The hospital costs of complications following major abdominal surgery: a retrospective cohort study.

OBJECTIVE: Postoperative complications following major abdominal surgeries is a pressing concern for hospital care and health economics. Given the paucity of available cost data for patients undergoing major abdominal surgery, we evaluated the number and the severity of postoperative complications following major abdominal surgeries and calculated the costs borne by a single centre university hospital within an Australian healthcare system. RESULTS: The overall incidence of postoperative complications for 1790 adult patients undergoing major abdominal surgeries (i.e., colonic, liver, small bowel resections and Whipple procedures) between January 2013 and June 2018 was 75.2%. Of these complications, 56.9% were minor (Clavien-Dindo (CVD) Grades I or II) and 15.5% were major (CVD Grades III or IV). As the severity of complications increased, median adjusted total hospital costs rose significantly, with a median (interquartile range [IQR]) of AUD 29,519.70 (IQR 21,828.80-40,527.90) in CVD Grade II versus AUD 50,702.40 (IQR 35,866.00-69,296.80) in CVD Grade III (p <.001). Further, developing one, two or three complications resulted in significantly increased hospital costs by AUD 2618.30 (13.3% increase), AUD 3605.50 (16.2% increase) and AUD 3173.00 (12.3% increase) (p <.0001), respectively, with an exponential spike in costs incurred by patients who developed more than three complications (AUD 23,719.70; 81.7% increase; p < 0001).

Multimodal intrathecal analgesia (MITA) with morphine for reducing postoperative opioid use and acute pain following hepato-pancreato-biliary surgery: A multicenter retrospective study.

INTRODUCTION: The optimal analgesic modality for patients undergoing hepato-pancreato-biliary (HPB) surgery remains unknown. The analgesic effects of a multimodal intrathecal analgesia (MITA) technique of intrathecal morphine (ITM) in combination with clonidine and bupivacaine compared to ITM alone have not been investigated in these patients. METHODS: We performed a multicenter retrospective study of patients undergoing complex HPB surgery who received ITM, bupivacaine, and clonidine (MITA group) or ITM-only (ITM group) as part of their perioperative analgesia strategy. The primary outcome was the unadjusted oral morphine equivalent daily dose (oMEDD) in milligrams on postoperative day 1. After adjusting for age, body mass index, hospital allocation, type of surgery, operation length, and intraoperative opioid use, postoperative oMEDD use was investigated using a bootstrapped quantile regression model. Other prespecified outcomes included postoperative pain scores, opioid-related adverse events, major complications, and length of hospital stay. RESULTS: In total, 118 patients received MITA and 155 patients received ITM-only. The median (IQR) cumulative oMEDD use on postoperative day 1 was 20.5 mg (8.6:31.0) in the MITA group and 52.1 mg (18.0:107.0) in the ITM group (P < 0.001). There was a variation in the magnitude of the difference in oMEDD use between the groups for different quartiles. For the MITA group, on postoperative day 1, patients in the 25th percentile required 14.0 mg less oMEDD (95% CI: -25.9 to -2.2; P = 0.025), patients in the 50th percentile required 27.8 mg less oMEDD (95% CI: -49.7 to -6.0; P = 0.005), and patients in the 75th percentile required 38.7 mg less oMEDD (95% CI: -72.2 to -5.1; P = 0.041) compared to patients in the same percentile of the ITM group. Patients in the MITA group had significantly lower pain scores in the postoperative recovery unit and on postoperative days 1 to 3. The incidence of postoperative respiratory depression was low (<1.5%) and similar between groups. Patients in the MITA group had a significantly higher incidence of postoperative hypotension requiring vasopressor support. However, no significant differences were observed in major postoperative complications, or the length of hospital stay. CONCLUSION: In patients undergoing complex HPB surgery, the use of MITA, consisting of ITM in combination with intrathecal clonidine and bupivacaine, was associated with reduced postoperative opioid use and resulted in superior postoperative analgesia without risk of respiratory depression when compared to patients who received ITM alone. A randomized prospective clinical trial investigating these two intrathecal analgesic techniques is justified.

Syncope-Do We Need AI?

