Evaluating pharmacological treatments for excessive daytime sleepiness in obstructive sleep apnea: A comprehensive network meta-analysis and systematic review.

Obstructive sleep apnea (OSA) is associated with excessive daytime sleepiness (EDS). Pharmacotherapy offers a potential treatment approach for EDS in OSA patients. This systematic review and meta-analysis aimed to assess the efficacy and safety of pharmacological interventions for alleviating EDS in patients with OSA. Following PRISMA guidelines, we included randomized controlled trials investigating pharmacological treatments for EDS in adult OSA until August 2023. We conducted meta-analysis, subgroup, and meta-regression analyses using a random effects model. Finally, a network meta-analysis synthesized direct and indirect evidence, followed by a comprehensive safety analysis. We included 32 articles in the meta-analysis (n = 3357). Pharmacotherapy showed a significant improvement in the Epworth Sleepiness Scale (ESS) score (Mean Difference (MD) -2.73, (95 % Confidence Interval (CI) [-3.25, -2.20], p < 0.01) and Maintenance of Wakefulness Test (MWT) score (MD 6.00 (95 % CI [2.66, 9.33] p < 0.01). Solriamfetol, followed by Pitolisant and modafinil, exhibited the greatest ESS reduction, while Danavorexton, followed by Solriamfetol and MK-7288, had the strongest impact on MWT. MK-7288 had the most total adverse events (AEs), followed by Danavorexton and armodafinil. Pharmacological Interventions significantly alleviate EDS in OSA patients but with heterogeneity across medications. Treatment decisions should involve a personalized assessment of patient factors and desired outcomes.

The spatial and temporal structure of neural activity across the fly brain.

What are the spatial and temporal scales of brainwide neuronal activity? We used swept, confocally-aligned planar excitation (SCAPE) microscopy to image all cells in a large volume of the brain of adult Drosophila with high spatiotemporal resolution while flies engaged in a variety of spontaneous behaviors. This revealed neural representations of behavior on multiple spatial and temporal scales. The activity of most neurons correlated (or anticorrelated) with running and flailing over timescales that ranged from seconds to a minute. Grooming elicited a weaker global response. Significant residual activity not directly correlated with behavior was high dimensional and reflected the activity of small clusters of spatially organized neurons that may correspond to genetically defined cell types. These clusters participate in the global dynamics, indicating that neural activity reflects a combination of local and broadly distributed components. This suggests that microcircuits with highly specified functions are provided with knowledge of the larger context in which they operate.

Whole-food plant-based diet reduces daytime sleepiness in patients with OSA.

Consumption of a diet high in saturated fat has been associated with daytime sleepiness. A whole-food plant-based (WFPB) dietary pattern, which is low in saturated fat, has been shown to be beneficial in a variety of health conditions. We assessed the effect of a short-term (21 days) WFPB diet intervention on daytime sleepiness in 14 patients with obstructive sleep apnea (OSA). We found a mean decrease of 3.8 points (SD = 3.3, p = 0.003) on the Epworth Sleepiness Scale (ESS) after switching from a standard Western diet to a WFPB diet. Our results suggest that a WFPB diet could be a viable dietary intervention to reduce symptom of daytime sleepiness.

Neuronal birthdate reveals topography in a vestibular brainstem circuit for gaze stabilization.

Across the nervous system, neurons with similar attributes are topographically organized. This topography reflects developmental pressures. Oddly, vestibular (balance) nuclei are thought to be disorganized. By measuring activity in birthdated neurons, we revealed a functional map within the central vestibular projection nucleus that stabilizes gaze in the larval zebrafish. We first discovered that both somatic position and stimulus selectivity follow projection neuron birthdate. Next, with electron microscopy and loss-of-function assays, we found that patterns of peripheral innervation to projection neurons were similarly organized by birthdate. Finally, birthdate revealed spatial patterns of axonal arborization and synapse formation to projection neuron outputs. Collectively, we find that development reveals previously hidden organization to the input, processing, and output layers of a highly conserved vertebrate sensorimotor circuit. The spatial and temporal attributes we uncover constrain the developmental mechanisms that may specify the fate, function, and organization of vestibulo-ocular reflex neurons. More broadly, our data suggest that, like invertebrates, temporal mechanisms may assemble vertebrate sensorimotor architecture.

High-speed light-sheet microscopy for the in-situ acquisition of volumetric histological images of living tissue.

