Separate Lobes Research Articles

Clinicopathological Description from the Largest Series of Patients with the Novel Pro106Leu MPL gene Mutation Associated with Hereditary Thrombocythemia

Background: Hereditary thrombocythemia (HT) has been reported in Japanese and African populations in association with S505N, and N35K c-Mpl mutations, respectively. A novel Pro106Leu germ-line mutation in the c-Mpl gene has recently been shown to be associated with HT in Arabic population. Clinical and bone marrow (BM) features of Pro106Leu mutation are largely unknown. Methods: The molecular genetic databases at two tertiary hospitals in Riyadh, King Abdulaziz medical city (KAMC) and King Saud University medical city (KSUMC), were searched to identify all patients (pts) with MPL Pro106Leu mutation. Clinical and pathological data were retrospectively collected. BM aspiration and biopsy were independently reviewed retrospectively by two consultant hematopathologists and agreement was reached by a consensus review. Simple descriptive statistics were used to summarize the results. A univariate subgroup analysis, comparing the hematologic parameters between the homozygous and heterozygous genotypes was conducted using Pearson Chi-Square and t-tests. Results: A total of 115 pts with Pro106Leu MPL mutation were included, 86 (75%) from KAMC and 29 (25%) from KSUMC. All pts were ethnically Arabs. Median age was 33 years (yrs) (range: 0.4-68), 65 (56.5%) were female, and 31 (27%) were pediatric pts (age <18 yrs). MPL Pro106Leu mutation was homozygous in 87 (75.7%) pts, and heterozygous in 28 (24.3%). Spleen was enlarged in 3 (3%) pts, not documented in 15 (13%), and normal in 97 (84%). History of bleeding was documented among 11 (10%) pts. Thrombosis history was positive in 5 (4%) pts only, unavailable in 6 (5%), and negative in 104 (90%). Family history of thrombocytosis was reported in 46 (40%), but family history was not documented in 20 (17%). Common comorbidities include: autoimmune disease in 33 (29%), diabetes 21 (18%), and hypertension 20 (17%). Reasons for MPL testing was: abnormal routine blood work 79 (69%), family history of thrombocytosis 23 (20%), or others 13 (11%). Thrombocytosis [platelet (plt) counts > 450 x109/L] was documented in 107 (93%) pts, normal in 4 (3.5%), and low in 4 (3.5%) at the time of diagnosis of Pro106Leu mutation. See figure 1. The median plt count at the time of diagnosis of MPL Pro106Leu mutation was 667 x 109/L (range: 13-1473). The median mean plt volume was 8 fL (range 6.1-10.2), white blood cell count 8.4 x 109/L (2.46-68.35), absolute neutrophil count 5 x 109/L (1.01- 21.19), hemoglobin 132 gm/L (85-148), mean corpuscular volume 84.1 fL (57-117.3), mean corpuscular hemoglobin 27.7 pg (18-37.5), mean corpuscular hemoglobin concentration 327 g/dL (300-351), and red cell distribution width 13.6 (10.9-22.8). Ferritin less than 30 was seen in 40 (35%) pts, 27 of whom were women. No ferritin done in 14 pts. Iron stores (based on bone marrow, ferritin and iron saturation) were adequate in 56 (49%), inadequate in 49 (43%), and not documented in 10 (9%). BCR-ABL, JAK2 and CALR were only detected in 1 pt each. One pt was not tested for CALR mutation. All other pts were negative for the three mutations. Out of all 115 pts, 33 (29%) had an evaluable BM. BM cellularity ranged from 20-100 %, 12/33 (36%) were hypocellular, 17/33 (52%) normocellular, and 4/33 (12%) hypercellular. Megakaryocyte (meg) morphology revealed dysplastic changes in 20 (60%) (hypolobated megs or with separated lobes), only 7 (21%) of cases had cloudlike megs but none had staghorn or giant megs as described in essential thrombocythemia. BM megs were increased in 29 (87%). Small size megs were seen in 15/33 (45%). Clustering of megs was seen in the majority of the cases 30/33 (90%) of whom, 29(87%) had loose and 20 (60%) dense clusters. On univariate analysis (see tables 1-2), homozygous genotype was associated with higher plt count. Total of 65 (57%) pts were prescribed aspirin, and 16 (14%) hydroxyurea. At the time of last follow-up 114 (99%) of pts were alive. The median follow-up was 7.8 yrs from the time of thrombocytosis (ranged from 0-24.8). No case developed disease progression to myelofibrosis. One pt was diagnosed with T-lymphoblastic lymphoma and later died from treatment complications and another pt was diagnosed with CML. Conclusion: Pro106Leu mutation is associated with marked thrombocytosis at a younger age with a low risk of thrombosis. Homozygous genotype is associated with a significantly higher plt count. BM usually shows either normo- or hypocellular marrow with increased megs proliferation, and clustering. Disclosures No relevant conflicts of interest to declare.

