Small Human Studies Research Articles

Total adiponectin in indigenous Melanesians on Kitava.

Experimental and small human studies have indicated that high total adiponectin levels have beneficial cardiometabolic effects. In contrast, however, high total adiponectin levels are also associated with higher all-cause and cardiovascular mortality in thoroughly adjusted epidemiological studies. To gain further insight into these seemingly contradictory results, we report results on total adiponectin from the indigenous Melanesian population of Kitava, Trobriand Islands, Papua New Guinea, where an apparent absence of cardiometabolic disease has been previously reported. Fasting levels of serum total adiponectin were measured cross-sectionally in ≥40-year-old Kitavans (n = 102) and Swedish controls matched for age and sex (n = 108). Multivariable linear regression was used for the analysis of associations with total adiponectin when controlled for group, sex, smoking, hypertension and/or type 2 diabetes, age, and body mass index. Total adiponectin was lower for Kitavans compared to Swedish controls (Median [Mdn] 4.6 μg/mL, range 1.0-206 μg/mL and Mdn 9.7 μg/mL, range 3.1-104 μg/mL, respectively, r = .64, p < .001). Lower total adiponectin was associated with Kitavan group, male sex (only in Swedish controls), smoking (only in Kitavans and Swedish controls combined), younger age (not in Swedish controls), higher BMI, lower total, low-density lipoprotein, high-density lipoprotein (HDL) (only in Kitavans and Swedish controls combined), and non-HDL cholesterol, and higher anti-PC IgG (only in Kitavans and Swedish controls combined). Total adiponectin in Kitavans was significantly lower than in Swedish controls.

The microbiota-gut-brain-immune interface in the pathogenesis of neuroinflammatory diseases: a narrative review of the emerging literature.

Research is beginning to elucidate the sophisticated mechanisms underlying the microbiota-gut-brain-immune interface, moving from primarily animal models to human studies. Findings support the dynamic relationships between the gut microbiota as an ecosystem (microbiome) within an ecosystem (host) and its intersection with the host immune and nervous systems. Adding this to the effects on epigenetic regulation of gene expression further complicates and strengthens the response. At the heart is inflammation, which manifests in a variety of pathologies including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Multiple Sclerosis (MS). Generally, the research to date is limited and has focused on bacteria, likely due to the simplicity and cost-effectiveness of 16s rRNA sequencing, despite its lower resolution and inability to determine functional ability/alterations. However, this omits all other microbiota including fungi, viruses, and phages, which are emerging as key members of the human microbiome. Much of the research has been done in pre-clinical models and/or in small human studies in more developed parts of the world. The relationships observed are promising but cannot be considered reliable or generalizable at this time. Specifically, causal relationships cannot be determined currently. More research has been done in Alzheimer's disease, followed by Parkinson's disease, and then little in MS. The data for MS is encouraging despite this. While the research is still nascent, the microbiota-gut-brain-immune interface may be a missing link, which has hampered our progress on understanding, let alone preventing, managing, or putting into remission neurodegenerative diseases. Relationships must first be established in humans, as animal models have been shown to poorly translate to complex human physiology and environments, especially when investigating the human gut microbiome and its relationships where animal models are often overly simplistic. Only then can robust research be conducted in humans and using mechanistic model systems.

Cannabinoid Use and Obstructive Sleep Apnea: A Retrospective Cohort Study.

Obstructive sleep apnea (OSA) is a sleep disorder with no widely accepted pharmacological therapy. Cannabinoids have been suggested to reduce OSA severity in small human studies. The purpose of this retrospective cohort study was to explore the association of self-reported cannabis use on OSA severity and sleep parameters in a large cohort of adults undergoing in-laboratory polysomnography. Sleep and medication data were collected for all consecutive adults who completed diagnostic polysomnography at Sunnybrook Health Sciences Centre from 2010 to 2022. Multivariable linear regression models were employed that adjusted for age, sex, and BMI (minimally adjusted model), as well as medication and comorbidity data (maximally adjusted model). An exploratory subgroup analysis was additionally run in patients with moderate to severe OSA. Of 6,958 individuals (mean age 54.7 ± 16.3, BMI 29.1 ± 6.8, 51.0% female), 71 reported cannabis use. In our minimally adjusted models, cannabis use predicted a reduced respiratory disturbance index (RDI) (β: -4.8 [95% CI: -9.4, -0.2]; p = 0.042); this association became nonsignificant in the fully adjusted models. In an exploratory analysis of patients with moderate to severe OSA (n = 613), cannabis use (n = 7) predicted increased stage N3 sleep (β: 33.5 [95% CI: 15.6, 51.4]; p < 0.001) and decreased REM sleep (β: 16.0 [95% CI: 0.3, 31.7]; p = 0.046). Self-reported cannabis use was not associated with OSA severity after adjusting for confounders. In an exploratory subgroup analysis of patients with moderate to severe OSA, cannabis use impacted sleep architecture. Future studies should further explore these findings.

