Association between fatigue and depressive symptoms in persons with post-COVID-19 condition: a post hoc analysis.

OBJECTIVE: Post-COVID-19 Condition (PCC) is a prevalent, persistent and debilitating phenomenon occurring three or more months after resolution of acute COVID-19 infection. Fatigue and depressive symptoms are commonly reported in PCC. We aimed to further characterize PCC by assessing the relationship between fatigue and depressive symptom severity in adults with PCC. METHODS: A post hoc analysis was conducted on data retrieved from a randomized, double-blinded, placebo-controlled study evaluating vortioxetine for cognitive deficits in persons with PCC. We sought to determine the relationship between baseline fatigue [i.e. Fatigue Severity Scale (FSS) total score] and baseline depressive symptom severity [i.e. 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR-16) total score] in adults with PCC. RESULTS: The statistical analysis included baseline data from 142 participants. After adjusting for age, sex, education, employment status, history of major depressive disorder (MDD) diagnosis, self-reported physical activity, history of documented acute SARS-CoV-2 infection and body mass index (BMI), baseline FSS was significantly correlated with baseline QIDS-SR-16 (ß = 0.825, p = .001). CONCLUSION: In our sample, baseline measures of fatigue and depressive symptoms are correlated in persons living with PCC. Individuals presenting with PCC and fatigue should be screened for the presence and severity of depressive symptoms. Guideline-concordant care should be prescribed for individuals experiencing clinically significant depressive symptoms. Fatigue and depressive symptom severity scores were not pre-specified as primary objectives of the study. Multiple confounding factors (i.e. disturbance in sleep, anthropometrics and cognitive impairment) were not collected nor adjusted for in the analysis herein. TRIAL REGISTRATION: Unrestricted Research Grant from H. Lundbeck A/S, Copenhagen, Denmark. ClinicalTrials.gov Identifier: NCT05047952.

Comparing suicide completion rates in bipolar I versus bipolar II disorder: A systematic review and meta-analysis.

BACKGROUND: Bipolar disorder (BD) has a high disease burden and the highest mortality risk in BD comes from suicide. Bipolar disorder type II (BD-II) has been described as a milder form of bipolar disorder; however, extant literature is inconsistent with this description and instead describe illness burden and notably suicidality comparable to persons with bipolar I disorder (BD-I). Towards quantifying the hazard of BD-II, herein we aim via systematic review and meta-analysis to evaluate the rates of completed suicide in BD-I and BD-II. METHOD: We conducted a literature search on PubMed, OVID (Embase, Medline) and PsychINFO databases from inception to June 30th, 2023, according to PRISMA guidelines. Articles were selected based on the predetermined eligibility criteria. A meta-analysis was performed, comparing the risk of completed suicide between individuals diagnosed with BD-I to BD-II. RESULTS: Four out of eight studies reported higher suicide completion rates in persons living with BD-II when compared to persons living with BD-I; however, two of the studies reported non-significance. Two studies reported significantly higher suicide completion rates for BD-I than BD-II. The pooled odds ratio of BD-II suicide rates to BD-I was 1.00 [95 % CI = 0.75, 1.34]. LIMITATIONS: The overarching limitation is the small number of studies and heterogeneity of studies that report on suicide completion in BD-I and BD-II. CONCLUSION: Our study underscores the severity of BD-II, with a risk for suicide not dissimilar from BD-I. The greater propensity to depression, comorbidity and rapid-cycling course reported in BD-II are contributing factors to the significant mortality hazard in BD-II.

Assessing the Effects of Metabolic Disruption, Body Mass Index and Inflammation on Depressive Symptoms in Post-COVID-19 Condition: A Randomized Controlled Trial on Vortioxetine.

