Phosphate toxicity and SERCA2a dysfunction in sudden cardiac arrest.

Almost half of the people who die from sudden cardiac arrest have no detectable heart disease. Among children and young adults, the cause of approximately one-third of deaths from sudden cardiac arrest remains unexplained after thorough examination. Sudden cardiac arrest and related sudden cardiac death are attributed to dysfunctional cardiac ion-channels. The present perspective paper proposes a pathophysiological mechanism by which phosphate toxicity from cellular accumulation of dysregulated inorganic phosphate interferes with normal calcium handling in the heart, leading to sudden cardiac arrest. During cardiac muscle relaxation following contraction, SERCA2a pumps actively transport calcium ions into the sarcoplasmic reticulum, powered by ATP hydrolysis that produces ADP and inorganic phosphate end products. Reviewed evidence supports the proposal that end-product inhibition of SERCA2a occurs as increasing levels of inorganic phosphate drive up phosphate toxicity and bring cardiac function to a sudden and unexpected halt. The paper concludes that end-product inhibition from ATP hydrolysis is the mediating factor in the association of sudden cardiac arrest with phosphate toxicity. However, current technology lacks the ability to directly measure this pathophysiological mechanism in active myocardium, and further research is needed to confirm phosphate toxicity as a risk factor in individuals with sudden cardiac arrest. Moreover, phosphate toxicity may be reduced through modification of dietary phosphate intake, with potential for employing low-phosphate dietary interventions to reduce the risk of sudden cardiac arrest.

Breast cancer, alcohol, and phosphate toxicity.

Alcohol consumption is associated with an increased risk of breast cancer, even at low alcohol intake levels, but public awareness of the breast cancer risk associated with alcohol intake is low. Furthermore, the causative mechanisms underlying alcohol's association with breast cancer are unknown. The present theoretical paper uses a modified grounded theory method to review the research literature and propose that alcohol's association with breast cancer is mediated by phosphate toxicity, the accumulation of excess inorganic phosphate in body tissue. Serum levels of inorganic phosphate are regulated through a network of hormones released from the bone, kidneys, parathyroid glands, and intestines. Alcohol burdens renal function, which may disturb the regulation of inorganic phosphate, impair phosphate excretion, and increase phosphate toxicity. In addition to causing cellular dehydration, alcohol is an etiologic factor in nontraumatic rhabdomyolysis, which ruptures cell membranes and releases inorganic phosphate into the serum, leading to hyperphosphatemia. Phosphate toxicity is also associated with tumorigenesis, as high levels of inorganic phosphate within the tumor microenvironment activate cell signaling pathways and promote cancer cell growth. Furthermore, phosphate toxicity potentially links cancer and kidney disease in onco-nephrology. Insights into the mediating role of phosphate toxicity may lead to future research and interventions that raise public health awareness of breast cancer risk and alcohol consumption.

Automated Regularized Deconvolution for Eliminating Extra-Column Effects in Fast High-Efficiency Separations.

With the introduction of ultrahigh efficiency columns and fast separations, the need to eliminate peak deformation contributed by the instrument must be effectively solved. Herein, we develop a robust framework to automate deconvolution and minimize its artifacts, such as negative dips, wild noise oscillations, and ringing, by combining regularized deconvolution and Perona-Malik (PM) anisotropic diffusion methods. A asymmetric generalized normal (AGN) function is proposed to model the instrumental response for the first time. With no-column data at various flow rates, the interior point optimization algorithm extracts the parameters describing instrumental distortion. The column-only chromatogram was reconstructed using the Tikhonov regularization technique with minimal instrumental distortion. For illustration, four different chromatography systems are used in fast chiral and achiral separations with 2.1 and 4.6 mm i.d. columns. Ordinary HPLC data can approach highly optimized UHPLC data. Similarly, in fast HPLC-circular dichroism (CD) detection, 8000 plates were gained for a fast chiral separation. Moment analysis of deconvolved peaks confirms correction of the center of mass, variance, skew, and kurtosis. This approach can be easily integrated and used with virtually any separation and detection system to provide enhanced analytical data.

Dysregulated phosphate metabolism in autism spectrum disorder: associations and insights for future research.