Histological examinations typically require the excision of tissue, followed by its fixation, slicing, staining, mounting and imaging, with timeframes ranging from minutes to days. This process may remove functional tissue, may miss abnormalities through under-sampling, prevents rapid decision-making, and increases costs. Here, we report the feasibility of microscopes based on swept confocally aligned planar excitation technology for the volumetric histological imaging of intact living tissue in real time. The systems' single-objective, light-sheet geometry and 3D imaging speeds enable roving image acquisition, which combined with 3D stitching permits the contiguous analysis of large tissue areas, as well as the dynamic assessment of tissue perfusion and function. Implemented in benchtop and miniaturized form factors, the microscopes also have high sensitivity, even for weak intrinsic fluorescence, allowing for the label-free imaging of diagnostically relevant histoarchitectural structures, as we show for pancreatic disease in living mice, for chronic kidney disease in fresh human kidney tissues, and for oral mucosa in a healthy volunteer. Miniaturized high-speed light-sheet microscopes for in-situ volumetric histological imaging may facilitate the point-of-care detection of diverse cellular-level biomarkers.

Trends and Resource Utilization in Kawasaki Disease Hospitalizations in the United States, 2008-2017.

OBJECTIVES: To explore trends in hospitalization rate, resource use, and outcomes of Kawasaki Disease (KD) in children in the United States from 2008 to 2017. METHODS: This was a retrospective, serial cross-sectional analysis of pediatric hospitalizations with International Classification of Disease diagnostic codes for KD in the National Inpatient Sample. Hospitalization rates per 100 000 populations were calculated and stratified by age group, gender, race, and US census region. Prevalence of coronary artery aneurysms (CAA) were expressed as proportions of KD hospitalizations. Resource use was defined in terms of length of stay and hospital cost. Cochran-Armitage and Jonckheere-Terpstra trend tests were used for categorical and continuous variables, respectively. P <.05 was considered significant. RESULTS: A total of 43 028 pediatric hospitalizations identified with KD, yielding an overall hospitalization rate of 5.5 per 100 000 children. The overall KD hospitalization rate remained stable over the study period (P = .18). Although KD hospitalization rates differed by age group, gender, race, and census region, a significant increase was observed among Native Americans (P = .048). Rates of CAA among KD hospitalization increased from 2.4% to 6.8% (P = .04). Length of stay remained stable at 2 to 3 days, but inflation-adjusted hospital cost increased from $6819 in 2008 to $10 061 in 2017 (Ptrend < 0.001). CONCLUSIONS: Hospitalization-associated costs and rates of CAA diagnostic codes among KD hospitalizations increased, despite a stable KD hospitalization rate between 2008 and 2017. These findings warrant further investigation and confirmation with databases with granular clinical information.

Trends of HIV-Related Cancer Mortality between 2001 and 2018: An Observational Analysis.

The burden of AIDS-defining cancers has remained relatively steady for the past two decades, whilst the burden of non-AIDS-defining cancer has increased. Here, we conduct a study to describe mortality trends attributed to HIV-associated cancers in 31 countries. We extracted HIV-related cancer mortality data from 2001 to 2018 from the World Health Organization Mortality Database. We computed age-standardized death rates (ASDRs) per 100,000 population using the World Standard Population. Data were visualized using Locally Weighted Scatterplot Smoothing (LOWESS). Data for females were available for 25 countries. Overall, there has been a decrease in mortality attributed to HIV-associated cancers among most of the countries. In total, 18 out of 31 countries (58.0%) and 14 out of 25 countries (56.0%) showed decreases in male and female mortality, respectively. An increasing mortality trend was observed in many developing countries, such as Malaysia and Thailand, and some developed countries, such as the United Kingdom. Malaysia had the greatest increase in male mortality (+495.0%), and Canada had the greatest decrease (-88.5%). Thailand had the greatest increase in female mortality (+540.0%), and Germany had the greatest decrease (-86.0%). At the endpoint year, South Africa had the highest ASDRs for both males (16.8/100,000) and females (19.2/100,000). The lowest was in Japan for males (0.07/100,000) and Egypt for females (0.028/100,000).

Trends of HIV Mortality between 2001 and 2018: An Observational Analysis.