DIFFUSE ALVEOLAR HEMORRHAGE AS A CONSEQUENCE OF MICROSCOPIC POLYANGIITIS DUE TO COVID-19

SESSION TITLE: Fellows' COVID-19 SESSION TYPE: Fellow Case Reports PRESENTED ON: October 18-21, 2020 INTRODUCTION: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a small vessel vasculitis of which microscopic polyangiitis (MPA) is a subset. They are known to cause life threatening renal failure and/or pulmonary hemorrhage. Viruses are a known trigger of vasculitis, including MPA. (1) We present a case of MPA caused by COVID-19 presenting as diffuse alveolar hemorrhage (DAH) CASE PRESENTATION: 55 year old female with a past medical history of hemorrhagic stroke, hypertension & asthma who presented with respiratory distress & severe hypoxemia. At the time of intubation, a moderate amount of blood was suctioned from her endotracheal tube. She was profoundly hypoxemic & required 100% FiO2 and PEEP 18 cmH2O. A SARS CoV2 PCR test was positive. Other admission laboratory values were significant for a creatinine of 4.9 mg/dL (baseline: 0.8mg/dL), hemoglobin of 8 g/dL (baseline: 11.8g/dL), ferritin 569 ng/mL, D-dimer 3.18 ug/mL, CRP 62.8 mg/L, ESR 118 mm/hr. Chest X-ray showed dense bilateral airspace opacities. A CT scan showed extensive bilateral consolidations with air bronchograms that were not typical for a COVID-19 pneumonia (Image 1) except in the apices where these dense consolidations had a peripheral pattern. She was admitted to the medical ICU where she continued to have bleeding into her endotracheal tubing. Bronchoscopy showed blood in the airways diffusely with no focality to the bleeding. A bronchoalveolar lavage was performed of two separate lobes, and was notable for progressively bloody aliquots consistent with DAH. Because of concern for a pulmonary-renal syndrome, rheumatologic testing was performed. She was empirically treated with high dose intravenous steroids and plasmapheresis. Unfortunately, profound hypoxia persisted and family elected to withdraw life-sustaining therapies. Two days after her death, serologies revealed a mildly positive ANA and a strongly positive anti-MPO ANCA, suggesting the diagnosis of MPA. DISCUSSION: While the primary signs and symptoms of COVID-19 are fever, cough, and dyspnea, other reported manifesations include kawasaki-like disease in children (2) and cutaneous manifestations such as livedo reticularis (3). We believe that in our case the patient’s infection with COVID-19 & its subsequent increased inflammatory state led to her developing MPA vasculitis with subsequent pulmonary-renal syndrome complicated by diffuse alveolar hemorrhage, rapidly progressive renal failure and ultimately death. Her clinical and serologic picture were consistent with a diagnosis of microscopic polyangiitis. It is unclear whether our patient had a smoldering vasculitis that was triggered by the hyper-inflammatory nature of COVID-19 or whether this virus caused a vasculitis de novo. CONCLUSIONS: With vasculitis potentially being one of COVID-19's presenting symptoms, prompt diagnosis and intervention is essential in improving outcomes. Reference #1: Yates M, Watts R. ANCA-associated vasculitis. Clin Med (Lond). 2017;17(1):60-64. doi:10.7861/clinmedicine.17-1-60 Reference #2: Viner RM, Whittaker E. Kawasaki-like disease: emerging complication during the COVID-19 pandemic [published online ahead of print, 2020 May 13]. Lancet. 2020;10.1016/S0140-6736(20)31129-6. doi:10.1016/S0140-6736(20)31129-6 Reference #3: Sachdeva M, Gianotti R, Shah M, et al. Cutaneous manifestations of COVID-19: Report of three cases and a review of literature [published online ahead of print, 2020 Apr 29]. J Dermatol Sci. 2020;S0923-1811(20)30149-3. doi:10.1016/j.jdermsci.2020.04.011 DISCLOSURES: no disclosure on file for Christopher Damiano; No relevant relationships by Elie Fares, source=Web Response no disclosure on file for Catherine Kuntz; No relevant relationships by Kriti Pathak, source=Web Response