Studies of autism spectrum disorder (ASD) related to exposure to toxic levels of dietary phosphate are lacking. Phosphate toxicity from dysregulated phosphate metabolism can negatively impact almost every major organ system of the body, including the central nervous system. The present paper used a grounded theory-literature review method to synthesise associations of dysregulated phosphate metabolism with the aetiology of ASD. Cell signalling in autism has been linked to an altered balance between phosphoinositide kinases, which phosphorylate proteins, and the counteracting effect of phosphatases in neuronal membranes. Glial cell overgrowth in the developing ASD brain can lead to disturbances in neuro-circuitry, neuroinflammation and immune responses which are potentially related to excessive inorganic phosphate. The rise in ASD prevalence has been suggested to originate in changes to the gut microbiome from increasing consumption of additives in processed food, including phosphate additives. Ketogenic diets and dietary patterns that eliminate casein also reduce phosphate intake, which may account for many of the suggested benefits of these diets in children with ASD. Dysregulated phosphate metabolism is causatively linked to comorbid conditions associated with ASD such as cancer, tuberous sclerosis, mitochondrial dysfunction, diabetes, epilepsy, obesity, chronic kidney disease, tauopathy, cardiovascular disease and bone mineral disorders. Associations and proposals presented in this paper offer novel insights and directions for future research linking the aetiology of ASD with dysregulated phosphate metabolism and phosphate toxicity from excessive dietary phosphorus intake.

Low dietary sodium potentially mediates COVID-19 prevention associated with whole-food plant-based diets.

Compared with an omnivorous Western diet, plant-based diets containing mostly fruits, vegetables, grains, legumes, nuts and seeds, with restricted amounts of foods of animal origin, are associated with reduced risk and severity of COVID-19. Additionally, inflammatory immune responses and severe acute respiratory symptoms of COVID-19, including pulmonary oedema, shortness of breath, fever and nasopharyngeal infections, are associated with Na toxicity from excessive dietary Na. High dietary Na is also associated with increased risks of diseases and conditions that are co-morbid with COVID-19, including chronic kidney disease, hypertension, stroke, diabetes and obesity. This article presents evidence that low dietary Na potentially mediates the association of plant-based diets with COVID-19 prevention. Processed meats and poultry injected with sodium chloride contribute considerable amounts of dietary Na in the Western diet, and the avoidance or reduction of these and other processed foods in whole-food plant-based (WFPB) diets could help lower overall dietary Na intake. Moreover, high amounts of K in plant-based diets increase urinary Na excretion, and preagricultural diets high in plant-based foods were estimated to contain much lower ratios of dietary Na to K compared with modern diets. Further research should investigate low Na in WFPB diets for protection against COVID-19 and co-morbid conditions.

Parkinson's Disease Etiology: Insights and Associations with Phosphate Toxicity.

The present paper investigated the association of Parkinson's disease etiology with phosphate toxicity, a pathophysiological condition in which dysregulated phosphate metabolism causes excessive inorganic phosphate sequestration in body tissue that damages organ systems. Excessive phosphate is proposed to reduce Complex I function of the mitochondrial electron transport chain in Parkinson's disease and is linked to opening of the mitochondrial permeability transition pore, resulting in increased reactive oxygen species, inflammation, DNA damage, mitochondrial membrane depolarization, and ATP depletion causing cell death. Parkinson's disease is associated with α-synuclein and Lewy body dementia, a secondary tauopathy related to hyperphosphorylation of tau protein, and tauopathy is among several pathophysiological pathways shared between Parkinson's disease and diabetes. Excessive phosphate is also associated with ectopic calcification, bone mineral disorders, and low levels of serum vitamin D in patients with Parkinson's disease. Sarcopenia and cancer in Parkinson's disease patients are also associated with phosphate toxicity. Additionally, Parkinson's disease benefits are related to low dietary phosphate intake. More studies are needed to investigate the potential mediating role of phosphate toxicity in the etiology of Parkinson's disease.

Phosphate toxicity and tumorigenesis.

In this article, we briefly summarized evidence that cellular phosphate burden from phosphate toxicity is a pathophysiological determinant of cancer cell growth. Tumor cells express more phosphate cotransporters and store more inorganic phosphate than normal cells, and dysregulated phosphate homeostasis is associated with the genesis of various human tumors. High dietary phosphate consumption causes the growth of lung and skin tumors in experimental animal models. Additional studies show that excessive phosphate burden induces growth-promoting cell signaling, stimulates neovascularization, and is associated with chromosome instability and metastasis. Studies have also shown phosphate is a mitogenic factor that affects various tumor cell growth. Among epidemiological evidence linking phosphate and tumor formation, the Health Professionals Follow-Up Study found that high dietary phosphate levels were independently associated with lethal and high-grade prostate cancer. Further research is needed to determine how excessive dietary phosphate consumption influences initiation and promotion of tumorigenesis, and to elucidate prognostic benefits of reducing phosphate burden to decrease tumor cell growth and delay metastatic progression. The results of such studies could provide the basis for therapeutic modulation of phosphate metabolism for improved patient outcome.