Syncope is a form of transient loss of consciousness (TLOC) resulting from cerebral hypoperfusion and is characterized by rapid onset, short duration and spontaneous complete recovery [...].

Ancestral reproductive bias in branching processes.

Consider a branching process whose reproduction law is homogeneous. Sampling a single cell uniformly from the population at a time [Formula: see text] and looking along the sampled cell's ancestral lineage, we find that the reproduction law is heterogeneous-the expected reproductive output of ancestral cells on the lineage from time 0 to time T continuously increases with time. This 'inspection paradox' is due to sampling bias, that cells with a larger number of offspring are more likely to have one of their descendants sampled by virtue of their prolificity. The bias's strength changes with the random population size and/or the sampling time T. Our main result explicitly characterises the evolution of reproduction rates and sizes along the sampled ancestral lineage as a mixture of Poisson processes, which simplifies in special cases. The ancestral bias helps to explain recently observed variation in mutation rates along lineages of the developing human embryo.

Time-restricted ketogenic diet in amyotrophic lateral sclerosis: a case study.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder. The most devastating variant is bulbar-onset ALS, which portends a median survival of 24 months from the onset of symptoms. Abundant evidence indicates that neuron metabolism and mitochondrial function are impaired in ALS. Metabolic strategies, particularly fasting and ketogenic diet protocols, alter neuron metabolism and mitochondria function in a manner that may mitigate the symptoms of this disorder. We report the case of a 64-year-old man with a 21-month history of progressive, deteriorating bulbar-onset ALS, with an associated pseudobulbar affect, who implemented a time-restricted ketogenic diet (TRKD) for 18 months. During this time, he improved in ALS-related function (7% improvement from baseline), forced expiratory volume (17% improvement), forced vital capacity (13% improvement), depression (normalized), stress levels (normalized), and quality of life (19% improvement), particularly fatigue (23% improvement). His swallowing impairment and neurocognitive status remained stable. Declines were measured in physical function, maximal inspiratory pressure, and maximal expiratory pressure. Weight loss was attenuated and no significant adverse effects occurred. This case study represents the first documented occurrence of a patient with ALS managed with either a fasting or ketogenic diet protocol, co-administered as a TRKD. We measured improved or stabilized ALS-related function, forced expiratory volume, forced vital capacity, swallowing, neurocognitive status, mood, and quality of life. Measurable declines were restricted to physical function, maximal inspiratory pressure, and maximal expiratory pressure. Now over 45 months since symptom onset, our patient remains functionally independent and dedicated to his TRKD.

Novel Machine Learning Approach to Predict and Personalize Length of Stay for Patients Admitted with Syncope from the Emergency Department.

Background: Syncope, a common problem encountered in the emergency department (ED), has a multitude of causes ranging from benign to life-threatening. Hospitalization may be required, but the management can vary substantially depending on specific clinical characteristics. Models predicting admission and hospitalization length of stay (LoS) are lacking. The purpose of this study was to design an effective, exploratory model using machine learning (ML) technology to predict LoS for patients presenting with syncope. Methods: This was a retrospective analysis using over 4 million patients from the National Emergency Department Sample (NEDS) database presenting to the ED with syncope between 2016−2019. A multilayer perceptron neural network with one hidden layer was trained and validated on this data set. Results: Receiver Operator Characteristics (ROC) were determined for each of the five ANN models with varying cutoffs for LoS. A fair area under the curve (AUC of 0.78) to good (AUC of 0.88) prediction performance was achieved based on sequential analysis at different cutoff points, starting from the same day discharge and ending at the longest analyzed cutoff LoS ≤7 days versus >7 days, accordingly. The ML algorithm showed significant sensitivity and specificity in predicting short (≤48 h) versus long (>48 h) LoS, with an AUC of 0.81. Conclusions: Using variables available to triaging ED clinicians, ML shows promise in predicting hospital LoS with fair to good performance for patients presenting with syncope.

Financial burden of postoperative complications following colonic resection: A systematic review.

