Effects of developmental exposure to individual and combined PFAS on development and behavioral stress responses in larval zebrafish.

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals known for their widespread use and persistence in the environment. Laboratory and epidemiological studies investigating these compounds have signaled their neurotoxic and endocrine-disrupting propensities, prompting further research into their effects on behavioral stress responses and their potential role as risk factors for stress-related disorders such as anxiety and depression. This study elucidates the ramifications of early developmental exposures to individual and combined PFAS on the development and behavioral stress responses of larval zebrafish (Danio rerio), an established model in toxicological research. Wild-type zebrafish embryos were enzymatically dechorionated and exposed to PFOS, PFOA, PFHxS, and PFHxA between 6 and 120 h post-fertilization (hpf). We targeted environmentally relevant concentrations stemming from the USEPA 2016 Hazard Advisory Limit (HAL, 0.07 µg/L) and folds higher (0.35, 0.7, 1.75, and 3.5 µg/L). Evaluations at 120 hpf encompassed mortality, overall development, developmental defects, and larval activity both at baseline stress levels and following exposure to acute stressors (acoustic and visual). Larval exposure to PFOA, PFOS, or PFHxS (0.07 µg/L or higher) elicited significant increases in mortality rates, which capped at 23.1%. Exposure to individual chemicals resulted in limited effects on overall development but increased the prevalence of developmental defects in the body axis, swim bladder, pigmentation, and eyes, as well as the prevalence of yolk sac and pericardial edemas. Larval activity at baseline stress levels and following exposure to acute stimuli was significantly altered. Combined exposure to all four chemicals intensified the breadth of developmental and behavioral alterations, suggesting possible additive or synergistic effects. Our findings shed light on the developmental and neurobehavioral disturbances associated with developmental exposure to PFAS at environmentally relevant concentrations, the added risks of combined exposures to these chemicals, and their possible role as environmental risk factors for stress-related disorders.

Seasonal changes in free 25-(OH)D and vitamin D metabolite ratios and their relationship with psychophysical stress markers in male professional football players.

Introduction: Novel markers of vitamin D status are currently being investigated, including free 25-(OH)D (25-(OH)DF) and the vitamin D metabolite ratio (24,25-(OH)2D3:25-(OH)D3; VMR). The VMR may provide additional functional information on vitamin D metabolism in athletes. Therefore, the main objective of the current study was to evaluate 25-(OH)DF, bioavailable 25-(OH)D (25-(OH)DB), VMR, and psychophysical stress markers during different training periods over a half-season. The second aim was to assess the association between vitamin D binding protein (VDBP), total and free 25-(OH)D, VMRs, and psychophysical stress markers in professional football players. Moreover, we examined the relationship between 25-(OH)D3 and vitamin D metabolites (24,25-(OH)2D3, 3-epi-25-(OH)D3) to determine if training loads in different training periods influenced the vitamin D metabolome. Methods: Twenty professional football players were tested at six different time points across half a year (V1-June; V2-July; V3-August; V4-October; V5-December; V6-January). Results: Analyses indicated a significant seasonal rhythm for VDBP, and total 25-(OH)D (25-(OH)DT), 25-(OH)DB, 24,25-(OH)2D3, 3-epi-25-(OH)D3, 25-(OH)D3:24,25-(OH)2D3, and 24,25-(OH)2D3:25-(OH)D3 VMRs throughout the training period. No correlation was detected between 25-(OH)DT, 25-(OH)DB, 25-(OH)DF, vitamin D metabolites, VMRs, VDBP, and ferritin, liver enzymes (aspartate transaminase [AST] and alanine transaminase [ALT]), creatine kinase (CK), cortisol, testosterone, and testosterone-to-cortisol ratio (T/C) in each period (V1-V6). However, there was a strong statistically significant correlation between 25-(OH)D3 and 24,25-(OH)D3 in each training period. Conclusion: In conclusion, a seasonal rhythm was present for VDBP, 25-(OH)DT, 25-(OH)DB, vitamin D metabolites (24,25-(OH)2D3, 3-epi-25-(OH)D3), and VMRs (25-(OH)D3:24,25-(OH)2D3, 25-(OH)D3:3-epi-25-(OH)D3). However, no rhythm was detected for 25-(OH)DF and markers of psychophysical stress (ferritin, liver enzymes, CK, testosterone, cortisol, and T/C ratio). Moreover, the relationships between free and total 25-(OH)D with psychophysical stress markers did not demonstrate the superiority of free over total measurements. Furthermore, training loads in different training periods did not affect resting vitamin D metabolite concentrations in football players.