Sodium Toxicity in the Nutritional Epidemiology and Nutritional Immunology of COVID-19.

Dietary factors in the etiology of COVID-19 are understudied. High dietary sodium intake leading to sodium toxicity is associated with comorbid conditions of COVID-19 such as hypertension, kidney disease, stroke, pneumonia, obesity, diabetes, hepatic disease, cardiac arrhythmias, thrombosis, migraine, tinnitus, Bell's palsy, multiple sclerosis, systemic sclerosis, and polycystic ovary syndrome. This article synthesizes evidence from epidemiology, pathophysiology, immunology, and virology literature linking sodium toxicological mechanisms to COVID-19 and SARS-CoV-2 infection. Sodium toxicity is a modifiable disease determinant that impairs the mucociliary clearance of virion aggregates in nasal sinuses of the mucosal immune system, which may lead to SARS-CoV-2 infection and viral sepsis. In addition, sodium toxicity causes pulmonary edema associated with severe acute respiratory syndrome, as well as inflammatory immune responses and other symptoms of COVID-19 such as fever and nasal sinus congestion. Consequently, sodium toxicity potentially mediates the association of COVID-19 pathophysiology with SARS-CoV-2 infection. Sodium dietary intake also increases in the winter, when sodium losses through sweating are reduced, correlating with influenza-like illness outbreaks. Increased SARS-CoV-2 infections in lower socioeconomic classes and among people in government institutions are linked to the consumption of foods highly processed with sodium. Interventions to reduce COVID-19 morbidity and mortality through reduced-sodium diets should be explored further.

Outcome Reporting Bias in COVID-19 mRNA Vaccine Clinical Trials.

Relative risk reduction and absolute risk reduction measures in the evaluation of clinical trial data are poorly understood by health professionals and the public. The absence of reported absolute risk reduction in COVID-19 vaccine clinical trials can lead to outcome reporting bias that affects the interpretation of vaccine efficacy. The present article uses clinical epidemiologic tools to critically appraise reports of efficacy in Pfzier/BioNTech and Moderna COVID-19 mRNA vaccine clinical trials. Based on data reported by the manufacturer for Pfzier/BioNTech vaccine BNT162b2, this critical appraisal shows: relative risk reduction, 95.1%; 95% CI, 90.0% to 97.6%; p = 0.016; absolute risk reduction, 0.7%; 95% CI, 0.59% to 0.83%; p < 0.000. For the Moderna vaccine mRNA-1273, the appraisal shows: relative risk reduction, 94.1%; 95% CI, 89.1% to 96.8%; p = 0.004; absolute risk reduction, 1.1%; 95% CI, 0.97% to 1.32%; p < 0.000. Unreported absolute risk reduction measures of 0.7% and 1.1% for the Pfzier/BioNTech and Moderna vaccines, respectively, are very much lower than the reported relative risk reduction measures. Reporting absolute risk reduction measures is essential to prevent outcome reporting bias in evaluation of COVID-19 vaccine efficacy.

Stress, inflammation, depression, and dementia associated with phosphate toxicity.

Depression and dementia are predicted to increase within aging global populations. Pathophysiological effects of phosphate toxicity, dysregulated amounts of accumulated phosphorus in body tissue, are under-investigated in association with stress, inflammation, depression, and dementia. A comparative analysis of concepts in cited sources from the research literature was used to synthesize novel themes exploring the disease-oriented neuroscience effects of phosphate toxicity. Phosphate toxicity is associated with activation of cellular stress response systems and inflammation. Cortisol released by the hypothalamic-pituitary-adrenal axis responds to stress and inflammation associated with phosphate toxicity and depression. In a reciprocal interaction, phosphate toxicity is capable of harming adrenal gland function, possibly leading to adrenal insufficiency and depression. Furthermore, Alzheimer's disease is associated with hyperphosphorylated tau which self-assembles into neurofibrillary tangles from excessive amounts of phosphate in the brain and central nervous system. Future research should investigate dietary phosphate modification to reduce potential pathophysiological effects of phosphate toxicity in stress, inflammation, depression, and cognitive decline which affects global populations.

Unattended Hoist Extraction of an Intubated Patient From Mountainous Terrain.