Substantial decrease of PFAS with anion exchange resin treatment – A clinical cross-over trial

BackgroundPer- and polyfluoroalkyl substances (PFAS) are heat and stain resisting chemicals. They are persistent, bioaccumulating and spread ubiquitously. Many hotspots where humans are exposed to high levels of PFAS have been reported. A few small observational studies in humans suggest that treatment with an Anion Exchange Resin (AER) decreases serum PFAS. This first clinical controlled crossover study aimed to assess whether AER decreases perfluorooctanesulfonic acid (PFOS) in highly exposed adults. MethodsAn open label 1:1 randomized treatment sequence crossover study with allocation to oral AER (cholestyramine 4 g three times daily) or observation for 12 weeks was conducted among citizens from a PFAS hotspot. Main inclusion criteria was serum PFOS > 21 ng/mL. Primary endpoint was change in serum PFOS levels between treatment and observational period. ResultsIn total, 45 participants were included with a mean age of 50 years (SD 13). Serum PFOS baseline median was 191 ng/mL (IQR: 129–229) and decreased with a mean of 115 ng/mL (95 % CI: 89–140) on treatment, and 4.3 ng/mL in observation period corresponding to a decrease of 60 % (95 % CI: 53–67; p < 0.0001). PFHxS, PFOA, PFNA and PFDA decreased during treatment between 15 and 44 %. No serious adverse events were reported. ConclusionsOral treatment with AER significantly lowered serum PFOS concentrations suggesting a possible treatment for enhancing elimination of PFOS in highly exposed adults.

(096) Use of GLP-1 Agonists Associated with Diagnosis of Hypogonadism in Large Retrospective Cohort

Abstract Introduction Glucagon-like peptide receptor agonist (GLP-1a) medications are a novel treatment for type 2 diabetes mellitus (DM), receiving US FDA approval for this indication in 2017. The use of these medications is increasing rapidly for both diabetes and weight loss, and FDA approval was granted for treatment of obesity in 2021. There is evidence that these medications have a direct effect on the hypothalamic-pituitary-gonadal (HPG) axis in animal studies and mixed findings in small human studies. The effects on the HPG axis in humans with long-term use has not been described. Objective To determine if there is a correlation between use of GLP-1a medications and subsequent diagnosis of hypogonadism in men. Methods The Marketscan Research database was queried for men who received a prescription for any GLP-1a medication from 2017 to 2020. The length of time on the medication was then compared to subsequent diagnosis of hypogonadism for up to one year after initiation of treatment. Men with a preexisting diagnosis of hypogonadism were excluded. Results The initial query yielded 116,704 patients receiving a prescription for GLP-1a medication. Of these, 26,668 received the prescription for at least 1 year. Of those with prescription duration &amp;gt;1 year, 1,075 (4.0%) men had a new diagnosis of hypogonadism within the next year following GLP1a initiation. The mean age of men was similar between those with and without hypogonadism (50.33 vs 50.26, p = 0.8). Using point-biserial correlation, the length of time on the medication was compared with a new diagnosis of hypogonadism. There was a weak but significant correlation between the time on the medication and new diagnosis of hypogonadism (rpb = -0.015, p = 0.015) Conclusions This large cohort of patients shows a significant correlation between the length of time taking GLP-1a and the subsequent development of hypogonadism within one year of initiating treatment. Along with prior research, this study raises concerns about the use of GLP1a medication and possible long term effects its use. Disclosure No.

Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction

Tongxinluo, a traditional Chinese medicine compound, has shown promise in in vitro, animal, and small human studies for myocardial infarction, but has not been rigorously evaluated in large randomized clinical trials. To investigate whether Tongxinluo could improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Randomized, double-blind, placebo-controlled clinical trial was conducted among patients with STEMI within 24 hours of symptom onset from 124 hospitals in China. Patients were enrolled from May 2019 to December 2020; the last date of follow-up was December 15, 2021. Patients were randomized 1:1 to receive either Tongxinluo or placebo orally for 12 months (a loading dose of 2.08 g after randomization, followed by the maintenance dose of 1.04 g, 3 times a day), in addition to STEMI guideline-directed treatments. The primary end point was 30-day major adverse cardiac and cerebrovascular events (MACCEs), a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke. Follow-up for MACCEs occurred every 3 months to 1 year. Among 3797 patients who were randomized, 3777 (Tongxinluo: 1889 and placebo: 1888; mean age, 61 years; 76.9% male) were included in the primary analysis. Thirty-day MACCEs occurred in 64 patients (3.4%) in the Tongxinluo group vs 99 patients (5.2%) in the control group (relative risk [RR], 0.64 [95% CI, 0.47 to 0.88]; risk difference [RD], -1.8% [95% CI, -3.2% to -0.6%]). Individual components of 30-day MACCEs, including cardiac death (56 [3.0%] vs 80 [4.2%]; RR, 0.70 [95% CI, 0.50 to 0.99]; RD, -1.2% [95% CI, -2.5% to -0.1%]), were also significantly lower in the Tongxinluo group than the placebo group. By 1 year, the Tongxinluo group continued to have lower rates of MACCEs (100 [5.3%] vs 157 [8.3%]; HR, 0.64 [95% CI, 0.49 to 0.82]; RD, -3.0% [95% CI, -4.6% to -1.4%]) and cardiac death (85 [4.5%] vs 116 [6.1%]; HR, 0.73 [95% CI, 0.55 to 0.97]; RD, -1.6% [95% CI, -3.1% to -0.2%]). There were no significant differences in other secondary end points including 30-day stroke; major bleeding at 30 days and 1 year; 1-year all-cause mortality; and in-stent thrombosis (<24 hours; 1-30 days; 1-12 months). More adverse drug reactions occurred in the Tongxinluo group than the placebo group (40 [2.1%] vs 21 [1.1%]; P = .02), mainly driven by gastrointestinal symptoms. In patients with STEMI, the Chinese patent medicine Tongxinluo, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly improved both 30-day and 1-year clinical outcomes. Further research is needed to determine the mechanism of action of Tongxinluo in STEMI. ClinicalTrials.gov Identifier: NCT03792035.

Interactions between extracorporeal support and the cardiopulmonary system.

This review describes the intricate physiological interactions involved in the application of extracorporeal therapy, with specific focus on cardiopulmonary relationships. Extracorporeal therapy significantly influences cardiovascular and pulmonary physiology, highlighting the necessity for clinicians to understand these interactions for improved patient care. Veno-arterial extracorporeal membrane oxygenation (veno-arterial ECMO) unloads the right ventricle and increases left ventricular (LV) afterload, potentially exacerbating LV failure and pulmonary edema. Veno-venous (VV) ECMO presents different challenges, where optimal device and ventilator settings remain unknown. Influences on right heart function and native gas exchange as well as end-expiratory lung volumes are important concepts that should be incorporated into daily practice. Future studies should not be limited to large clinical trials focused on mortality but rather address physiological questions to advance the understanding of extracorporeal therapies. This includes exploring optimal device and ventilator settings in VV ECMO, standardizing cardiopulmonary function monitoring strategies, and developing better strategies for device management throughout their use. In this regard, small human or animal studies and computational physiological modeling may contribute valuable insights into optimizing the management of extracorporeal therapies.

Significant gut microbiota related to patterns of drinking and alcohol relapse in patients with alcoholic hepatitis undergoing stool transplant or corticosteroid therapy.