STEROID DEPENDENT CHRONIC EOSINOPHILIC PNEUMONIA: A WIN FOR IL-5 ANTAGNONISM IN AN ACTIVE DUTY SERVICE MEMBER

SESSION TITLE: Fellows Diffuse Lung Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Chronic eosinophilic pneumonia (CEP) is characterized by a clinical syndrome which includes pulmonary symptoms, eosinophilia greater than 25% in bronchoalveolar lavage, and characteristic radiographic abnormalities. Corticosteroids are the mainstay of therapy. There is no standard alternative for steroid-refractory/dependent CEP, however, reports suggest anti-IL5 therapies may be an option. We present the case of a non-asthmatic, active duty service member with steroid dependent CEP who had a dramatic clinical response to mepolizumab. CASE PRESENTATION: A 47-year-old African American female presented to us for persistent productive cough and dyspnea despite multiple rounds of steroids and antibiotics for “recurrent upper respiratory infections”. Our evaluation was notable for thoracic lymphadenopathy and diffuse ground glass opacities on CT, a positive environmental allergy screen, IgE of > 4,000 IU/mL and an absolute serum eosinophil count of over 3,400. Pulmonary function testing, to include bronchoprovocation testing was normal. A diagnosis of allergic bronchopulmonary aspergillosis (ABPA) was excluded due to negative precipitins panel and lack of classic radiographic findings. Bronchoscopic evaluation revealed tissue eosinophilia with eosinophilic granuloma formation and no evidence of vasculitis. BAL from two separate lobes revealed a cell differential > 25% eosinophils with all infectious testing negative. An ANCA panel was positive for PR3, however, subsequent work up to include numerous biopsies of various sites, was not consistent with Eosinophilic Granulomatosis with Polyangitis (EGPA), especially in this non-asthmatic. We started steroid therapy for CEP which resulted in clinical improvement, however, our patient could not be weaned below 20mg daily without resulting in symptom relapse. For her steroid-dependent CEP we trialed mepolizumab, resolving her symptoms and radiographic findings, allowing cessation of all steroids DISCUSSION: IL-5 antagnosts, like mepolizumab, bind and neutralize IL-5 thereby inhibiting eosinophil production, activation and chemotaxis (1). They are used in eosinophilic asthma to relieve airway inflammation. In CEP, eosinophils also drive chronic inflammation. Steroids are classically considered the cornerstone of therapy for these patients and can generally be weaned, however, in this case the patient had steroid dependent disease necessitating consideration for alternative therapies. In the literature, anti-IL-5 therapy is non-asthmatics is discussed, however, to the best of our knowledge, there is only one published case documenting successful use of mepolizumab in CEP (2). CONCLUSIONS: Mepolizumab appears to be a promising therapy for patients with CEP and may be considered in patients who do not respond to, or are dependent on, steroids. More research must be done into such non-steroidal agents to reduce exposure to steroids and their side effects. Reference #1: 1. Garrett JK, Jameson SC, Thomson B, et al. Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol. 2004;113(1):115-9. Reference #2: 2 To M, Kono Y, Yamawaki S, et al. A case of chronic eosinophilic pneumonia successfully treated with mepolizumab. J Allergy Clin Immunol Pract. 2018;6(5):1746-1748.e1. DISCLOSURES: No relevant relationships by Cyrus Askin, source=Web Response No relevant relationships by Tyson Sjulin, source=Web Response

Regional emphysema score is associated with tumor location and poor prognosis in completely resected NSCLC patients

BackgroundLung cancer is a frequent comorbidity of chronic obstructive pulmonary disease (COPD). However, the local risk of developing lung cancer related to regional emphysema distribution and clinical outcome has not been investigated. Our aim was to evaluate the impact of regional emphysema score (RES) on tumor location and prognosis in non-small cell lung cancer (NSCLC) patients.MethodsWe enrolled 457 patients who underwent curative surgery for NSCLC at seven hospitals at The Catholic University of Korea from 2014 to 2018. Emphysema was visually assessed for each lobe, with the lingula as a separate lobe. Semi-quantitative emphysema scoring was classified as follows: 0 = none, 0.5 = 1 to 10%, 1 = 11 to 25%, 2 = 26 to 50%, 3 = 51 to 75%, and 4 = 76 to 100%. An RES was given to each of the six lung zone: the upper, middle, and lower lobes in the right and left lungs.ResultsThere were 145 patients in the high RES (≥ 3) group and 312 in the low RES (< 3) group. The mean RES in each lobe with cancer was significantly higher than that in other lobes without cancer (0.51 vs. 0.37, P < 0.001). This group showed significantly shorter disease-free survival (P < 0.001), in addition, presence of COPD, low diffusing capacity of the lung for carbon monoxide (< 80), smoking status, and poor differentiation were more frequent in this group. Also, cancer in a lobe with a higher RES (odds ratio (OR) = 1.56; 95% confidence interval (CI:1.01–2.42; P = 0.04), pathologic stage ≥ III (OR = 2.23; 95% CI: 1.28–3.89; P < 0.001), and poor differentiation (OR = 1.99; 95% CI: 1.22–3.21; P < 0.001) were independent factors for tumor recurrence.ConclusionsThe regional severity of emphysema by visual qualification was associated with the location of lung cancer, and was an independently poor prognostic factor for tumor recurrence in completely resected NSCLC patients.

Ultrastructure of the intestinal system in unfed larvae of Limnesia maculata (O.F. Müller, 1776) (Acariformes, Limnesiidae)