BACKGROUND: Colonic resection is a common surgical procedure that is associated with a high rate of postoperative complications. Postoperative complications are expected to be major contributors to hospital costs. Therefore, this systematic review aims to outline the health costs of postoperative complications following colon resection surgery. METHODS: MEDLINE, Excerpta Medica database, Cochrane, and Economics literature medical databases were searched from 2010 to 2019 to identify English studies containing an economic evaluation of postoperative complications following colonic resection in adult patients. All surgical techniques and indications for colon resection were included. Eligible study designs included randomized trials, comparative observational studies, and conference abstracts. RESULTS: Thirty-four articles met the eligibility criteria. We found a high overall complication incidence with associated increased costs ranging from $2290 to $43,146. Surgical site infections and anastomotic leak were shown to be associated with greater resource utilization relative to other postoperative complications. Postoperative complications were associated with greater incidence of hospital readmission, which in turn is highlighted as a significant financial burden. Weak evidence demonstrates increased complication incidence and costlier complications with open colon surgery as compared to laparoscopic surgery. Notably, we identified a vast degree of heterogeneity in study design, complication reporting and costing methodology preventing quantitative analysis of cost results. CONCLUSIONS: Postoperative complications in colonic resection appear to be associated with a significant financial burden. Therefore, large, prospective, cost-benefit clinical trials investigating preventative strategies, with detailed and consistent methodology and reporting standards, are required to improve patient outcomes and the cost-effectiveness of our health care systems.

Impact of a Ketogenic Diet on Sporadic Inclusion Body Myositis: A Case Study.

Sporadic inclusion body myositis (IBM) is a chronic inflammatory and degenerative muscle disease with limited treatment options; no therapy can alter its natural course. Ketogenic diets are theoretically capable of suppressing inflammation, enhancing cell bioenergetics, alleviating mitochondria dysfunction, and stimulating autophagy, which may be beneficial in IBM. We report the case of a 52-year-old woman with worsening IBM who pursued a modified ketogenic diet for 1 year. Adverse effects were mild and resolved 3 weeks into the diet. Prior to starting her ketogenic diet, despite the use of a walking stick at all times, she was experiencing one to two falls per week as well as swallowing difficulties, musculoskeletal pain, and depression. Moreover, magnetic resonance imaging (MRI) of the bilateral thighs during the year prior to the diet indicated worsening muscle inflammation and a 14% decrease in thigh muscle volume, which corresponded to a 4% decrease in the ratio of thigh muscle to thigh total volume. After 1 year on her ketogenic diet, our patient regained independent walking, and her swallowing difficulties, pain, and depression resolved. She maintained her strength, improved in every test of function, enhanced her quality of life, and lowered her blood creatine kinase. MRI of the bilateral thighs during the year of the diet indicated stabilized muscle inflammation and a 2.9% decrease in thigh muscle volume, which in the context of diet-induced fat loss corresponded to a sustained 1% increase in the ratio of thigh muscle to thigh total volume. This case is unique in that a ketogenic diet was utilized as the primary treatment strategy for a patient with confirmed IBM, culminating in substantial clinical improvement, stabilized muscle inflammation, and a slowed rate of muscle atrophy. Our patient has remained on her ketogenic diet for over 2 years now and continues to enjoy a full and independent life.

The hospital costs of complications following colonic resection surgery: A retrospective cohort study.

BACKGROUND: Colonic resection is a common surgical procedure associated with a high rate of postoperative complications. The aim of this observational study is to estimate the in-hospital costs of complications and to identify perioperative variables associated with complication development following colon resection surgery. MATERIALS AND METHODS: We conducted a single-centre cohort study with retrospective data collection of 487 patients undergoing colonic resection surgery between 2013 and 2018. Postoperative complications were graded according to the Clavien-Dindo classification system. In-hospital cost of index admission is reported in 2019 United States Dollars. Regression modelling was used to investigate the relationship of a priori selected perioperative variables and presence of complications and costs. RESULTS: Overall complication prevalence was 69.6% (95%CI:65.5%-73.7%). Median [interquartile range] cost of patients with postoperative complications was significantly increased as compared to patients without complications ($17,963 [13,533:25,178] vs $12,578 [10,196:16,140]; p < 0.0001). Clavien-Dindo Grade I, II, III and IV complications increased costs by 15.8%, 36.8%, 169.4% and 240.1% respectively (p < 0.0001). Presence of complications was significantly associated with Charlson Comorbidity Index (Odds ratio (OR) per 1-unit increase: 1.09; 95%CI:1.02 to 1.17), preoperative albumin levels (OR per 1-unit increase: 0.94; 95%CI:0.90 to 0.98) and open as compared to laparoscopic resection (OR: 2.41; 95%CI:1.32 to 4.42). CONCLUSIONS: There is a high prevalence of complications following colonic resection surgery. Postoperative complications, including minor complications (Clavien-Dindo Grade I-II), were associated with a significant increase in hospital costs and are a key target for cost containment strategies.