Alcohol-induced gut microbiota (GM) alterations are linked to alcohol use disorder (AUD) pathogenesis. Healthy donor stool transplant (fecal microbiota transplant [FMT]) reduced alcohol desire and improved clinical outcomes in small animal and human studies. Baseline and post-therapy-related GM changes in a real-world cohort with severe alcohol-related liver disease and AUD, patterns of drinking, and relapse have not been studied. We prospectively analyzed retrospective clinical data and stored samples to examine GM alterations in a cohort of severe alcohol-associated hepatitis (SAH) patients who underwent FMT or corticosteroid treatment followed for at least 12 months. The GM changes at baseline in the context of a pattern of drinking (binge vs. every day) and baseline and post-treatment alcohol relapse status (relapser vs. non-relapser). We identified 28 patients on FMT and 25 on corticosteroids who survived 1 year post-treatment. After necessary exclusions, the final cohort for various grouped GM analysis included 16 patients in the FMT arm and 14 on corticosteroids. Pedobacter and Streptophyta species at the commencement of treatment predicted alcohol relapse in steroid-ineligible patients receiving FMT and steroid-treated patients, respectively. At 6-12 months post-FMT, non-relapsers had elevated short-chain fatty acid-producing bacterial taxa linked with lower alcohol cravings. Alcohol relapse was significantly more in those on steroid therapy and was associated with the upregulation of the nucleotide metabolism pathway related to ethanol metabolism. We demonstrate pertinent baseline and post-treatment intestinal bacterial alterations that impact patterns of AUD patterns and relapse in SAH patients in the context of the therapy offered.

A Feasibility Study of AlzLife 40 Hz Sensory Therapy in Patients with MCI and Early AD.

Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) are debilitating diseases that affect millions of individuals and have notoriously limited treatment options. One emerging therapy, non-invasive 40 Hz sensory therapy delivered through light and sound has previously shown promise in improving cognition in Alzheimer Disease (AD) rodent models. Small studies in humans have proven safe and tolerable, however exploration of feasibility and utility is limited. The purpose of this study is to examine the feasibility of this treatment in a human population through a smart tablet application that emits light and sound waves at 40 Hz to the user over the span of 1 h a day. Confirmation of entrainment of 40 Hz stimulation in the cerebral cortex was performed via EEG. 27 preliminary subjects with subjective cognitive complaints, Mild Cognitive Impairment, or AD were enrolled in the study; 11 participants completed 6 months of therapy. Of those that discontinued treatment, other health issues and difficulties with compliance were the most common causes. Participants were followed with Montreal Cognitive Assessment (MOCA) and Boston Cognitive Assessment (BOCA). For participants with subjective cognitive complaints, 2 of the 4 had improved MOCA score and 1 of 4 had improved BOCA score. For the participant with MCI, his MOCA score improved. For AD participants, 2 out of 6 had improved MOCA score and 3 of the 6 stayed stable, while 3 of 6 BOCA score improved. 4 of 11 participants specifically increased their MOCA scores in the Memory Index section. Of the 8 participants/caregivers able to speak to perceived usefulness of the study, 6 spoke to at least some level of benefit. Of these 6, 2 enrolled with subjective cognitive complaint, 1 had MCI, and 3 had AD. The therapy did not have reported side effects. However, those who did not finish the study experienced issues obtaining and operating a smart tablet independently as well as complying with the therapy. Overall, further exploration of this treatment modalities efficacy is warranted.

Alpha Hope, via Molecular Hydrogen and Pyrroloquinoline Quinone, Dose-Dependently Increases Nrf2 and PGC-1α Levels in C2C12 Myoblasts

Alpha Hope is a dietary supplement containing pyrroloquinoline quinone and elemental magnesium, which produces molecular hydrogen (H2 gas) when dissolved in water. We determined the impact of Alpha Hope on Nrf-2, peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), and citrate synthase (CS) activity in C2C12 myoblasts. Alpha Hope was titrated to three concentrations of pyrroloquinoline quinone (PQQ) (10 nM, 100 nM, 1000 nM) and treated on C2C12 for 48 h. Nrf-2 and PGC-1α levels were measured using Western blot analysis. CS activity was measured according to previously described methods. Treatment significantly increased Nrf-2 and PGC-1α protein levels in C2C12 myoblasts, with no change for CS. For Nrf-2, values for both the 100 nM (p = 0.046) and 1000 nM (p = 0.011) concentrations were higher than control. For PGC-1α, values for both the 100 nM (p = 0.039) and 1000 nM (p = 0.017) concentrations were higher than control. In a small human pilot study, subjects consumed the Alpha Hope product daily for four weeks, with no adverse effects, with some subjects noted as “responders” to treatment. Alpha Hope can significantly increase both Nrf-2 and PGC-1α in a concentration-dependent manner. Healthy men and women who ingest the product daily can do so without adverse effects.

