Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial.

BACKGROUND: Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm. OBJECTIVES: To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. METHODS: A 6-week randomised, crossover, double-blinded and placebo-controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6. RESULTS: Between December 2014 and 2017, 22 participants were recruited - 20 completed both arms, and 21 were analysed. The pump was well-tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid-sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1/3, 33.3% pump) and a planned procedure (1/1, 100% pump). There was a small number of expected AEs: infusion site bruising/itching (3/5, 60% pump), intercurrent illness requiring extra (3/7, 42% pump) and no extra (4/6, 66% pump) steroid. CONCLUSIONS: These findings support the administration of hormone therapy that mimics physiology.

Hospital-physician Integration and Value-based Payment: Early Results From MIPS.

BACKGROUND: Hospital-physician integration is often justified as a driver of clinical quality improvement due to joint resources covering a broad spectrum of care. Value-based programs, such as the Medicare Merit-Based Incentive Payment System (MIPS), are intended to tie financial incentives to clinical quality, which may confer an advantage on such integrated practices. OBJECTIVES: We assessed the relationship between hospital-physician integration and MIPS performance by comparing hospital-integrated practices and independent practices. RESEARCH DESIGN: This was a cross-sectional study using data from the Quality Payment Program for the performance year 2020. SUBJECTS: Physician practices with a valid MIPS composite score in performance year 2020. MEASURES: Hospital integration was based on whether at least 75% of a practice's physicians either billed most of their services using hospital outpatient department codes or billed through a hospital tax identifier. The primary outcome was the MIPS quality category score, and the secondary outcomes were the specific quality measures reported by practice groups. RESULTS: Of the 20 most frequently reported measures, 14 were common in both groups. No difference was observed in the quality category score between hospital-integrated practices and independent practices in either unadjusted comparisons or after adjusting for practice characteristics, including practice size, geography, specialty mix, and case mix. In the secondary outcome models for specific quality measures, hospital-integrated practices achieved higher scores on most overlap measures but not all. CONCLUSIONS: The findings on quality category score suggest that hospital integration does not confer much advantage in the context of MIPS quality performance.

Surveillance and treatment of primary hepatocellular carcinoma (aka. STOP HCC): protocol for a prospective cohort study of high-risk patients for HCC using GALAD-score.

BACKGROUND: Vietnam and Saudi Arabia have high disease burden of primary hepatocellular carcinoma (HCC). Early detection in asymptomatic patients at risk for HCC is a strategy to improve survival outcomes in HCC management. GALAD score, a serum-based panel, has demonstrated promising clinical utility in HCC management. However, in order to ascertain its potential role in the surveillance of the early detection of HCC, GALAD needs to be validated prospectively for clinical surveillance of HCC (i.e., phase IV biomarker validation study). Thus, we propose to conduct a phase IV biomarker validation study to prospectively survey a cohort of patients with advanced fibrosis or compensated cirrhosis, irrespective of etiologies, using semi-annual abdominal ultrasound and GALAD score for five years. METHODS: We plan to recruit a cohort of 1,600 patients, male or female, with advanced fibrosis or cirrhosis (i.e., F3 or F4) and MELD ≤ 15, in Vietnam and Saudi Arabia (n = 800 each). Individuals with a liver mass ≥ 1 cm in diameter, elevated alpha-fetoprotein (AFP) (≥ 9 ng/mL), and/or elevated GALAD score (≥ -0.63) will be scanned with dynamic contrast-enhanced magnetic resonance imaging (MRI), and a diagnosis of HCC will be made by Liver Imaging Reporting and Data System (LiRADS) assessment (LiRADS-5). Additionally, those who do not exhibit abnormal imaging findings, elevated AFP titer, and/or elevated GALAD score will obtain a dynamic contrast-enhanced MRI annually for five years to assess for HCC. Only MRI nearest to the time of GALAD score measurement, ultrasound and/or AFP evaluation will be included in the diagnostic validation analysis. MRI will be replaced with an abdominal computed tomography scan when MRI results are poor due to patient conditions such as movement etc. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced MRI will not be carried out in study sites in both countries. Bootstrap resampling technique will be used to account for repeated measures to estimate standard errors and confidence intervals. Additionally, we will use the Cox proportional hazards regression model with covariates tailored to the hypothesis under investigation for time-to-HCC data as predicted by time-varying biomarker data. DISCUSSION: The present work will evaluate the performance of GALAD score in early detection of liver cancer. Furthermore, by leveraging the prospective cohort, we will establish a biorepository of longitudinally collected biospecimens from patients with advanced fibrosis or cirrhosis to be used as a reference set for future research in early detection of HCC in the two countries. TRIAL REGISTRATION: Name of the registry: ClinicalTrials.gov Registration date: 22 April 2022 Trial registration number: NCT05342350 URL of trial registry record.