INTRODUCTION: To date, there are no therapeutics that have gained regulatory approval by the United States Food and Drug Administration (FDA) for the treatment of post-COVID-19 condition (PCC), a debilitating condition characterized by cognitive impairment and mood symptoms. Additionally, persistent inflammation, metabolic dysfunction, and risks associated with an elevated body mass index (BMI) have been observed. Herein, we aimed to assess the efficacy of vortioxetine in improving depressive symptoms among individuals with PCC,  as modulated by inflammation, metabolic dysfunction, and BMI. METHODS: In this post-hoc analysis, we present preliminary data obtained from an 8-week randomized, double-blind, placebo-controlled trial. Participants included  adults aged 18 years and older residing in Canada who were experiencing symptoms of World Health Organization (WHO)-defined PCC. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled, 147 were randomized (1:1) to receive vortioxetine (5-20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change from baseline to endpoint in the 16-Item Quick Inventory of Depressive Symptomatology Self-Report Questionnaire (QIDS-SR-16). RESULTS: Our findings revealed significant effects for time (χ2 = 9.601, p = 0.002), treatment (χ2 = 9.135, p = 0.003), and the treatment × time × CRP × TG-HDL × BMI interaction (χ2 = 26.092, p < 0.001) on PCC-related depressive symptoms in the adjusted model. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint as compared to placebo (mean difference = - 5.41, SEM = 1.335, p < 0.001). CONCLUSION: Overall, vortioxetine significantly improved depressive symptoms among participants with PCC in the adjusted model. Notably, individuals with baseline markers of increased inflammation, metabolic disruption, and elevated BMI exhibited a more pronounced antidepressant effect at endpoint. TRIAL REGISTRATION NUMBER: NCT05047952 (ClinicalTrials.gov).

Impacts of metabolic disruption, body mass index and inflammation on cognitive function in post-COVID-19 condition: a randomized controlled trial on vortioxetine.

BACKGROUND: Post-COVID-19 Condition (PCC), as defined by the World Health Organization (WHO), currently lacks any regulatory-approved treatments and is characterized by persistent and debilitating cognitive impairment and mood symptoms. Additionally, metabolic dysfunction, chronic inflammation and the associated risks of elevated body mass index (BMI) have been reported. In this study, we aim to investigate the efficacy of vortioxetine in improving cognitive deficits in individuals with PCC, accounting for the interaction of metabolic dysfunction, elevated inflammation and BMI. METHODS: This is a post-hoc analysis of an 8-week randomized, double-blind, placebo-controlled trial that was conducted among adults aged 18 years and older living in Canada who were experiencing WHO-defined PCC symptoms. The recruitment of participants began in November 2021 and concluded in January 2023. A total of 200 individuals were enrolled, where 147 were randomized in a 1:1 ratio to receive either vortioxetine (5-20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change in the Digit Symbol Substitution Test (DSST) score from baseline to endpoint. RESULTS: Our findings showed significant effects for time (χ2 = 7.771, p = 0.005), treatment (χ2 = 7.583, p = 0.006) and the treatment x time x CRP x TG-HDL x BMI interaction (χ2 = 11.967, p = 0.018) on cognitive function. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint (mean difference = 0.621, SEM = 0.313, p = 0.047). CONCLUSION: Overall, vortioxetine demonstrated significant improvements in cognitive deficits among individuals with baseline markers of metabolic dysfunction, elevated inflammation and higher BMI at endpoint as compared to placebo. TRIAL REGISTRATION: NCT05047952 (ClinicalTrials.gov; Registration Date: September 17, 2021).

Red Blood Cells as Therapeutic Target to Treat Sickle Cell Disease.

Significance: Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue, severe acute painful crises requiring hospitalization and opioids, strokes, multiorgan damage, and a shortened life span. Symptoms may appear shortly after birth, and, in less developed countries, most children with SCD die before attaining age 5. Hematopoietic stem cell transplant and gene therapy offer a curative therapeutic approach, but, due to many challenges, are limited in their availability and effectiveness for a majority of persons with SCD. A critical unmet need is to develop safe and effective novel targeted therapies. A wide array of drugs currently undergoing clinical investigation hold promise for an expanded pharmacological armamentarium against SCD. Recent Advances: Hydroxyurea, the most widely used intervention for SCD management, has improved the survival in the Western world and more recently, voxelotor (R-state-stabilizer), l-glutamine, and crizanlizumab (anti-P-selectin antibody) have been approved by the Food and Drug Administration (FDA) for use in SCD. The recent FDA approval emphasizes the need to revisit the advances in understanding the core pathophysiology of SCD to accelerate novel evidence-based strategies to treat SCD. The biomechanical breakdown of erythrocytesis, the core pathophysiology of SCD, is associated with intrinsic factors, including the composition of hemoglobin, membrane integrity, cellular volume, hydration, andoxidative stress. Critical Issues and Future Directions: In this context, this review focuses on advances in emerging nongenetic interventions directed toward the therapeutic targets intrinsic to sickle red blood cells (RBCs), which can prevent impaired rheology of RBCs to impede disease progression and reduce the sequelae of comorbidities, including pain, vasculopathy, and organ damage. In addition, given the intricate pathophysiology of the disease, it is unlikely that a single pharmacotherapeutic intervention will comprehensively ameliorate the multifaceted complications associated with SCD. However, the availability of multiple drug options affords the opportunity for individualized therapeutic regimens tailored to specific SCD-related complications. Furthermore, it opens avenues for combination drug therapy, capitalizing on distinct mechanisms of action and profiles of adverse effects.