The financial burden of complications following rectal resection: A cohort study.

To investigate the costs associated with postoperative complications following rectal resection.Rectal resection is a major surgical procedure that carries a significant risk of complications. The occurrence of complications following surgery has both health and financial consequences. There are very few studies that examine the incidence and severity of complications and their financial implications following rectal resection.We identified 381 consecutive patients who underwent a rectal resection within a major university hospital. Patients were included using the International Classification of Diseases (ICD) codes. Complications in the postoperative period were reported using the validated Clavien-Dindo classification system. Both the number and severity of complications were recorded. Activity-based costing methodology was used to report financial outcomes. Preoperative results were also recorded and assessed.A 76.9% [95% CI: 68.3:86.2] of patients experienced one or more complications. Patients who had a complication had a median total cost of $22,567 [IQR 16,607:33,641]. Patients who did not have a complication had a median total cost of $15,882 [IQR 12,971:19,861]. The adjusted additional median cost for patients who had a complication was $5308 [95% CI: 2938:7678] (P < .001). Patients who experienced a complication tended to undergo an open procedure (P = .001), were emergent patients (P = .003), preoperatively had lower albumin levels (36 vs 38, P = .0003) and were anemic (P = .001).Complications following rectal resection are common and are associated with increased costs. Our study highlights the importance of evaluating and preventing complications in the postoperative period.

Health costs of post-operative complications following rectal resection: a systematic review.

BACKGROUND: Post-operative complications following rectal resection pose significant health and cost implications for patients and health providers. The objective of this study is to review the associated cost of complications following rectal resection. This included reporting on the proportion and severity of these complications, associated length of stay and surgical technique used. Studies were sourced from Embase OVID, MEDLINE OVID (ALL) and Cochrane Library databases by utilizing a search strategy. METHODS: This search contained studies from 1 January 2010 until 13 February 2019. Studies were included from the year 2010 to account for the implementation of enhanced recovery after surgery protocols. Studies that reported the financial cost associated with complications were included. Any indication for rectal resection was considered. Data was extracted into a formatted table and a narrative synthesis was performed. RESULTS: We identified 13 eligible studies for inclusion. There was strong evidence to suggest that complications are associated with increased costs. There was considerable variation as to the costs attributable to complications ($1443 (P < 0.001) to $17 831 (P < 0.0012), n = 12). The presence of complications was associated with an increased length of stay (5.54 (P-value not given) to 21.04 (P < 0.0001) days, n = 7). There was significant variation in the proportion of complications (6.41 to 64.71%, n = 8). Weak evidence existed around surgical technique used and the associated cost of complications. There was considerable heterogeneity among included studies. CONCLUSIONS: Complications following rectal resection increased health costs. Costs should be standardized and provide a clear methodology for their calculation. Complications should be standardized and include a grading of severity.

The Mysterious Case of an Athletic Woman with Recurrent Syncope and a "Normal" Heart.

A 53-year-old female with a history of sports participation presented to a community hospital emergency department for collapse. She was given a LifeVest® wearable cardioverter-defibrillator (WCD) (Zoll Medical Corp., Chelmsford, MA, USA) and scheduled to undergo cardiac magnetic resonance imaging (MRI) with gadolinium enhancement at a tertiary center. However, before the scheduled MRI scan could be performed, she developed tachycardia, for which the WCD alarmed. A dual-chamber implantable cardioverter-defibrillator was subsequently implanted. Assessment of a patient with syncope requires consideration of the idea that a life-threatening and recurrent arrhythmia may be a cause for the problem. However, current guidelines do not cover the routine use of WCDs in syncope. Additionally, the patient described here did not clearly meet United States Food and Drug Administration indications for the provision of an external defibrillator. We present this case to provoke discussion among colleagues regarding this patient's treatment plan.