Airway management and maintenance of adequate ventilation during a patient's unattended helicopter rescue hoist extraction present unique challenges to the air medical provider. We present the case of a critically injured patient requiring emergent airway management and subsequent extrication via hoist from challenging, near-vertical terrain, which illustrates the logistical challenges of providing high-quality, neuroprotective mechanical ventilation in an austere air medical scenario.

Potential interaction of inflammatory hyperemia and hyperphosphatemia in tumorigenesis.

The present article proposes that the association of inflammation with cancer is potentially mediated by the interaction of inflammatory hyperemia and hyperphosphatemia. Hyperemia increases blood flow rate and blood volume, and hyperphosphatemia is caused by elevated serum levels of dysregulated inorganic phosphate. It is hypothesized that the interaction of inflammatory hyperemia and hyperphosphatemia circulates increased amounts of inorganic phosphate to the tumor microenvironment, where increased uptake of inorganic phosphate through sodium-phosphate cotransporters is sequestered in cells. Elevated levels of intracellular phosphorus increase biosynthesis of ribosomal RNA, leading to increased protein synthesis that supports tumor growth. The present article also proposes that the interaction of inflammatory hyperemia and hyperphosphatemia may help explain a chemopreventive mechanism associated with NSAIDs.

Historical Analysis: Editors' Reflections on 50 Years of the Journal of Pediatric Psychology.

OBJECTIVE: This article provides an historical perspective on the Journal of Pediatric Psychology (JPP) on the occasion of its 50th anniversary. METHODS: Former and current editors of JPP participated in a symposium at the 2019 Society of Pediatric Psychology Annual Conference (SPPAC), each highlighting prominent types of articles published during their terms, the influence of these papers over time, and their reflections on the next 50 years of the journal. Their presentations were summarized and integrated for this article. Additional data on editorial teams, special issues, and publication metrics over time are included. RESULTS: The data demonstrate changes over time in the growth, scope, and impact of JPP. The article also shows the consistency in areas of emphasis over time. Anticipated topics for the future were quite consistent across editors and included increased use of technology, broader attention to teams and approaches, and methodological advances as the field will continue to grow. CONCLUSIONS: This article provides an unusual collaboration among editors of JPP, providing an historical perspective on the journal's growth over time and anticipation of continued impact into the future.

Deriving a provisional tolerable intake for intravenous exposure to silver nanoparticles released from medical devices.

Silver nanoparticles (AgNP) are incorporated into medical devices for their anti-microbial characteristics. The potential exposure and toxicity of AgNPs is unknown due to varying physicochemical particle properties and lack of toxicological data. The aim of this safety assessment is to derive a provisional tolerable intake (pTI) value for AgNPs released from blood-contacting medical devices. A literature review of in vivo studies investigating critical health effects induced from intravenous (i. v.) exposure to AgNPs was evaluated by the Annapolis Accords principles and Toxicological Data Reliability Assessment Tool (ToxRTool). The point of departure (POD) was based on an i. v. 28-day repeated AgNP (20 nm) dose toxicity study reporting an increase in relative spleen weight in rats with a 5% lower confidence bound of the benchmark dose (BMDL05) of 0.14 mg/kg bw/day. The POD was extrapolated to humans by a modifying factor of 1,000 to account for intraspecies variability, interspecies differences and lack of long-term toxicity data. The pTI for long-term i. v. exposure to 20 nm AgNPs released from blood-contacting medical devices was 0.14 µg/kg bw/day. This pTI may not be appropriate for nanoparticles of other physicochemical properties or routes of administration. The methodology is appropriate for deriving pTIs for nanoparticles in general.

Oral Radiographic Evidence of Secondary Hyperparathyroidism in an End-Stage Renal Failure Patient: A Case Report.

BACKGROUND: The authors report a case of a 42-year-old woman with End Stage Renal Disease (ESRD) undergoing dialysis therapy with the relative loss of tooth root lamina dura and several mandibular radiolucencies. Secondary hyperparathyroidism related to End Stage Renal Disease may result in the loss of bone density and radiolucent lesions, which has been previously described as Brown tumor. Findings significant for hyperparathyroidism may befound on routine dental imaging. RESULTS: The patient was evaluated, and treatment was initiated for her dental conditions. She is at present still on the kidney transplant waiting list. CONCLUSION: Patients with End Stage Renal Disease and hyperparathyroidism require communication and cooperation between dentists and physicians. PRACTICAL IMPLICATIONS: It is important for dentists to consider Brown tumor as a possible diagnosis of radiolucent jaw lesions.

A biokinetic model for nickel released from cardiovascular devices.

