microvascular plug versus platinum-fibered microcoils for embolization of aneurysm sac side branches before endovascular aortic aneurysm repair

BackgroundPreemptive selective embolization of aneurysm sac side branches (ASSBs) has been proposed to prevent type II endoleak after endovascular aortic aneurysm repair (EVAR). This study aimed to explore if an embolization strategy using microvascular plugs (MVP) reduces intervention time and radiation dose compared to platinum-fibered microcoils. Furthermore, the effectiveness of the devices in occluding the treated artery was assessed.MethodsSixty patients scheduled for EVAR underwent percutaneous preemptive embolization of ASSBs using MVPs or coils after a 1:1 randomization. Follow-up imaging was performed during aortic stentgraft implantation.ResultsOverall, 170 ASSBs were successfully occluded (83 arteries by MVPs and 87 by coils) and no acute treatment failure occurred. The mean procedure time was significantly lower in the group treated with MVPs (55 ± 4 min) compared to coil occlusion (67 ± 3 min; p = 0.018), which was paralleled by a numerically lower radiation dose (119 Gy/cm2 vs. 140 Gy/cm2; p = 0.45). No difference was found for contrast agent use (34 ml MVP group vs 35 ml coil group; p = 0.87). At follow-up, reopening of lumbar arteries was seen in nine cases (four after coil embolization; five after MVPs).ConclusionBoth microvascular plugs and coils can be effectively used for preemptive embolization of aneurysm sac side branches before EVAR. Use of plugs offers a benefit in terms of intervention time.Trial registrationClinicalTrials.gov Identifier: NCT03842930 Registered 15 February 2019.Graphical

Patient experiences and needs in cancer care– results from a nationwide cross-sectional study in Germany

BackgroundPatient-centredness has become a central quality indicator for oncology care. Elements include shared decision-making, patient navigation and integration of psychosocial care, which impact patient-reported and clinical outcomes. Despite efforts to promote patient-centred care in Germany in recent decades, implementation remains fragmented. Further, research on patient experiences with cancer care and its determinants is limited. Therefore, this study examines which patient- and facility-specific factors are associated with patient-centred quality care delivery.MethodsA cross-sectional study was conducted among 1,121 cancer patients in acute treatment, rehabilitation, and aftercare for different cancer entities across Germany. A participatory developed questionnaire was used. Outcome measures were the quality of physician-patient interaction and provision of psychosocial care during acute care. Predictors comprised patient-specific characteristics and treatment facility-specific factors. Multiple linear regression and multivariate binary logistic regression analyses were performed. In addition, a content analysis of open-ended comments on the patients’ overall cancer care needs was applied.ResultsMultiple linear regression analysis showed recent diagnosis (β=−0.12, p = < 0.001), being male (β=−0.11, p = 0.003), and having a preference for passive decision-making (β=−0.10, p = 0.001) to be significantly associated with higher interaction quality, but not age, education and health insurance type. An overall low impact of patient characteristics on interaction quality was revealed (adj. R2 = 0.03). Binary logistic regression analysis demonstrated the availability of central contact persons (OR = 3.10, p < 0.001) followed by recent diagnosis (p < 0.001), having breast cancer (p < 0.001) and being female (OR = 1.68, p < 0.05) to significantly predict offering psycho-oncological counselling to patients in acute care facilities. The availability of peer support visiting services (OR = 7.17, p < 0.001) and central contact persons (OR = 1.87, p < 0.001) in the care facility, breast cancer diagnosis (p < 0.001) and a higher level of education (p < 0.05) significantly increased the odds of patients receiving information about peer support in the treatment facility. Despite relatively satisfactory quality of physician-patient interactions in cancer care (M = 3.5 (± 1.1)), many patients expressed that better patient-centred communication and coordinated, comprehensive cancer care are needed.ConclusionThe findings reflect effective developments and improvements in cancer care and suggest that patients’ social characteristics are less decisive for delivering patient-centred quality care than systemic factors surrounding the care facilities. They can serve to inform oncology care in Germany.

Auricular Therapy for Migraine.

