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Journal of Neurosciences in Rural... 2023The growing prevalence of dementia makes it important for us to better understand its pathophysiology and treatment modalities, to improve the quality of life of... (Review)
Review
The growing prevalence of dementia makes it important for us to better understand its pathophysiology and treatment modalities, to improve the quality of life of patients and caregivers. Alzheimer's disease (AD), a neurodegenerative disease, is the most common form of amnestic dementia in the geriatric population. Pathophysiology of AD is widely attributed to aggregation of amyloid-beta (Aβ) plaques and hyperphosphorylation of tau proteins. Initial treatment modalities aimed to increase brain perfusion in a non-specific manner. Subsequent therapy focused on rectifying neurotransmitter imbalance in the brain. Newer drugs modify the progression of the disease by acting against aggregated Aβ plaques. However, not all drugs used in therapy of AD have been granted approval by the United States Food and Drug Administration (FDA). This review categorizes and summarizes the FDA-approved drugs in the treatment of AD in a manner that would make it a convenient reference for researchers and practicing physicians alike. Drugs that mitigate symptoms of dementia may be categorized into mitigators of Behavioral and Psychological Symptoms of Dementia (BPSD), and mitigators of cognitive decline. BPSD mitigators include brexpiprazole, an atypical antipsychotic with a once-daily dosage suited to treat agitation in dementia patients, and suvorexant, an orexin receptor antagonist used to treat sleep disturbances. Cognitive decline mitigators include cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine and glutamate inhibitors such as memantine. Donepezil is the most commonly prescribed drug. It is cheap, well-tolerated, and may be prescribed orally once daily, or as a transdermal patch once weekly. It increases ACh levels, enhances oligodendrocyte differentiation and also protects against Aβ toxicity. However, regular cardiac monitoring is required due to reports of cardiac conduction side effects. Rivastigmine requires a twice-daily oral dosage or once-daily replacement of transdermal patch. It has fewer cardiac side effects than donepezil, but local application-site reactions have been noted. Galantamine, in addition to improving cognitive symptoms in a short span of time, also delays the development of BPSDs and has minimal drug-drug interactions by virtue of having multiple metabolic pathways. However, cardiac conduction disturbances must be closely monitored for. Memantine, a glutamate regulator, acts as an anti-Parkinsonian agent and an antidepressant, in addition to improving cognition and neuroprotection, and requires a once-daily dosage in the form of immediate-release or sustained-release oral tablets. Disease-modifying drugs such as aducanumab and lecanemab reduce the Aβ burden. Both act by binding with fibrillary conformations of Aβ plaques in the brain. These drugs have a risk of causing amyloid-related imaging abnormalities, especially in persons with ApoE4 gene. Aducanumab is administered once every 4 weeks and lecanemab once every 2 weeks. The decision on the choice of the drug must be made after considering the availability of drug, compliance of patient (once-daily vs. multiple doses daily), cost, specific comorbidities, and the risk-benefit ratio for the particular patient. Other non-pharmacological treatment modalities must also be adopted to have a holistic approach toward the treatment of AD.
PubMed: 38059250
DOI: 10.25259/JNRP_356_2023 -
International Journal of Geriatric... Dec 2020The global COVID-19 pandemic has caused rapid and monumental changes around the world. Older people, who already experience higher rates of social isolation and... (Review)
Review
OBJECTIVES
The global COVID-19 pandemic has caused rapid and monumental changes around the world. Older people, who already experience higher rates of social isolation and loneliness, are more susceptible to adverse effects as a result of the social distancing protocols enacted to slow the spread of COVID-19. Based on prior outbreaks, we speculate the detrimental outcomes and offer solutions.
METHODS
Reviewing the literature on the detrimental effects of social isolation and loneliness and higher mortality in the older population. Utilizing psychological study outcomes from prior major outbreaks such as in SARS, Ebola, H1N1 influenza, and Middle East respiratory syndrome offer predictions and the susceptibility in the geriatric age group.
RESULTS
Organizations such as the WHO, Centers for Disease Control, and American Association of Retired Persons have put measures in place to provide networking on a local, regional, and national level. These efforts are designed to start mitigating such detrimental effects. A necessary follow-up to this pandemic will be gathering data on unique populations such as the geriatric community, to better mitigate adverse outcomes given the certainty that COVID-19 will not be the last global viral outbreak.
CONCLUSIONS
The results of worsened social isolation and loneliness is associated with significantly increased morbidity and mortality in the geriatric population. Various solutions including virtual interactions with loved ones, engaging in physical activity, continuing any spiritual or religious prayers remotely, and community services to provide aid for the older population are all efforts to minimize social isolation and loneliness.