Many alloys used in cardiovascular device applications contain high levels of nickel, which if released in sufficient quantities, can lead to adverse health effects. While nickel release from these devices is typically characterized through the use of in-vitro immersion tests, it is unclear if the rate at which nickel is released from a device during in-vitro testing is representative of the release rate following implantation in the body. To address this uncertainty, we have developed a novel biokinetic model that combines a traditional toxicokinetic compartment model with a physics-based model to estimate nickel release from an implanted device. This model links the rate of in-vitro nickel release from a cardiovascular device to serum nickel concentrations, an easily measured endpoint, to estimate the rate and extent of in-vivo nickel release from an implanted device. The model was initially parameterized using data in the literature on in-vitro nickel release from a nickel-containing alloy (nitinol) and baseline serum nickel levels in humans. The results of this first step were then used to validate specific components of the model. The remaining unknown quantities were fit using serum values reported in patients following implantation with nitinol atrial occluder devices. The model is not only consistent with levels of nickel in serum and urine of patients following treatment with the atrial occluders, but also the optimized parameters in the model were all physiologically plausible. The congruity of the model with available data suggests that it can provide a framework to interpret nickel biomonitoring data and use data from in-vitro nickel immersion tests to estimate in-vivo nickel release from implanted cardiovascular devices.

Risk-benefit assessment for antibiotic prophylaxis in asplenic dental patients.

A review of the published literature revealed that discourse on the topic of antibiotic prophylaxis guidelines for the asplenic dental patient is limited and that guidelines regarding this issue have not been updated for years. The review determined that the professional protocol for the treatment of asplenic dental patients has changed over the last 30 years, particularly with reference to adult patients. Furthermore, as dentists and physicians now understand that blood-borne bacteremias are produced from everyday occurrences such as chewing and toothbrushing, bacteremias secondary to dental procedures are no longer viewed as seriously as in the past; therefore, the guidelines for antibiotic prophylaxis have changed. Antibiotic prophylaxis is not routinely indicated prior to dental procedures for asplenic adult dental patients without risk factors. However, antibiotic prophylaxis should be considered for young children, immunocompromised patients with underlying causative disease, or any patient during the first 3 years after a splenectomy.

Periodontics and Oral-Systeric Relationships: Diabetes.

The oral cavity is a part of the body. The health of the oral cavity affects the health of the entire body. This relationship is reciprocal, as the overall health of an individual will also affect the health of that individual's oral cavity. Periodontal disease is a common, chronic inflammatory disease affecting the supporting structures of the teeth. It has been proposed that periodontal disease is a risk factor for systemic diseases such as diabetes.

Simulation-based end-of-life care training during surgical clerkship: assessment of skills and perceptions.

BACKGROUND: Assessment of interpersonal and psychosocial competencies during end-of-life care training is essential. This study reports the relationship between simulation-based end-of-life care Objective Structured Clinical Examination ratings and communication skills, trust, and self-assessed empathy along with the perceptions of students regarding their training experiences. METHOD: Medical students underwent simulation-based end-of-life care OSCE training that involved standardized patients who evaluated students' communication skills and physician trust with the Kalamazoo Essential Elements Communication Checklist and the Wake Forest Physician Trust Scale. Students also completed the Jefferson Scale of Physician Empathy. Pearson correlation was used to examine the relationship between OSCE performance grades and communication, trust, and empathy scores. Student comments were analyzed using the constant comparative method of analysis to identify dominant themes. RESULTS: The 389 students (mean age 26.6 ± 2.8 y; 54.5% female) had OSCE grades that were positively correlated with physician trust scores (r = 0.325, P < 0.01) and communication skills (r = 0.383, P < 0.01). However, OSCE grades and self-reported empathy were not related (r = 0.021, P = 0.68). Time of clerkship differed for OSCE grade and physician trust scores; however, there was no trend identified. No differences were noted between the time of clerkship and communication skills or empathy. Overall, students perceived simulation-based end-of-life care training to be a valuable learning experience and appreciated its placement early in clinical training. CONCLUSIONS: We found that simulation-based OSCE training in palliative and end-of-life care can be effectively conducted during a surgery clerkship. Moreover, the standardized patient encounters combined with the formal assessment of communication skills, physician trust, and empathy provide feedback to students at an early phase of their professional life. The positive and appreciative comments of students regarding the opportunity to practice difficult patient conversations suggest that attention to these professional characteristics and skills is a valued element of clinical training and conceivably a step toward better patient outcomes and satisfaction.