Migraine brings hours or even days of disability, affecting 15% of the US population and one billion people worldwide. Migraine treatments have improved over the years and there is now a range of non-pharmacologic therapies that can be administered as monotherapy, combined with pharmacologic therapy or combined with other non-pharmacologic therapies to give greater options for those who do not tolerate, do not respond to, or who wish to reduce or avoid pharmacologic treatments. We conducted a review of the literature on auricular therapy as acute or preventive treatment for migraine, searching the databases of MEDLINE and ClinicalTrials.gov from 2013 to 2023. A total of 43 articles contained at least one search term, with three studies specific to acute or prevention of migraine (one for acute only, one for prevention only and one for both acute and prevention). The population was limited to, adults with migraine ages 18 or older, with the administration of auricular therapy as the intervention. While there have been studies on the use of auricular therapy for pain on two specific standardized auricular therapies, Battlefield Acupuncture (BFA) and National Acupuncture Detoxification Association (NADA), neither of these protocols were utilized in any of the studies specific to migraine management. Each of the three studies used different techniques, with one using acupuncture needles and five specific points and two using semi-permanent needles (remained in for a few days) that were placed in areas that showed high activity. Each of these studies showed auricular therapy to have benefit for the management of migraine. However, the authors of each of the studies recommended further studies. Auricular therapy may be a helpful adjunctive treatment to abort a current migraine attack or aid in reducing the frequency or severity of migraine attacks.

On the mechanism of wogonin against acute monocytic leukemia using network pharmacology and experimental validation

Wogonin is a natural flavone compound from the plant Scutellaria baicalensis, which has a variety of pharmacological activities such as anti-cancer, anti-virus, anti-inflammatory, and immune regulation. However, the potential mechanism of wogonin remains unknown. This study was to confirm the molecular mechanism of wogonin for acute monocytic leukemia treatment, known as AML-M5. The potential action targets between wogonin and acute monocytic leukemia were predicted from databases. The compound-target-pathway network and protein-protein interaction network (PPI) were constructed. The enrichment analysis of related targets and molecular docking were performed. The network pharmacological results of wogonin for AML-M5 treatment were verified using the THP-1 cell line. 71 target genes of wogonin associated with AML-M5 were found. The key genes TP53, SRC, AKT1, RELA, HSP90AA1, JUN, PIK3R1, and CCND1 were preliminarily found to be the potential central targets of wogonin for AML-M5 treatment. The PPI network analysis, GO analysis and KEGG pathway enrichment analysis demonstrated that the PI3K/AKT signaling pathway was the significant pathway in the wogonin for AML-M5 treatment. The antiproliferative effects of wogonin on THP-1 cells of AML-M5 presented a dose-dependent and time-dependent manner, inducing apoptosis, blocking the cell cycle at the G2/M phase, decreasing the expressions of CCND1, CDK2, and CyclinA2 mRNA, as well as AKT and p-AKT proteins. The mechanisms of wogonin on AML-M5 treatment may be associated with inhibiting cell proliferation and regulating the cell cycle via the PI3K/AKT signaling pathway.

Blood parameters in pediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

Patients with myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) clinically present e.g. with acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM) or aquaporin-4-IgG (AQP4-IgG) negative neuromyelitis optica spectrum disorders (NMOSD)-like phenotypes. We aimed to analyze and compare blood parameters in children with MOGAD, AQP4-IgG-positive NMOSD (hence NMOSD), multiple sclerosis (MS) and healthy controls (HC). We evaluated differences in complete blood counts (CBC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and C-reactive protein (CRP) between these four groups and within the groups between clinical attack, acute treatment and remission. Our cohort consisted of 174 children and adolescents with a total of 550 timepoints: 66 patients had MOGAD (202 timepoints), 11 NMOSD (76 timepoints), 58 MS (219 timepoints) and 39 were HC (53 timepoints). At clinical attack, leukocyte counts were elevated in MOGAD compared to remission (p<0.001) and compared to all other groups (p<0.001). NLR was high in MOGAD and NMOSD, and PLR was high in NMOSD, however, after correction for multiple testing these findings did not remain significant. While glucocorticoids caused an increase of leukocyte counts and NLR in NMOSD and MS, these values remained stable during acute treatment in MOGAD. In remission, NLR normalized in MOGAD, while it stayed high in NMOSD. PLR increased in NMOSD and was significantly higher compared to all other groups. Some blood parameters, mainly leukocyte and differential counts, might help clinicians to evaluate disease activity, differentiate relapses from pseudo-relapses and even distinguish between different disease entities.

Cytomegalovirus Infection in Adult Patients with Inflammatory Bowel Disease: A Literature Review.

