Irregular Breathing Research Articles

A comprehensive quality assurance procedure for 4D CT commissioning and periodic QA.

The 4D computed tomography (CT) simulation is an essential procedure for tumors exhibiting breathing-induced motion. However, to date there are no established guidelines to assess the characteristics of existing systems and to describe meaningful performance. We propose a commissioning quality assurance (QA) protocol consisting of measurements and acquisitions that assess the mechanical and computational operation for 4D CT with both phase and amplitude-based reconstructions, for regular and irregular respiratory patterns. The 4D CT scans of a QUASAR motion phantom were acquired for both regular and irregular breathing patterns. The hardware consisted of the Canon Aquilion Exceed LB CT scanner used in conjunction with the Anzai laser motion monitoring system. The nominal machine performance and reconstruction were demonstrated with measurements using regular breathing patterns. For irregular breathing patterns the performance was quantified through the analysis of the target motion in the superior and inferior directions, and the volume of the internal target volume (ITV). Acquisitions were performed using multiple pitches and the reconstructions were performed using both phase and amplitude-based binning. The target was accurately captured during regular breathing. For the irregular breathing, the measured ITV exceeded the nominal ITV parameters in all scenarios, but all deviations were less than the reconstructed slice thickness. The mismatch between the nominal pitch and the actual breathing rate did not affect markedly the size of the ITV. Phase and normalized amplitude binning performed similarly. We demonstrated a framework for measuring and quantifying the initial performance of 4D CT simulation scans that can also be applied during periodic QAs. The regular breathing provided confidence that the hardware and the software between the systems performs adequately. The irregular breathing data suggest that the system may be expected to capture in excess the target motion and geometry, but the deviation is expected to be within the slice thickness.

Weakness in both lower limbs for 1 week and blepharoptosis for 3 days in a boy aged 1 year and 7 months.

A boy, aged 1 year and 7 months, was hospitalized due to weakness in both lower limbs and blepharoptosis, which showed progressive aggravation and developed into irregular breathing. Neurological examinations showed lethargy, blepharoptosis, grade 4 muscle strength of both upper limbs, grade 3 muscle strength of both lower limbs, and disappearance of tendon reflex. Laboratory tests revealed albuminocytological dissociation in cerebrospinal fluid, disappearance of H reflex, and positive serum anti-GD1b IgG. The boy was finally diagnosed with Guillain-Barré syndrome (GBS) overlapping with Miller-Fisher syndrome and Bickerstaff brainstem encephalitis. He recovered and was discharged after treatment including immunoglobulin, plasma exchange, and respiratory support. The GBS overlap syndromes in children have strong clinical heterogeneity due to the injury of both peripheral nerve and brainstem, among which anti-GD1b antibody-related GBS overlap syndromes have special clinical manifestations and complex neuroelectrophysiological changes and are thus difficult to diagnose. Nerve conduction velocity tests, especially H reflex test, should be performed for children with weakness in both lower limbs and blepharoptosis.

Oral Feeding of an Antioxidant Cocktail as a Therapeutic Strategy in a Mouse Model of Rett Syndrome: Merits and Limitations of Long-Term Treatment

Rett syndrome (RTT) is a severe neurodevelopmental disorder that typically arises from spontaneous germline mutations in the X-chromosomal methyl-CpG binding protein 2 (MECP2) gene. For the first 6–18 months of life, the development of the mostly female patients appears normal. Subsequently, cognitive impairment, motor disturbances, hand stereotypies, epilepsy, and irregular breathing manifest, with previously learned skills being lost. Early mitochondrial impairment and a systemic oxidative burden are part of the complex pathogenesis, and contribute to disease progression. Accordingly, partial therapeutic merits of redox-stabilizing and antioxidant (AO) treatments were reported in RTT patients and Mecp2-mutant mice. Pursuing these findings, we conducted a full preclinical trial on male and female mice to define the therapeutic value of an orally administered AO cocktail composed of vitamin E, N-acetylcysteine, and α-lipoic acid. AO treatment ameliorated some of the microcephaly-related aspects. Moreover, the reduced growth, lowered blood glucose levels, and the hippocampal synaptic plasticity of Mecp2−/y mice improved. However, the first-time detected intensified oxidative DNA damage in Mecp2-mutant cortex persisted. The behavioral performance, breathing regularity, and life expectancy of Mecp2-mutant mice did not improve upon AO treatment. Long-term-treated Mecp2+/− mice eventually became obese. In conclusion, the AO cocktail ameliorated a subset of symptoms of the complex RTT-related phenotype, thereby further confirming the potential merits of AO-based pharmacotherapies. Yet, it also became evident that long-term AO treatment may lose efficacy and even aggravate the metabolic disturbances in RTT. This emphasizes the importance of a constantly well-balanced redox balance for systemic well-being.