Since the beginning of the epidemic in the early 1980s, HIV-related illnesses have led to the deaths of over 32.7 million individuals. The objective of this study was to describe current mortality rates for HIV through an observational analysis of HIV mortality data from 2001 to 2018 from the World Health Organization (WHO) Mortality Database. We computed age-standardized death rates (ASDRs) per 100,000 people using the World Standard Population. We plotted trends using locally weighted scatterplot smoothing (LOWESS). Data for females were available for 42 countries. In total, 31/48 (64.60%) and 25/42 (59.52%) countries showed decreases in mortality in males and females, respectively. South Africa had the highest ASDRs for both males (467.7/100,000) and females (391.1/100,000). The lowest mortalities were noted in Egypt for males (0.2/100,000) and in Japan for females (0.01/100,000). Kyrgyzstan had the greatest increase in mortality for males (+6998.6%). Estonia had the greatest increase in mortality for females (+5877.56%). The disparity between Egypt (the lowest) and South Africa (the highest) was 3042-fold for males. Between Japan and South Africa, the disparity was 43,454-fold for females. Although there was a decrease in mortality attributed to HIV among most of the countries studied, a rising trend remained in a number of developing countries.

Predictors of Length of Stay and Cost of Hospitalization of Neonatal Abstinence Syndrome in the United States.

Background The incidence rate and economic burden of neonatal abstinence syndrome (NAS) are increasing in the United States (US). We explored the link between the length of stay (LOS) and hospitalization cost for neonatal abstinence syndrome in 2018. Methods This was a cross-sectional analysis of the 2018 national inpatient sample database. Newborn hospitalizations with neonatal abstinence syndrome and their accompanying comorbid conditions were identified using the International Classification of Diseases, 10th Edition diagnostic codes. Logistic regression was used to determine the impact of length of stay and the co-morbidities on inflation-adjusted hospital costs. Results The incidence of neonatal abstinence syndrome was 7.1 per 1000 births (95% CI 6.8-7.3) in 2018. The majority had Medicaid (84.1%), with a neonatal abstinence syndrome incidence of 13.2 (95% CI: 12.8-13.6). In adjusted analysis, every one-day increase in length of stay increased the hospital cost by $1,685 (95% CI: 1,639-1,731). Neonatal abstinence syndrome hospitalizations with Medicaid had a longer length of stay by 1.8 days (95% CI: 0.5-3.1). Co-morbidities further increased the length of stay: seizures: 13.8 days; sepsis: 4.1 days; respiratory complications: 4.4 days; and feeding problems: 5.8 days. Those at urban teaching hospitals had a longer length of stay by 7.3 days (95% CI: 5.8-8.8). Co-morbidities increased hospital cost as follows: seizures: $71,380; sepsis: $12,837; respiratory complications: $8,268; feeding problems: $7,737. The cost of hospitalization at large bed-size hospitals and urban teaching was higher by $5,243 and $12,005, respectively. Conclusion The incidence rate of neonatal abstinence syndrome remained high and was resource-intensive in 2018. Co-morbid conditions and hospitalization at urban teaching hospitals were major contributors to increased length of stay and hospital costs.

Surgical Teams' Attitudes About Surgical Safety and the Surgical Safety Checklist at 10 Years: A Multinational Survey.

To assess health care professionals' attitudes on the Surgical Safety Checklist ("the Checklist") in resource-rich health systems and provide insights on strategies for optimizing Checklist use. Background: In use for over a decade, the Checklist is a safety instrument aimed at improving operating room communication, teamwork, and evidence-based safety practices. Methods: An online survey was sent to surgeons, nurses, and anesthesiologists in 5 high-income countries (Canada, the United States, the United Kingdom, Australia, and New Zealand). Survey results were analyzed using SPSS. Results: A total of 2032 health care professionals completed the survey. Of these respondents, 47.6% were nurses, 70.5% were women, 65.1% were from the United States, and 50.0% had 20 years of experience or more in their role. Most respondents felt the Checklist positively impacted patient safety (70.9%), team communication (73.1%), and teamwork (58.9%). Only 50.3% of respondents were satisfied their team's use of the Checklist, and only 47.5% reported team members stopping to fully participate in the process. More nurses lacked confidence regarding their role in the Checklist process than surgeons and anesthesiologists combined (8.9% vs 4.3%). Fewer surgeons and anesthesiologists than nurses felt they received adequate training on the Checklist's use (57.8% vs 76.7%). Conclusions: While most respondents perceive the Checklist as enhancing patient safety, not all surgical team members are actively engaging with its use. To enhance buy-in and meaningful use of the Checklist, health systems should provide more training on the Checklist with respect to its purpose and strengthening teamwork.