Topics: Aged; Aged, 80 and over; COVID-19; Coronavirus Infections; Humans; Influenza A Virus, H1N1 Subtype; Loneliness; Pandemics; SARS-CoV-2; Social Isolation
PubMed: 32748545
DOI: 10.1002/gps.5389 -
Frontiers in Pharmacology 2021There is a need for countermeasures to mitigate lethal acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). In WAG/RijCmcr rats, ARS...
There is a need for countermeasures to mitigate lethal acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). In WAG/RijCmcr rats, ARS occurs by 30-days following total body irradiation (TBI), and manifests as potentially lethal gastrointestinal (GI) and hematopoietic (H-ARS) toxicities after >12.5 and >7 Gy, respectively. DEARE, which includes potentially lethal lung and kidney injuries, is observed after partial body irradiation >12.5 Gy, with one hind limb shielded (leg-out PBI). The goal of this study is to enhance survival from ARS and DEARE by polypharmacy, since no monotherapy has demonstrated efficacy to mitigate both sets of injuries. For mitigation of ARS following 7.5 Gy TBI, a combination of three hematopoietic growth factors (polyethylene glycol (PEG) human granulocyte colony-stimulating factor (hG-CSF), PEG murine granulocyte-macrophage-CSF (mGM-CSF), and PEG human Interleukin (hIL)-11), which have shown survival efficacy in murine models of H-ARS were tested. This triple combination (TC) enhanced survival by 30-days from ∼25% to >60%. The TC was then combined with proven medical countermeasures for GI-ARS and DEARE, namely enrofloxacin, saline and the angiotensin converting enzyme inhibitor, lisinopril. This combination of ARS and DEARE mitigators improved survival from GI-ARS, H-ARS, and DEARE after 7.5 Gy TBI or 13 Gy PBI. Circulating blood cell recovery as well as lung and kidney function were also improved by TC + lisinopril. Taken together these results demonstrate an efficacious polypharmacy to mitigate radiation-induced ARS and DEARE in rats.
PubMed: 34079456
DOI: 10.3389/fphar.2021.634477 -
Frontiers in Cellular and Infection... 2021Total body irradiation (TBI) has been demonstrated to alter the intestinal microbiome, but the effects of successful small molecule ionizing radiation mitigators on the...
Total body irradiation (TBI) has been demonstrated to alter the intestinal microbiome, but the effects of successful small molecule ionizing radiation mitigators on the intestinal microbiome are not well-known. Our survival experiments examined the effects of anti-cell death radiation mitigators on and in conjunction with the host's microbiota. Mice received 9.25 Gy TBI and then were administered radiation mitigators 24 hours later. Passed stool were collected pre-irradiation, then on days 1, 3, 5, 7, 10, 14, 21, and 30 post-irradiation for 16S rRNA gene (V4 region) sequencing. The Cox proportional hazards (CPH) model was fit with taxonomic composition (time varying covariates) and treatment as predictors. In the first experiment, mice were administered drugs for "granulocyte stimulation and anti-apoptosis" in four protocol combinations: JP4-039 (anti-apoptosis), granulocyte colony-stimulating factor (G-CSF, granulopoietic precursor cell stimulator), both mitigators, and control. Survival improved relative to control (30.0%) for G-CSF (80%, p-value = 0.025), G-CSF/JP4-039 (70%, p-value = 0.084), but not for JP4-039 (50.0%). In the second experiment, mice were administered mitigation drugs "inhibiting programmed cell death" pathways: JP4-039 (anti-apoptosis), necrostatin-1 (anti-necroptosis), and baicalein (anti-ferroptosis), in eight combinations. The survival of JP4-039/baicalein (60.0%, p-value = 0.010) and JP4-039/baicalein/necrostatin-1 (60.0%, p-value = 0.06) treatment combinations were significantly different from the control (26.7%). The JP4-039/necrostatin-1 (46.7%) and baicalein/necrostatin-1 (40.0%) and singlet treatment combinations (26.7%) were not significantly different from the control. Despite differences between the baseline microbiota compositions of the two experiments, consistent changes in composition after irradiation were found: decreased post-irradiation, relative to baseline. By day 7, microbiota perturbations had incompletely reversed, and no drug-specific differences were identifiable. The CPH model identified and members of , including , as protective and as deleterious. By day 30, the microbiota of surviving mice had not returned to baseline, but the differences between experiments suggest the resultant microbiota composition of the survivors are stochastic or batch specific in nature, rather than a requirement for survival. In conclusion, the study determined that key taxa identified in fecal samples, when applied towards the prediction of TBI survival, improves the survival model relative to treatment information alone.