Chest examinations in children with real-time magnetic resonance imaging: first clinical experience

BackgroundReal-time magnetic resonance imaging (MRI) based on a fast low-angle shot technique 2.0 (FLASH 2.0) is highly effective against artifacts caused due to the bulk and pulmonary and cardiac motions of the patient. However, to date, there are no reports on the application of this innovative technique to pediatric lung MRI.ObjectiveThis study aimed to identify the limits of resolution and image quality of real-time lung MRI in children and to assess the types and minimal size of lesions with these new sequences.Materials and methodsIn this retrospective study, pathological lung findings in 87 children were classified into 6 subgroups, as detected on conventional MRI: metastases and tumors, consolidation, scars, hyperinflation, interstitial pathology and bronchiectasis. Subsequently, the findings were grouped according to size (4–6 mm, 7–9 mm and ≥ 10 mm) and evaluated for visual delineation of the findings (0 = not visible, 1 = hardly visible and 2 = well visualized).ResultsReal-time MRI allows for diagnostic, artifact-free thorax images to be obtained, regardless of patient movements. The delineation of findings strongly correlates with the size of the pathology. Metastases, consolidation and scars were visible at 100% when larger than 9 mm. In the 7–9 mm subgroup, the visibility was 83% for metastases, 88% for consolidation and 100% for scars in T2/T1 weighting. Though often visible, smaller pathological lesions of 4–6 mm in size did not regularly meet the expected diagnostic confidence: The visibility of metastases was 18%, consolidation was 64% and scars was 71%. Diffuse interstitial lung changes and hyperinflation, known as “MR-minus pathologies,” were not accessible to real-time MRI.ConclusionThe method provides motion robust images of the lung and thorax. However, the lower sensitivity for small lung lesions is a major limitation for routine use of this technique. Currently, the method is adequate for diagnosing inflammatory lung diseases, atelectasis, effusions and lung scarring in children with irregular breathing patterns or bulk motion on sedation-free MRI. A medium-term goal is to improve the diagnostic accuracy of small nodules and interstitial lesions.

Quality assurance of a breathing controlled four-dimensional computed tomography algorithm.

Four-dimensional computed tomography (4DCT) scans are standardly used for radiotherapy planning of tumors subject to respiratory motion. Based on online analysis and automatic adaption of scan parameters to the patient's individual breathing pattern, a new breathing-controlled 4DCT (i4DCT) algorithm attempts to counteract irregular breathing and thus prevent artifacts. The aim of this study was to perform an initial quality assurance for i4DCT. To validate the i4DCT algorithm, phantom measurements were performed to evaluate geometric accuracy (diameter, volume, eccentricity), image quality (dose-normalized contrast-noise-ratio, CT number accuracy), and correct representation of motion amplitude of simulated tumor lesions. Furthermore, the impact of patient weight and resulting table flexion on the measurements was investigated. Static three-dimensional CT (3DCT) scans were used as ground truth. The median volume deviation magnitude between 4DCT and 3DCT was<2% (<0.2cm3). The volume differences ranged from -8% (-1.0cm3) to 3% (0.4cm3). Median tumor diameter deviation magnitudes were<2% (<0.7mm) for regular and<3.5% (<1.0mm) for irregular breathing. For eccentricity, a median deviation magnitude of<0.05 for regular and<0.08 for irregular breathing curves was found. The respiratory amplitude was represented with a median accuracy of<0.5mm. CT numbers and dose-normalized contrast-noise-ratio showed no clinically relevant difference between 4DCT and 3DCT. Table flexion proved to have no clinically relevant impact on geometric accuracy. The breathing-controlled algorithm provides in general good results regarding image quality, geometric accuracy, and correct depiction of motion amplitude for regular and irregular breathing.

Primary Breathing Survey Emergency with Oxygen Need Optimization and Nurse Caring on Covid-19 Patients in IGD UKI RSU Jakarta: Case Study

Emergency in Covid-19 is a respiratory tract infection caused by a new type of coronavirus (SARS-CoV-2) so that it can cause a decrease in oxygen levels in patients with saturation &lt;95% Objective: To carry out emergency nursing care for19 patients Covid-. 19 with the measures in Primary Survey and Secondary Survey order to increase oxygen saturation &gt;95%, reduce shortness of breath, regular breathing rhythm with a frequency of 20x/minute, symmetrical chest movements, and no chest muscle retraction Methods: The method of case study results uses a descriptive approach with a process approach. nursing care, independent action by monitoring the frequency of breath and oxygen saturation as well as giving the semi-fowler position, collaborative action by giving high concentration oxygen Non-Rebreathing Mask 10 liters/minute. Results: The patient's shortness of breath has been reduced with oxygen saturation increasing 99%, chest movement is symmetrical, irregular breathing rhythm 24x/minute is still partially resolved and the patient does not appear restless after being given high concentrations of oxygen. Conclusion: It takes speed and attitude caring towards patients to overcome anxiety and empathy, especially being a good listener by always providing support so that patients are always motivated to recover and providing independent action and the right collaboration of health workers so that the handling of Covid-19 can be resolved

Medullary astrocytes mediate irregular breathing patterns generation in chronic heart failure through purinergic P2X7 receptor signalling.