Vitamin D Status in Bipolar Disorder.

Vitamin D status may impact acute affective symptomatology and the severity of symptoms in patients with bipolar disorder (BD). Therefore, this cross-sectional study analyzed 25(OH)D, 24,25(OH)2D, and the vitamin D metabolite ratio (VMR) in BD and correlated the results with clinical affective symptomatology and functionality. The inactive precursor 25(OH)D, and its principal catabolite 24,25(OH)2D, were measured simultaneously with a validated liquid chromatography-tandem mass spectrometry method in 170 BD outpatients and 138 healthy controls. VMR was calculated as follows: VMR = 100×(24,25(OH)2D/25(OH)D). The psychometric assessment comprised: Beck Depression Inventory-II, Hamilton Depression Rating Scale, Young Mania Rating Scale, Global Assessment of Functioning, and number of suicide attempts. We did not find a significant difference between patients and controls in the concentrations of 25(OH)D and 24,25(OH)2D. Additionally, the VMR was comparable in both groups. The calculations for the clinical parameters showed a negative correlation between the Young Mania Rating Scale and 24,25(OH)2D (r = -0.154, p = 0.040), as well as the Young Mania Rating Scale and the VMR (r = -0.238, p = 0.015). Based on the small effect size and the predominantly euthymic sample, further exploration in individuals with manic symptoms would be needed to confirm this association. In addition, long-term clinical markers and an assessment in different phases of the disease may provide additional insights.

The Influence of Vitamin D Status on Cognitive Ability in Patients with Bipolar Disorder and Healthy Controls.

Recent evidence on the association between vitamin D and cognition in mentally healthy individuals is inconsistent. Furthermore, the link between vitamin D and cognitive ability in individuals with bipolar disorder has not been studied yet. Thus, we aimed to investigate the association between 25-hydroxyvitamin D (25(OH)D), 24,25 dihydroxyvitamin D (24,25(OH)2D, the vitamin D metabolite ratio (VMR) and cognition in a cohort of euthymic patients with bipolar disorder. Vitamin D metabolites were measured simultaneously by liquid-chromatography tandem mass-spectrometry in serum samples from 86 outpatients with bipolar disorder and 93 healthy controls. Neither the inactive precursor 25(OH)D, nor the primary vitamin D catabolite 24,25(OH)2D, or the vitamin D metabolite ratio were significantly associated with the domains "attention", "memory", or "executive function" in individuals with bipolar disorder and healthy controls. Further, no vitamin D deficiency effect or interaction group × vitamin D deficiency was found in the cognitive domain scores. In summary, the present study does not support vitamin D metabolism as a modulating factor of cognitive function in euthymic BD patients. Considering the current study's cross-sectional design, future research should expand these results in a longitudinal setting and include additional aspects of mental health, such as manic or depressive symptoms, long-term illness course and psychopharmacological treatment.

Cerebral Vasomotor Reactivity in COVID-19: A Narrative Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the respiratory system but can also lead to neurological complications. Among COVID-19 patients, the endothelium is considered the Achilles heel. A variety of endothelial dysfunctions may result from SARS-CoV-2 infection and subsequent endotheliitis, such as altered vascular tone, oxidative stress, and cytokine storms. The cerebral hemodynamic impairment that is caused is associated with a higher probability of severe disease and poor outcomes in patients with COVID-19. This review summarizes the most relevant literature on the role of vasomotor reactivity (VMR) in COVID-19 patients. An overview of the research articles is presented. Most of the studies have supported the hypothesis that endothelial dysfunction and cerebral VMR impairment occur in COVID-19 patients. Researchers believe these alterations may be due to direct viral invasion of the brain or indirect effects, such as inflammation and cytokines. Recently, researchers have concluded that viruses such as the Human Herpes Virus 8 and the Hantavirus predominantly affect endothelial cells and, therefore, affect cerebral hemodynamics. Especially in COVID-19 patients, impaired VMR is associated with a higher risk of severe disease and poor outcomes. Using VMR, one can gain valuable insight into a patient's disease progression and make more informed decisions regarding appropriate treatment options. A new pandemic may develop with the COVID-19 virus or other viruses, making it essential that healthcare providers and researchers remain focused on developing new strategies for improving survival in such patients, particularly those with cerebrovascular risk factors.