Impact of Hyperoncotic Albumin on Duration of Vasopressor Support in Septic Shock: A Propensity Score-Matched Analysis.

BACKGROUND: While albumin has not been shown to reduce mortality in sepsis and septic shock, a tertiary analysis of a large trial suggested that it may reduce the duration of vasopressor use in septic shock. OBJECTIVE: We sought to test if 25% albumin administration was associated with reduced cumulative vasopressor use in septic shock in a real-world setting. METHODS: This was a retrospective, propensity score-matched cohort study of septic shock in which patients receiving albumin were compared with a matched cohort of those not receiving albumin. The primary outcome was days alive and free of vasopressors. RESULTS: The matched cohort included 335 patients who received albumin and 335 who did not. The days alive and free of vasopressors were similar between the albumin and no albumin groups: 17.4 (0-24.8) versus 19.4 (0-25.3); P = 0.160. Similarly, in-hospital mortality was no different between groups (46.9% vs 44.8%; P = 0.587). Receipt of albumin was associated with fewer ventilator-free and intensive care unit (ICU)-free days: 0 (0-19) versus 11 (0-23), P = 0.007, and 0 (0-18) versus 10.6 (0-22.1), P = 0.002, respectively. CONCLUSION AND RELEVANCE: Albumin use in septic shock was not associated with additional days alive and free of vasopressors or in-hospital mortality. The finding of fewer ventilator- and ICU-free days may reflect selection of patients who were critically ill for longer periods of time before or after albumin administration. Additional study is needed to clarify the impact that timing may have on the effectiveness of albumin in septic shock.

A Systematic Review of the Cardiovascular Manifestations and Outcomes in the Setting of Coronavirus-19 Disease.

The impact of coronavirus disease, 2019 (COVID-19), has been profound. Though COVID-19 primarily affects the respiratory system, it has also been associated with a wide range of cardiovascular (CV) manifestations portending extremely poor prognosis. The principal hypothesis for CV involvement is through direct myocardial infection and systemic inflammation. We conducted a systematic review of the current literature to provide a foundation for understanding the CV manifestations and outcomes of COVID-19. PubMed and EMBASE databases were electronically searched from the inception of the databases through 27 April 2020. A second literature review was conducted to include major trials and guidelines that were published after the initial search but before submission. The inclusion criteria for studies to be eligible were case reports, case series, and observation studies reporting CV outcomes among patients with COVID-19 infection. This review of the current COVID-19 disease and CV outcomes literature revealed a myriad of CV manifestations with potential avenues for treatment and prevention. Future studies are required to understand on a more mechanistic level the effect of COVID-19 on the myocardium and thus provide avenues to improve mortality and morbidity.

Glioma-Induced Alterations in Neuronal Activity and Neurovascular Coupling during Disease Progression.

Diffusely infiltrating gliomas are known to cause alterations in cortical function, vascular disruption, and seizures. These neurological complications present major clinical challenges, yet their underlying mechanisms and causal relationships to disease progression are poorly characterized. Here, we follow glioma progression in awake Thy1-GCaMP6f mice using in vivo wide-field optical mapping to monitor alterations in both neuronal activity and functional hemodynamics. The bilateral synchrony of spontaneous neuronal activity gradually decreases in glioma-infiltrated cortical regions, while neurovascular coupling becomes progressively disrupted compared to uninvolved cortex. Over time, mice develop diverse patterns of high amplitude discharges and eventually generalized seizures that appear to originate at the tumors' infiltrative margins. Interictal and seizure events exhibit positive neurovascular coupling in uninfiltrated cortex; however, glioma-infiltrated regions exhibit disrupted hemodynamic responses driving seizure-evoked hypoxia. These results reveal a landscape of complex physiological interactions occurring during glioma progression and present new opportunities for exploring novel biomarkers and therapeutic targets.

Use of fomepizole, n-acetylcysteine, and hemodialysis for massive acetaminophen overdose.