SummaryBackgroundBreathing disorders (BD) (apnoeas/hypopneas, periodic breathing) are highly prevalent in chronic heart failure (CHF) and are associated with altered central respiratory control. Ample evidence identifies the retrotrapezoid nucleus (RTN) as an important chemosensitivity region for ventilatory control and generation of BD in CHF, however little is known about the cellular mechanisms underlying the RTN/BD relationship. Within the RTN, astrocyte‐mediated purinergic signalling modulates respiration, but the potential contribution of RTN astrocytes to BD in CHF has not been explored.MethodsSelective neuron and/or astrocyte-targeted interventions using either optogenetic and chemogenetic manipulations in the RTN of CHF rats were used to unveil the contribution of the RTN on the development/maintenance of BD, the role played by astrocytes in BD and the molecular mechanism underpinning these alterations.FindingsWe showed that episodic photo-stimulation of RTN neurons triggered BD in healthy rats, and that RTN neurons ablation in CHF animals eliminates BD. Also, we found a reduction in astrocytes activity and ATP bioavailability within the RTN of CHF rats, and that chemogenetic restoration of normal RTN astrocyte activity and ATP levels improved breathing regularity in CHF. Importantly, P"X/ P2X7 receptor (P2X7r) expression was reduced in RTN astrocytes from CHF rats and viral vector-mediated delivery of human P2X7 P2X7r into astrocytes increases ATP bioavailability and abolished BD.InterpretationOur results support that RTN astrocytes play a pivotal role on BD generation and maintenance in the setting CHF by a mechanism encompassing P2X7r signalling.FundingThis study was funded by the National Research and Development Agency of Chile (ANID).

Reduced expression of SOD2 in the Retrotrapezoid nucleus is associated with enhanced ventilatory chemoreception: implications for breathing disorders in heart failure

Enhanced chemoreflex drive and irregular breathing patterns are both hallmarks in heart failure (HF). The Retrotrapezoid nucleus (RTN), a main area for central chemoreception, contribute to maintain both heightened chemoreflex drive and irregular breathing in experimental HF. Recently, we found that high levels of reactive oxygen species (ROS) within the RTN of HF rats were closely linked to the enhanced central chemoreflex and the generation of breathing disorders. Despite this evidence, the effects of ROS on RTN‐mediated chemoreception and the precise mechanism(s) associated with ROS generation in the RTN has not been previously studied. However, pro/anti‐oxidant enzymes gene screening in RTN from HF rats revealed reduce expression of super oxide dismutase 2 (SOD2). Therefore, in the present study we aimed to determine whether reductions in SOD2 expression in healthy subjects resembles i) high RTN ROS levels, ii) heightened chemoreflex drive, and iii) generation of breathings disorders observed in HF animals. Accordingly, breathing function and central chemoreflex drive were assessed in freely moving heterozygous SOD2+/‐ mice by unrestrained whole‐body plethysmography. ROS levels were determined in brainstem sections containing the RTN using dihydroethidium staining. SOD2 protein expression and tissue localization were determined by immunoblot and immunofluorescence, respectively. SOD2+/‐ mice displayed reduced SOD2 protein expression (65.6 ± 3.2 vs. 100.0 ± 5.8 %; SOD2+/‐ vs. WT, respectively) and high ROS levels at the RTN compared to WT littermates (2.50 ± 0.46 vs. 1.00 ± 0.05 a.u.; SOD2+/‐ vs. WT, respectively). In addition, SOD2+/‐mice displayed an exacerbated ventilatory response to hypercapnia compared to WT mice (3.5 ± 0.2 vs. 1.9 ± 0.2 ml/min/10g; SOD2+/‐ vs. WT, respectively). Importantly, the latter was closely linked to RTN ROS production since a positive correlation (p&lt;0.05) between ROS levels and the hypercapnic ventilatory response was found only in SOD2+/‐animals. Furthermore, SOD2+/‐ mice showed overt signs of disordered breathing while resting at eupneic conditions compared to WT mice as evidenced by large increases in ventilatory instability and apneas/hypoapneas incidence (AHI: 7.7 ± 0.9 vs. 3.4 ± 0.6 events/hr; SOD2+/‐ vs. WT, respectively). Lastly, we found that SOD2 expression is preferentially confined to RTN neurons rather than to medullary astrocytes. Our results shows that reductions in the SOD2 gene expression in healthy rodents mimic the respiratory phenotype observed in experimental HF and suggests that reduced expression of SOD2 within the RTN of HF animals may account for the local increases in ROS production, the enhanced central chemoreflex drive and the generation/maintenance of irregular breathing patterns.