Quantifying hospital environmental ventilation using carbon dioxide monitoring - a multicentre study.

The COVID-19 pandemic has highlighted the importance of environmental ventilation in reducing airborne pathogen transmission. Carbon dioxide monitoring is recommended in the community to ensure adequate ventilation. Dynamic measurements of ventilation quantifying human exhaled waste gas accumulation are not conducted routinely in hospitals. Instead, environmental ventilation is allocated using static hourly air change rates. These vary according to the degree of perceived hazard, with the highest change rates reserved for locations where aerosol-generating procedures are performed, where medical/anaesthetic gases are used and where a small number of high-risk infective or immunocompromised patients may be isolated to reduce cross-infection. We aimed to quantify the quality and distribution of ventilation in hospital by measuring carbon dioxide levels in a two-phased prospective observational study. First, under controlled conditions, we validated our method and the relationship between human occupancy, ventilation and carbon dioxide levels using non-dispersive infrared carbon dioxide monitors. We then assessed ventilation quality in patient-occupied (clinical) and staff break and office (non-clinical) areas across two hospitals in Scotland. We selected acute medical and respiratory wards in which patients with COVID-19 are cared for routinely, as well as ICUs and operating theatres where aerosol-generating procedures  are performed routinely. Between November and December 2022, 127,680 carbon dioxide measurements were obtained across 32 areas over 8 weeks. Carbon dioxide levels breached the 800 ppm threshold for 14% of the time in non-clinical areas vs. 7% in clinical areas (p < 0.001). In non-clinical areas, carbon dioxide levels were > 800 ppm for 20% of the time in both ICUs and wards, vs. 1% in operating theatres (p < 0.001). In clinical areas, carbon dioxide was > 800 ppm for 16% of the time in wards, vs. 0% in ICUs and operating theatres (p < 0.001). We conclude that staff break, office and clinical areas on acute medical and respiratory wards frequently had inadequate ventilation, potentially increasing the risks of airborne pathogen transmission to staff and patients. Conversely, ventilation was consistently high in the ICU and operating theatre clinical environments. Carbon dioxide monitoring could be used to measure and guide improvements in hospital ventilation.

Mitotic index maximization with no effect on radiation-induced dicentric chromosome frequency.

PURPOSE: The dicentric chromosome (Dic) assay, which is the gold standard for biological dose assessment in radiation emergency medicine, requires an analysis of at least 500 lymphocyte metaphases or 100 Dic aberrations. Therefore, peripheral blood culture conditions able to obtain a high frequency of metaphases for efficient dose evaluation should be optimized. However, the type of blood cultures [i.e. whole blood (WB) or isolated peripheral blood mononuclear cell (PBMC)-culture] and blood volume differ between biodosimetry laboratories. The purpose of this study is to investigate the blood volume at which a high mitotic index (MI) is obtained in peripheral WB-culture and isolated PBMC-culture, and to examine the possible effect of blood volume on radiation-induced Dic frequency. MATERIALS AND METHODS: Peripheral blood was collected from three healthy donors with their informed consent. The complete and differential blood counts were performed using an automated hematology analyzer. After blood count, peripheral blood was irradiated with 0 or 2 Gy X-ray. Blood was cultured with phytohemagglutinin (180 µg/ml) and demecolcine　(0.05 µg/ml) for 48 h. The MI and Dic frequency were analyzed in 5, 10, 15, 20, 25, and 30% WB-cultures and 0.6, 1.2, 1.8, 2.4, 3.0, 3.6, and 4.2 ml WB-equivalent PBMC-cultures. RESULTS: In WB-culture, MI showed the highest value (∼22%) in 5-15% WB-culture and then gradually decreased to ∼9% with 30% WB-culture. MI peaked at 36 and 31% in 1.8 and 2.4 ml-WB equivalent volumes for PMBC-cultures, respectively. MI progressively decreased as the amount of PBMCs increased. Although individual differences were observed in the MI values among the three subjects, all the subjects showed the same tendency and higher MI was seen in PBMC than WB-cultures. However, these factors had no significant impact on the yield of Dics. In all culture conditions, the estimated dose calculated based on the Dic frequency was equivalent to the absorbed dose of ex vivo X-ray-irradiated blood. CONCLUSION: While MI was affected by the blood culture type and the volume of cultured blood, Dic yield did not differ significantly between these conditions. These results could be used by relevant laboratories to optimize MI in certain circumstances.