Assessing the radiation response of lung cancer with different gene mutations using genetically engineered mice.

PURPOSE: Non-small cell lung cancers (NSCLC) are a heterogeneous group of carcinomas harboring a variety of different gene mutations. We have utilized two distinct genetically engineered mouse models of human NSCLC (adenocarcinoma) to investigate how genetic factors within tumor parenchymal cells influence the in vivo tumor growth delay after one or two fractions of radiation therapy (RT). MATERIALS AND METHODS: Primary lung adenocarcinomas were generated in vivo in mice by intranasal delivery of an adenovirus expressing Cre-recombinase. Lung cancers expressed oncogenic Kras(G12D) and were also deficient in one of two tumor suppressor genes: p53 or Ink4a/ARF. Mice received no radiation treatment or whole lung irradiation in a single fraction (11.6 Gy) or in two 7.3 Gy fractions (14.6 Gy total) separated by 24 h. In each case, the biologically effective dose (BED) equaled 25 Gy10. Response to RT was assessed by micro-CT 2 weeks after treatment. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to assess the integrity of the p53 pathway, the G1 cell-cycle checkpoint, and apoptosis. RESULTS: Tumor growth rates prior to RT were similar for the two genetic variants of lung adenocarcinoma. Lung cancers with wild-type (WT) p53 (LSL-Kras; Ink4a/ARF(FL/FL) mice) responded better to two daily fractions of 7.3 Gy compared to a single fraction of 11.6 Gy (P = 0.002). There was no statistically significant difference in the response of lung cancers deficient in p53 (LSL-Kras; p53(FL/FL) mice) to a single fraction (11.6 Gy) compared to 7.3 Gy × 2 (P = 0.23). Expression of the p53 target genes p21 and PUMA were higher and bromodeoxyuridine uptake was lower after RT in tumors with WT p53. CONCLUSION: Using an in vivo model of malignant lung cancer in mice, we demonstrate that the response of primary lung cancers to one or two fractions of RT can be influenced by specific gene mutations.

The utility of micro-CT and MRI in the assessment of longitudinal growth of liver metastases in a preclinical model of colon carcinoma.

RATIONALE AND OBJECTIVES: Liver is a common site for distal metastases in colon and rectal cancer. Numerous clinical studies have analyzed the relative merits of different imaging modalities for detection of liver metastases. Several exciting new therapies are being investigated in preclinical models. But, technical challenges in preclinical imaging make it difficult to translate conclusions from clinical studies to the preclinical environment. This study addresses the technical challenges of preclinical magnetic resonance imaging (MRI) and micro-computed tomography (CT) to enable comparison of state-of-the-art methods for following metastatic liver disease. MATERIALS AND METHODS: We optimized two promising preclinical protocols to enable a parallel longitudinal study tracking metastatic human colon carcinoma growth in a mouse model: T2-weighted MRI using two-shot PROPELLER (Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction) and contrast-enhanced micro-CT using a liposomal contrast agent. Both methods were tailored for high throughput with attention to animal support and anesthesia to limit biological stress. RESULTS AND CONCLUSIONS: Each modality has its strengths. Micro-CT permitted more rapid acquisition (<10 minutes) with the highest spatial resolution (88-micron isotropic resolution). But detection of metastatic lesions requires the use of a blood pool contrast agent, which could introduce a confound in the evaluation of new therapies. MRI was slower (30 minutes) and had lower anisotropic spatial resolution. But MRI eliminates the need for a contrast agent and the contrast-to-noise between tumor and normal parenchyma was higher, making earlier detection of small lesions possible. Both methods supported a relatively high-throughput, longitudinal study of the development of metastatic lesions.

Temporal and spectral imaging with micro-CT.