Role of medullary cardiorespiratory neurons on the maintenance of altered sleep function in heart failure

Sleep‐disordered breathing (SDB) and sleep fragmentation (SF) (i.e. repetitive short interruptions of sleep) are frequently reported in heart failure (HF) patients. Interestingly, SDB and SF has been both closely associated with the generation of breathing disorders. Importantly, our previous work showed that partial ablation of pre‐sympathetic catecholaminergic neurons (C1) located at the rostral ventrolateral medulla (RVLM) results in marked improvements in breathing disorders in rats with HF. However, the contribution of RVLM‐C1 neurons on sleep‐related disorders in the setting of cardiac failure has not been previously studied. Therefore, we aimed to determine the contribution of RVLM‐C1 neurons on sleep architecture in HF. Adult male Sprague‐Dawley rats (250 g) underwent volume overload to induce HF. After four weeks, anti‐dopamine β‐hydroxylase‐saporin (DβH–SAP: 2.5ng/150nl; or saline) was used to selectively destroy RVLM‐C1 neurons (‐12.36 mm AP from bregma; ± 2.2 mm ML; 8.5 mm DV). Breathing function was determined by unrestrained whole‐body plethysmograph and sleep function/sleep stages were assessed in electroencephalogram and electromyogram recordings obtained for chronic implanted leads. Compared to Sham rats, HF animals displayed no differences in the total time spent in rapid eye movement (REM) and non‐rapid eye movement (nREM) sleep stages. However, duration of each nREM epoch was significantly (p&lt;0.05) lower in HF rats (3.4 ± 0.3 vs. 2.2 ± 0.2 min, Sham vs. HF, respectively). Accordingly, HF rats showed an increased number of nREM epochs compared to Sham animals (12.0 ± 2 vs. 17 ± 2 events/h, Sham vs. HF, respectively). Interestingly, HF rats displayed loss of ventilatory stability compared to Sham rats only at nREM sleep (Irregularity score, nREM: 12.1 ± 2.0 vs. 15.9 ± 1.8%; REM: 22.9 ± 2.0 vs 24.1 ± 3.2%; Sham vs. HF, respectively). Furthermore, the incidence of sigh‐triggered arousal events during nREM sleep was increased in HF rats. Conversely, sleep probability was decreased by ~35% in HF animals compared to Sham animals. Remarkably, ablation of RVLM‐C1 neurons with DβH–SAP in HF improved nREM breathing regularity and restores normal nREM sleep duration (3.4 ± 0.3 vs. 3.1 ± 0.3 min, Sham vs. HF+DβH–SAP, respectively). In addition, DβH–SAP treatment in HF decreased sigh‐triggered arousals by ~45% being the outcome a reduction in SF in HF rats that underwent C1 ablation. Our data shows that irregular breathing is closely linked to altered sleep in HF rats and support a role for RVLM‐C1 neurons on sleep regulation in the setting of HF.

Muscle Sympathetic Nerve Reactivity to Trier Social Stress Test

Muscle sympathetic nerve activity (MSNA) responses to laboratory mental stress are highly variable, making characterization of the sympathoneural response difficult to infer. However, most commonly used mental stress tasks (i.e., mental arithmetic, Stroop Color Word Task, etc.) are primarily cognitive tasks. Further, interpretation of MSNA reactivity to these stressors can be challenging due to irregular breathing patterns, limb movement, etc. The current study assesses MSNA reactivity to the Trier Social Stress Test (TSST), an ecologically valid evaluative social stress task that utilizes an anticipatory stress period free of confounds such as irregular breathing and movement found in other mental stress tasks. The primary purpose of the present study was to assess MSNA during the stress‐anticipation period, as well as during the socially evaluated portion of the task. We hypothesized that MSNA would be elevated during both phases of the task. Sixteen healthy adults (12 female, 26 ± 1 years, 24 ± 1 kg/m2) participated in a morning autonomic function test consisting of simultaneous recordings of heart rate (HR, electrocardiogram), beat‐to‐beat blood pressure (finger plethysmography), and MSNA (microneurography) during a 10‐minute resting baseline followed by the TSST. The TSST consists of a speech preparation period (5 min), a public speech (5 min), and mental arithmetic task (5 min) in front of two laboratory judges and video recording. After completion of the TSST, participants were assessed throughout a 5‐minute recovery. MSNA was obtained throughout all tasks in 12 individuals. Compared to baseline, mean arterial pressure (MAP) significantly increased during the anticipatory phase (Δ8 ± 2 mmHg, p&lt;.001), increased further during the speech (Δ25 ± 3 mmHg, p&lt;.001) and arithmetic (Δ23 ± 3 mmHg, p&lt;.001), and returned to anticipatory levels during recovery (Δ10 ± 1 mmHg, p&lt;.001). Similarly, HR was elevated during the anticipatory (Δ8 ± 2 bpm, p=.002), and increased further during the speech (Δ24 ± 5 bpm, p&lt;.001) and arithmetic (Δ19 ± 4 bpm, p&lt;.001) phases, but fully returned to baseline levels during recovery (Δ2 ± 1 bpm p=.232). MSNA burst frequency was significantly reduced during the anticipatory phase (Δ‐5 ± 2 bursts/min, p=.014) and tended to be reduced during mental arithmetic (Δ‐5 ± 2 bursts/min, p=.058), while MSNA burst incidence was reduced during the anticipatory (Δ‐9 ± 3 bursts/100hb, p=.008) and arithmetic (Δ‐11 ± 4 bursts/100hb, p=.016) phases. In 7 individuals, MSNA signal quality allowed assessment of MSNA total area. While total MSNA appeared to increase during the speech portion of the TSST, this effect did not reach significance (Δ8906 ± 4547 arbitrary units, p=.098). Contrary to our hypothesis, while blood pressure and HR were significantly elevated, MSNA was reduced in response to social stress, likely due to baroreflex inhibition. Further, our findings exhibit previously observed inter‐individual variability in MSNA responsiveness to mental stress, even during anticipatory stress, suggesting that this variability is conserved between various laboratory stressors.