Acetaminophen poisoning is the leading cause of liver transplantation within the United States, accounting for nearly 56,000 emergency department patient visits each year. Although n-acetylcysteine is commonly successful in preventing acetaminophen toxicity when given in a timely manner, reports do exist demonstrating n-acetylcysteine therapy failure, commonly in the setting of a massive ingestion. We present the use of a novel antidote cocktail of n-acetylcysteine, fomepizole, and hemodialysis to treat a massive acetaminophen ingestion. A 55-year old male with a past medical history significant for bipolar disorder and past suicidal ideation presented to the emergency department after being found unresponsive at home. Medical workup was significant for an estimated seven-hour acetaminophen level of 883 mcg/mL, with concomitant metabolic acidosis. The patient was diagnosed with severe acetaminophen poisoning and was promptly administered n-acetylcysteine. Due to the severity of the patient's ingestion and the concern for additional coingestants, the patient was also given fomepizole therapy and later underwent hemodialysis for more rapid toxin clearance. After a four-day stay in the hospital the patient was discharged to a mental-health facility with no signs of systemic injury.

Real-time volumetric microscopy of in vivo dynamics and large-scale samples with SCAPE 2.0.

The limited per-pixel bandwidth of most microscopy methods requires compromises between field of view, sampling density and imaging speed. This limitation constrains studies involving complex motion or fast cellular signaling, and presents a major bottleneck for high-throughput structural imaging. Here, we combine high-speed intensified camera technology with a versatile, reconfigurable and dramatically improved Swept, Confocally Aligned Planar Excitation (SCAPE) microscope design that can achieve high-resolution volumetric imaging at over 300 volumes per second and over 1.2 GHz pixel rates. We demonstrate near-isotropic sampling in freely moving Caenorhabditis elegans, and analyze real-time blood flow and calcium dynamics in the beating zebrafish heart. The same system also permits high-throughput structural imaging of mounted, intact, cleared and expanded samples. SCAPE 2.0's significantly lower photodamage compared to point-scanning techniques is also confirmed. Our results demonstrate that SCAPE 2.0 is a powerful, yet accessible imaging platform for myriad emerging high-speed dynamic and high-throughput volumetric microscopy applications.

High-speed 3D imaging of cellular activity in the brain using axially-extended beams and light sheets.

As optical reporters and modulators of cellular activity have become increasingly sophisticated, the amount that can be learned about the brain via high-speed cellular imaging has increased dramatically. However, despite fervent innovation, point-scanning microscopy is facing a fundamental limit in achievable 3D imaging speeds and fields of view. A range of alternative approaches are emerging, some of which are moving away from point-scanning to use axially-extended beams or sheets of light, for example swept confocally aligned planar excitation (SCAPE) microscopy. These methods are proving effective for high-speed volumetric imaging of the nervous system of small organisms such as Drosophila (fruit fly) and D. Rerio (Zebrafish), and are showing promise for imaging activity in the living mammalian brain using both single and two-photon excitation. This article describes these approaches and presents a simple model that demonstrates key advantages of axially-extended illumination over point-scanning strategies for high-speed volumetric imaging, including longer integration times per voxel, improved photon efficiency and reduced photodamage.

Noncontact three-dimensional mapping of intracellular hydromechanical properties by Brillouin microscopy.

Current measurements of the biomechanical properties of cells require physical contact with cells or lack subcellular resolution. Here we developed a label-free microscopy technique based on Brillouin light scattering that is capable of measuring an intracellular longitudinal modulus with optical resolution. The 3D Brillouin maps we obtained of cells in 2D and 3D microenvironments revealed mechanical changes due to cytoskeletal modulation and cell-volume regulation.

MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression.

Although dispensable for normal pancreatic function, STAT3 signaling is frequently activated in pancreatic cancers. Consistent downregulation of expression of microRNA let-7 is also characteristic of pancreatic ductal adenocarcinoma (PDAC) biopsy specimens. We demonstrate in this study that re-expression of let-7 in poorly-differentiated PDAC cell lines reduced phosphorylation/activation of STAT3 and its downstream signaling events and reduced the growth and migration of PDAC cells. Let-7 re-expression did not repress expression of STAT3 protein or its activator cytokine interleukin 6 (IL-6). However, let-7 re-expression enhanced cytoplasmic expression of suppressor of cytokine signaling 3 (SOCS3), which blocks STAT3 activation by JAK2. Our study thus identified a mechanism by which STAT3 signaling can be inhibited in pancreatic cancer cells by modifying let-7 expression.