PURPOSE: Micro-CT is widely used for small animal imaging in preclinical studies of cardiopulmonary disease, but further development is needed to improve spatial resolution, temporal resolution, and material contrast. We present a technique for visualizing the changing distribution of iodine in the cardiac cycle with dual source micro-CT. METHODS: The approach entails a retrospectively gated dual energy scan with optimized filters and voltages, and a series of computational operations to reconstruct the data. Projection interpolation and five-dimensional bilateral filtration (three spatial dimensions + time + energy) are used to reduce noise and artifacts associated with retrospective gating. We reconstruct separate volumes corresponding to different cardiac phases and apply a linear transformation to decompose these volumes into components representing concentrations of water and iodine. Since the resulting material images are still compromised by noise, we improve their quality in an iterative process that minimizes the discrepancy between the original acquired projections and the projections predicted by the reconstructed volumes. The values in the voxels of each of the reconstructed volumes represent the coefficients of linear combinations of basis functions over time and energy. We have implemented the reconstruction algorithm on a graphics processing unit (GPU) with CUDA. We tested the utility of the technique in simulations and applied the technique in an in vivo scan of a C57BL∕6 mouse injected with blood pool contrast agent at a dose of 0.01 ml∕g body weight. Postreconstruction, at each cardiac phase in the iodine images, we segmented the left ventricle and computed its volume. Using the maximum and minimum volumes in the left ventricle, we calculated the stroke volume, the ejection fraction, and the cardiac output. RESULTS: Our proposed method produces five-dimensional volumetric images that distinguish different materials at different points in time, and can be used to segment regions containing iodinated blood and compute measures of cardiac function. CONCLUSIONS: We believe this combined spectral and temporal imaging technique will be useful for future studies of cardiopulmonary disease in small animals.

4D micro-CT using fast prospective gating.

Micro-CT is currently used in preclinical studies to provide anatomical information. But, there is also significant interest in using this technology to obtain functional information. We report here a new sampling strategy for 4D micro-CT for functional cardiac and pulmonary imaging. Rapid scanning of free-breathing mice is achieved with fast prospective gating (FPG) implemented on a field programmable gate array. The method entails on-the-fly computation of delays from the R peaks of the ECG signals or the peaks of the respiratory signals for the triggering pulses. Projection images are acquired for all cardiac or respiratory phases at each angle before rotating to the next angle. FPG can deliver the faster scan time of retrospective gating (RG) with the regular angular distribution of conventional prospective gating for cardiac or respiratory gating. Simultaneous cardio-respiratory gating is also possible with FPG in a hybrid retrospective/prospective approach. We have performed phantom experiments to validate the new sampling protocol and compared the results from FPG and RG in cardiac imaging of a mouse. Additionally, we have evaluated the utility of incorporating respiratory information in 4D cardiac micro-CT studies with FPG. A dual-source micro-CT system was used for image acquisition with pulsed x-ray exposures (80 kVp, 100 mA, 10 ms). The cardiac micro-CT protocol involves the use of a liposomal blood pool contrast agent containing 123 mg I ml(-1) delivered via a tail vein catheter in a dose of 0.01 ml g(-1) body weight. The phantom experiment demonstrates that FPG can distinguish the successive phases of phantom motion with minimal motion blur, and the animal study demonstrates that respiratory FPG can distinguish inspiration and expiration. 4D cardiac micro-CT imaging with FPG provides image quality superior to RG at an isotropic voxel size of 88 µm and 10 ms temporal resolution. The acquisition time for either sampling approach is less than 5 min. The radiation dose associated with the proposed method is in the range of a typical micro-CT dose (256 mGy for the cardiac study). Ignoring respiration does not significantly affect anatomic information in cardiac studies. FPG can deliver short scan times with low-dose 4D micro-CT imaging without sacrificing image quality. FPG can be applied in high-throughput longitudinal studies in a wide range of applications, including drug safety and cardiopulmonary phenotyping.

4D micro-CT for cardiac and perfusion applications with view under sampling.