Accumulation of pathological Ataxin‐7 in the medulla leads to hypoglossal (XII) motor unit pathology

SCA7 is an autosomal dominant neurological disorder caused by a deleterious CAG repeat expansion in the coding region of the ataxin‐7 gene on chromosome 3. Patients with infantile SCA‐7 have the largest repeat expansion characterized by progressive loss of coordination, dysarthria, dysphagia, retinal degeneration and respiratory distress. These infants succumb to death due to severe hypotonia, aspiration pneumonia and respiratory failure. Our objective is to comprehensively analyze the underlying mechanisms that result in upper airway pathology which exacerbates respiratory insufficiency in SCA7. To do this, we will use an infantile SCA7 mouse model: SCA7266Q Knock‐in (KI) mouse. SCA7266Q KI mice exhibit progressive respiratory dysfunction along with irregular breathing and prolonged apneic events with a significant loss of hypoglossal (XII) motoneurons in the medulla. The XII motoneurons innervate the tongue to maintain the shape, stiffness and position of the tongue and regulate the upper airway patency. Therefore, we hypothesize that the expression of pathological ataxin‐7 in the medulla causes XII motor unit pathology leading to upper airway pathology. To confirm if the reduced number of motoneurons resulted in hypoglossal nerve pathology, we analyzed the efferent nerve output of the XII nerve of 9‐week‐old WT control and SCA72666Q KI mice during eupnea and hypercapnia (7% CO2). Later we performed post‐mortem histological analysis of the XII respiratory centers in the medulla and XII nerves. Specifically, we used immunohistochemistry to identify the cells that accumulate ataxin‐7 and we performed TUNEL assay to evaluate the extent of neurodegeneration in the XII motor pool. We analyzed the demyelination of the nerves by light microscopy and electron microscopy. To identify the cellular mechanisms involved in the XII pathology, we performed transcriptome analysis by bulk RNA sequencing of the medulla and confirmed the findings with qPCR.ResultsXII nerve efferent output is blunted at baseline and hypercapnic challenge in SCA7266QKI mice. There is increased TUNEL+ cells in the XII motor pool with intranuclear accumulation of ataxin‐7 in the astrocytes. Further, demyelination is present in the XII nerves in SCA7266QKI mice. RNA sequencing data of the medulla supports these findings and reveals diminished expression of the transcripts regulating the myelination pathway such as Plp1. There is also a significant decrease in activation of astrocytes with attenuated expression of neurotransmitter transporter such as Slc6a9 and Slc710 that are critical for breathing. In conclusion, intranuclear accumulation of ataxin‐7 in SCA7266QKI mice modulates transcription of astrocytes and influences different signaling pathways that result in neurodegeneration, demyelination, and decreased efferent XII nerve output. These findings are clinically relevant and emphasize the importance of neuropathology that results in dysphagia, aspiration pneumonia and respiratory failure in infantile SCA7.

GABAergic and Glycinergic Synaptic Transmission in Respiratory‐Controlling Kolliker‐Fuse Neurons in Female and Male Rett Syndrome Mice