Fidelity of 3D Printed Brains from MRI Scan in Children with Pathology (Prior Hypoxic Ischemic Injury).

Cortical injury on the surface of the brain in children with hypoxic ischemic injury (HII) can be difficult to demonstrate to non-radiologists and lay people using brain images alone. Three-dimensional (3D) printing is helpful to communicate the volume loss and pathology due to HII in children's brains. 3D printed models represent the brain to scale and can be held up against models of normal brains for appreciation of volume loss. If 3D printed brains are to be used for formal communication, e.g., with medical colleagues or in court, they should have high fidelity of reproduction of the actual size of patients' brains. Here, we evaluate the size fidelity of 3D printed models from MRI scans of the brain, in children with prior HII. Twelve 3D prints of the brain were created from MRI scans of children with HII and selected to represent a variety of cortical pathologies. Specific predetermined measures of the 3D prints were made and compared to measures in matched planes on MRI. Fronto-occipital length (FOL) and bi-temporal/bi-parietal diameters (BTD/BPD) demonstrated high interclass correlations (ICC). Correlations were moderate to weak for hemispheric height, temporal height, and pons-cerebellar thickness. The average standard error of measurement (SEM) was 0.48 cm. Our results demonstrate high correlations in overall measurements of each 3D printed model derived from brain MRI scans versus the original MRI, evidenced by high ICC values for FOL and BTD/BPD. Measures with low correlation values can be explained by variability in matching the plane of measurement to the MRI slice orientation.

Species Distribution and Antifungal Susceptibility Pattern of Candida Recovered from Intensive Care Unit Patients, Vietnam National Hospital of Burn (2017-2019).

INTRODUCTION: Candida species is the most common cause of invasive fungal infection. With the wide variation in species distribution and antifungal susceptibility of causative agents, local epidemiological profiles are needed to provide effective guidelines for the treatment of invasive candidiasis. OBJECTIVE: To find out the species distribution and antifungal susceptibilities of Candida strains isolated from patients in an intensive care unit (ICU) of Vietnam. METHODS: All patients in ICU of Vietnam National Hospital of Burn with Candida isolation reported from January 2017 to December 2019 were retrospectively studied. Species identification and antifungal susceptibility testing were performed using VITEK 2 Compact. The identification was reconfirmed by sequencing of the internal transcribed spacer regions when needed. RESULTS: A total of 186 yeasts belonging to ten species were collected. The most common agent was C. tropicalis (45.7%), followed by C. albicans (42.4%), and C. parapsilosis (7.53%). The isolated yeasts showed less susceptibility to fluconazole (resistant rate R 10.7%) than to micafungin, caspofungin, flucytosine and amphotericin B (R 0%, 0.6%, 2.3% and 3.4%, respectively, p < 0.05). C. albicans isolates were more susceptible to fluconazole (R 5.2%) than C. tropicalis (R 15.7%). Resistance to voriconazole was seen only among C. albicans (3.9%) and C. tropicalis isolates (9.9%). CONCLUSION: Non-albicans species (especially C. tropicalis) is the predominant species, and there is a significant proportion of isolates with reduced susceptibility to azole but not to echinocandin.

Liver transplant mortality and morbidity following preoperative radiotherapy for hepatocellular carcinoma.

BACKGROUND: Radiotherapy (RT) can be used for tumor downstaging and as a bridge to transplantation in hepatocellular carcinoma (HCC), but its effect on surgical complications is unknown. Therefore, we investigated post-transplant mortality and acute readmission rates in HCC with and without preoperative RT using the National Cancer Database (NCDB). METHODS: After exclusion, 11,091 transplant patients were analyzed, 165 of whom received RT prior to transplant. Multivariable binomial logistic regression analysis identified characteristics associated with use of RT, and factors associated with increased 30/90-day mortality and 30-day readmission, following propensity matching. RESULTS: Although RT (median 40 Gy in 5 fractions) was more often delivered to larger tumors and advanced stages, it resulted in 59% downstaging rate, 39% pathologic complete response rate, and a median of 4 additional months to transplantation. Crude 30/90-day mortality rates were both 1.2% with preoperative RT, compared to 2.7% and 4.4% without. The 30-day readmission rate was 5.5% with RT and 10.7% without it. Propensity matched analysis demonstrated no statistical differences in 30/90-day mortality and a lower 30-day readmission rate with preoperative RT. Age >58, stage III disease, lack of transarterial chemoembolization, and shorter time to transplant independently predicted higher 90-day mortality. CONCLUSION: Preoperative RT for HCC did not increase postoperative mortality or length of stay following liver transplant.

