Recurrent ischaemic cerebrovascular events as presenting manifestations of myeloproliferative neoplasms.

BACKGROUND AND PURPOSE: Myeloproliferative neoplasms (MPNs) - polycythemia vera, essential thrombocythemia and primary myelofibrosis - are associated with increased risk for ischaemic cerebrovascular events (ICVEs). Due to their low prevalence, MPNs often remain undiagnosed as the cause of ICVEs. METHODS: Case records at the University of Tübingen between 2014 and 2017 were screened to identify patients with MPN-related ICVEs. Clinical features, brain imaging, laboratory findings, applied treatments and neurological outcomes were assessed. RESULTS: In all, 3318 patients with ICVEs were identified, and amongst them 17 patients with MPN-related ICVEs were included in a retrospective study. In 58% of these patients, ICVEs were the first manifestation of the underlying MPN; 24% presented with transient ischaemic attack and 76% with ischaemic stroke. Potentially concurrent ICVE etiologies were noted in 70% of the patients. The majority (94%) of patients were positive for the JAK2 V617F mutation, whilst in 29% recurrent ICVEs (range two to three) were noted prior to MPN diagnosis. Early MPN diagnosis and management was the only significant prognostic factor for ICVE recurrence (P < 0.001). DISCUSSION: Evidence is provided that, although rare, MPNs represent an underdiagnosed cause of recurrent ICVEs. High clinical awareness is warranted to identify an underlying MPN in patients presenting with sustained, abnormal blood count findings. Clinical algorithms for prompt MPN diagnosis and initiation of MPN treatment (e.g. cytoreductive therapy, phlebotomy) are required. As MPN management comprises a significant protective factor against ICVE recurrence, induction of MPN treatment should be regarded as an integral component of secondary stroke prevention in MPN-associated ICVEs.

In vivo assessment of tumor heterogeneity in WHO 2016 glioma grades using diffusion kurtosis imaging: Diagnostic performance and improvement of feasibility in routine clinical practice.

PURPOSE: To assess the diagnostic performance of normalized and non-normalized diffusion kurtosis imaging (DKI) metrics extracted from different tumor volume data for grading glioma according to the integrated approach of the revised 2016 WHO classification. MATERIALS AND METHODS: Sixty patients with histopathologically confirmed glioma, who provided written informed consent, were retrospectively assessed between 01/2013 and 08/2016 from a prospective trial approved by the local institutional review board. Mean kurtosis (MK) and mean diffusivity (MD) metrics from DKI were assessed by two blinded physicians from four different volumes of interest (VOI): whole solid tumor including (VOItu-ed) and excluding perifocal edema (VOItu), infiltrative zone (VOIed), and single slice of solid tumor core (VOIslice). Intra-class correlation coefficient (ICC) was calculated to assess inter-rater agreement. One-way ANOVA was used to compare MK between 2016 CNS WHO tumor grades. Friedman's test compared MK and MD of each VOI. Spearman's correlation coefficient was used to correlate MK with 2016 CNS WHO tumor grades. ROC analysis was performed on MK for significant results. RESULTS: The MK assessment showed excellent inter-rater agreement for each VOI (ICC, 0.906-0.955). MK was significantly lower in IDHmutant astrocytoma (0.40±0.07), than in 1p/19q-confirmed oligodendroglioma (0.54±0.10, P=0.001) or IDHwild-type glioblastoma (0.68±0.13, P<0.001). MK and 2016 WHO tumor grades were strongly and positively correlated (VOItu-ed, r=0.684; VOItu, r=0.734; VOIed, r=0.625; VOIslice, r=0.698; P<0.001). CONCLUSIONS: Non-normalized MK values obtained from VOItu and VOIslice showed the best reproducibility and highest diagnostic performance for stratifying glioma according to the integrated approach of the recent 2016 WHO classification.

[Upper Airway Stimulation in OSA]. / Hypoglossusstimulation bei OSAS.