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by severe motor behavior disturbances including breathing problems. RTT is caused by silencing mutations in the methyl‐CpG binding protein 2 (MeCP2) gene located on the X chromosome. Accordingly, girls and women account for the majority of RTT patients. The genetic nature of RTT lends itself to study in mice with loss of function mutations in the MeCP2 gene. Importantly, RTT mice display breathing irregularities similar to human patients. Insufficient inhibitory neurotransmission in the brainstem respiratory network is thought to contribute to the breathing problems in RTT. In the pontine Kölliker‐Fuse (KF) area of RTT mice, there are fewer GABAergic axon terminals and injection of a GABA reuptake antagonist alleviates breathing problems in vivo. However, no one has examined the physiology of GABA or glycine synapses in the KF of RTT mice. In the present work, we tested the hypothesis that GABAergic and glycinergic synapses are deficient in the KF of RTT mice. We performed whole‐cell voltage clamp recordings from KF neurons contained in brain slices of MeCP2‐deficient RTT mice and wild type littermates. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in the KF neurons of male RTT mice was reduced compared to wild type (WT) littermates. In contrast, female RTT mice showed no change in sIPSC frequency in the KF compared to control, despite having breathing abnormalities. The amplitude of sIPSCs in the KF of female mice were smaller compared to WT littermates, whereas male RTT mice showed no change in amplitude compared to WT littermates. These results spotlight the importance of studying respiratory controlling KF neurons in both male and female RTT mice, and suggest that reductions in IPSC frequency and amplitude are not sufficient to explain the breathing irregularities observed in RTT in females and males, respectively.

Binge drinking‐like behavior in juvenile rats causes long‐lasting cardiorespiratory dysfunction that persists until adulthood

Harmful alcohol abuse is associated with serious psychosocial and health damage, including cardiac and neurological morbidities. Americans drink 40% more than the global average and adolescents are the heaviest drinkers, displaying a pathological consumption pattern termed “binge drinking”, consisting in short episodes of heavy alcohol intake followed by long withdrawal periods. Despite adolescent binge drinking (ABD) drives severe impairments in neurological and cardiorespiratory function, there are no current health policies to prevent ABD or its physiological consequences. Indeed, little is known about the long‐term consequences of ABD in adulthood physiology. Therefore, we aimed to investigate the potential harmful effects of ABD on cardiac and respiratory (patho)physiology in the adult life. Sixteen male juvenile Sprague‐Dawley rats underwent ABD‐like alcohol administration protocol or control treatment, consisting of 2‐days “ON” and 2‐days “OFF” doses of ethanol (3.0 g/kg, 25% w/v in saline administered i. p.) beginning on post‐natal day (PND) 25 until PND 38. Once rats reached adulthood (PND80), respiratory and cardiac function were respectively assessed by whole‐body plethysmography and intraventricular pressure‐volume loops. Compared to controls, adult rats exposed to ABD displayed no differences in resting blood pressure, heart rate and pulmonary ventilation, but they showed a significant (p&lt;0.05) increase in the breath‐to‐breath interval variability (40.8 ± 2.8 vs. 25.6 ± 2.3 ms; ABD vs. Control, respectively) and in the incidence of apneas/hypoapneas (AHI: 5.83 ± 0.40 vs. 2.50 ± 0.37 events/h; ABD vs. Control, respectively). Intraventricular cardiac function analysis using PV‐loops revealed a reduction in left ventricular compliance in ABD animals, evidenced by the augmented slope of the end diastolic pressure‐volume relationship (EDPVR: 0.0303 ± 0.006 vs. 0.009 ± 0.001 mmHg/µL; ABD vs. Control). Also, we found that ABD induced cardiac autonomic imbalance estimated by low/high frequency ratio of heart rate variability (LFHRV/HFHRV: 1.59 ± 0.23 vs. 1.01 ± 0.08) and increased arrhythmia incidence (53.6 ± 12.7 vs. 21.7 ± 5.7 events/h; ABD vs. Control). Our results shows that binge drinking in adolescence causes long‐lasting cardiorespiratory dysfunction that includes at least cardiac diastolic dysfunction, autonomic imbalance, and generation of irregular breathing all of them persisting until the adulthood.1Laboratory of Cardiorespiratory Control, Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile. 2Biomedical Department, Facultad of Health Science, Universidad de Antofagasta. 3Centro de Excelencia de Biomedicina en Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile. 4Centro de Envejecimiento y Regeneración CARE‐UC, Pontificia Universidad Católica de Chile, Santiago, Chile.

Data-driven gated CT: An automated respiratory gating method to enable data-driven gated PET/CT.