MEG Assessment of Expressive Language in Children Evaluated for Epilepsy Surgery.

Establishing language dominance is an important step in the presurgical evaluation of patients with refractory epilepsy. In the absence of a universally accepted gold-standard non-invasive method to determine language dominance in the preoperative assessment, a range of tools and methodologies have recently received attention. When applied to pediatric age, many of the proposed methods, such as functional magnetic resonance imaging (fMRI), may present some challenges due to the time-varying effects of epileptogenic lesions and of on-going seizures on maturational phenomena. Magnetoencephalography (MEG) has the advantage of being insensitive to the distortive effects of anatomical lesions on brain microvasculature and to differences in the metabolism or vascularization of the developing brain and also provides a less intimidating recording environment for younger children. In this study we investigated the reliability of lateralized synchronous cortical activation during a verb generation task in a group of 28 children (10 males and 18 females, mean age 12 years) with refractory epilepsy who were evaluated for epilepsy surgery. The verb generation task was associated with significant decreases in beta oscillatory power (13-30 Hz) in frontal and temporal lobes. The MEG data were compared with other available presurgical non-invasive data including cortical stimulation, neuropsychological and fMRI data on language lateralization where available. We found that the lateralization of MEG beta power reduction was concordant with language dominance determined by one or more different assessment methods (i.e. cortical stimulation mapping, neuropsychological, fMRI or post-operative data) in 89% of patients. Our data suggest that qualitative hemispheric differences in task-related changes of spectral power could offer a promising insight into the contribution of dominant and non-dominant hemispheres in language processing and may help to characterize the specialization and lateralization of language processes in children.

Stereotactic Body Radiation Therapy: A New Strategy for Loco-Regional Treatment for Hepatocellular Carcinoma While Awaiting Liver Transplantation.

BACKGROUND: Trans-arterial chemoembolization and radiofrequency ablation are commonly used for control of hepatocellular carcinoma (HCC) on liver transplant (LTx) waiting list. Stereotactic body radiation therapy (SBRT) was introduced to our institution for HCC as a bridging or downsizing therapy to LTx. PATIENTS AND METHODS: Twenty-five HCC lesions in 22 patients were treated with SBRT while waiting for LTx from January 2010 to December 2015. Nineteen of these patients received deceased donor LTx. SBRT was defined as 40-50 Gy delivered in 4-6 fractions. Pre- and post-liver transplant outcome were analyzed in addition to the dropout rate and tumor response to SBRT. RESULTS: Median size of original tumors was 3.2 cm (2.0-8.9), and median size of tumor after SBRT was significantly smaller at 0.9 cm (0-3.2) in the explanted livers (p < 0.01). The dropout rate was 9%, and they were only downsized patients outside of Milan criteria. Liver disease did not progress between pre- and post-SBRT except one patient. Twenty-eight percent of treated HCCs showed complete pathologic response, and 22% had extensive partial response with some residual tumor. No HCC recurrence was experienced after LTx. CONCLUSION: SBRT is indicated to be safe, effective treatment for HCC on LTx waiting list, and it leads to satisfactory post-liver transplant outcomes.

Cardio-hepatic risk assessment by CMR imaging in liver transplant candidates.

BACKGROUND: The preoperative workup of orthotopic liver transplantation (OLT) patients is practically complex given the need for multiple imaging modalities. We recently demonstrated in our proof-of-concept study the value of a one-stop-shop approach using cardiovascular MRI (CMR) to address this complex problem. However, this approach requires further validation in a larger cohort, as detection of hepatocellular carcinoma (HCC) as well as cardiovascular risk assessment is critically important in these patients. We hypothesized that coronary risk assessment and HCC detectability is acceptable using the one-stop-shop CMR approach. METHODS: In this observational study, patients underwent CMRI evaluation including cardiac function, stress CMR, thoracoabdominal MRA, and abdominal MRI on a standard MRI scanner in one examination. RESULTS: Over 8 years, 252 OLT candidates underwent evaluation in the cardiac MRI suit. The completion rates for each segment of the CMR examination were 99% for function, 95% completed stress CMR, 93% completed LGE for viability, 85% for liver MRI, and 87% for MRA. A negative CMR stress examination had 100% CAD event-free survival at 12 months. A total of 63 (29%) patients proceeded to OLT. Explant pathology confirmed detection/exclusion of HCC. CONCLUSIONS: This study further defines the population suitable for the one-stop-shop CMR concept for preop evaluation of OLT candidates providing a road map for integrated testing in this complex patient population for evaluation of cardiac risk and detection of HCC lesions.