Micro-CT is commonly used in preclinical studies to provide anatomical information. There is growing interest in obtaining functional measurements from 4D micro-CT. We report here strategies for 4D micro-CT with a focus on two applications: (i) cardiac imaging based on retrospective gating and (ii) pulmonary perfusion using multiple contrast injections/rotations paradigm. A dual source micro-CT system is used for image acquisition with a sampling rate of 20 projections per second. The cardiac micro-CT protocol involves the use of a liposomal blood pool contrast agent. Fast scanning of free breathing mice is achieved using retrospective gating. The ECG and respiratory signals are used to sort projections into ten cardiac phases. The pulmonary perfusion protocol uses a conventional contrast agent (Isovue 370) delivered by a micro-injector in four injections separated by 2 min intervals to allow for clearance. Each injection is synchronized with the rotation of the animal, and each of the four rotations is started with an angular offset of 22.5 from the starting angle of the previous rotation. Both cardiac and perfusion protocols result in an irregular angular distribution of projections that causes significant streaking artifacts in reconstructions when using traditional filtered backprojection (FBP) algorithms. The reconstruction involves the use of the point spread function of the micro-CT system for each time point, and the analysis of the distribution of the reconstructed data in the Fourier domain. This enables us to correct for angular inconsistencies via deconvolution and identify regions where data is missing. The missing regions are filled with data from a high quality but temporally averaged prior image reconstructed with all available projections. Simulations indicate that deconvolution successfully removes the streaking artifacts while preserving temporal information. 4D cardiac micro-CT in a mouse was performed with adequate image quality at isotropic voxel size of 88 µm and 10 ms temporal resolution. 4D pulmonary perfusion images were obtained in a mouse at 176 µm and 687 ms temporal resolution. Compared with FBP reconstruction, the streak reduction ratio is 70% and the contrast to noise ratio is 2.5 times greater in the deconvolved images. The radiation dose associated with the proposed methods is in the range of a typical micro-CT dose (0.17 Gy for the cardiac study and 0.21 Gy for the perfusion study). The low dose 4D micro-CT imaging presented here can be applied in high-throughput longitudinal studies in a wide range of applications, including drug safety and cardiopulmonary phenotyping.

Left atrial mechanical responses to right ventricular pacing in heart failure patients: implications for atrial fibrillation.

BACKGROUND: RV pacing (RVP), even with preserved atrioventricular (AV) synchrony, may lead to left atrial (LA) enlargement and atrial fibrillation. However, inciting events are unknown. We hypothesized that RVP acutely impairs LA function by mechanisms affecting atrial contraction and/or ventricular diastole. METHODS: LA function in ICD patients (n = 31, LVEF ≤ 40%) and controls (n = 14, LVEF > 50%) was contrasted between intrinsic conduction versus RVP during asynchronous (ICD, n = 17, control, n = 7), and synchronous (ICD, n = 14, control, n = 14) pacing at long (LAVd, 107 ±16 ms) and short (SAVd, 31 ± 5 ms) AV delays. LA maximal volume (LA(Max)), minimal volume (LA(Min)), and emptying fraction {LA(EmF) = (LA(Max) -LA(Min))/LA(Max)} were measured echocardiographically. Six-segment mean mitral annular tissue doppler E' (global E') assessed diastolic recoil during baseline and LAVd. RESULTS: In the ICD group, LA(Min) increased by 42% (P < 0.0009) during VVI, by 31% (P = 0.0002) during SAVd, and by 17% (P < 0.0007) during LAVd. LA(EmF) decreased by 44% (P < 0.0008), 27% (P < 0.0001), and by 15% (P = 0.003) during VVI, SAVd, and LAVd respectively. LA(Max) was unaltered. Global E' was reduced by 12%. In control, LA(Min) increased and LA(EmF) decreased significantly during VVI (82 and 58%) and SAVd (46 and 41%), but not during LAVd. CONCLUSION: In patients with LV dysfunction, RVP acutely impaired LA emptying, and increased minimal volume, most prominently when atrial contraction was impeded (VVI, DDD-SAVd) but also when completed (DDD-LAVd), indicating impaired diastolic recoil as an important mechanism. When LV function was normal, similar changes were present when atrial filling is impeded (VVI, SAVd), but not when completed (LAVd).

