Olfactory Dysfunction in Children: A Scoping Review.

OBJECTIVE: Olfactory disorders are well-studied in the adult population, however, there is a paucity of literature characterizing olfactory dysfunction in pediatric patients. The purpose of this scoping review was to identify known causes of olfactory loss in pediatric populations, clarify the extent of use and validity of smell tests, and summarize current therapies for olfactory loss. DATA SOURCES: PubMed, Ovid MEDLINE, and Web of Science. REVIEW METHODS: Databases were systematically searched in September 2020. Two independent reviewers conducted the title and abstract screen, followed by review of full-texts for inclusion based on preset inclusion and exclusion criteria. Extracted data included study type, age/age-range of participants, gender, radiological evidence of olfactory dysfunction, types and results of smell tests used, etiology of olfactory loss, and therapies employed for olfactory loss. RESULTS: A total of 103 articles (n = 1654) were eligible for final data extraction. The University of Pennsylvania Smell Identification Test was used most frequently for smell testing (21% of studies). In total, 45 causes of olfactory dysfunction have been elucidated by this study: 22 congenital and 23 acquired. Few therapies were described, and all were specific to the etiology of olfactory loss. CONCLUSION: Olfactory dysfunction has a wide range of etiologies in the pediatric population, and clinicians should have a diagnostic algorithm for how to identify a cause should they encounter it in practice. If no etiology can be identified, education around safety should be provided to both the patient and their caregivers.

Disseminated Lyme disease and dilated cardiomyopathy: A systematic review.

Lyme carditis is a well-established manifestation of early disseminated Lyme infection, yet the relationship between late disseminated Lyme disease and the development of dilated cardiomyopathy (DCM) remains unclear. The present systematic review aims to summarize existing literature on the association between late disseminated Lyme disease and DCM. A systematic review was conducted in PubMed, Embase, CENTRAL, and MEDLINE databases, after which a total of 11 observational studies (n = 771) were ultimately included for final data extraction. Although most studies (7/11) identified evidence associating Borrelia-infection with DCM, further research is required to isolate late disseminated Borrelia infection as a causative agent of DCM.

Inhibiting pyruvate kinase muscle isoform 2 regresses group 2 pulmonary hypertension induced by supra-coronary aortic banding.

INTRODUCTION: Group 2 pulmonary hypertension (PH) has no approved PH-targeted therapy. Metabolic remodelling, specifically a biventricular increase in pyruvate kinase muscle (PKM) isozyme 2 to 1 ratio, occurs in rats with group 2 PH induced by supra-coronary aortic banding (SAB). We hypothesize that increased PKM2/PKM1 is maladaptive and inhibiting PKM2 would improve right ventricular (RV) function. METHODS: Male, Sprague-Dawley SAB rats were confirmed to have PH by echocardiography and then randomized to treatment with a PKM2 inhibitor (intraperitoneal shikonin, 2 mg/kg/day) versus 5% DMSO (n = 5/group) or small interfering RNA-targeting PKM2 (siPKM2) versus siRNA controls (n = 7/group) by airway nebulization. RESULTS: Shikonin-treated SAB rats had milder PH (PAAT 32.1 ± 1.3 vs 22.1 ± 1.2 ms, P = .0009) and lower RV systolic pressure (RVSP) (31.5 ± 0.9 vs 55.7 ± 1.9 mm Hg, P < .0001) versus DMSO-SAB rats. siPKM2 nebulization reduced PKM2 expression in the RV, increased PAAT (31.7 ± 0.7 vs 28.0 ± 1.3 ms, P = .025), lowered RVSP (30.6 ± 2.6 vs 42.0 ± 4.0 mm Hg, P = .032) and reduced diastolic RVFW thickness (0.69 ± 0.04 vs 0.85 ± 0.06 mm, P = .046). Both shikonin and siPKM2 regressed PH-induced medial hypertrophy of small pulmonary arteries. CONCLUSION: Increases in PKM2/PKM1 in the RV contribute to RV dysfunction in group 2 PH. Chemical or molecular inhibition of PKM2 restores the normal PKM2/PKM1 ratio, reduces PH, RVSP and RVH and regresses adverse PA remodelling. PKM2 merits consideration as a therapeutic cardiac target for group 2 PH.

Higher Mortality in Women After Coronary Artery Bypass: Meta-analysis and Bias Analysis of Confounding.