O-066 Transdermal testosterone prior to ovarian stimulation for in vitro fertilization in women with poor ovarian response. A multicenter multinational double-blind placebo-controlled randomized trial (The T-TRANSPORT)

Abstract Study question Does administration of 2 months of transdermal testosterone prior to ovarian stimulation for IVF/ICSI increase clinical pregnancy rates in Bologna criteria poor ovarian responders? Summary answer Pre-treatment with 5.5mg testosterone for 2 months prior to ovarian stimulation for IVF/ICSI does not increase clinical pregnancy rates as compared with placebo. What is known already The role of androgens in the treatment of infertile women has been extensively investigated over the last 20 years. Early animal studies and small human studies supported a potentially beneficial role of androgen pretreatment for the management of poor ovarian responders. Still, available evidence regarding androgen administration remains inconclusive, and clinical guidelines do not support their use in infertile women, mainly due to the lack of robust evidence regarding efficacy, the small sample sizes, the lack of data regarding safety, and the lack of uniform dose and duration of testosterone pretreatment for poor ovarian responders. Study design, size, duration T-TRANSPORT is the first multicenter multinational superiority phase III, double-blind placebo-controlled randomized trial aiming to detect differences in clinical pregnancy rates between testosterone transdermal gel or placebo for the treatment of poor responders. A sample size of 400 women was calculated, with an interim analysis prespecified to be performed after 70% of recruitment, to determine continuation, sample size re-calculation, or early termination for futility, based on the conditional power reached (≥80%, 40-80% and &amp;lt;20%, respectively). Participants/materials, setting, methods T-TRANSPORT included women 18-43 years old from 10 centers and 4 European countries (Spain, Belgium, Denmark and Switzerland) randomized between 2015-2022. Women with poor ovarian response according to the Bologna criteria were randomly assigned 1:1 (stratified by center and age group (&amp;lt;36, 36-39 and ≥40 years old)) to receive either 5.5mg of transdermal testosterone or placebo for ∼60 days prior to initiation of ovarian stimulation for IVF/ICSI. Main results and the role of chance Overall, 316 poor responders were included and 290 patients were randomized. Based on the prespecified interim analysis, recruitment stopped when 70% of the patients have completed their treatment and blinded data were analyzed. Patients were categorized as group A and Group B until the decision of the DSMB board to break the randomization code is taken. Ovarian stimulation outcomes did not differ between groups, with a (mean ± SD) number of oocytes retrieved 3.42±2.25 vs. 3.69±2.72, number of MII oocytes 2.75±2.06 vs. 2.83±1.91 and number of embryos 1.46±1.22 vs. 1.90±1.92, for the comparison of Group A vs. Group B, respectively. Clinical pregnancy rates were comparable between groups, Group A: 17.42% vs. Group B 16.30%, RR (95%CI):1.07(0.64-1.79). Analysis of the results per-age strata also failed to demonstrate significant differences between groups in women &amp;lt;36 (Group A:24% vs. Group B: 17.9%), 36-39 (A: 21.4% vs. B:20%) and ≥40 years old (A:10% vs. B:12.3%) Finally, no severe adverse events were observed in any of the groups that led to treatment discontinuation. Comparison of androgenic adverse events showed differences for hirsutism A:7.10% vs. B:14.07% and acne A:16.13% vs. B:21.48%, whereas very few cases of alopecia A:1.29% vs. B:2.22% and voice deepening (A:1.29% vs. B:0%) were reported. Limitations, reasons for caution All patients, per protocol, underwent D3 embryo transfer. In addition, the study duration exceeded 7 years, owing to a temporary halt during the COVID-19 pandemic. Finally, the results presented here are blinded data which will be unblinded by the time of presentation based on the interim analysis performed. Wider implications of the findings Testosterone pre-treatment prior to IVF/ICSI does not increase clinical pregnancy rates in poor ovarian responders. Planned posthoc analyses within the T-TRANSPORT trial aim to investigate whether testosterone may affect ovarian reserve markers, follicular fluid biomarkers, cumulus cells gene expression, and libido in women with poor ovarian response. Study funding Yes. Funding source Funding by commercial/corporate company(ies). The study received Unrestricted grants by Ferring Pharmaceuticals, BESINS international and Roche Diagnostics. Testosterone and placebo gel were provided by BESINS INTERNATIONAL. Trial registration number NCT02418572