Lung perfusion imaging in small animals using 4D micro-CT at heartbeat temporal resolution.

PURPOSE: Quantitative in vivo imaging of lung perfusion in rodents can provide critical information for preclinical studies. However, the combined challenges of high temporal and spatial resolution have made routine quantitative perfusion imaging difficult in small animals. The purpose of this work is to demonstrate 4D micro-CT for perfusion imaging in rodents at heartbeat temporal resolution and isotropic spatial resolution. METHODS: We have recently developed a dual tube/detector micro-CT scanner that is well suited to capture first pass kinetics of a bolus of contrast agent used to compute perfusion information. Our approach is based on the paradigm that similar time density curves can be reproduced in a number of consecutive, small volume injections of iodinated contrast agent at a series of different angles. This reproducibility is ensured by the high-level integration of the imaging components of our system with a microinjector, a mechanical ventilator, and monitoring applications. Sampling is controlled through a biological pulse sequence implemented in LABVIEW. Image reconstruction is based on a simultaneous algebraic reconstruction technique implemented on a graphic processor unit. The capabilities of 4D micro-CT imaging are demonstrated in studies on lung perfusion in rats. RESULTS: We report 4D micro-CT imaging in the rat lung with a heartbeat temporal resolution (approximately 150 ms) and isotropic 3D reconstruction with a voxel size of 88 microm based on sampling using 16 injections of 50 microL each. The total volume of contrast agent injected during the experiments (0.8 mL) was less than 10% of the total blood volume in a rat. This volume was not injected in a single bolus, but in multiple injections separated by at least 2 min interval to allow for clearance and adaptation. We assessed the reproducibility of the time density curves with multiple injections and found that these are very similar. The average time density curves for the first eight and last eight injections are slightly different, i.e., for the last eight injections, both the maximum of the average time density curves and its area under the curve are decreased by 3.8% and 7.2%, respectively, relative to the average time density curves based on the first eight injections. The radiation dose associated with our 4D micro-CT imaging is 0.16 Gy and is therefore in the range of a typical micro-CT dose. CONCLUSIONS: 4D micro-CT-based perfusion imaging demonstrated here has immediate application in a wide range of preclinical studies such as tumor perfusion, angiogenesis, and renal function. Although our imaging system is in many ways unique, we believe that our approach based on the multiple injection paradigm can be used with the newly developed flat-panel slip-ring-based micro-CT to increase their temporal resolution in dynamic perfusion studies.

Quantitative blood flow measurements in the small animal cardiopulmonary system using digital subtraction angiography.

PURPOSE: The use of preclinical rodent models of disease continues to grow because these models help elucidate pathogenic mechanisms and provide robust test beds for drug development. Among the major anatomic and physiologic indicators of disease progression and genetic or drug modification of responses are measurements of blood vessel caliber and flow. Moreover, cardiopulmonary blood flow is a critical indicator of gas exchange. Current methods of measuring cardiopulmonary blood flow suffer from some or all of the following limitations--they produce relative values, are limited to global measurements, do not provide vasculature visualization, are not able to measure acute changes, are invasive, or require euthanasia. METHODS: In this study, high-spatial and high-temporal resolution x-ray digital subtraction angiography (DSA) was used to obtain vasculature visualization, quantitative blood flow in absolute metrics (ml/min instead of arbitrary units or velocity), and relative blood volume dynamics from discrete regions of interest on a pixel-by-pixel basis (100 x 100 microm2). RESULTS: A series of calibrations linked the DSA flow measurements to standard physiological measurement using thermodilution and Fick's method for cardiac output (CO), which in eight anesthetized Fischer-344 rats was found to be 37.0 +/- 5.1 ml/min. Phantom experiments were conducted to calibrate the radiographic density to vessel thickness, allowing a link of DSA cardiac output measurements to cardiopulmonary blood flow measurements in discrete regions of interest. The scaling factor linking relative DSA cardiac output measurements to the Fick's absolute measurements was found to be 18.90 x CODSA = COFick. CONCLUSIONS: This calibrated DSA approach allows repeated simultaneous visualization of vasculature and measurement of blood flow dynamics on a regional level in the living rat.