Human cytomegalovirus (HCMV) is classified within the Herpesvirales order and is prevalent in 50%‒80% of the general population. Most carriers experience this infection without noticeable clinical symptoms. HCMV causes a lifelong latent infection that can be reactivated due to immune disorders and inflammation. The reactivation of HCMV becomes particularly significant when it coincides with inflammatory bowel disease (IBD). While cytomegalovirus (CMV) colitis in IBD patients was identified years ago, the role of CMV in triggering flare-ups, acute severe colitis, treatment resistance, and other outcomes in IBD patients experiencing CMV reactivation remains a subject of ongoing debate. In this review, we aim to address an updated insight into aspects related to the CMV colitis in IBD patients including epidemiology, risk factors, clinical features, diagnostic tests, histology, place of immunosuppressants and indications for antiviral treatment. We suggest for personalized and thorough assessment based on the disease phase and colitis severity when prescribing drugs to these patients. Furthermore, we emphasize the importance of regular patient follow-up to monitor drug side effects, ensuring treatment success, and minimizing the risk of colectomy.

Recent advances in CAR-T cell therapy for acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a fatal and refractory haematologic cancer that primarily affects adults. It interferes with bone marrow cell proliferation. Patients have a 5 years survival rate of less than 30% despite the availability of several treatments, including chemotherapy, allogeneic haematopoietic stem cell transplantation (Allo-HSCT), and receptor antagonist drugs. Allo-HSCT is the mainstay of acute myeloid leukaemia treatment. Although it does work, there are severe side effects, such as graft-versus-host disease (GVHD). In recent years, chimeric antigen receptor (CAR)-T cell therapies have made significant progress in the treatment of cancer. These engineered T cells can locate and recognize tumour cells invivo and release a large number of effectors through immune action to effectively kill tumour cells. CAR-T cells are among the most effective cancer treatments because of this property. CAR-T cells have demonstrated positive therapeutic results in the treatment of acute myeloid leukaemia, according to numerous clinical investigations. This review highlights recent progress in new targets for AML immunotherapy, and the limitations, and difficulties of CAR-T therapy for AML.

Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.

Screening of amino acids as a safe energy source for isolated rat pancreatic acini.

Amino acids play an essential role in protein synthesis, metabolism and survival of pancreatic acini. Adequate nutritional support is important for acute pancreatitis treatment. However, high concentrations of arginine and lysine may induce acute pancreatitis. The study aimed to identify the most suitable L-amino acids as safe energy sources for pancreatic acinar cells. Pancreatic acini were isolated from male Wistar rats. Effects of amino acids (0.1-20 mM) on uncoupled respiration of isolated acini were studied with a Clark electrode. Cell death was evaluated with fluorescent microscopy and DNA gel electrophoresis. Among the tested amino acids, glutamate, glutamine, alanine, lysine and aspartate were able to stimulate the uncoupled respiration rate of isolated pancreatic acini, while arginine, histidine and asparagine were not. Lysine, arginine and glutamine (20 mM) caused complete loss of plasma membrane integrity of acinar cells after 24 h of incubation. Glutamine also caused early (2-4 h) cell swelling and blebbing. Aspartate, asparagine and glutamate only moderately decreased the number of viable cells, while alanine and histidine were not toxic. DNA fragmentation assay and microscopic analysis of nuclei showed no evidence of apoptosis in cells treated with amino acids. Alanine and glutamate are safe and effective energy sources for mitochondria of pancreatic acinar cells.

THE EFFICACY OF ANTIBIOTICS IN ACUTE APPENDICITIS TREATMENT : A COMPREHENSIVE SYSTEMATIC REVIEW

Background: Acute appendicitis has been the most common cause of lower abdominal pain leading to emergency visits worldwide. To avoid major complications, appendectomy has remained the standard treatment for uncomplicated acute appendicitis for over a century. The aim: The aim of this study to show about the efficacy of antibiotics in acute appendicitis treatment. Methods: By the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. This search approach, publications that came out between 2014 and 2024 were taken into account. Several different online reference sources, like Pubmed, SagePub, and Sciencedirect were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: Five publications were found to be directly related to our ongoing systematic examination after a rigorous three-level screening approach. Subsequently, a comprehensive analysis of the complete text was conducted, and additional scrutiny was given to these articles. Conclusion: The therapeutic effects of antibiotics and appendicectomy were comparable for the treatment of acute appendicitis.

Ictal Cotard delusion as a manifestation of nonconvulsive status epilepticus: A case report and commentary.