Fetal Alcohol Spectrum Disorder and Iron Homeostasis

Prenatal alcohol exposure results in a spectrum of behavioral, cognitive, and morphological abnormalities collectively referred to as fetal alcohol spectrum disorder (FASD). FASD presents with significant phenotypic variability and may be modified by gestational variables such as maternal nutritional status. Iron serves a critical function in the development of and processes within central nervous system (CNS) structures. Gestational iron deficiency alters CNS development and may contribute to neurodevelopmental impairment in FASD. This review explores the relationship between iron deficiency and fetal alcohol spectrum disorder as described in small animal and human studies. Consideration is given to the pathophysiologic mechanisms linking iron homeostasis and prenatal alcohol exposure. Existing data suggest that iron deficiency contributes to the severity of FASD and provide a mechanistic explanation linking these two conditions.

Patients with pseudoxanthoma elasticum (PXE) do not have dyslipidemia

Abstract Background Pseudoxanthoma elasticum (PXE) is a rare genetic disease caused by low inorganic pyrophosphate and is characterized by medial arterial calcification, leading to peripheral arterial disease and ischemic cerebral disease. Animal studies and small human studies have reported an association between PXE and dyslipidemia and therefore suggest that atherosclerosis is a second pathway contributing to cardiovascular disease in PXE patients. The association between PXE and dyslipidemia was however not consistent across these studies and there are several biological hypotheses proposed where the affected gene in PXE (ABCC6) could affect the cholesterol pathway: ABCC might influence HMA-CoA reductase – and increase total cholesterol and LDL-c – on one hand, but there is also evidence that points toward influence of ABCC6 on the reversed cholesterol pathway, influencing HDL-c. This study is important to analyze if PXE subjects, from the larges PXE cohort in the world, indeed do have a different a different lipid profile compared to well matched controls. Purpose To evaluate whether PXE patients have a different lipid profile compared to non-PXE patients. Methods A cross-sectional patient-control study was done at the Dutch Expertise Center for PXE in the University Medical Center Utrecht. Patients were all diagnosed conform the Plomp cirteria. The control population consisted of acquaintances of PXE patients, excluding first and second-degree relatives. Total cholesterol, LDL-c, HDL-c and triglycerides were assessed in both patients and controls and if lipid-lowering treatment (LLT) was used pre-treatment levels were calculated using known effects of LLT on lipids. To eliminate the imbalances between patients and controls, we used Coursened Exact Matching (CEM), to investigate the effect of PXE on lipids. Results The study population included 323 PXE patients and 57 controls. Their characteristics are displayed in Figure 1. After CEM 186 patients (weighted means: age 57.8±9.9 years, 58% females, BMI 25.5±2.9 kg/m2) and 52 controls (age 57.3±43.1 years, 58% females, BMI 25.5±17 kg/m2) were left for analyses. The univariate, weighted regression analysis of the effect of having PXE on lipid profile shows that the differences in lipids between patients and controls were 0.22 mmol/L for total cholesterol (p=0.299), 0.15 mmol/L for LDL-c (p=0.524), 0.07 mmol/L for HDL-c (p=0.314) and 0.10 mmol/L for triglycerides (p=0.433). A sensitivity analysis where only the crude values of untreated subjects were included in the analysis showed that LDL-c was sginficantly lower in PXE-patients. Probably due to the fact that only the very healthy PXE patients were included. Conclusion There are no differences in levels of total cholesterol, LDL-c, HDL-c, and triglycerides between PXE patients and matched controls. Funding Acknowledgement Type of funding sources: None.

The role of the ADVanced Organ Support (ADVOS) system in critically ill patients with multiple organ failure.