BACKGROUND: Some studies suggest that the observed higher mortality in women compared with men after coronary artery bypass grafting (CABG) is due to confounding. Our meta-analysis aimed to (1) summarize the effect of sex on mortality after CABG and (2) identify whether unmeasured confounding likely explains the apparent higher mortality in women. METHODS: We searched MEDLINE, Embase, and CENTRAL databases for studies examining sex and 30-day mortality after CABG. We used random-effects meta-analysis to estimate the summary odds ratio (OR) of mortality in women versus men using (1) unadjusted study results and (2) adjusted study results. Available confounders data from included studies were identified. Using the OR of measured confounders and the risk of death to inform unmeasured confounding effects, we performed bias analysis simulation to correct potential unmeasured confounding in the summary OR. RESULTS: From 7,138 retrieved studies, 112 were included (N = 5,008,262 patients); 25 studies reported adjusted OR (N = 770,450 patients). Overall 30-day mortality was 4.9% in women versus 3.3% in men. The unadjusted summary OR (1.81; 95% confidence interval, 1.72-1.91) and adjusted summary OR (1.40, 95% confidence interval, 1.35-1.45) demonstrated women had an increased risk for 30-day mortality compared with men. Simulations correcting for unmeasured confounding mostly ranged from 1.05 to 1.80, which supports a higher risk for death in women after CABG. CONCLUSIONS: The findings of this review suggest that confounding is unlikely to account for the increased risk for mortality in women after CABG and that biological factors have a causal effect.

Genetic syndromes with diabetes: A systematic review.

Previous reviews and clinical guidelines have identified 10-20 genetic syndromes associated with diabetes, but no systematic review has been conducted to date. We provide the first comprehensive catalog for syndromes with diabetes mellitus. We conducted a systematic review of MEDLINE, Embase, CENTRAL, PubMed, OMIM, and Orphanet databases for case reports, case series, and observational studies published between 1946 and January 15, 2020, that described diabetes mellitus in adults and children with monogenic or chromosomal syndromes. Our literature search identified 7,122 studies, of which 160 fulfilled inclusion criteria. Our analysis of these studies found 69 distinct diabetes syndromes. Thirty (43.5%) syndromes included diabetes mellitus as a cardinal clinical feature, and 56 (81.2%) were fully genetically elucidated. Sixty-three syndromes (91.3%) were described more than once in independent case reports, of which 59 (93.7%) demonstrated clinical heterogeneity. Syndromes associated with diabetes mellitus are more numerous and diverse than previously anticipated. While knowledge of the syndromes is limited by their low prevalence, future reviews will be needed as more cases are identified. The genetic etiologies of these syndromes are well elucidated and provide potential avenues for future gene identification efforts, aid in diagnosis and management, gene therapy research, and developing personalized medicine treatments.

Oxygen sensing, mitochondrial biology and experimental therapeutics for pulmonary hypertension and cancer.

The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.

Cerebral oximetry and preventing neurological complication post-cardiac surgery: a systematic review.

OBJECTIVES: This systematic review aims to provide an up-to-date summary of the current literature examining the relationship between intraoperative regional cerebral oxygen saturation and neurological complications after cardiac surgery. METHODS: Observational and interventional studies investigating the link between regional cerebral oxygen saturation and postoperative delirium, cognitive dysfunction and stroke were included. After database searching and study screening, study characteristics and major findings were extracted. RESULTS: Twenty-seven studies were identified. Of the observational studies (n = 17), 8 reported that regional cerebral oxygen desaturations were significantly associated with neurological complications after cardiac surgery. Of the interventional studies (n = 10), 3 provided evidence for monitoring cerebral oximetry during cardiac surgery as a means of reducing incidence of postoperative cognitive dysfunction or stroke. There was significant heterogeneity in the tools and rigor used to diagnose neurological complications. CONCLUSIONS: Studies to date show an inconsistent relationship between regional cerebral oxygen saturation and neurological outcomes after cardiac surgery, and lack of clear benefit of targeting cerebral oximetry to minimize neurological complications. Standardized assessments, definitions of impairment and desaturation thresholds will help determine the benefits of cerebral oximetry monitoring during cardiac surgery.

Mitochondria in the Pulmonary Vasculature in Health and Disease: Oxygen-Sensing, Metabolism, and Dynamics.