Factors associated with breast cancer mammography screening and breast self-examination in Irish women: results from the Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: BreastCheck is Ireland's breast screening service which offers biennial mammograms to women aged 50-69. Practicing regular breast self-examination (BSE) enhances women's awareness and increases their perception of their susceptibility to the risk of breast cancer, possibly increasing their likelihood of attending a screening programme which reduces breast cancer mortality. Research is needed to identify the promotors and barriers to both attending breast cancer screening and practicing BSE. PURPOSE: The aim of this study was to determine the promotors and barriers associated with attending breast cancer screening and practicing BSE in Irish women. MATERIALS AND METHODS: Data from the participants of TILDA wave 3 (2014-2015) was used, the participant population included females only (≥50 years old), a total of 3575 women. Bivariate analysis was used to identify variables that were significantly associated with having had a mammogram since the last interview (wave 2) or regularly checking their breasts for lumps (BSE). Regression analysis was then used to determine the effect the significant variables had on predicting the likelihood of participants attending breast screening or practicing BSE. RESULTS: Over half (55%) of all women over the age of 50 had a mammogram since wave 2 was completed (2012) and two thirds reported practicing regular BSE. The factors associated with having attended for breast cancer screening were: having private health insurance (OR = 1.86, 95%CI = 1.45-2.380), and practicing BSE (OR = 1.683, 95%CI = 1.344-2.107). The factors found to be associated with practicing regular BSE were: higher quality of life (OR = 1.035, 95%CI = 1.015-1.057), higher BMI (OR = 1.118, 95%CI = 1.020-1.226), being married (OR = 1.436, 95%CI = 1.190-1.732) and attending mammogram screening (OR = 1.691, 95%CI = 1.353-2.114). CONCLUSION: Regular participation in mammography screening reduces breast cancer mortality. Women eligible for BreastCheck were significantly more likely to attend screening. BSE is associated with increased attendance at screening. Health-care professionals should encourage BSE in order to increase screening uptake.

Pain in Hemophilia: Unexplored Role of Oxidative Stress.

Hemophilia is the most common X-linked bleeding diathesis caused by the genetic deficiency of coagulation factors VIII or IX. Despite treatment advances and improvements in clinical management to prevent bleeding, management of acute and chronic pain remains to be established. Repeated bleeding of the joints leads to arthropathy, causing pain in hemophilia. However, mechanisms underlying the pathogenesis of pain in hemophilia remain underexamined. Herein, we describe the novel perspectives on the role for oxidative stress in the periphery and the central nervous system that may contribute to pain in hemophilia. Specifically, we cross examine preclinical and clinical studies that address the contribution of oxidative stress in hemophilia and related diseases that affect synovial tissue to induce acute and potentially chronic pain. This understanding would help provide potential treatable targets using antioxidants to ameliorate pain in hemophilia.

Extended Reality International Grand Rounds: An Innovative Approach to Medical Education in the Pandemic Era.

PROBLEM: While bedside training has always presented its own unique challenges, the COVID-19 pandemic era has intensified barriers to suitable provider and trainee experiences for both patient care and medical education. APPROACH: This project introduced an innovative solution with the Extended Reality International Grand Rounds, a collaboration between the University of Michigan Center for Medical and Surgical Extended Reality and Imperial College London. Three complex cases were presented to trainees through a wireless, extended reality (XR) headset and augmented by holographic visual aids and expert commentary. This pilot rounding experience was performed through the first-person view of one clinician at the bedside. OUTCOMES: In 2020, 140 attendees participated in XR International Grand Rounds, and 82 (59%) and 61 (44%) completed pre- and postsurveys, respectively. Survey analysis showed that the majority of respondents (65, 79.3%) had very little to no baseline experience with XR technologies and nearly all (75, 91.5%) agreed that the development and implementation of XR curricula are important in medical training, indicating an unmet need. Nearly all respondents (59, 96.7%) found value in the ability to visualize patients' clinical findings in the XR rounding experience and 60 (98.4%) found value in the ability to visualize patient-specific imaging and test findings in an XR format. Limiting exposure to high-risk patients and care team members with this innovative format was believed to be important to 79 (96.3%) respondents at baseline and that perception was unchanged following the event. NEXT STEPS: This solution to a long-standing dilemma, newly stressed by a unique era in medicine, was a successful collaboration using state-of-the-art XR technology. Next steps will include introducing more advanced physical exam visualization and detection and comprehensive evaluation of the patient experience, as well as expanding the international experience in a format that is scalable to other interested institutions.