Analytical performance specifications for the measurement uncertainty of 24,25-dihydroxyvitamin D examinations.

OBJECTIVES: The exploration of the metabolites in the degradation pathways of vitamin D (VTD) has gained importance in recent years and simultaneous quantitation of twenty-five-hydroxy vitamin D (25(OH)D) mass concentration together with 24,25-dihydroxyvitamin D (24,25(OH)2D) has been proposed as a newer approach to define VTD deficiency. Yet, no data are available on 24,25(OH)2D biological variation (BV). In this study, we evaluated 24,25(OH)2D's BV on the European Biological Variation Study (EuBIVAS) cohort samples to determine if analytical performance specifications (APS) for 24,25(OH)2D could be generated. METHODS: Six European laboratories recruited 91 healthy participants. 25(OH)D and 24,25(OH)2D concentrations in K3-EDTA plasma were examined weekly for up to 10 weeks in duplicate with a validated LC-MS/MS method. The Vitamin D Metabolite Ratio (24,25(OH)2D divided by 25(OH)D × 100) was also calculated at each time point. RESULTS: Linear regression of the mean 24,25(OH)2D concentrations at each blood collection showed participants were not in steady state. Variations of 24,25(OH)2D over time were significantly positively associated with the slopes of 25(OH)D concentrations over time and the concentration of 25(OH)D of the participant at inclusion, and negatively associated with body mass index (BMI), but not with age, gender, or location of the participant. The variation of the 24,25(OH)2D concentration in participants over a 10 weeks period was 34.6%. Methods that would detect a significant change linked to the natural production of 24,25(OH)2D over this period at p<0.05 would need a relative measurement uncertainty (u%)<14.9% while at p<0.01, relative measurement uncertainty should be <10.5%. CONCLUSIONS: We have defined for the first time APS for 24,25(OH)2D examinations. According to the growing interest in this metabolite, several laboratories and manufacturers might aim to develop specific methods for its determination. The results presented in this paper are thus necessary prerequisites for the validation of such methods.

Physical and visual evaluations of CT image quality of large low-contrast objects with visual model-based iterative reconstruction technique: a phantom study.

We aimed to verify whether the image quality of large low-contrast objects can be improved using visual model-based iterative reconstruction (VMR) while maintaining the visibility of conventional filtered back projection (FBP) and reducing radiation dose through physical and visual evaluation. A 64-row multi-slice CT system with SCENARIA View (FUJIFILM healthcare Corp. Tokyo, Japan) was used. The noise power spectrum (NPS), task-based transfer function (TTF), and signal-to-noise ratio (SNR) were physically evaluated. A low contrast object as a substitute for a liver mass was visually evaluated. In the noise measurement, STD1 showed an 18% lower noise compared to FBP. STR4 was able to reduce noise by 58% compared to FBP. The NPS of VMR was similar to those of FBP from low to high spatial frequency. The NPS of VMR reconstructions showed a similar variation with frequency as FBP reconstructions. STD1 showed the highest 10% TTF, and higher 10% TTF was observed with lower VMR level. The SNR of VMR was close to that of FBP, and higher SNR was observed with higher VMR level. In the results of the visual evaluation, there was no significant difference in visual evaluation between STD1 and FBP (p = 0.99) and between STD2 and FBP (p = 0.56). We found that the NPS of VMR images was similar to that of FBP images, and it can reduce noise and radiation dose by 25% and 50%, respectively, without decreasing the visual image quality compared to FBP.

The effect of EMG magnitude on the masseter vestibular evoked myogenic potential (mVEMP).