Technical report: 3D printing of the brain for use as a visual-aid tool to communicate MR imaging features of hypoxic ischaemic injury at term with non-physicians.

3D printing has been used in several medical applications. There are no reports however of 3D printing of the brain in children for demonstrating pathology to non-medical professionals such as lawyers. We printed 3D models of the paediatric brain from volumetric MRI in cases of severe and moderate hypoxic ischaemic injury as well as a normal age matched control, as follows: MRI DICOM data was converted to NifTI (Neuroimaging Informatics Technology Initiative) format; segmentation of the brain into CSF, grey, and white matter was performed; the segmented data was converted to STL format and printed on a commercially available scanner. The characteristic volume loss and surface features of hypoxic ischaemic injury are visible in these models, which could be of value in the communication of the nature and severity of such an insult in a court setting as they can be handled and viewed from up close.

Determination of retinal surface area.

Previous attempts at determining retinal surface area and surface area of the whole eye have been based upon mathematical calculations derived from retinal photographs, schematic eyes and retinal biopsies of donor eyes. 3-dimensional (3-D) ocular magnetic resonance imaging (MRI) allows a more direct measurement, it can be used to image the eye in vivo, and there is no risk of tissue shrinkage. The primary purpose of this study is to compare, using T2-weighted 3D MRI, retinal surface areas for superior-temporal (ST), inferior-temporal (IT), superior-nasal (SN) and inferior-nasal (IN) retinal quadrants. An ancillary aim is to examine whether inter-quadrant variations in area are concordant with reported inter-quadrant patterns of susceptibility to retinal breaks associated with posterior vitreous detachment (PVD). Seventy-three adult participants presenting without retinal pathology (mean age 26.25 ± 6.06 years) were scanned using a Siemens 3-Tesla MRI scanner to provide T2-weighted MR images that demarcate fluid-filled internal structures for the whole eye and provide high-contrast delineation of the vitreous-retina interface. Integrated MRI software generated total internal ocular surface area (TSA). The second nodal point was used to demarcate the origin of the peripheral retina in order to calculate total retinal surface area (RSA) and quadrant retinal surface areas (QRSA) for ST, IT, SN, and IN quadrants. Mean spherical error (MSE) was -2.50 ± 4.03D and mean axial length (AL) 24.51 ± 1.57 mm. Mean TSA and RSA for the RE were 2058 ± 189 and 1363 ± 160 mm2 , respectively. Repeated measures anova for QRSA data indicated a significant difference within-quadrants (P < 0.01) which, contrasted with ST (365 ± 43 mm2 ), was significant for IT (340 ± 40 mm2 P < 0.01), SN (337 ± 40 mm2 P < 0.01) and IN (321 ± 39 mm2 P < 0.01) quadrants. For all quadrants, QRSA was significantly correlated with AL (P < 0.01) and exhibited equivalent increases in retinal area/mm increase in AL. Although the differences between QRSAs are relatively small, there was evidence of concordance with reported inter-quadrant patterns of susceptibility to retinal breaks associated with PVD. The data allow AL to be converted to QRSAs, which will assist further work on inter-quadrant structural variation.

Curved reformat of the paediatric brain MRI into a 'flat-earth map' - standardised method for demonstrating cortical surface atrophy resulting from hypoxic-ischaemic encephalopathy.

Hypoxic-ischaemic encephalopathy is optimally imaged with brain MRI in the neonatal period. However neuroimaging is often also performed later in childhood (e.g., when parents seek compensation in cases of alleged birth asphyxia). We describe a standardised technique for creating two curved reconstructions of the cortical surface to show the characteristic surface changes of hypoxic-ischaemic encephalopathy in children imaged after the neonatal period. The technique was applied for 10 cases of hypoxic-ischaemic encephalopathy and also for age-matched healthy children to assess the visibility of characteristic features of hypoxic-ischaemic encephalopathy. In the abnormal brains, fissural or sulcal widening was seen in all cases and ulegyria was identifiable in 7/10. These images could be used as a visual aid for communicating MRI findings to clinicians and other interested parties.