The intestinal system of unfed fresh-water mite larvae Limnesia maculata (O.F. Müller, 1776) (Acariformes, Limnesiidae) has been studied with transmission electron microscopy. The intestinal system is composed of the foregut, including the pharynx and the esophagus, the sac-like blind midgut and the excretory organ. The pharynx begins with the mouth covered by the labrum. The pharynx runs along the bottom of the gnathosoma and shows ventral dilators. No valves are expressed between the pharynx and the esophagus. The esophagus possesses strongly plicate walls and, before entering the midgut, passes through the brain. The sac-like midgut does not reveal a well-pronounced lumen, developed epithelium and separate lobes. It consists of the two cell types of endoderm origin mixed in the midgut volume. The first type – the vacuolated cells – does not possess Golgi bodies and lysosomal apparatus and shows electron-lucent vacuoles with a granular inclusion inside. These cells apparently do not take part in digestion of the embryonic yolk. The second type – the non-vacuolated cells – shows both, a well developed Golgi complex and large heterolysosomes, and obviously digests the embryonic yolk. Consequently, they may be attributed as specialized vitellophages. Nevertheless, both cell types may take part in formation of the definitive midgut epithelium. The sac-like thin-walled excretory organ is strongly dilated and contains the embryonic wastes in the form of electron-dense globules and birefringent particles. No muscle envelope surrounds the excretory organ. The embryonic wastes together with wastes accumulated during feeding may be evacuated from the organ only after completion of feeding. The excretory canal on this developmental stage is not connected with the excretory organ. It opens to the outside with a simple slit-like excretory pore. Before feeding, larvae have to pass the process of the post-molt development before their midgut would be ready to receive nutrients.

Pre-chirp managed self-phase modulation for efficient generation of wavelength-tunable energetic femtosecond pulses

Self-phase-modulation-enabled spectral selection (SESS) allows generation of widely tunable femtosecond pulses. We propose pre-chirp managed SESS, in which the excitation pulse is properly pre-chirped to control the fiber-optic nonlinear spectral broadening and hence generate separated spectral lobes—a feature demanded by SESS. Besides offering improved efficiency compared with conventional energy-tuned SESS, this new method is able to reshape an input pulse of unwanted shape into a bell-shaped pulse that is desired for implementing SESS. The excellent energy scalability of pre-chirp managed SESS can produce megawatt-level femtosecond pulses widely tunable in the wavelength range of 0.86–1.3 µm. Such a powerful source is well suited to drive multiphoton microscopy to achieve deep-tissue imaging.

Different Principles Govern Different Scales of Brain Folding.

The signature folds of the human brain are formed through a complex and developmentally regulated process. In vitro and in silico models of this process demonstrate a random pattern of sulci and gyri, unlike the highly ordered and conserved structure seen in the human cortex. Here, we account for the large-scale pattern of cortical folding by combining advanced fetal magnetic resonance imaging with nonlinear diffeomorphic registration and volumetric analysis. Our analysis demonstrates that in utero brain growth follows a logistic curve, in the absence of an external volume constraint. The Sylvian fissure forms from interlobar folding, where separate lobes overgrow and close an existing subarachnoid space. In contrast, other large sulci, which are the ones represented in existing models, fold through an invagination of a flat surface, a mechanistically different process. Cortical folding is driven by multiple spatially and temporally different mechanisms; therefore regionally distinct biological process may be responsible for the global geometry of the adult brain.

Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): a prospective, comparative study

Transbronchial lung cryobiopsy (TBLC) is a novel technique for sampling lung tissue for interstitial lung disease diagnosis. The aim of this study was to establish the diagnostic accuracy of TBLC compared with surgical lung biopsy (SLB), in the context of increasing use of TBLC in clinical practice as a less invasive biopsy technique. COLDICE was a prospective, multicentre, diagnostic accuracy study investigating diagnostic agreement between TBLC and SLB, across nine Australian tertiary hospitals. Patients with interstitial lung disease aged between 18 and 80 years were eligible for inclusion if they required histopathological evaluation to aid diagnosis, after detailed baseline evaluation. After screening at a centralised multidisciplinary discussion (MDD), patients with interstitial lung disease referred for lung biopsy underwent sequential TBLC and SLB under one anaesthetic. Each tissue sample was assigned a number between 1 and 130, allocated in a computer-generated random sequence. Encoded biopsy samples were then analysed by masked pathologists. At subsequent MDD, de-identified cases were discussed twice with either TBLC or SLB along with clinical and radiological data, in random non-consecutive order. Co-primary endpoints were agreement of histopathological features in TBLC and SLB for patterns of definite or probable usual interstitial pneumonia, indeterminate for usual interstitial pneumonia, and alternative diagnosis; and for agreement of consensus clinical diagnosis using TBLC and SLB at MDD. Concordance and κ values were calculated for each primary endpoint. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12615000718549. Between March 15, 2016, and April 15, 2019, we enrolled 65 patients (31 [48%] men, 34 [52%] women; mean age 66·1 years [SD 9·3]; forced vital capacity 83·7% [SD 14·2]; diffusing capacity for carbon monoxide 63·4% [SD 12·8]). TBLC (7·1 mm, SD 1·9) and SLB (46·5 mm, 14·9) samples were each taken from two separate ipsilateral lobes. Histopathological agreement between TBLC and SLB was 70·8% (weighted κ 0·70, 95% CI 0·55-0·86); diagnostic agreement at MDD was 76·9% (κ 0·62, 0·47-0·78). For TBLC with high or definite diagnostic confidence at MDD (39 [60%] of 65 cases), 37 (95%) were concordant with SLB diagnoses. In the 26 (40%) of 65 cases with low-confidence or unclassifiable TBLC diagnoses, SLB reclassified six (23%) to alternative high-confidence or definite MDD diagnoses. Mild-moderate airway bleeding occurred in 14 (22%) patients due to TBLC. The 90-day mortality was 2% (one of 65 patients), following acute exacerbation of idiopathic pulmonary fibrosis. High levels of agreement between TBLC and SLB for both histopathological interpretation and MDD diagnoses were shown. The TBLC MDD diagnoses made with high confidence were particularly reliable, showing excellent concordance with SLB MDD diagnoses. These data support the clinical utility of TBLC in interstitial lung disease diagnostic algorithms. Further studies investigating the safety profile of TBLC are needed. University of Sydney, Hunter Medical Research Institute, Erbe Elektromedizin, Medtronic, Cook Medical, Rymed, Karl-Storz, Zeiss, and Olympus.