Introduction: The masseter vestibular evoked myogenic potential (mVEMP) is a bilaterally generated, electromyographically (EMG)-mediated response innervated by the trigeminal nerve. The purpose of the present investigation was to 1) determine whether subjects could accurately achieve and maintain a range of EMG target levels, 2) to examine the effects of varied EMG levels on the latencies and amplitudes of the mVEMP, and 3) to investigate the degree of side-to-side asymmetry and any effects of EMG activation. Methods: Subjects were nine neurologically and otologically normal young adults. A high-intensity tone burst was presented monaurally while subjects were seated upright and asked to match a range of EMG target levels by clenching their teeth. Recordings were made from the ipsilateral and contralateral masseter muscles referenced to the ear being monaurally stimulated. Results: We found that the tonic EMG target had no effect on mVEMP latency. Additionally, although mVEMP amplitudes "scaled" to the EMG target, there was a tendency for the subjects' EMG level to "undershoot" the EMG target levels greater than 50 µV. While some individuals did generate differences in EMG activation between sides, there were no significant differences on average EMG activation between sides. Further, while average corrected amplitude asymmetry was similar across EMG targets, some individuals demonstrated large, corrected amplitude asymmetry ratios. Conclusions: The results of this investigation suggest that, as with cVEMP recordings, the underlying EMG activation may vary between subjects and could impact mVEMP amplitudes, yet could be mitigated by amplitude correction techniques. Further it is important to be aware that even young normal subjects have difficulty maintaining large, tonic EMG activity during the mVEMP recording.

Characterization of a method to study urodynamics and bladder nociception in male and female mice.

OBJECTIVES: Abdominal electromyogram or visceromotor response (VMR) elicited by bladder distension is a validated as a measure of bladder nociception in mice, however it is not without its limitations. The aim of this study is to address some of these limitations and validate voiding evoked VMR as a measure of bladder nociception mice. METHODS: Using both male and female C57BL/6 mice we assessed the VMR response to cytometry- induced voiding before and after instillation of 0.5% acetic acid into the bladder. We then delivered intravesical lidocaine to confirm the VMR response as nociceptive. VMR and correlative cystometric bladder pressures were analyzed. RESULTS: We found that the VMR can be evoked by continuous fluid infusion into the bladder of both male and female mice. This response is potentiated after bladder injury and can be attenuated by administration of a local anesthetic, providing strong evidence that this method can be used to evaluate bladder nociception. Further, evaluation of cystometric pressure traces obtained during VMR recording revealed that intercontraction intervals were not altered after bladder injury in either male or female mice. However, we did observe a decrease in peak threshold pressures after bladder injury in female mice, which could be rescued by lidocaine administration. CONCLUSIONS: In conclusion, this technique can measure the VMR and bladder nociception associated with voiding in both female and male mice. Although confounds still exist with the use of anesthesia, further exploration of non-anesthetized voiding-evoked VMR is warranted.

Simultaneous measurement of 25(OH)-vitamin D and 24,25(OH)2-vitamin D to define cut-offs for CYP24A1 mutation and vitamin D deficiency in a population of 1200 young subjects.

Background Simultaneous measurement of 25(OH)D and 24,25(OH)2D is a new tool for predicting vitamin D deficiency and allows evaluating CYP24A1 lack of function. Interpretation of 24,25(OH)2D should be performed according to 25(OH)D levels and a ratio, called the vitamin D metabolite ratio (VMR) has been proposed for such a purpose. Unfortunately, the VMR can be expressed in different ways and cannot be used if 24,25(OH)2D concentrations are undetectable. Here, we propose evaluating the enzyme activity taking into consideration the probability that a normal population presents undetectable 24,25(OH)2D concentrations according to 25(OH)D levels. We thus retrospectively measured 25(OH)D and 24,25(OH)2D in a population of 1200 young subjects to evaluate the 25(OH)D threshold above which the enzyme was induced. Methods Serum samples from 1200 infants, children, adolescent and young adults were used to simultaneously quantify 25(OH)D and 24,25(OH)2D by LCMS/MS. Results Median (interquartile range [IQR]) levels were 20.6 (14.4-27.2) ng/mL for 25(OH)D. 172 subjects (14.3%) presented 24,25(OH)2D values below the LOQ. When 25(OH)D values were <11 ng/mL, 63.1% of subjects presented undetectable 24,25(OH)2D concentrations. Percentage decreased with increasing 25(OH)D values to become 19.7% for 25(OH)D comprised between 12 and 15 ng/mL, 5.1% for 25(OH)D between 16 and 20 and 0.7% for 25(OH)D >21 ng/mL. Conclusions We suggest using a statistical approach to evaluate CYP24A1 function according to 25(OH)D concentrations. Our results also show that vitamin D deficiency, as defined biochemically, could be around 20 ng/mL in infants, children, adolescent and young adults and that vitamin D deficiency could be evaluated on a more individual basis.