Psychosis of epileptic origin can present a wide range of cognitive and affective symptoms and is often underrecognized. Usually occurring in the inter- and postictal phase, epileptic psychosis is mostly related to temporal lobe epilepsy. Here, we describe the clinical presentation and diagnostic workup including routine EEG recording and brain MRI of a 63-year-old woman expressing isolated nihilistic delusions comprising belief of being dead and denial of self-existence. EEG showed an ictal pattern fulfilling the Salzburg criteria of nonconvulsive status epilepticus and brain MRI revealed extensive peri-ictal hyperperfusion. Delusional symptoms and EEG abnormalities subsided after acute antiseizure treatment. Our case illustrates how nihilistic delusions can occur as a direct clinical correlate of seizure activity, thereby expanding the spectrum of ictal neuropsychiatric phenomena in temporal lobe epilepsy and highlighting the need to consider an epileptic origin in patients presenting with psychotic symptoms.

Cognitive and everyday functioning after bacterial brain abscess: a prospective study of functional recovery from 8 weeks to 1 year post-treatment

ABSTRACT Objective A bacterial brain abscess may damage surrounding brain tissue by mass effect, inflammatory processes, and bacterial toxins. The aim of this study was to examine cognitive and functional outcomes at 8 weeks and 1 year following acute treatment. Methods Prospective study of 20 patients with bacterial brain abscess (aged 17–73 years; 45% females) with neuropsychological assessment at 8 weeks and 1 year post-treatment. Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) and Patient Competence Rating Scale (PCRS) were used to assess everyday functioning and administered to patients and informants. Results Cognitive impairment was found in 30% of patients at 8 weeks and 22% at 1 year. Significant improvements were seen on tests of perceptual reasoning, attention, verbal fluency, and motor abilities (p < 0.05). At 1 year, 45% had returned to full-time employment. Nevertheless, patients and their informants obtained scores within the normal range on measures of everyday functioning (PCRS and BRIEF-A) at 8 weeks and 1 year. No significant improvements on these measures emerged over time. Conclusion Residual long-term cognitive impairment and diminished work ability affected 22% and 45% of patients one year after BA. Persistent cognitive impairment emphasizes the importance of prompt acute treatment and cognitive rehabilitation.

Barriers and enablers of post-COVID-19 acute care follow-up in Nigeria from service providers' perspective: a nominal group technique.

Despite modest efforts to study and document the complications that arise after acute treatment of patients with coronavirus disease, its ramifications and regional variations are yet to be clearly understood. Progress in sub-Saharan Africa, notably Nigeria, has been impeded by patient disengagement from care and insufficient or non-existent follow-up arrangements. The aim of this study was to describe the barriers and enablers for follow-up services after discharge from COVID-19 care pathway in Nigeria. Seventeen experts involved directly in the care of patients with COVID-19 participated in brainstorming using the nominal group technique during a national workshop to review the new guidelines for COVID-19 case management in Nigeria. Participants discussed the barriers and facilitators of post-acute care follow-up of patients discharged from COVID-19 pathway and ranked their recommendations to arrive at three major factors per question. Participants were mostly middle aged and predominantly clinicians. The top three barriers were patients' perception of their symptom severity, lack of organizational clarity/structure/policies on follow-up care after discharge, and financial constraints. Similarly, participants identified providers' initiated education on the reasons for follow-up at discharge, written organizational policies/structure and clarity and free follow-up services as the top three facilitators. This study has enumerated barriers to follow-up care after discharge patients with coronavirus disease and highlighted providers, institutional and governmental responses that will facilitator follow-up care after discharge of patients with COVID-19. The implication is that, there is need for clear institutional guidelines for tracking and documenting post-COVID condition. In the future, it would be necessary to assess the achievements and shortcomings of post-COVID condition tracking in Nigeria through the use of implementation science outcomes.

Cytotoxic stress caused by azalamellarin D (AzaD) interferes with cellular protein translation by targeting the nutrient-sensing kinase mTOR.