Transbronchial Lung Cryobiopsy for Interstitial Lung Disease Diagnosis: Results of the COLDICE Study

Background: Transbronchial lung cryobiopsy (TBLC) is a novel technique for sampling lung tissue for interstitial lung disease (ILD) diagnosis. Despite its increasing use, the diagnostic accuracy of TBLC compared to surgical lung biopsy (SLB) remains unclear. Methods: We conducted a prospective, multicentre study investigating diagnostic agreement between TBLC and SLB. After screening at a centralised multi-disciplinary discussion (MDD), ILD patients referred for lung biopsy underwent sequential TBLC and SLB under one anaesthetic. Blinded analysis of biopsy samples was conducted by 3 pathologists, individually and by consensus. At subsequent MDD, deidentified cases were discussed twice with either TBLC or SLB along with clinical and radiological data, in random non-consecutive order. Primary endpoints were: 1) agreement of histopathological features in TBLC and SLB for patterns of definite/probable usual interstitial pneumonia (UIP), indeterminate for UIP and diagnosis; and for 2) agreement of consensus clinical diagnosis using TBLC and SLB at MDD. Concordance and kappa values were calculated. Findings: 65 patients (31 males; age 66·1±9·3yrs; FVC 84·7±14·2%; DLCO 63·4±13·8%) were enrolled. TBLC (7·1±1·9mm) and SLB samples (46·5±14·9mm) were each taken from two separate ipsilateral lobes. Histopathological agreement between TBLC and SLB was 70·8%, weighted κ 0·70 (95%CI 0·55-0·86); diagnostic agreement at MDD was 76·9%, κ 0·62 (95%CI 0·47-0·78). For TBLC with high/definite diagnostic confidence at MDD (39/65, 60% cases), 37 (94·9%) were concordant with SLB diagnoses. In the 26/65 (40.0%) with low-confidence/unclassifiable TBLC diagnoses, SLB reclassified only 6 (23.1%) to alternative high/definite MDD diagnoses. Mild-moderate airway bleeding occurred in 14 (21.5%) patients due to TBLC. Interpretation: High agreement between TBLC and SLB for histopathological patterns and MDD diagnoses support the clinical utility of TBLC in ILD diagnostic algorithms. Trial Registration: Australian New Zealand Clinical Trials Registry http://www.anzctr.org.au/ study ID ACTRN12615000718549. Funding Statement: University of Sydney, Hunter Medical Research Institute, Erbe Elektromedizin GmbH, Medtronic, Cook Medical, Rymed, Karl-Storz, Zeiss and Olympus. Declaration of Interests: LKT received study-related unrestricted educational grants or inkind support from the aforementioned commercial entities, on behalf of the COLDICE Investigator Team. TJC reports grants, personal fees and non-financial support from Boehringer Ingelheim, grants and personal fees from Roche, grants from Galapagos, grants from Actelion, grants from Bayer, outside the submitted work. MPV sits on the advisory boards of Medtronic and Edwards Lifesciences, and consults for Edwards Lifesciences and Abbott. GR provides consultation for Bellerophon, Biogen, BMS, FibroGen, Gilead, Nitto, Revistan, Promedior, Sanofi, Veracyte, Roche-Genentech, Avalyn and Boehringer Ingelheim. JM is an unpaid collaborator in the Veracyte BRAVE Trial. Ethics Approval Statement: Ethics approval of the trial protocol was provided by an independent ethics committee at each participating site. Both the steering committee and data and safety monitoring board provided trial oversight, including contemporaneous review of all safety events. Participants gave fully informed consent.

Systems tracts and their bounding surfaces in the low- accommodation Upper Mannville group, Saskatchewan, Canada