BackgroundMulti‐organ failure characterized by acute kidney injury, liver dysfunction, and respiratory failure is a complex condition associated with high mortality, for which multiple individual support devices may be simultaneously required. This review aims to appraise the current evidence for the ADVanced Organ Support (ADVOS) system, a novel device integrating liver, lung, and kidney support with blood detoxification.MethodsWe performed a literature review of the PubMed database to identify human and animal studies evaluating the ADVOS system.ResultsIn porcine models of acute liver injury and small clinical studies in humans, ADVOS significantly enhanced the elimination of water‐soluble and protein‐bound toxins and metabolites, including creatinine, ammonia, blood urea nitrogen, and lactate. Cardiovascular parameters (mean arterial pressure, cerebral perfusion pressure, and cardiac index) and renal function were improved. ADVOS clears carbon dioxide (CO2) effectively with rapid correction of pH abnormalities, achieving normalization of CO2, and bicarbonate levels. In patients with COVID‐19 infection, ADVOS enables rapid correction of acid–base disturbance and respiratory acidosis. ADVOS therapy reduces mortality in multi‐organ failure and has been shown to be safe with minimal adverse events.ConclusionsFrom the small observational studies analyzed, ADVOS demonstrates excellent detoxification of water‐soluble and protein‐bound substances. In particular, ADVOS permits the correction of metabolic and respiratory acidosis through the fluid‐based direct removal of acid and CO2. ADVOS is associated with significant improvements in hemodynamic and biochemical parameters, a trend toward improved survival in multi‐organ failure, and is well‐tolerated. Larger randomized trials are now necessary to further validate these encouraging results.

Phasic flow patterns of right versus left coronary arteries in patients undergoing clinical physiological assessment.

Coronary blood flow in humans is known to be predominantly diastolic. Small studies in animals and humans suggest that this is less pronounced or even reversed in the right coronary artery (RCA). This study aimed to characterise the phasic patterns of coronary flow in the left versus right coronary arteries of patients undergoing invasive physiological assessment. We analysed data from the Iberian-Dutch-English Collaborators (IDEAL) study. A total of 482 simultaneous pressure and flow measurements from 301 patients were included in our analysis. On average, coronary flow was higher in diastole both at rest and during hyperaemia in both the RCA and LCA (mean diastolic-to-systolic velocity ratio [DSVR] was, respectively, 1.85±0.70, 1.76±0.58, 1.53±0.34 and 1.58±0.43 for LCArest, LCAhyp, RCArest and RCAhyp, p<0.001 for between-vessel comparisons). Although the type of RCA dominance affected the DSVR magnitude (RCAdom=1.55±0.35, RCAco-dom=1.40±0.27, RCAnon-dom=1.35; standard deviation not reported as n=3), systolic flow was very rarely predominant (DSVR was greater than or equal to 1.00 in 472/482 cases [97.9%] overall), with equal prevalence in the LCA. Stenosis severity or microvascular dysfunction had a negligible impact on DSVR in both the RCA and LCA (DSVR x hyperaemic stenosis resistance R2 =0.018, p=0.03 and DSVR x coronary flow reserve R2 <0.001, p=0.98). In patients with coronary artery disease undergoing physiological assessment, diastolic flow predominance is seen in both left and right coronary arteries. Clinical interpretation of coronary physiological data should therefore not differ between the left and the right coronary systems.

2022 Interim Guidance to Health Care Providers for Basic and Advanced Cardiac Life Support in Adults, Children, and Neonates With Suspected or Confirmed COVID-19: From the Emergency Cardiovascular Care Committee and Get With The Guidelines-Resuscitation Adult and Pediatric Task Forces of the American Heart Association in Collaboration With the American Academy of Pediatrics, American Association for Respiratory Care, the Society

2022 Interim Guidance to Health Care Providers for Basic and Advanced Cardiac Life Support in Adults, Children, and Neonates With Suspected or Confirmed COVID-19: From the Emergency Cardiovascular Care Committee and Get With The Guidelines-Resuscitation Adult and Pediatric Task Forces of the American Heart Association in Collaboration With the American Academy of Pediatrics, American Association for Respiratory Care, the Society