In lung vascular cells, mitochondria serve a canonical metabolic role, governing energy homeostasis. In addition, mitochondria exist in dynamic networks, which serve noncanonical functions, including regulation of redox signaling, cell cycle, apoptosis, and mitochondrial quality control. Mitochondria in pulmonary artery smooth muscle cells (PASMC) are oxygen sensors and initiate hypoxic pulmonary vasoconstriction. Acquired dysfunction of mitochondrial metabolism and dynamics contribute to a cancer-like phenotype in pulmonary arterial hypertension (PAH). Acquired mitochondrial abnormalities, such as increased pyruvate dehydrogenase kinase (PDK) and pyruvate kinase muscle isoform 2 (PKM2) expression, which increase uncoupled glycolysis (the Warburg phenomenon), are implicated in PAH. Warburg metabolism sustains energy homeostasis by the inhibition of oxidative metabolism that reduces mitochondrial apoptosis, allowing unchecked cell accumulation. Warburg metabolism is initiated by the induction of a pseudohypoxic state, in which DNA methyltransferase (DNMT)-mediated changes in redox signaling cause normoxic activation of HIF-1α and increase PDK expression. Furthermore, mitochondrial division is coordinated with nuclear division through a process called mitotic fission. Increased mitotic fission in PAH, driven by increased fission and reduced fusion favors rapid cell cycle progression and apoptosis resistance. Downregulation of the mitochondrial calcium uniporter complex (MCUC) occurs in PAH and is one potential unifying mechanism linking Warburg metabolism and mitochondrial fission. Mitochondrial metabolic and dynamic disorders combine to promote the hyperproliferative, apoptosis-resistant, phenotype in PAH PASMC, endothelial cells, and fibroblasts. Understanding the molecular mechanism regulating mitochondrial metabolism and dynamics has permitted identification of new biomarkers, nuclear and CT imaging modalities, and new therapeutic targets for PAH. © 2020 American Physiological Society. Compr Physiol 10:713-765, 2020.

Personal Health Coaching as a Type 2 Diabetes Mellitus Self-Management Strategy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Personal health coaching (PHC) programs have become increasingly utilized as a type 2 diabetes mellitus (T2DM) self-management intervention strategy. This article evaluates the impact of PHC programs on glycemic management and related psychological outcomes. DATA SOURCES: Electronic databases (CINAHL, MEDLINE, PubMed, PsycINFO, and Web of Science). STUDY INCLUSION AND EXCLUSION CRITERIA: Randomized controlled trials (RCT) published between January 1990 and September 2017 and focused on the effectiveness of PHC interventions in adults with T2DM. DATA EXTRACTION: Using prespecified format guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework. DATA SYNTHESIS: Quantitative synthesis for primary (ie, hemoglobin A1c [HbA1c]) and qualitative synthesis for selected psychological outcomes. RESULTS: Meta-analyses of 22 selected publications showed PHC interventions favorably impact HbA1c levels in studies with follow-ups at ≤3 months (-0.32% [95% confidence interval, CI = -0.55 to -0.09%]), 4 to 6 months (-0.50% [95% CI = -0.65 to -0.35%], 7 to 9 months (-0.66% [95% CI = -1.04 to -0.28%]), and 12 to 18 months (-0.24% [95% CI = -0.38 to -0.10%]). Subsequent subgroup analyses led to no conclusive patterns, except for greater magnitude of effect size in studies with conventional (2-arm) RCT design. CONCLUSIONS: The PHC appears effective in improving glycemic control. Further research is required to assess the effectiveness of specific program components, training, and supervision approaches and to determine the cost-effectiveness of PHC interventions.

Probiotic supplementation can positively affect anxiety and depressive symptoms: a systematic review of randomized controlled trials.

Gastrointestinal microbiota, consisting of microbial communities in the gastrointestinal tract, play an important role in digestive, metabolic, and immune functioning. Preclinical studies on rodents have linked behavioral and neurochemical changes in the central nervous system with deficits or alterations in these bacterial communities. Moreover, probiotic supplementation in rodents has been shown to markedly change behavior, with correlated changes in central neurochemistry. While such studies have documented behavioral and mood-related supplementation effects, the significance of these effects in humans, especially in relation to anxiety and depression symptoms, are relatively unknown. Thus, the purpose of this paper was to systematically evaluate current literature on the impact of probiotic supplementation on anxiety and depression symptoms in humans. To this end, multiple databases, including Medline, PsycINFO, PubMed, Scopus, and Web of Science were searched for randomized controlled trials published between January 1990 and January 2016. Search results led to a total of 10 randomized controlled trials (4 in clinically diagnosed and 6 in non-clinical samples) that provided limited support for the use of some probiotics in reducing human anxiety and depression. Despite methodological limitations of the included trials and the complex nature of gut-brain interactions, results suggest the detection of apparent psychological benefits from probiotic supplementation. Nevertheless a better understanding of developmental, modulatory, and metagenomic influences on the GI microbiota, specifically as they relate to mood and mental health, represent strong priorities for future research in this area.