Anatomical basis of obstructive sleep apnea (OSA) is the collapse of the pharynx during sleep. It is considered as a result of complex interactions of structural and neuromuscular factors. Depth of sleep and body position have modulating effects. Although different areas of obstruction were identified, studies show that the sleep-mediated obstruction frequently occurs in the base of tongue area.Continuous positive airway pressure (CPAP) is the standard treatment for obstructive sleep apnea syndrome (OSAS) since more than 30 years. In several studies, treatment compliance was approximately 70%. So CPAP intolerance requires alternative surgical and non-surgical treatments.Functional electrical stimulation of upper airway muscles was investigated in the early 1980s. Studies have shown that stimulation of certain muscle groups increases the upper airway lumen. The major role of the hypoglossal nerve in upper airway obstruction was detected. The XII. cranial nerve innervates the genioglossus muscle, which stabilizes the anterior oropharynx substantially. Whereas a complete stimulation of the nerve leads to co-activation of other muscles including constrictors, the selective stimulation of anterior nerve branches causes advancement of the genioglossus.For hypoglossal nerve stimulation (HNS), the Inspire™ system and the ImThera™ device are currently approved in Europe. After extensive studies in animals and clinical examination of the concept of hypoglossal nerve stimulation (HNS), the results of the multicenter, prospective STAR study (Stimulation Therapy for Apnea Reduction) with the Inspire system were recently published. This study revealed that HNS can prevent the pharyngeal collapse without waking up the patient from sleep. The HNS with this device resulted in a significant improvement of both objective and subjective parameters of the severity of OSA.Electrical stimulation of the hypoglossal nerve is a new treatment for patients with moderate to severe OSA, who do not tolerate standard treatment.

Clinical and imaging findings in children with non-syndromic lambdoid synostosis.

UNLABELLED: True unilateral lambdoid synostosis is a very rare type of craniosynostosis. Patients present with unilateral posterior plagiocephaly. The differentiation between frequent, simple positional (deformational) posterior plagiocephaly and lambdoid synostosis is not easy and to date subject of controversy. Accurate and early diagnosis is important, because treatment is different. Simple positional plagiocephaly responds to conservative treatment, but craniosynostosis may require neurosurgical intervention. We analyzed clinical presentation of five patients in whom non-syndromic lambdoid synostosis was confirmed by CT imaging, in one additionally by high-resolution ultrasound, and finally neurosurgical intervention. However, clinical inspection alone did not reliably identify infants with lambdoid synostosis. CONCLUSION: Diagnosis of lambdoid synostosis is not always possible based on clinical inspection alone. To confirm the diagnosis imaging is recommended. There is evidence that high-resolution ultrasound can be used first-line in the future.

High-pitch dual-source CT angiography of supra-aortic arteries: assessment of image quality and radiation dose.

INTRODUCTION: High-pitch CT angiography (CTA) is a recent innovation that allows significant shortening of scan time with volume coverage of 43 mm per second. The aim of our study was to assess this technique in CTA of the head and neck. METHODS: CTA of supra-aortic arteries was performed in 50 patients using two acquisition protocols: conventional single-source 64-slice (pitch 1.2) and high-pitch dual-source 128-slice CT (pitch 3.2). Subjective and objective image quality of supra-aortic vessel ostia as well as intra- and extra-cranial segments was retrospectively assessed by blinded readers and radiation dose compared between the two protocols. RESULTS: Conventional and high-pitch CTA achieved comparable signal-to-noise ratios in arterial (54.3 ± 16.5 versus 57.3 ± 14.8; p = 0.50) and venous segments (15.8 ± 6.7 versus 18.9 ± 8.9; p = 0.21). High-pitch scanning was, however, associated with sharper delineation of vessel contours and image quality significantly improved at the level of supra-aortic vessel ostia (p < 0.0001) as well as along the brachiocephalic trunk (p < 0.0001), the subclavian arteries (p < 0.0001), proximal common carotid arteries (p = 0.01), and vertebral V1 segments (p < 0.0001). Using the high-pitch mode, the dose-length product was reduced by about 35% (218.2 ± 30 versus 141.8 ± 20 mGy × cm). CONCLUSIONS: Due to elimination of transmitted cardiac motion, high-pitch CTA of the neck improves image quality in the proximity of the aortic arch while significantly lowering radiation dose. The technique thus qualifies as a promising alternative to conventional spiral CTA and may be particularly useful for identification of ostial stenosis.