Transcranial Doppler ultrasonography in neurological surgery and neurocritical care.

Transcranial Doppler (TCD) ultrasonography is an inexpensive, noninvasive means of measuring blood flow within the arteries of the brain. In this review, the authors outline the technology underlying TCD ultrasonography and describe its uses in patients with neurosurgical diseases. One of the most common uses of TCD ultrasonography is monitoring for vasospasm following subarachnoid hemorrhage. In this setting, elevated blood flow velocities serve as a proxy for vasospasm and can herald the onset of ischemia. TCD ultrasonography is also useful in the evaluation and management of occlusive cerebrovascular disease. Monitoring for microembolic signals enables stratification of stroke risk due to carotid stenosis and can also be used to clarify stroke etiology. TCD ultrasonography can identify patients with exhausted cerebrovascular reserve, and after extracranial-intracranial bypass procedures it can be used to assess adequacy of flow through the graft. Finally, assessment of cerebral autoregulation can be performed using TCD ultrasonography, providing data important to the management of patients with severe traumatic brain injury. As the clinical applications of TCD ultrasonography have expanded over time, so has their importance in the management of neurosurgical patients. Familiarity with this diagnostic tool is crucial for the modern neurological surgeon.

Vestibulo masseteric reflex and acoustic masseteric Reflex. Normative data and effects of age and gender.

OBJECTIVE: To provide normative data for the Vestibulo-Masseteric Reflex (VMR) and Acoustic-Masseteric Reflex (AMR) in healthy subjects, stratified for age and gender. METHODS: A total of 82 healthy subjects (M:F 43:39, mean age 39.3 ±â€¯18.4 years, range 13-79 years) underwent recording of click-evoked VMR and AMR (0.1 ms duration, 5 Hz frequency) from active masseter muscles. Masseter responses to uni- and bilateral stimulation were recorded in a zygomatic and a mandibular configuration, according to the position of the reference electrode. Stimulation intensity curves were recorded for each reflex in ten subjects (mean age 20.7 ±â€¯8.1 years). Gender effect was investigated in 62 subjects and age effect was analyzed in six 10-subject groups aged from <25 to >65 years. Onset and peak latencies, interpeak intervals, raw and corrected amplitudes, latency and amplitude asymmetries were analyzed. RESULTS: VMR had a higher elicitation rate than AMR. For both reflexes, rates of elicitation, and corrected amplitudes were higher in the zygomatic configuration, and bilateral stimulation elicited larger responses. Best acoustic ranges of elicitation were 98-113 dB for AMR and 128-138 dB for VMR. Reflex latencies were shorter in females than males. Frequency and amplitude of VMR and AMR decreased substantially over 55 year olds. CONCLUSIONS: VMR and AMR can be easily performed in any clinical neurophysiology laboratory. SIGNIFICANCE: These reflexes can find application in the investigation of brainstem function in central neurological disorders.