Abstract Sequence stratigraphic interpretations of paralic successions can be challenging, because such settings are commonly controlled by a combination of allogenic controls and autogenic processes, leading to complex depositional architectures. In low-accommodation systems where parasequences are less than 15 m thick, the challenges in recognizing discrete stratigraphic surfaces are exacerbated by limited vertical separation between surfaces or their outright erosional amalgamation, requiring high-resolution facies analysis to resolve their geometries. Herein, we present criteria derived from core data and well logs to differentiate between allogenic and autogenic surfaces in a low-accommodation paralic setting, using the Lower Cretaceous Mannville Group of west-central Saskatchewan, Canada as a case study. The upper part of the Mannville Group (Sparky, Waseca and McLaren formations) displays complex stratigraphic relationships related to base-level changes. Marine flooding surfaces (MFS) and transgressive surfaces of erosion (TSE) of 3rd and 4th order record allogenic changes ( e.g., basin subsidence and/or eustatic changes in sea level), and are used to define parasequence boundaries of strandplain-shoreface successions. Deltaic deposits not only possess these allogenic transgressive surfaces, but autogenic 5th-order flooding surfaces, which are broadly similar in appearance, as well. These autogenic surfaces record responses to channel avulsion or lobe abandonment, separate discrete delta lobes, and display limited lateral extents. Shoreface-related flooding surfaces, by contrast, bound true allogenic parasequences and, therefore, have regional correlatability. The Waseca Formation also possesses surfaces related to base-level fall. To the north, a subtle regressive surface of marine erosion (RSME) marks the base of the falling stage systems tract. Elsewhere, a widespread subaerial unconformity (SU) separates the Waseca into lower and upper members. In most areas, the SU is amalgamated with surfaces generated by later base-level rise. Upper Mannville strata in the study area, therefore, can be separated into parts of two depositional sequences. The main deposits of the lower sequence comprise a highstand systems tracts (HST) in the Sparky Formation. The base of the Lower Waseca Member marks the onset of a transgressive systems tract (TST), associated with widespread shoreline retreat. A 3rd-order maximum flooding surface (MxFS) marks the end of transgression and resumption of normal progradational regression in a highstand systems tract associated with the Lower Waseca Member. Following highstand normal regression, a major base-level fall initiated a subaerial unconformity that marks the base of the upper sequence. Fluvial valley incision led to sediment bypass and deposition of forced regressive and lowstand shoreface and delta complexes of the falling stage systems tract (FSST) and lowstand systems tract (LST), respectively, in the northern part of the study area. Pedogenic modification of subaerially exposed sediment occurred in interfluve areas. Ensuing TST accumulation was initially confined to the tidal-fluvial estuarine infill of the incised valleys and transgressive bay deposits of the Upper Waseca Member. The Upper Waseca is capped by a 3rd-order maximum flooding surface (MxFS), which separates it from the overlying McLaren Formation. This marks the return to regional shoreline progradational regression and corresponds to the highstand systems tract (HST) of the upper sequence.

The glacial landsystem of Hoffellsjökull, SE Iceland: contrasting geomorphological signatures of active temperate glacier recession driven by ice lobe and bed morphology

ABSTRACTA 1:14 500 scale glacial geomorphology and surficial geology map of the foreland of Hoffellsjökull, southeast Iceland is used to assess the glacial landsystem signature of the contrasting glacier-climate interactions of two separate flow lobes within one outlet glacier. This constitutes a valuable modern analogue for employing glacial geomorphological signatures as palaeoclimate indicators in ancient deglaciated terrains. The landsystem signatures of the glacier’s two flow lobes, Svínafellsjökull and Hoffellsjökull, are distinctly different. Svínafellsjökull displays inset and seasonally climatically-tuned push moraine sequences and subglacially streamlined surfaces typical of active temperate glaciers on sloping piedmont forelands. Hoffellsjökull displays the landform-sediment assemblages typical of outwash-head/depositional overdeepening scenarios, upon which closely-spaced composite push moraines reflect a long term quasi-stationary snout at and near the Little Ice Age maximum prior to 2000. Moraine spacing on the Svínafellsjökull foreland reflects an overall trend of annual recession punctuated by quasi-stability and/or readvance in the mid-1950s-1960 and 1975–2000 as recorded by two arcuate zones of closely-spaced and partially overprinted sawtooth and hairpin moraines. The pattern of moraine distribution here also reflects spatio-temporal changes in moraine-forming processes as dictated by changes in a combination of proglacial drainage characteristics and structural glaciology or crevasse architecture. The subglacial footprint of the Svínafellsjökull foreland contains features worthy of future research attention, including an arcuate zone of overridden moraines potentially indicative of a regional Holocene ice advance, prominent flutings and debris stripes potentially indicative of groove-ploughing and point-source bedrock plucking respectively, and relatively large drumlins.

Propagation properties of optical bottle beam in turbulence

We study the propagation properties of optical bottle beams in turbulent atmosphere. By allowing the mathematical expression of source plane to cover both the symmetric and asymmetric forms, the beam is propagated through turbulence using random phase screens. On the source plane, the intensity profile of the bottle beam resembles a dark hollow beam with an outside ring for symmetric cases, whereas it becomes divided into two or more separate lobes for the asymmetric cases. During propagation, both symmetric and asymmetric beams concentrate the intensity toward the center, eventually assuming a Gaussian shape, where this process seems to be more rapid for the former beam types. The rising trend of the kurtosis parameter of bottle beams changes to a falling trend when the refractive index structure constant is reduced from 10 − 14 to 10 − 13 m − 2/3.

Bone Marrow Morphology Associated With Germline RUNX1 Mutations in Patients With Familial Platelet Disorder With Associated Myeloid Malignancy.