Outcome after whole brain radiotherapy alone in intracranial leptomeningeal carcinomatosis from solid tumors.

BACKGROUND: The purpose of the present study was to investigate outcome after whole brain radiotherapy (WBRT) alone as a palliative treatment without concomitant chemotherapy for intracranial leptomeningeal carcinomatosis (LMC). PATIENTS AND METHODS: Overall survival and treatment response were retrospectively analyzed in 27 consecutive patients with LMC from breast and lung cancer. All patients had evidence of intracranial manifestations of LMC. Seven potential prognostic factors were evaluated. RESULTS: Median overall survival (OS) for the entire group was 8.1 weeks. OS rates after 6 and 12 months were 26% and 15%, respectively. Improvement of neurological deficits was observed in 3 patients. In 3 of 4 patients with follow-up MRI studies, a decreased size of contrast-enhanced lesions was observed. Prognostic factors for improved OS on univariate analysis were absence of cranial nerve dysfunction, Karnofsky Performance Score (KPS) > 60%, and time interval > 35 months between the initial diagnosis of malignant disease and development of LMC. On multivariate analysis, absence of cranial nerve dysfunction remained the only significant prognosticator for OS (median 3.7 vs. 19.4 weeks, p < 0.001). CONCLUSION: WBRT alone is an effective palliative treatment for patients unfit/unsuitable for chemotherapy and low performance status suffering from intracranial LMC. However, prognostic factors should be considered in order to identify patients who are likely to benefit from WBRT.

An asthma collaboration to reduce childhood asthma disparities on the Navajo Nation: Trial protocol for the Community Asthma Program.

Navajo children disproportionately experience poor asthma outcomes. Following a one-year community engagement period with key stakeholders from the Navajo Nation, the Community Asthma Program (CAP) was created using evidenced based programs with the goal of reducing asthma disparities among Navajo children. CAP is being evaluated with a six-year, multi-site step-wedge design in three Navajo communities: Tuba City, Chinle and Fort Defiance, Arizona. The primary outcome is asthma exacerbations defined as use of systemic oral corticosteroids, asthma hospitalizations, asthma related ED visits, and ICU admissions. Asthma exacerbations will be measured using data from the electronic medical records of the three community health care centers. Secondary outcomes include will changes in asthma-related events and asthma control. The RE-AIM ( R each and representativeness, 2) E ffectiveness, 3) A doption, 4) I mplementation, and 5) M aintenance) framework is being used to guide the implementation evaluation which includes iterative collection and analysis of process data to identify facilitators and barriers, describe relevant organizational contexts, and inform strategies for dissemination. The CAP intervention requires community engagement and participation, building community capacity, incorporating evidenced-based guidelines and practices while ensuring program strategies actively involve Navajo community members during all steps of the intervention. The outcome of this trial will allow us to determine the effectiveness of a multi-component, community-focused intervention to improve asthma in a tribal community.

[Hypopharyngeal carcinoma and red ear drum]. / Hypopharynxkarzinom und gerötetes Trommelfell.

A 46-year-old male patient with an unresectable hypopharyngeal carcinoma was treated with primary radio-chemotherapy. At follow-up, the patient presented with a red ear drum and combined hearing loss. Because of radiotherapy-induced tubal dysfunction, paracentesis was performed. Biopsy of the polypoid middle ear mucosa revealed petrous bone infiltration of hypopharyngeal carcinoma. MRI studies revealed paracarotideal tumor infiltration to the petrous bone and the middle ear arising from a cervical retropharyngeal lymph node metastasis.