Stereotactic body radiotherapy (SBRT) with or without surgery for primary and metastatic liver tumors.

OBJECTIVES: We report single center experience on the outcome and toxicity of SBRT alone or in combination with surgery for inoperable primary and metastatic liver tumors between 2007 and 2014. PATIENTS AND METHODS: Patients with 1-4 hepatic lesions and tumor diameter ≤9 cm received SBRT at 46.8Gy ± 3.7 in 4-6 fractions. The primary end point was local control with at least 6 months of radiographic followup, and secondary end points were toxicity and survival. RESULTS: Eighty-seven assessable patients (114 lesions) completed liver SBRT for hepatoma (39) or isolated metastases (48) with a median followup of 20.3 months (range 1.9-64.1). Fourteen patients underwent liver transplant with SBRT as a bridging treatment or for tumor downsizing. Eight patients completed hepatic resections in combination with planned SBRT for unresectable tumors. Two-year local control was 96% for hepatoma and 93.8% for metastases; it was 100% for lesions ≤4 cm. Two-year overall survival was 82.3% (hepatoma) and 64.3% (metastases). No incidence of grade >2 treatment toxicity was observed. CONCLUSION: In this retrospective analysis we demonstrate that liver SBRT alone or in combination with surgery is safe and effective for the treatment of isolated inoperable hepatic malignancies and provides excellent local control rates.

The value of Magnetoencephalography to guide electrode implantation in epilepsy.

To investigate if Magnetoencephalography (MEG) can add non-redundant information to guide implantation sites for intracranial recordings (IR). The contribution of MEG to intracranial recording planning was evaluated in 12 consecutive patients assessed pre-surgically with MEG followed by IR. Primary outcome measures were the identification of focal seizure onset in IR and favorable surgical outcome. Outcome measures were compared to those of 12 patients matched for implantation type in whom non-invasive pre-surgical assessment suggested clear hypotheses for implantation (non-MEG group). In the MEG group, non-invasive assessment without MEG was inconclusive, and MEG was then used to further help identify implantation sites. In all MEG patients, at least one virtual MEG electrode generated suitable hypotheses for the location of implantations. No differences in outcome measures were found between non-MEG and MEG groups. Although the MEG group included more complex patients, it showed similar percentage of successful implantations as the non-MEG group. This suggests that MEG can contribute to identify implantation sites where standard methods failed.

Stereotactic Body Radiation Therapy (SBRT) for Hepatocellular Carcinoma (HCC) With Single Photon Emission Computed Tomography (SPECT) Functional Treatment Planning in Patients With Advanced Hepatic Cirrhosis.

Purpose: We report on the feasibility and outcomes of liver stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) with single-photon emission computed tomography (SPECT) functional treatment planning in patients with Child-Pugh (CP) B/C cirrhosis. Methods and Materials: Liver SPECT with 99mTc-sulfur colloid was coregistered to treatment planning computed tomography (CT) for the guided avoidance of functional hepatic parenchyma during SBRT. Functional liver volumes (FLVs) obtained from SPECT were compared with anatomic liver volumes defined on the planning CT. Radiation dose constraints were adapted exclusively to FLV. Local control, toxicity, and survival were reported with at least 6 months of radiographic follow-up. Pre- and posttransplant outcomes were analyzed in a subset of patients who completed SBRT as a bridge to liver transplant. Model of End-Stage Liver Disease was used to score hepatic function before and after SBRT completion. Results: With a median follow-up of 32 months, 45 patients (58 lesions) with HCC and CP-B/C cirrhosis received SBRT to a median dose of 45 Gy (3-5 fractions). FLV loss (34%, P < .001) was observed in all patients, and the functional and anatomic liver volumes matched well in a control group of noncirrhotic/non-HCC patients. Despite marked functional parenchyma retraction, the amount of FLV on SPECT exposed to the threshold irradiation was significantly less than the CT liver volumes (P < .001) because of the optimized beam placement during dosimetry planning. Twenty-three patients (51%) successfully completed orthotopic liver transplant, with a median time to transplant of 9.2 months. With 91% in-field local control, the overall 2-year survival was 65% (90% after the orthotopic liver transplant), with no incidence of radiation-induced liver disease observed within 3 to 4 months or accelerated CP class migration from B to C within the first 6 months post-SBRT. Mean Model of End-Stage Liver Disease-Na score was not significantly elevated at 3-month intervals after SBRT completion. Conclusions: Functional treatment planning with 99mTc sulfur colloid SPECT/CT allows identification and avoidance of functional hepatic parenchyma in patients with CP-B/C cirrhosis, leading to low toxicity and satisfactory transplant outcomes.