Germline mutations in RUNX1 result in autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM). To characterize the hematopathologic features associated with a germline RUNX1 mutation, we reviewed a total of 42 bone marrow aspirates from 14 FPDMM patients, including 24 cases with no cytogenetic clonal abnormalities, and 18 with clonal karyotypes or leukemia. We found that all aspirate smears had ≥10% atypical megakaryocytes, predominantly characterized by small forms with hypolobated and eccentric nuclei, and forms with high nuclear-to-cytoplasmic ratios. Core biopsies showed variable cellularity and variable numbers of megakaryocytes with similar features to those in the aspirates. Granulocytic and/or erythroid dysplasia (≥10% cells per lineage) were present infrequently. Megakaryocytes with separate nuclear lobes were increased in patients with myelodysplastic syndrome (MDS) and acute leukemia. Comparison to an immune thrombocytopenic purpura cohort confirms increased megakaryocytes with hypolobated eccentric nuclei in FPDMM patients. As such, patients with FPDMM often have atypical megakaryocytes with small hypolobated and eccentric nuclei even in the absence of clonal cytogenetic abnormalities; these findings are related to the underlying RUNX1 germline mutation and not diagnostic of MDS. Isolated megakaryocytic dysplasia in patients with unexplained thrombocytopenia should raise the possibility of an underlying germline RUNX1 mutation.

White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers.336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function).Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers – in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load – a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year.In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial.

Origin of paleovalleys on the Rio Grande do Sul Shield (Brazil): Implications for the extent of late Paleozoic glaciation in west-central Gondwana

The location, longevity, and geographic extent of late Paleozoic ice centers in west-central Gondwana remain ambiguous. Paleovalleys on the Rio Grande do Sul Shield of southernmost Brazil have previously been interpreted as fjords carved by outlet glaciers that originated in Africa and emptied into the Paraná Basin (Brazil). In this study, the sedimentology, stratigraphy, and provenance of sediments infilling two such paleovalleys (the Mariana Pimentel and Leão paleovalleys) were examined in order to test the hypothesis that an ice center over present day Namibia drained across southernmost Brazil during the Carboniferous and Permian. Contrary to previous findings, the facies assemblage from within the paleovalleys is inconsistent with a fjord setting and no clear evidence for glaciation was observed. The facies show a transition from a non-glacial lacustrine/estuarine environment, to a fluvial-dominated setting, and finally to a restricted marine/estuarine environment. Detrital zircon results present a single population of Neoproterozoic ages (c. 800–550 Ma) from the paleovalley fill that matches the ages of underlying igneous and metamorphic basement (Dom Feliciano Belt) and is incongruent with African sources that contain abundant older (Mesoproterozoic, Paleoproterozoic, and Archean) zircons. Furthermore, results suggest that the formation of the paleovalleys and the deposition of their fill were controlled by the reactivation of Neoproterozoic basement structures during the Carboniferous and Permian. The lack of evidence for glaciation in these paleovalleys highlights the need for detailed studies of supposed late Paleozoic glacial deposits. These results are supportive of the hypothesis that well-established glacial sediments on the Rio Grande do Sul Shield (southern margin of the Paraná Basin) may be the product of a separate lobe extending north across Uruguay, rather than a single, massive ice sheet draining west from Africa.

Validation of automated lobe segmentation on paired inspiratory-expiratory chest CT in 8-14 year-old children with cystic fibrosis.

ObjectivesDensitometry on paired inspiratory and expiratory multidetector computed tomography (MDCT) for the quantification of air trapping is an important approach to assess functional changes in airways diseases such as cystic fibrosis (CF). For a regional analysis of functional deficits, an accurate lobe segmentation algorithm applicable to inspiratory and expiratory scans is beneficial.Materials and methodsWe developed a fully automated lobe segmentation algorithm, and subsequently validated automatically generated lobe masks (ALM) against manually corrected lobe masks (MLM). Paired inspiratory and expiratory CTs from 16 children with CF (mean age 11.1±2.4) acquired at 4 time-points (baseline, 3mon, 12mon, 24mon) with 2 kernels (B30f, B60f) were segmented, resulting in 256 ALM. After manual correction spatial overlap (Dice index) and mean differences in lung volume and air trapping were calculated for ALM vs. MLM.ResultsThe mean overlap calculated with Dice index between ALM and MLM was 0.98±0.02 on inspiratory, and 0.86±0.07 on expiratory CT. If 6 lobes were segmented (lingula treated as separate lobe), the mean overlap was 0.97±0.02 on inspiratory, and 0.83±0.08 on expiratory CT. The mean differences in lobar volumes calculated in accordance with the approach of Bland and Altman were generally low, ranging on inspiratory CT from 5.7±52.23cm3 for the right upper lobe to 17.41±14.92cm3 for the right lower lobe. Higher differences were noted on expiratory CT. The mean differences for air trapping were even lower, ranging from 0±0.01 for the right upper lobe to 0.03±0.03 for the left lower lobe.ConclusionsAutomatic lobe segmentation delivers excellent results for inspiratory and good results for expiratory CT. It may become an important component for lobe-based quantification of functional deficits in cystic fibrosis lung disease, reducing necessity for user-interaction in CT post-processing.

Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities.