The accuracy of positron emission tomography (PET) quantification and localization can be compromised if a misregistered computed tomography (CT) is used for attenuation correction (AC) in PET/CT. As data-driven gating (DDG) continues to grow in clinical use, these issues are becoming more relevant with respect to solutions for gated CT. In this work, a new automated DDG CT method was developed to provide average CT and DDG CT for AC of PET and DDG PET, respectively. An automatic DDG CT was developed to provide the end-expiratory (EE) and end-inspiratory (EI) phases of images from low-dose cine CT images, with all phases being averaged to generate an average CT. The respiratory phases of EE and EI were determined according to lung region Hounsfield unit (HU) values and body outline contours. The average CT was used for AC of baseline PET and DDG CT at EE phase was used for AC of DDG PET at the quiescent or EE phase. The EI and EE phases obtained with DDG CT were used for assessing the magnitude of respiratory motion. The proposed DDG CT was compared to two commercial CT gating methods: (1) 4D CT (external device based) and (2) D4D CT (DDG based) in 38 patient datasets with respect to respiratory phase image selection, lung HU, lung volume, and image artifacts. In a separate set of twenty consecutive PET/CT studies containing a mix of 18 F-FDG, 68 Ga-Dotatate, and 64 Cu-Dotatate scans, the proposed DDG CT was compared with D4D CT for impacts on registration and quantification in DDG PET/CT. In the EE phase, the images selected by DDG CT and 4D CT were identical 62.5% ± 21.6% of the time, whereas DDG CT and D4D CT were 6.5% ± 9.7%, and 4D CT and D4D CT were 8.6% ± 12.2%. These differences in EE phase image selection were significant (p < 0.0001). In the EI phase, the images selected by DDG CT and 4D CT were identical 68.2% ± 18.9% of the time, DDG CT and D4D CT were 63.9% ± 18.8%, and 4D CT and D4D CT were 61.2% ± 19.8%. These differences were not significant. The mean lung HU and volumes were not statistically different (p > 0.1) among the three methods. In some studies, DDG CT was better than D4D or 4D CT in the appropriate selection of the EE and EI phases, and D4D CT was found to reverse the EE and EI phases or not select the correct images by visual inspection. A statistically significant improvement of DDG CT over D4D CT for AC of DDG PET was also demonstrated with PET quantification analysis. When irregular breath cycles were present in the cine CT, DDG CT could be used to replace average CT for the improved AC of baseline PET. A new automatic DDG CT was developed to tackle the issues of misregistration and tumor motion in PET/CT imaging. DDG CT was significantly more consistent than D4D CT in selecting the EE phase images as the clinical standard of 4D CT. When compared to both commercial gated CT methods of 4D CT and D4D CT, DDG CT appeared to be more robust in the lower lung and upper diaphragm regions where misregistration and tumor motion often occur. DDG CT offered improved AC for DDG PET relative to D4D CT. In cases with irregular respiratory motion, DDG CT improved AC over average CT for baseline PET. The new DDG CT provides the benefits of 4D CT without the need for external device gating.

3D Kinect Camera Scheme with Time-Series Deep-Learning Algorithms for Classification and Prediction of Lung Tumor Motility.

This paper proposes a time-series deep-learning 3D Kinect camera scheme to classify the respiratory phases with a lung tumor and predict the lung tumor displacement. Specifically, the proposed scheme is driven by two time-series deep-learning algorithmic models: the respiratory-phase classification model and the regression-based prediction model. To assess the performance of the proposed scheme, the classification and prediction models were tested with four categories of datasets: patient-based datasets with regular and irregular breathing patterns; and pseudopatient-based datasets with regular and irregular breathing patterns. In this study, ‘pseudopatients’ refer to a dynamic thorax phantom with a lung tumor programmed with varying breathing patterns and breaths per minute. The total accuracy of the respiratory-phase classification model was 100%, 100%, 100%, and 92.44% for the four dataset categories, with a corresponding mean squared error (MSE), mean absolute error (MAE), and coefficient of determination (R2) of 1.2–1.6%, 0.65–0.8%, and 0.97–0.98, respectively. The results demonstrate that the time-series deep-learning classification and regression-based prediction models can classify the respiratory phases and predict the lung tumor displacement with high accuracy. Essentially, the novelty of this research lies in the use of a low-cost 3D Kinect camera with time-series deep-learning algorithms in the medical field to efficiently classify the respiratory phase and predict the lung tumor displacement.

Performance Evaluation of Amplitude and Phase Respiratory Gating Methods on Continuous-Bed-Motion Whole-Body PET Studies

Positron emission tomography (PET) scanners with the feature of continuous-bed-motion (CBM) that allows efficient whole-body dynamic scans and customized imaging protocols have been made commercially available in recent years. As the bed motion has to be reasonably slow in order to achieve sufficient count statistics, the blurring effect induced by respiratory motion is inevitable, and adequate gating methods should be applied. The aim of this study is to identify a relatively reliable gating method for CBM whole-body scans with respect to breathing pattern variability. Two methods: 1) equal amplitude gating (EAG) and 2) phase gating (PG) initially developed for the single-bed imaging protocol are evaluated using CBM data for subjects with a regular breathing pattern, irregular breathing pattern with baseline shift, and irregular breathing pattern with prolonged end expiration. The potential influence of the scan duration on the performance of the applied gating methods is taken into account as well. Based on the results, we suggest that the PG method is relatively reliable for all studied breathing patterns, while the EAG method could introduce severe artifacts in the presence of the baseline shift.

Gratification disorder in a toddler: perils of excess screen time

Infantile gratification (masturbation) is a self-stimulatory psychological behavior that is often misdiagnosed as epilepsy. It is more common in girls, occurs at 2-3 years of age and is often associated with perspiration, irregular breathing and grunting, but no loss of consciousness. Occasionally this is associated with child abuse or other psychopathology.