Transgenic mice lacking class I major histocompatibility complex-restricted T cells have delayed viral clearance and increased mortality after influenza virus challenge.

To investigate the role of CD8+ T lymphocytes in recovery from influenza pneumonia, we used transgenic mice either homozygous (-/-) or heterozygous (+/-) for beta 2-microglobulin (beta 2-M) gene disruption. These mice lack major histocompatibility complex-restricted class I (CD8+) T cells. We found that after challenge with a nonlethal influenza virus, the beta 2-M (-/-) mice had significantly delayed pulmonary viral clearance. Furthermore, after challenge with a more virulent influenza virus, the beta 2-M (-/-) mice had a significantly higher mortality rate than did control mice. Thus, CD8+ T cells are important in recovery from virulent influenza infections, but other host defense mechanisms can clear the respiratory tract of more benign infections.

The in vivo influence of white matter fiber orientation towards B(0) on T2* in the human brain.

It is well known that, at higher field strength, T2*-weighted images show an extensive heterogeneity in white matter fiber bundles. The basis of this phenomenon is still under discussion, as many factors, such as iron concentration, myelination and tissue microstructure, could influence relaxation times. Furthermore, fiber direction in relation to the main magnetic field seems to influence T2* relaxation times. In this study, diffusion tensor imaging and T2* measurements were combined in seven subjects with the head in a normal and tilted position. It was shown that fiber orientation has a strong influence on T2* in the human brain, with the average T2* value changing from 49 ms for a perpendicular orientation to B(0) to 57 ms for a parallel orientation to B(0). Nevertheless, T2* times showed a wide variety of values at any orientation towards B(0).

Transgenic rabbit production with simian immunodeficiency virus-derived lentiviral vector.

Transgenic rabbit is the preferred disease model of atherosclerosis, lipoprotein metabolism and cardiovascular diseases since upon introducing genetic mutations of human genes, rabbit models reflect human physiological and pathological states more accurately than mouse models. Beyond that, transgenic rabbits are also used as bioreactors to produce pharmaceutical proteins in their milk. Since in the laboratory rabbit the conventional transgenesis has worked with the same low efficiency in the last twenty five years and truly pluripotent embryonic stem cells are not available to perform targeted mutagenesis, our aim was to adapt lentiviral transgenesis to this species. A simian immunodeficiency virus based replication defective lentiviral vector was used to create transgenic rabbit through perivitelline space injection of fertilized oocytes. The enhanced green fluorescent protein (GFP) gene was placed under the ubiquitous CAG promoter. Transgenic founder rabbits showed mosaic pattern of GFP expression. Transgene integration and expression was revealed in tissues derived from all three primary germ layers. Transgene expression was detected in the developing sperm cells and could get through the germ line without epigenetic silencing, albeit with very low frequency. Our data show for the first time, that lentiviral transgenesis could be a feasible and viable alternative method to create genetically modified laboratory rabbit.

Digital Communication Technology: Does Offering a Choice of Modality Improve Medication Adherence and Outcomes in a Persistent Asthma Population?

BACKGROUND: Use of digital communication technology has shown potential to improve asthma adherence and outcomes. Few studies have looked at patient preference around mode of medication reminders used to improve and maintain asthma medication adherence. OBJECTIVE: To determine if, in a population already receiving automated medication reminders, offering a choice for preferred mode of reminder (text, email, phone) would improve their adherence and asthma outcomes over a 1-year period. METHODS: This was a pragmatic, randomized controlled trial conducted at Kaiser Permanente Colorado involving 7522 adult patients with persistent asthma. Study patients were randomized to receive usual care or their choice of medication reminder. Differences between the 2 groups in both medication adherence and asthma outcomes were then assessed over the following year. RESULTS: Only 30% of those offered a choice of medication reminder modality responded by making a choice, with 52% preferring text messaging. There was less of a decrease in adherence rate over the 1-year period in those who made a choice regarding the mode of medication refill reminder. There was no difference in asthma outcomes between those who did make a choice compared with those who did not make a choice regarding the mode of medication refill reminder. CONCLUSION: In a patient population already receiving medication reminders, offering a choice about what type of technology-enabled asthma medication reminder patients wanted did not improve outcomes but did enable a subgroup to better maintain their medication adherence.