Dysfunction of basal ganglia functional connectivity associated with subjective and cognitive fatigue in multiple sclerosis.

Objectives: Central fatigue is one of the most common symptoms in multiple sclerosis (MS). It has a profound impact on quality of life and a negative effect on cognition. Despite its widespread impact, fatigue is poorly understood and very difficult to measure. Whilst the basal ganglia has been implicated in fatigue the nature of its role and involvement with fatigue is still unclear. The aim of the present study was to establish the role of the basal ganglia in MS fatigue using functional connectivity measures. Methods: The present study examined the functional connectivity (FC) of the basal ganglia in a functional MRI study with 40 female participants with MS (mean age = 49.98 (SD = 9.65) years) and 40 female age-matched (mean age = 49.95 (SD = 9.59) years) healthy controls (HC). To measure fatigue the study employed the subjective self-report Fatigue Severity Scale and a performance measure of cognitive fatigue using an alertness-motor paradigm. To distinguish physical and central fatigue force measurements were also recorded. Results: The results suggest that decreased local FC within the basal ganglia plays a key role in cognitive fatigue in MS. Increased global FC between the basal ganglia and the cortex may sub serve a compensatory mechanism to reduce the impact of fatigue in MS. Conclusion: The current study is the first to show that basal ganglia functional connectivity is associated with both subjective and objective fatigue in MS. In addition, the local FC of the basal ganglia during fatigue inducing tasks could provide a neurophysiological biomarker of fatigue.

Dynamic facial expressions evoke distinct activation in the face perception network: a connectivity analysis study.

Very little is known about the neural structures involved in the perception of realistic dynamic facial expressions. In the present study, a unique set of naturalistic dynamic facial emotional expressions was created. Through fMRI and connectivity analysis, a dynamic face perception network was identified, which is demonstrated to extend Haxby et al.'s [Haxby, J. V., Hoffman, E. A., & Gobbini, M. I. The distributed human neural system for face perception. Trends in Cognitive Science, 4, 223-233, 2000] distributed neural system for face perception. This network includes early visual regions, such as the inferior occipital gyrus, which is identified as insensitive to motion or affect but sensitive to the visual stimulus, the STS, identified as specifically sensitive to motion, and the amygdala, recruited to process affect. Measures of effective connectivity between these regions revealed that dynamic facial stimuli were associated with specific increases in connectivity between early visual regions, such as the inferior occipital gyrus and the STS, along with coupling between the STS and the amygdala, as well as the inferior frontal gyrus. These findings support the presence of a distributed network of cortical regions that mediate the perception of different dynamic facial expressions.

Proteasome inhibition with bortezomib: an effective therapy for severe antibody mediated rejection after renal transplantation.

Antibody-mediated rejection (AMR) following renal transplantation is less responsive to conventional anti-rejection therapies. Plasmapheresis (PP), intravenous immunoglobulin (IVIg), rabbit antithymocyte globulin (rATG) and rituximab deplete immature B-cells but not mature plasma cells. The proteasome inhibitor bortezomib has activity against mature plasma cell, the source of damaging donor-specific antibody (DSA).We present the successful use of bortezomib in 2 patients who developed AMR following kidney transplantation. The first patient was a 54-year-old white female who received living-unrelated kidney transplantation from her husband. She developed severe AMR early after transplantation with rising DSA titers consistent with an anamnestic immune response by memory cells to the donor antigens. Renal function deteriorated despite treatment with pulse methylprednisolone (MP), PP and IVIg. After initiation of therapy with bortezomib, DSA titers became negative and serum creatinine returned to baseline with histological resolution of AMR. The second patient was a 19-year-old white male who received deceased donor kidney transplantation and developed AMR within 2 weeks, refractory to therapy with pulse MP, PP and IVIg with rising DSA. Bortezomib use resulted in disappearance of DSA and renal function improvement. Both patients tolerated the treatment well with stable renal function at last follow-up. The novel mechanisms of action and preliminary results with bortezomib are encouraging, but require larger studies and longer follow-up.