'They don't actually join the dots': An exploration of organizational change in Irish opiate community treatment services.

BACKGROUND: People who use community-based drug treatment services spend a considerable amount of their time in treatment in direct contact with frontline staff. These staff are also fundamental to supporting the implementation of change to meet service user needs. Yet, very little is known about staff perspectives on the process and internal dynamics of drug treatment services, their views about what makes services work effectively, and how services can more effectively adopt to changes in practice. AIM AND METHOD: Conducted across Irish community opiate prescribing services and drawing on data from 12 in-depth qualitative interviews with frontline staff. This paper examines the narratives of staff about the factors which influence the dynamics and process of treatment services, particularly in relation to the implantation of change. FINDINGS: Change itself was described both in respect of how a service responded to immediate service user needs or supported planned change. Little distinction was made in respect of service attributes which facilitated a response in either context. Overwhelmingly, staff contextualised current service effectiveness, historical change, and desired change in how effectively their services met service user needs, which was also viewed as a significant motivation for change. Differences in operational standards across services in terms of practices, policy implementation, job roles, divisions between professional groups, and recruitment and retention of staff inhibited change adoption. Factors which were identified in terms of inhibiting or facilitating planned change were consistent with the wider literature on change implementation but provided unique insights in the context of substance misuse services. CONCLUSIONS: A range of interdependent factors which influence an 'eco-system' of service delivery were identified. Effective policy implementation in Ireland remains aspirational, but findings reported in this paper have important implications for future planning and design of services for people who use drugs, and provide a good basis for further investigation.

International Mixed Reality Immersive Experience: Approach via Surgical Grand Rounds.

BACKGROUND: Coronavirus disease 2019 created unintended but significant experiential barriers for surgical learners to interact at the bedside for teaching/case presentations. We hypothesized that an international grand rounds using the Microsoft HoloLens 2 extended reality (XR) headset would create an improved bedside-learning experience compared to traditional grand rounds formats. STUDY DESIGN: From December 2020 to March 2021, the world's first 2 international mixed reality grand rounds events using the HoloLens 2 headset were held, broadcasting transatlantically (between the University of Michigan and the Imperial College of London) bedside rounding experiences on 5 complex surgical patients to an international audience of 325 faculty, residents, and medical trainees. Participants completed pre- and post-event surveys to assess their experience. RESULTS: Of the 325 participants, 267 (80%) completed pre-surveys, and 95 (29%) completed both the pre- and post-surveys. Respondents (average age, 38 y; 44% women, 56% men; 211 US, 56 UK) included 92 (34%) medical students and residents and 175 faculty and staff. In the pre-event survey, 76% had little or no earlier experience with XR devices, and 94% thought implementation of XR into medical curricula was valuable. In the post-survey, 96% thought telerounding using XR technology was important for the current era, and 99% thought the ability to visualize the examination, imaging, and laboratory results at bedside via XR rounding was highly valuable and that this format was superior to traditional grand rounds. CONCLUSIONS: Almost all of the participants in the mixed reality international grand rounds felt the immersive XR experiences-allowing visualization of clinical findings, imaging, and laboratory results at the patient's bedside-were superior to a traditional grand rounds format, and that it could be a valuable tool for surgical teaching and telerounding.

Effects of Selective Breeding, Voluntary Exercise, and Sex on Endocannabinoid Levels in the Mouse Small-Intestinal Epithelium.