Analogs of pyrrole alkaloid lamellarins exhibit anticancer activity by modulating multiple cellular events. Lethal doses of several lamellarins were found to enhance autophagy flux in HeLa cells, suggesting that lamellarins may modulate protein homeostasis through the interference of proteins or kinases controlling energy and nutrient metabolism. To further delineate molecular mechanisms and their targets, our results herein show that azalamellarin D (AzaD) cytotoxicity could cause translational attenuation, as indicated by a change in eIF2α phosphorylation. Intriguingly, acute AzaD treatment promoted the phosphorylation of GCN2, a kinase that transduces the integrated stress response (ISR), and prolonged exposure to AzaD could increase the levels of the phosphorylated forms of eIF2α and the other ISR kinase PKR. However, the effects of AzaD on ISR signaling were marginally abrogated in cells with genetic deletion of GCN2 and PKR, and evaluation of protein target engagement by CETSA revealed no significant interaction between AzaD and ISR kinases. Further investigation revealed that acute AzaD treatment negatively affected mTOR phosphorylation and signaling. The analyses by CETSA and computational modeling indicated that mTOR may be a possible protein target for AzaD. These findings indicate the potential for developing lamellarins as novel agents for cancer treatment.

Shared Vision for Improving Outcomes for Serious Fungal Diseases: Report of a Patient, Caregiver, and Clinician Summit

Abstract Background Recently, increasing focus on patient input into research and healthcare improvements has fostered expanded patient-centered advocacy efforts. This first pan-fungal disease summit, part of the MYCology Advocacy, Education &amp; Research (MyCARE) effort, brought together patients, caregivers, and mycology experts to better document patient experiences with invasive fungal disease (IFD) and establish priorities for mycology education, advocacy, and research. Methods Patients who had suffered from IFD, their caregivers, clinicians, industry representatives, government officials, and patient advocacy professionals were invited. Patients and caregivers shared their stories and struggles with IFD. Breakout sessions separated mycology experts from patients and caregivers for further discussions to identify commonalities and perceived gaps and to formulate recommendations. The two groups then reconvened to develop consensus recommendations. Results IFD patients and their caregivers shared experiences reflecting the typically lengthy pre-diagnosis, acute treatment, long-term treatment, and post-treatment recovery stages of IFD. They reported substantial physical, psychological, and financial burdens associated with the IFD experience, particularly related to delayed diagnoses. They reaffirmed a need for coordinated patient-centered education, peer support, and advocacy to document the burden of serious fungal infections. Mycology experts discussed strategies to address gaps in the mycology field, such as insufficient training, inadequate workforce support, and a need to partner more with patient groups. Conclusion A summit involving patients with IFD, family caregivers, and mycology experts identified a substantial non-clinical burden of disease associated with IFD. Patients and mycology experts prioritized several goals for education, advocacy, and research to raise awareness of IFD and improve outcomes.

Time-Dependent Long-Term Effect of Memantine Following Repetitive Mild Traumatic Brain Injury.

Repetitive mild traumatic brain injury (rmTBI, e.g. sports concussions) may be associated with both acute and chronic symptoms and neurological changes. Despite the common occurrence of these injuries, therapeutic strategies are limited. One potentially promising approach is N-methyl-d-aspartate receptor (NMDAR) blockade to alleviate the effects of post-injury glutamatergic excitotoxicity. Initial preclinical work using the NMDAR antagonist, memantine, suggests that immediate treatment following rmTBI improves a variety of acute outcomes. It remains unclear 1) whether acute memantine treatment has long-term benefits and 2) whether delayed treatment following rmTBI is beneficial, which are both clinically relevant concerns. To test this, animals were subjected to rmTBI via a weight drop model with rotational acceleration (five hits in five days) and randomized to memantine treatment either immediately, three-months, or six-months post-injury, with a treatment duration of one month. Behavioral outcomes were assessed at one-, four-, and seven-months post-injury. Neuropathological outcomes were characterized at seven-months post-injury. We observed chronic changes in behavior (anxiety-like behavior, motor coordination, spatial learning and memory), as well as neuroinflammation (microglia, astrocytes) and tau phosphorylation (T231). Memantine treatment, either immediately or six-months post-injury, appears to confer greater rescue of neuroinflammatory changes (microglia) than vehicle or treatment at the three-month time point. Although memantine is already being prescribed chronically to address persistent symptoms associated with rmTBI, this study represents the first evidence of which we are aware to suggest a small, but durable effect of memantine treatment in mild, concussive injuries. This effect suggests that memantine, while potentially beneficial, is insufficient to treat all aspects of rmTBI alone, and should be combined with other therapeutic agents in a multi-therapy approach, with attention given to the timing of treatment.

Lasmiditan: A Novel Drug for the Acute Treatment of Migraine

Lasmiditan: A Novel Drug for the Acute Treatment of Migraine