Excitation and Inhibition Imbalance in Rett Syndrome.

A loss of the excitation/inhibition (E/I) balance in the neural circuit has emerged as a common neuropathological feature in many neurodevelopmental disorders. Rett syndrome (RTT), a prevalent neurodevelopmental disorder that affects 1:10,000–15,000 women globally, is caused by loss-of-function mutations in the Methyl-CpG-binding Protein-2 (Mecp2) gene. E/I imbalance is recognized as the leading cellular and synaptic hallmark that is fundamental to diverse RTT neurological symptoms, including stereotypic hand movements, impaired motor coordination, breathing irregularities, seizures, and learning/memory dysfunctions. E/I balance in RTT is not homogeneously altered but demonstrates brain region and cell type specificity instead. In this review, I elaborate on the current understanding of the loss of E/I balance in a range of brain areas at molecular and cellular levels. I further describe how the underlying cellular mechanisms contribute to the disturbance of the proper E/I ratio. Last, I discuss current pharmacologic innervations for RTT and their role in modifying the E/I balance.

Variability of respiratory rate measurements in neonates- every minute counts

BackgroundRespiratory rate is difficult to measure, especially in neonates who have an irregular breathing pattern. The World Health Organisation recommends a one-minute count, but there is limited data to support this length of observation. We sought to evaluate agreement between the respiratory rate (RR) derived from capnography in neonates, over 15 s, 30 s, 120 s and 300 s, against the recommended 60 s.MethodsNeonates at two hospitals in Nairobi were recruited and had capnograph waveforms recorded using the Masimo Rad 97. A single high quality 5 min epoch was randomly chosen from each subject. For each selected epoch, the mean RR was calculated using a breath-detection algorithm applied to the waveform. The RR in the first 60 s was compared to the mean RR measured over the first 15 s, 30 s, 120 s, full 300 s, and last 60 s. We calculated bias and limits of agreement for each comparison and used Bland-Altman plots for visual comparisons.ResultsA total of 306 capnographs were analysed from individual subjects. The subjects had a median gestation age of 39 weeks with slightly more females (52.3%) than males (47.7%). The majority of the population were term neonates (70.1%) with 39 (12.8%) having a primary respiratory pathology. There was poor agreement between all the comparisons based on the limits of agreement [confidence interval], ranging between 11.9 [− 6.79 to 6.23] breaths per minute in the one versus 2 min comparison, and 34.7 [− 17.59 to 20.53] breaths per minute in the first versus last minute comparison. Worsening agreement was observed in plots with higher RRs.ConclusionsNeonates have high variability of RR, even over a short period of time. A slight degradation in the agreement is noted over periods shorter than 1 min. However, this is smaller than observations done 3 min apart in the same subject. Longer periods of observation also reduce agreement. For device developers, precise synchronization is needed when comparing devices to reduce the impact of RR variation. For clinicians, where possible, continuous or repeated monitoring of neonates would be preferable to one time RR measurements.

Does irregular breathing impact on respiratory gated radiation therapy of lung stereotactic body radiation therapy treatments?

The impact of irregular breathing on respiratory gated radiation therapy (RGRT) was evaluated for lung stereotactic body radiation therapy (SBRT) treatments. Measurements in the static mode were performed with different field sizes, depths of the measurements, breathing periods and duty cycles, using the Farmer ion chamber, PinPoint ion chamber, and microDiamond detector. The output constancy (OC) was evaluated between gated and nongated beams. Measurements in the dynamic mode for regular and irregular breathing in phase- and amplitude-gated modes, were performed with the amplitude of target motion from 5 mm to 25 mm, and breathing period from 3 to 6 s, for ion chamber, and film inserts. The dose discrepancy was evaluated for the ion chamber insert. The gamma passing rate was evaluated with film dosimetry. In the static mode, the maximum obtained OC was 0.8% using the Farmer ion chamber, 1% (p < 0.001) using the microDiamond detector, and 1.4% (p < 0.001) using the PinPoint ion chamber. In the dynamic mode, good agreement between planned and measured doses was obtained for regular breathing, 2.08 ± 0.48% (1.57 to 2.74%), which increased to 3.42 ± 1.24% (1.58 to 6.69%) for irregular breathing. The gamma passing rate of 3mm/3%, 3mm/2%, 3mm/1% and 2mm/2% was 99.4% ± 0.3, 98.2 ± 0.8%, 88.2 ± 3.0% and 96.4 ± 1.0% for regular and 97.2% ± 1.6%, 95.1 ± 2.6%, 85.6 ± 3.0% and 92.9 ± 2.9% for irregular breathing patterns (p < 0.01), respectively. For a slightly irregular breathing amplitude, lung SBRT cancer patients can be treated in the phase-gated mode.