The Role of Vitamin D in CKD Stages 3 to 4: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Deficiency of 25-hydroxyvitamin D (25[OH]D) is common in patients with chronic kidney disease stages 3 and 4 and is associated with poor outcomes. However, the evaluation and management of vitamin D deficiency in nephrology remains controversial. This article reports on the proceedings from a "controversies conference" on vitamin D in chronic kidney disease that was sponsored by the National Kidney Foundation. The report outlines the deliberations of the 3 work groups that participated in the conference. Until newer measurement methods are widely used, the panel agreed that clinicians should classify 25(OH)D "adequacy" as concentrations > 20ng/mL without evidence of counter-regulatory hormone activity (ie, elevated parathyroid hormone). The panel also agreed that 25(OH)D concentrations < 15ng/mL should be treated irrespective of parathyroid hormone level. Patients with 25(OH)D concentrations between 15 and 20ng/mL may not require treatment if there is no evidence of counter-regulatory hormone activity. The panel agreed that nutritional vitamin D (cholecalciferol, ergocalciferol, or calcifediol) should be supplemented before giving activated vitamin D compounds. The compounds need further study evaluating important outcomes that observational studies have linked to low 25(OH)D levels, such as progression to end-stage kidney disease, infections, fracture rates, hospitalizations, and all-cause mortality. We urge further research funding in this field.

Vitamin D and its metabolites: from now and beyond.

Total 25-hydroxyvitamin D is currently considered as the most representative metabolite of vitamin D status. There are a multitude of challenges that still deserve to be addressed and despite recent technological advances its determination remains complicated. This current review gives an abbreviated overview of the phases of development that vitamin D metabolite determination has gone through and discusses the difficulties that still require resolving. Furthermore, given the different platforms and methodologies available, the critical issue of standardization and all efforts made as far towards its realization have been discussed. And last but not least, the concepts of 'free' and 'bioavailable' vitamin D along with the 'Vitamin D Metabolism Ratio' have been discussed.

Pharmacological modulation of colorectal distension evoked potentials in conscious rats.

BACKGROUND: Cerebral evoked potentials (CEP) induced by colorectal distension (CRD) in conscious rats provides a novel method in studies of visceral sensitivity. The aim of this study was to explore the pharmacological effect on CEP of compounds known to reduce the visceromotor response to CRD. METHODS: Epidural electrodes were chronically implanted in eight female Sprague-Dawley rats. Evoked potentials were elicited by colorectal rapid balloon distensions (100 ms, 80 mmHg) and the effect of WIN55 (cannabinoid CB receptor agonist), clonidine (adrenergic α2 receptor agonist), MPEP (mGluR5 receptor antagonist), pregabalin (ligand of α2δ subunits in voltage-gated calcium channels) and baclofen (GABA-B receptor agonist) on amplitudes and latency of CEP were determined. RESULTS: WIN55 (0.1 µmol kg-1), clonidine (0.05 µmol kg-1), MPEP (10 µmol kg-1) and pregabalin (200 µmol kg-1) caused a significant, p < 0.05, reduction of the N2 to P2 peak-to-peak amplitude by 23 ±â€¯8%, 25 ±â€¯8%, 39 ±â€¯5%, and 47 ±â€¯6% respectively. Baclofen (9 µmol kg-1) induced a prolongation of the N2 peak latency of 18 ±â€¯4% but had no significant effect on the amplitudes. CONCLUSION: The obtained results suggest that MPEP, WIN55, clonidine, and pregabalin reduce visceral nociceptive input to the brain, whereas the lack of effect of baclofen on CRD evoked CEP amplitudes suggest that the effect on VMR is not due to a direct analgesic effect. Brain responses to colorectal distension provide a useful tool to evaluate pharmacological effects in rats and may serve as a valuable preclinical model for understanding pharmacological mechanisms related to visceral sensitivity.

Serum Calcitriol Concentrations and Kidney Function Decline, Heart Failure, and Mortality in Elderly Community-Living Adults: The Health, Aging, and Body Composition Study.