Systematic Assessment of Multispectral Voxel-Based Morphometry in Previously MRI-Negative Focal Epilepsy.

BACKGROUND AND PURPOSE: Voxel-based morphometry is widely used for detecting gray matter abnormalities in epilepsy. However, its performance with changing parameters, smoothing and statistical threshold, is debatable. More important, the potential yield of combining multiple MR imaging contrasts (multispectral voxel-based morphometry) is still unclear. Our aim was to objectify smoothing and statistical cutoffs and systematically compare the performance of multispectral voxel-based morphometry with existing T1 voxel-based morphometry in patients with focal epilepsy and previously negative MRI. MATERIALS AND METHODS: 3D T1-, T2-, and T2-weighted FLAIR scans were acquired for 62 healthy volunteers and 13 patients with MR imaging negative for focal epilepsy on a Magnetom Skyra 3T scanner with an isotropic resolution of 0.9 mm3. We systematically optimized the main voxel-based morphometry parameters, smoothing level and statistical cutoff, with T1 voxel-based morphometry as a reference. As a next step, the performance of multispectral voxel-based morphometry models, T1+T2, T1+FLAIR, and T1+T2+FLAIR, was compared with that of T1 voxel-based morphometry using gray matter concentration and gray matter volume analysis. RESULTS: We found the best performance of T1 at 12 mm and a T-threshold (statistical cutoff) of 3.7 for gray matter concentration analysis. When we incorporated these parameters, after expert visual interpretation of concordant and discordant findings, we identified T1+FLAIR as the best model with a concordant rate of 46.2% and a concordant rate/discordant rate of 1.20 compared with T1 with 30.8% and 0.67, respectively. Visual interpretation of voxel-based morphometry findings decreased concordant rates from 38.5%-46.2% to 15.4%-46.2% and discordant rates from 53.8%-84.6% to 30.8%-46.2% and increased specificity across models from 33.9%-40.3% to 46.8%-54.8%. CONCLUSIONS: Multispectral voxel-based morphometry, especially T1+FLAIR, can yield superior results over single-channel T1 in focal epilepsy patients with a negative conventional MR imaging.

A novel frameshift variant in the CADASIL gene NOTCH3: pathogenic or not?

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) represents the most common monogenic cause of adult-onset ischemic stroke and vascular dementia. It is caused by heterozygous missense mutations in the NOTCH3 gene, encoding a transmembrane receptor protein on vascular smooth muscle cells. Classical CADASIL mutations affect conserved cysteine residues of the Notch3 protein. By contrast, the role of non-canonical genetic variation in NOTCH3, in particular of variants causing a hypomorphic Notch3 protein, is subject to an ongoing scientific debate. In this context, we here report a novel NOTCH3 frameshift variant in exon 18 (NM_000435.2: c.2853_2857delTCCCG), causing a frameshift and introducing a premature stop codon, which was detected in a 43-year-old woman and her father. Both carriers of the variant were carefully evaluated, including serial follow-up in the index. Neither clinical nor imaging features provided convincing evidence for a classical CADASIL phenotype, thus reinforcing the concept of hypomorphic NOTCH3 variants most likely not being causative for CADASIL. Our finding, which is discussed in the light of the published literature, has practical implications for interpreting results of NOTCH3 molecular genetic testing as well as patient counseling.

Depiction of the Superior Petrosal Vein Complex by 3D Contrast-Enhanced MR Angiography.