The endocannabinoid (eCB) system in the gut communicates with the body and brain as part of the homeostatic mechanisms that affect energy balance. Although perhaps best known for its effects on energy intake, the eCB system also regulates voluntary locomotor behavior. Here, we examined gut eCB concentrations in relation to voluntary exercise, specifically in mice selectively bred for high voluntary wheel running behavior. We measured gut eCBs in four replicate non-selected Control (C) lines and four replicate lines of High Runner (HR) mice that had been selectively bred for 74 generations based on the average number of wheel revolutions on days 5 and 6 of a 6-day period of wheel access when young adults. On average, mice from HR lines run voluntarily on wheels ∼3-fold more than C mice on a daily basis. A recent study showed that circulating levels of primary endocannabinoids 2-arachidonoyl-sn-glycerol (2-AG) and anandamide (AEA) are altered by six days of wheel access, by acute wheel running, and differ between HR and C mice in sex-specific ways [1]. We hypothesized that eCBs in the upper small-intestinal epithelium (i.e., proximal jejunum), a region firmly implicated in eCB signaling, would differ between HR and C mice (linetype), between the sexes, between mice housed with vs. without wheels for six days, and would covary with amounts of acute running and/or home-cage activity (during the previous 30 minutes). We used the same 192 mice as in [1] , half males and half females, half HR and half C (all 8 lines), and half either given or not given access to wheels for six days. We assessed the eCBs, 2-AG and AEA, and their analogs docosahexaenoylglycerol (DHG), docosahexaenoylethanolamide (DHEA), and oleoylethanolamide (OEA). Both 2-AG and DHG showed a significant 3-way interaction of linetype, wheel access, and sex. In addition, HR mice had lower concentrations of 2-AG in the small-intestinal epithelium when compared to C mice, which may be functionally related to differences in locomotor activity or to differences in body composition and/or food consumption. Moreover, the amount of home-cage activity during the prior 30 min was a negative predictor of 2-AG and AEA concentrations in jejunum mucosa, particularly in the mice with no wheel access. Lastly, 2-AG, but not AEA, was significantly correlated with 2-AG in plasma in the same mice.

Climate change and expanding invasive species drive widespread declines of native trout in the northern Rocky Mountains, USA.

Climate change and invasive species are major threats to native biodiversity, but few empirical studies have examined their combined effects at large spatial and temporal scales. Using 21,917 surveys collected over 30 years, we quantified the impacts of climate change on the past and future distributions of five interacting native and invasive trout species throughout the northern Rocky Mountains, USA. We found that the occupancy of native bull trout and cutthroat trout declined by 18 and 6%, respectively (1993­2018), and was predicted to decrease by an additional 39 and 16% by 2080. However, reasons for these occupancy reductions markedly differed among species: Climate-driven increases in water temperature and decreases in summer flow likely caused declines of bull trout, while climate-induced expansion of invasive species largely drove declines of cutthroat trout. Our results demonstrate that climate change can affect ecologically similar, co-occurring native species through distinct pathways, necessitating species-specific management actions.

Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice.

BACKGROUND: Individuals with Fragile X syndrome (FXS) and autism spectrum disorder (ASD) exhibit an array of symptoms, including sociability deficits, increased anxiety, hyperactivity, and sensory hyperexcitability. It is unclear how endocannabinoid (eCB) modulation can be targeted to alleviate neurophysiological abnormalities in FXS as behavioral research reveals benefits to inhibiting cannabinoid (CB) receptor activation and increasing endocannabinoid ligand levels. Here, we hypothesize that enhancement of 2-arachidonoyl-sn-glycerol (2-AG) in Fragile X mental retardation 1 gene knock-out (Fmr1 KO) mice may reduce cortical hyperexcitability and behavioral abnormalities observed in FXS. METHODS: To test whether an increase in 2-AG levels normalized cortical responses in a mouse model of FXS, animals were subjected to electroencephalography (EEG) recording and behavioral assessment following treatment with JZL-184, an irreversible inhibitor of monoacylglycerol lipase (MAGL). Assessment of 2-AG was performed using lipidomic analysis in conjunction with various doses and time points post-administration of JZL-184. Baseline electrocortical activity and evoked responses to sound stimuli were measured using a 30-channel multielectrode array (MEA) in adult male mice before, 4 h, and 1 day post-intraperitoneal injection of JZL-184 or vehicle. Behavior assessment was done using the open field and elevated plus maze 4 h post-treatment. RESULTS: Lipidomic analysis showed that 8 mg/kg JZL-184 significantly increased the levels of 2-AG in the auditory cortex of both Fmr1 KO and WT mice 4 h post-treatment compared to vehicle controls. EEG recordings revealed a reduction in the abnormally enhanced baseline gamma-band power in Fmr1 KO mice and significantly improved evoked synchronization to auditory stimuli in the gamma-band range post-JZL-184 treatment. JZL-184 treatment also ameliorated anxiety-like and hyperactivity phenotypes in Fmr1 KO mice. CONCLUSIONS: Overall, these results indicate that increasing 2-AG levels may serve as a potential therapeutic approach to normalize cortical responses and improve behavioral outcomes in FXS and possibly other ASDs.