RATIONALE & OBJECTIVES: Lower 25-hydroxyvitamin D concentrations have been associated with risk for kidney function decline, heart failure, and mortality. However, 25-hydroxyvitamin D requires conversion to its active metabolite, calcitriol, for most biological effects. The associations of calcitriol concentrations with clinical events have not been well explored. STUDY DESIGN: Case-cohort study. SETTING & PARTICIPANTS: Well-functioning community-living older adults aged 70 to 79 years at inception who participated in the Health, Aging, and Body Composition (Health ABC) Study. PREDICTOR: Serum calcitriol measured using positive ion electrospray ionization-tandem mass spectrometry. OUTCOMES: Major kidney function decline (≥30% decline in estimated glomerular filtration rate from baseline), incident heart failure (HF), and all-cause mortality during 10 years of follow-up. ANALYTIC APPROACH: Baseline calcitriol concentrations were measured in a random subcohort of 479 participants and also in cases with major kidney function decline [n=397]) and incident HF (n=207) during 10 years of follow-up. Associations of serum calcitriol concentrations with these end points were evaluated using weighted Cox regression to account for the case-cohort design, while associations with mortality were assessed in the subcohort alone using unweighted Cox regression. RESULTS: During 8.6 years of mean follow-up, 212 (44%) subcohort participants died. In fully adjusted models, each 1-standard deviation lower calcitriol concentration was associated with 30% higher risk for major kidney function decline (95% CI, 1.03-1.65; P=0.03). Calcitriol was not significantly associated with incident HF (HR, 1.16; 95% CI, 0.94-1.47) or mortality (HR, 1.01; 95% CI, 0.81-1.26). We observed no significant interactions between calcitriol concentrations and chronic kidney disease status, baseline intact parathyroid or fibroblast factor 23 concentrations. LIMITATIONS: Observational study design, calcitriol measurements at a single time point, selective study population of older adults only of white or black race. CONCLUSIONS: Lower calcitriol concentrations are independently associated with kidney function decline in community-living older adults. Future studies will be needed to clarify whether these associations reflect lower calcitriol concentrations resulting from abnormal kidney tubule dysfunction or direct mechanisms relating lower calcitriol concentrations to more rapid loss of kidney function.

Electroacupuncture Attenuates Visceral Hypersensitivity by Inhibiting JAK2/STAT3 Signaling Pathway in the Descending Pain Modulation System.

Electroacupuncture (EA) has been used for treating visceral hypersensitivity (VH). However, the underlying molecular mechanism remains unclear. This study was aim to testify the effect of EA on ileitis-provoked VH, and to confirm whether EA attenuates VH through Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) signaling pathway in the periaqueductal gray (PAG)-the rostral ventromedial medulla (RVM)-the spinal cord dorsal horn (SCDH) axis. Methods: Goats were anesthetized and laparotomized for injecting 2,4,6-trinitro-benzene-sulfonic acid (TNBS)-ethanol solution (30mg TNBS dissolved in 40% ethanol) into the ileal wall to induce VH. EA was treated for 30min from day 7, then every 3 days for six times. VH was assessed by visceromotor response (VMR) and pain behavior response to 20, 40, 60, 80, and 100 mmHg colorectal distension pressures at day 7, 10, 13, 16, 19, and 22. The spinal cord in the eleventh thoracic vertebra and the brain were collected at day 22. The protein and mRNA levels of IL-6, JAK2, and STAT3 in the SCDH were detected with western blot and qPCR, respectively. The distribution of these substances was observed with immunohistochemistry in the ventrolateral PAG (vlPAG), RVM (mainly the nucleus raphe magnus, NRM), SCDH, the nucleus tractus solitaries (NTS) and the dorsal motor nucleus of vagi (DMV). Results: Goats administered with TNBS-ethanol solution showed diarrhea, enhanced VMR and pain behavior response, and increased IL-6, phosphorylated JAK2 and STAT3 (pJAK2 and pSTAT3) in the vlPAG, NRM, NTS and DMV, and their protein and mRNA levels in the SCDH. EA relieved diarrhea, VMR and pain behavior response, decreased IL-6, pJAK2 and pSTAT3 levels in the vlPAG, NRM, SCDH, NTS, and DMV except for pSTAT3 in the DMV, but did not affect mRNA level of these three substances in the SCDH. Conclusion: EA attenuates VH probably through inhibiting JAK2/STAT3 signaling pathway in the PAG-RVM-SCDH axis.

Multi-model-based interactive authoring environment for creating shareable medical knowledge.