BACKGROUND AND PURPOSE: Intraoperative obliteration of the superior petrosal vein complex has a relevant risk of postoperative complications. A large venous diameter and the absence of anastomoses have been previously suggested as possible risk factors. 3D contrast-enhanced MRA was evaluated for the identification of superior petrosal vein anatomy. MATERIALS AND METHODS: Twenty-five patients (10 men; age, 20-77 years) with a 3D-MRA (voxel size, 0.4 × 0.4 × 0.5 mm3) at 3T, including the posterior fossa, were retrospectively identified. Image evaluation was performed independently by 2 neuroradiologists with respect to overall image quality and the presence, location, size, tributaries, and anastomotic veins of the superior petrosal vein complex. Additionally, 8 neurosurgical cases with intraoperative validation of the venous anatomy were examined. RESULTS: All studies were of diagnostic image quality. Interobserver agreement was excellent for image-quality measurements (r = 0.751-0.982) and good for measured vessel size (r = 0.563-0.828). A total of 83 superior petrosal veins were identified. The distribution of drainage locations and identification of tributaries and anastomotic veins were consistent with previous anatomic studies. The results showed that 4.8% of superior petrosal veins had a diameter of >2 mm and lacked a visible anastomosis. All surgical cases showed excellent agreement between the MRA and the intraoperative observations. CONCLUSIONS: 3D-MRA with high resolution is appropriate for analyzing the size, course, tributaries, and anastomoses of the superior petrosal vein. A total of 4.8% of the identified superior petrosal veins had to be classified as potential high-risk veins. The measurements correlated with the intraoperative findings.

Demonstration of defective C3-receptor-mediated clearance by the reticuloendothelial system in patients with acquired immunodeficiency syndrome.

The function of macrophage C3 receptors was assessed in vivo by measuring the clearance of C3-sensitized autologous erythrocytes in seven acquired immunodeficiency syndrome (AIDS) patients, eight healthy homosexual men, eight healthy heterosexual men, and four infected controls. Healthy heterosexual men had an initial clearance of 50.1 +/- 2.0% of the inoculum, with a release of a small portion of these cells (10.9 +/- 1.3%) into the circulation. Healthy homosexual men had a greater initial clearance of 66.0 +/- 4.2% (P less than 0.01) followed by a similar release (14.0 +/- 3.3%). AIDS patients had an initial clearance of 60.6 +/- 7.5% but had a relatively large release of cells (25.6 +/- 3.2%) (P less than 0.005 vs. heterosexuals; P less than 0.05 vs. homosexuals), suggesting a failure of macrophage phagocytosis. Infected controls had an initial clearance of 59.4 +/- 4.9%, with a release of 19.6 +/- 3.8% (P = NS vs. AIDS). These data, in addition to Fc-receptor dysfunction, demonstrate a global reticuloendothelial system dysfunction in AIDS patients. This may contribute to their frequent infections with opportunistic pathogens and inappropriate immune responses against these microorganisms.

The effect of video-assisted oral feedback versus oral feedback on surgical communicative competences in undergraduate training.

PURPOSE: Feedback can significantly improve future performance. Reviewing one's performance by video is discussed as useful adjunct to debriefing, particularly for non-technical skills. Communicative competencies are an essential part of daily clinical practice; thus should be taught and assessed during undergraduate training. The aim of this study was to compare the educational value of video-assisted feedback versus oral feedback in communicative competencies in the surgical context. METHODS: Fourth-year medical students completed a 210-min training unit of 'taking patient's history and obtaining informed consents prior to surgery' using role plays. Oral feedback was received directly thereafter using agenda-led, outcome-based guidelines (ALOBA). In the study group, the role plays were video-taped and reviewed thereafter. Afterwards, students completed two OSCE stations, where they were assessed regarding their communicative competencies and the content of the clinical scenario. RESULTS: One-hundred students (49 receiving video-assisted feedback, 51 oral) participated in the study. Those receiving video-assisted feedback performed significantly better in overall score in both OSCE stations (p < 0.001), in all five assessed communicative competencies at taking patient history (p = 0.029 or better), and in 2 of 5 items at obtaining informed consent (p = 0.008, <0.001). The educational effect size for both tasks was large. CONCLUSION: Using our methodology, video-assisted feedback offered a significant educational benefit over oral feedback alone during a simulated patient encounter in a surgical context.