Topics: Animals; Mice; Mice, Inbred C57BL; Microbiota; RNA, Ribosomal, 16S; Radiation-Protective Agents; Whole-Body Irradiation
PubMed: 34621689
DOI: 10.3389/fcimb.2021.715396 -
Frontiers in Public Health 2021The purpose of this study was to provide a scoping review on how to address and mitigate burnout in the profession of clinical oncology. Also, it examines how... (Review)
Review
The purpose of this study was to provide a scoping review on how to address and mitigate burnout in the profession of clinical oncology. Also, it examines how artificial intelligence (AI) can mitigate burnout in oncology. We searched Ovid Medline, PubMed, Scopus, and Web of Science, for articles that examine how to address burnout in oncology. A total of 17 studies were found to examine how burnout in oncology can be mitigated. These interventions were either targeted at individuals (oncologists) or organizations where the oncologists work. The organizational interventions include educational (psychosocial and mindfulness-based course), art therapies and entertainment, team-based training, group meetings, motivational package and reward, effective leadership and policy change, and staff support. The individual interventions include equipping the oncologists with adequate training that include-communication skills, well-being and stress management, burnout education, financial independence, relaxation, self-efficacy, resilience, hobby adoption, and work-life balance for the oncologists. Similarly, AI is thought to be poised to offer the potential to mitigate burnout in oncology by enhancing the productivity and performance of the oncologists, reduce the workload and provide job satisfaction, and foster teamwork between the caregivers of patients with cancer. Burnout is common among oncologists and can be elicited from different types of situations encountered in the process of caring for patients with cancer. Therefore, for these interventions to achieve the touted benefits, combinatorial strategies that combine other interventions may be viable for mitigating burnout in oncology. With the potential of AI to mitigate burnout, it is important for healthcare providers to facilitate its use in daily clinical practices. These combinatorial interventions can ensure job satisfaction, a supportive working environment, job retention for oncologists, and improved patient care. These interventions could be integrated systematically into routine cancer care for a positive impact on quality care, patient satisfaction, the overall success of the oncological ward, and the health organizations at large.
Topics: Artificial Intelligence; Burnout, Professional; Humans; Job Satisfaction; Medical Oncology; Oncologists
PubMed: 34660505
DOI: 10.3389/fpubh.2021.677915 -
Frontiers in Pharmacology 2021We previously reported several vignettes on types and classes of drugs able to mitigate acute and, in at least one case, late radiation syndromes in mice. Most of these...
We previously reported several vignettes on types and classes of drugs able to mitigate acute and, in at least one case, late radiation syndromes in mice. Most of these had emerged from high throughput screening (HTS) of bioactive and chemical drug libraries using ionizing radiation-induced lymphocytic apoptosis as a readout. Here we report the full analysis of the HTS screen of libraries with 85,000 small molecule chemicals that identified 220 "hits." Most of these hits could be allocated by maximal common substructure analysis to one of 11 clusters each containing at least three active compounds. Further screening validated 23 compounds as being most active; 15 of these were cherry-picked based on drug availability and tested for their ability to mitigate acute hematopoietic radiation syndrome (H-ARS) in mice. Of these, five bore a 4-nitrophenylsulfonamide motif while 4 had a quinoline scaffold. All but two of the 15 significantly ( < 0.05) mitigated H-ARS in mice. We had previously reported that the lead 4-(nitrophenylsulfonyl)-4-phenylpiperazine compound (NPSP512), was active in mitigating multiple acute and late radiation syndromes in mice of more than one sex and strain. Unfortunately, the formulation of this drug had to be changed for regulatory reasons and we report here on the synthesis and testing of active analogs of NPSP512 (QS1 and 52A1) that have increased solubility in water and bioavailability while retaining mitigator activity against H-ARS ( < 0.0001) and other radiation syndromes. The lead quinoline 057 was also active in multiple murine models of radiation damage. Taken together, HTS of a total of 150,000 bioactive or chemical substances, combined with maximal common substructure analysis has resulted in the discovery of diverse groups of compounds that can mitigate H-ARS and at least some of which can mitigate multiple radiation syndromes when given starting 24 h after exposure. We discuss what is known about how these agents might work, and the importance of formulation and bioavailability.
PubMed: 34084139
DOI: 10.3389/fphar.2021.666776 -
Frontiers in Immunology 2023The mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin...
INTRODUCTION
The mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin expression and its impact on microbiota composition and mucosal tissue injury and evaluated the radio-mitigative effect of human α-defensin 5 (HD5).
METHODS
Adult mice were subjected to total body irradiation, and Paneth cell α-defensin expression was evaluated by measuring α-defensin mRNA by RT-PCR and α-defensin peptide levels by mass spectrometry. Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. HD5 was administered in a liquid diet 24 hours before or after irradiation. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by cytokine expression. Systemic inflammation was evaluated by measuring plasma cytokine levels.