The Utilization and Benefits of Telehealth Services by Health Care Professionals Managing Breast Cancer Patients during the COVID-19 Pandemic.

Telehealth is the delivery of many health care services and technologies to individuals at different geographical areas and is categorized as asynchronously or synchronously. The coronavirus disease 2019 (COVID-19) pandemic has caused major disruptions in health care delivery to breast cancer (BCa) patients and there is increasing demand for telehealth services. Globally, telehealth has become an essential means of communication between patient and health care provider. The application of telehealth to the treatment of BCa patients is evolving and increasingly research has demonstrated its feasibility and effectiveness in improving clinical, psychological and social outcomes. Two areas of telehealth that have significantly grown in the past decade and particularly since the beginning of the COVID-19 pandemic are telerehabilitation and teleoncology. These two technological systems provide opportunities at every stage of the cancer care continuum for BCa patients. We conducted a literature review that examined the use of telehealth services via its various modes of delivery among BCa patients particularly in areas of screening, diagnosis, treatment modalities, as well as satisfaction among patients and health care professionals. The advantages of telehealth models of service and delivery challenges to patients in remote areas are discussed.

Prospective Comparison of 24-Hour Urine Creatinine Clearance with Estimated Glomerular Filtration Rates in Chronic Renal Disease Patients of African Descent.

BACKGROUND: The 24-hour (24-h) creatinine clearance (CrCl) is the most common method for measuring GFR in clinical laboratories. However, the limitations of CrCl have resulted in the widespread acceptance of mathematically derived estimated glomerular filtration rate (eGFR) using Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in predicting eGFR. The aim of the study was to compare 24-h CrCl with eGFR derived from these formulae and to identify which could be the best alternative. METHOD: A prospective study was conducted involving 140 CKD patients. Creatinine and cystatin C concentrations were determined using the cobas 6000 analyzer. The eGFR was calculated using the CG formula, 4-variable MDRD and CKD-EPI equations, and Bland-Alman plots bias was determined. RESULTS: The CG and MDRD formulas had mean eGFR values similar to CrCl and correlation coefficients (r) were highest for CG (0.906) and lowest for MDRD (0.799). The CG equation was in agreement with 24-h CrCl in all but stage V CKD while the MDRD equation compared well in all except Stage IV CKD. The CG equation was positively biased (0.9857) while the MDRD had a negative bias (-0.05). CONCLUSION: The Cockcroft-Gault formula provides a more accurate assessment of GFR than 24-h CrCl and would be recommended as a substitute to provide the best estimate of GFR in our population.

UPLC-MS/MS Method for Analysis of Endocannabinoid and Related Lipid Metabolism in Mouse Mucosal Tissue.

The endocannabinoid system is expressed in cells throughout the body and controls a variety of physiological and pathophysiological functions. We describe robust and reproducible UPLC-MS/MS-based methods for analyzing metabolism of the endocannabinoids, 2-arachidonoyl-sn-glycerol and arachidonoyl ethanolamide, and related monoacylglycerols (MAGs) and fatty acid ethanolamides (FAEs), respectively, in mouse mucosal tissues (i.e., intestine and lung). These methods are optimized for analysis of activity of the MAG biosynthetic enzyme, diacylglycerol lipase (DGL), and MAG degradative enzymes, monoacylglycerol lipase (MGL) and alpha/beta hydrolase domain containing-6 (ABHD6). Moreover, we describe a novel UPLC-MS/MS-based method for analyzing activity of the FAE degradative enzyme, fatty acid amide hydrolase (FAAH), that does not require use of radioactive substrates. In addition, we describe in vivo pharmacological methods to inhibit MAG biosynthesis selectively in the mouse small-intestinal epithelium. These methods will be useful for profiling endocannabinoid metabolism in rodent mucosal tissues in health and disease.