OBJECTIVE: Technologically integrated healthcare environments can be realized if physicians are encouraged to use smart systems for the creation and sharing of knowledge used in clinical decision support systems (CDSS). While CDSSs are heading toward smart environments, they lack support for abstraction of technology-oriented knowledge from physicians. Therefore, abstraction in the form of a user-friendly and flexible authoring environment is required in order for physicians to create shareable and interoperable knowledge for CDSS workflows. Our proposed system provides a user-friendly authoring environment to create Arden Syntax MLM (Medical Logic Module) as shareable knowledge rules for intelligent decision-making by CDSS. METHODS AND MATERIALS: Existing systems are not physician friendly and lack interoperability and shareability of knowledge. In this paper, we proposed Intelligent-Knowledge Authoring Tool (I-KAT), a knowledge authoring environment that overcomes the above mentioned limitations. Shareability is achieved by creating a knowledge base from MLMs using Arden Syntax. Interoperability is enhanced using standard data models and terminologies. However, creation of shareable and interoperable knowledge using Arden Syntax without abstraction increases complexity, which ultimately makes it difficult for physicians to use the authoring environment. Therefore, physician friendliness is provided by abstraction at the application layer to reduce complexity. This abstraction is regulated by mappings created between legacy system concepts, which are modeled as domain clinical model (DCM) and decision support standards such as virtual medical record (vMR) and Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT). We represent these mappings with a semantic reconciliation model (SRM). RESULTS: The objective of the study is the creation of shareable and interoperable knowledge using a user-friendly and flexible I-KAT. Therefore we evaluated our system using completeness and user satisfaction criteria, which we assessed through the system- and user-centric evaluation processes. For system-centric evaluation, we compared the implementation of clinical information modelling system requirements in our proposed system and in existing systems. The results suggested that 82.05% of the requirements were fully supported, 7.69% were partially supported, and 10.25% were not supported by our system. In the existing systems, 35.89% of requirements were fully supported, 28.20% were partially supported, and 35.89% were not supported. For user-centric evaluation, the assessment criterion was 'ease of use'. Our proposed system showed 15 times better results with respect to MLM creation time than the existing systems. Moreover, on average, the participants made only one error in MLM creation using our proposed system, but 13 errors per MLM using the existing systems. CONCLUSION: We provide a user-friendly authoring environment for creation of shareable and interoperable knowledge for CDSS to overcome knowledge acquisition complexity. The authoring environment uses state-of-the-art decision support-related clinical standards with increased ease of use.

A Survey of Standard Information Models for Clinical Decision Support Systems.

HL7 CDA, vMR, and openEHR archetypes have been utilized as standard information models for clinical decision support systems. Compared to openEHR archetypes, vMR typically requires less time to develop and extend which makes it a good fit for rapid prototyping and pilot projects, while openEHR archetypes handle the data and semantic specification better. Using CDA for clinical decision support systems is discouraged due to its complexity, steep learning curve, and potential safety issues.

Analysis of the process of representing clinical statements for decision-support applications: a comparison of openEHR archetypes and HL7 virtual medical record.

Delivering patient-specific decision-support based on computer-interpretable guidelines (CIGs) requires mapping CIG clinical statements (data items, clinical recommendations) into patients' data. This is most effectively done via intermediate data schemas, which enable querying the data according to the semantics of a shared standard intermediate schema. This study aims to evaluate the use of HL7 virtual medical record (vMR) and openEHR archetypes as intermediate schemas for capturing clinical statements from CIGs that are mappable to electronic health records (EHRs) containing patient data and patient-specific recommendations. Using qualitative research methods, we analyzed the encoding of ten representative clinical statements taken from two CIGs used in real decision-support systems into two health information models (openEHR archetypes and HL7 vMR instances) by four experienced informaticians. Discussion among the modelers about each case study example greatly increased our understanding of the capabilities of these standards, which we share in this educational paper. Differing in content and structure, the openEHR archetypes were found to contain a greater level of representational detail and structure while the vMR representations took fewer steps to complete. The use of openEHR in the encoding of CIG clinical statements could potentially facilitate applications other than decision-support, including intelligent data analysis and integration of additional properties of data items from existing EHRs. On the other hand, due to their smaller size and fewer details, the use of vMR potentially supports quicker mapping of EHR data into clinical statements.