RESULTS
Ionizing radiation reduced the Paneth cell α-defensin expression and depleted α-defensin peptides in the intestinal lumen. α-Defensin down-regulation was associated with the time-dependent alteration of gut microbiota composition, increased gut permeability, and endotoxemia. Administration of human α-defensin 5 (HD5) in the diet 24 hours before irradiation (prophylactic) significantly blocked radiation-induced gut microbiota dysbiosis, disruption of intestinal epithelial tight junction and adherens junction, mucosal barrier dysfunction, and mucosal inflammatory response. HD5, administered 24 hours after irradiation (treatment), reversed radiation-induced microbiota dysbiosis, tight junction and adherens junction disruption, and barrier dysfunction. Furthermore, HD5 treatment also prevents and reverses radiation-induced endotoxemia and systemic inflammation.
CONCLUSION
These data demonstrate that radiation induces Paneth cell dysfunction in the intestine, and HD5 feeding prevents and mitigates radiation-induced intestinal mucosal injury, endotoxemia, and systemic inflammation.
Topics: Humans; Adult; Animals; Mice; Paneth Cells; alpha-Defensins; Dysbiosis; Endotoxemia; RNA, Ribosomal, 16S; Radiation Injuries; Cytokines; Inflammation
PubMed: 37638013
DOI: 10.3389/fimmu.2023.1174140 -
Journal of Biomedical Physics &... Dec 2021During deep space missions, astronauts are exposed to highly ionizing radiation, incl. neutrons, protons and heavy ions from galactic cosmic rays (GCR), solar wind (SW)... (Review)
Review
During deep space missions, astronauts are exposed to highly ionizing radiation, incl. neutrons, protons and heavy ions from galactic cosmic rays (GCR), solar wind (SW) and solar energetic particles (SEP). This increase the risks for cancerogenisis, damages in central nervous system (CNS), cardiovascular diseases, etc. Large SEP events can even cause acute radiation syndrome (ARS). Long term manned deep space missions will therefor require unique radiation protection strategies. Since it has been shown that physical shielding alone is not sufficient, this paper propose pre-flight screening of the aspirants for evaluation of their level of adaptive responses. Methods for boosting their immune system, should also be further investigated, and the possibility of using radiation effect modulators are discussed. In this paper, especially, the use of vitamin C as a promising non-toxic, cost-effective, easily available radiation mitigator (which can be used hours after irradiation), is described. Although it has previously been shown that vitamin C can decrease radiation-induced chromosomal damage in rodents, it must be further investigated before any conclusions about its radiation mitigating properties in humans can be concluded.
PubMed: 34904063
DOI: 10.31661/jbpe.v0i0.1193 -
Frontiers in Public Health 2022To mitigate morbidity, mortality, and impacts of heat-related illnesses (HRIs) on health, it was vital to implement a comprehensive framework for HRI prevention and... (Review)
Review
INTRODUCTION
To mitigate morbidity, mortality, and impacts of heat-related illnesses (HRIs) on health, it was vital to implement a comprehensive framework for HRI prevention and control. A recognized tool from the field of trauma prevention known as the Haddon matrix was applied. The matrix states that any event is affected by three factors: host, agent, and environment. In addition, another recognized tool known as the combined model was used in this study. The combined model is a three-dimensional model that includes the idea for the three axes of Haddon's matrix with the methodology of the community risk reduction (CRR) model.
AIM OF THE STUDY
To identify the environmental and individual risk factors of HRIs based on the Haddon matrix and the recommended prevention strategies by the CRR tool by using the combined model.
METHODOLOGY
An extensive literature review was conducted to assess all the risk factors associated with HRI, as well as preventive measures. Then the Haddon matrix was used to structure, separating human factors from technical and environmental details and timing. After that, the combined model was used to set all responses and mitigation measures for each element obtained from the Haddon matrix tool.
CONCLUSION
Projected increases in heat stress over the globe require the formulation and implementation of evidence-based HRI mitigation and preventive measures. In this study, we implemented the combined model that was utilized as a systematic strategy for the more theoretical framework of Haddon's matrix. Using the Haddon matrix to determine the HRI risk factors and the combined model to mitigate its impact was practical and helpful in planning, preparedness, and mitigating the HRIs during Hajj, provided a broad approach equivalent to the Swiss cheese model, and would facilitate an informed decision.
Topics: Humans; Mass Gatherings; Morbidity; Risk Factors
PubMed: 36062122
DOI: 10.3389/fpubh.2022.957576