The Role of Sodium Glucose Cotransporter-2 Inhibitors in Atherosclerotic Cardiovascular Disease: A Narrative Review of Potential Mechanisms.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of medication with broad cardiovascular benefits in those with type 2 diabetes, chronic kidney disease, and heart failure. These include reductions in major adverse cardiac events and cardiovascular death. The mechanisms that underlie their benefits in atherosclerotic cardiovascular disease (ASCVD) are not well understood, but they extend beyond glucose lowering. This narrative review summarises the ASCVD benefits of SGLT2 inhibitors seen in large human outcome trials, as well as the mechanisms of action explored in rodent and small human studies. Potential pathways include favourable alterations in lipid metabolism, inflammation, and endothelial function. These all require further investigation in large human clinical trials with mechanistic endpoints, to further elucidate the disease modifying benefits of this drug class and those who will benefit most from it.

Potential therapeutic effects of boswellic acids/Boswellia serrata extract in the prevention and therapy of type 2 diabetes and Alzheimer's disease.

The link between diabetes and cognitive dysfunction has been reported in many recent articles. There is currently no disease-modifying treatment available for cognitive impairment. Boswellia serrata (B. serrata) is used traditionally to treat chronic inflammatory diseases such as type 2 diabetes (T2D), insulin resistance (IR), and Alzheimer's disease (AD). This review aims to highlight current research on the potential use of boswellic acids (BAs)/B. serrata extract in T2D and AD. We reviewed the published information through June 2021. Studies have been collected through a search on online electronic databases (Academic libraries as PubMed, Scopus, Web of Science, and Egyptian Knowledge Bank). Accumulating evidence in preclinical and small human clinical studies has indicated that BAs/B. serrata extract has potential therapeutic effect in T2D and AD. According to most of the authors, the potential therapeutic effects of BAs/B. serrata extract in T2D and AD can be attributed to immunomodulatory, anti-inflammatory, antioxidant activity, and elimination of the senescent cells. BAs/B. serrata extract may act by inhibiting the IκB kinase/nuclear transcription factor-κB (IKK/NF-κB) signaling pathway and increasing the formation of selective anti-inflammatory LOX-isoform modulators. In conclusion, BAs/B. serrata extract may have positive therapeutic effects in prevention and therapy of T2D and AD. However, more randomized controlled trials with effective, large populations are needed to show a definitive conclusion about therapeutic efficacy of BAs/B. serrata extract in T2D and AD.

Advanced glycation endproducts and bone quality: practical implications for people with type 2 diabetes.

Individuals with type 2 diabetes (T2D) are at increased risk of fracture, often despite normal bone density. This observation suggests deficits in bone quality in the setting of abnormal glucose homeostasis. The goal of this article is to review recent developments in our understanding of how advanced glycation end products (AGEs) are incorporated into the skeleton with resultant deleterious effects on bone health and structural integrity in patients with T2D. The adverse effects of skeletal AGE accumulation on bone remodeling and the ability of the bone to deform and absorb energy prior to fracture have been demonstrated both at the bench as well as in small human studies; however, questions remain as to how these findings might be better explored in large, population-based investigations. Hyperglycemia drives systemic, circulating AGE formation with subsequent accumulation in the bone tissue. In those with T2D, studies suggest that AGEs diminish fracture resistance, though larger clinical studies are needed to better define the direct role of longstanding AGE accumulation on bone strength in humans as well as to motivate potential interventions to reverse or disrupt skeletal AGE deposition with the goal of fracture prevention.

Sleep disruptions and bone health: what do we know so far?

This review briefly summarizes the growing body of literature addressing the skeletal consequences of sleep and circadian disruption. The most recent data in the field suggest that the diurnal variation in bone turnover markers are because of endogenous circadian rhythmicity linked to clock genes in all bone cells; in a small human intervention study, cumulative sleep restriction with concurrent circadian disruption negatively alter bone turnover markers in a way that could explain the lower BMD and increased fracture risk identified in some prior night shift work studies; abnormal sleep duration and obstructive sleep apnea are associated with low BMD and increased fracture risk in some but not all studies. Normal physiology and some animal and human intervention studies suggest that sleep and circadian disruptions, such as night shift work, abnormal sleep durations and obstructive sleep apnea are detrimental to skeletal health. However, additional research in this area is needed to determine which sleep/circadian disturbances are most detrimental to skeletal health, the reversibility of such impairments, and underlying mechanisms.