Despite improvements in our understanding of the molecular basis of acute myeloid leukemia (AML), the association between genetic mutations with morphological dysplasia remains unclear. In this study, we evaluated and scored dysplasia in bone marrow (BM) specimens from 168 patients with de novo AML; none of these patients had cytogenetic abnormalities according to the 2016 World Health Organization Classification. We then performed targeted sequencing of diagnostic BM aspirates for recurrent mutations associated with myeloid malignancies. We found that cohesin pathway mutations [q (FDR-adjusted P)=0.046] were associated with a higher degree of megakaryocytic dysplasia and STAG2 mutations were marginally associated with greater myeloid lineage dysplasia (q=0.052). Frequent megakaryocytes with separated nuclear lobes were more commonly seen among cases with cohesin pathway mutations (q=0.010) and specifically in those with STAG2 mutations (q=0.010), as well as NPM1 mutations (q=0.022 when considering the presence of any vs. no megakaryocytes with separated nuclear lobes). RAS pathway mutations (q=0.006) and FLT3-ITD (q=0.006) were significantly more frequent in cases without evaluable erythroid cells. In univariate analysis of the 153 patients treated with induction chemotherapy, NPM1 mutations were associated with longer event-free survival (EFS) (P=0.042), while RUNX1 (P=0.042), NF1 (P=0.040), frequent micromegakaryocytes (P=0.018) and presence of a subclone (P=0.002) were associated with shorter EFS. In multivariable modeling, NPM1 was associated with longer EFS, while presence of a subclone and frequent micromegakaryocytes remained significantly associated with shorter EFS.

In-vivo Visualization of Iron Oxide Enhancement in Focal Pulmonary Inflammatory Lesions Using a Three-Dimensional Radial Gradient-Echo-Based Ultrashort Echo Time Sequence: A Preliminary Study.

ObjectiveTo preliminarily evaluate technical feasibility of a dual-echo ultrashort echo time (UTE) subtraction MR imaging by using concurrent dephasing and excitation (CODE) sequence for visualization of iron-oxide enhancement in focal inflammatory pulmonary lesions.Materials and MethodsA UTE pulmonary MR imaging before and after the injection of clinically usable superparamagnetic iron-oxide nanoparticles, ferumoxytol, was conducted using CODE sequence with dual echo times of 0.14 ms for the first echo and 4.15 ms for the second echo on 3T scanner in two rabbits concurrently having granulomatous lung disease and lung cancer in separate lobes. A mean ratio of standardized signal intensity (SI) was calculated for comparison of granulomatous lesion and cancer at first echo, second echo, and subtracted images. Lesions were pathologically evaluated with Prussian blue and immunohistochemistry staining.ResultsPost-contrast subtracted CODE images visualized exclusive enhancement of iron oxide in granulomatous disease, but not in the cancer (mean ratio of SI, 2.15 ± 0.68 for granulomatous lesion versus 1.00 ± 0.07 for cancer; p value = 0.002). Prussian blue and corresponding anti-rabbit macrophage IgG-staining suggested an intracellular uptake of iron-oxide nanoparticles in macrophages of granulomatous lesions.ConclusionDual-echo UTE subtraction MR imaging using CODE sequence depicts an exclusive positive enhancement of iron-oxide nanoparticle in rabbits in focal granulomatous inflammatory lesions.

Variations in human pulmonary fissures and lobes: a study conducted in nepalese cadavers.

The fissures of lungs are embryologically separating the bronchopulmonary segments, which later on persist in interlobar planes of fully developed lung. Fifty lungs (23 right side and 27 left side), obtained during routine dissection and preserved in formalin constituted the material for present study. In them, variations in fissures and lobes of lung were observed and compared with the previous studies. Seven right sided and 14 left sided lungs showed incomplete oblique fissure. Incomplete horizontal fissure of right lung was observed in eight lungs while it was completely missing in three specimens. A right lung with “lobe of the azygos vein” separated by a supernumerary fissure in medial surface was found. One of the right lung had both superior accessory fissure and inferior accessory fissure and four other right lungs and one left lung presented only with inferior accessory fissure. A vertical notch was found in middle lobe of one right lung. Eight left lungs exhibited with left minor fissure among them two lungs had lingula appearing as a separate lobe. Knowledge of variations in fissures and lobes is of interest to all medical professionals to exactly interpret radiographs, computed tomography scans, to diagnose, plan and modify a surgical procedure depending on the merit of the case and also in certain classical clinical cases pertaining to lung pathologies.

Pathophysiological mechanism of long-term noninvasive ventilation in stable hypercapnic patients with COPD using functional respiratory imaging.

IntroductionPatients with severe COPD often develop chronic hypercapnic respiratory failure. Their prognosis worsens and they are more likely to develop exacerbations. This has major influence on the health-related quality of life. Currently, there is no information about the success of long-term noninvasive ventilation (NIV) among patients who receive NIV in acute settings. Also, little is known about the pathophysiological mechanism of NIV.MethodsTen Global Initiative for Obstructive Lung Disease stage III and IV COPD patients with respiratory failure who were hospitalized following acute exacerbation were treated with NIV using a Synchrony BiPAP device for 6 months. Arterial blood gases and lung function parameters were measured. Low-dose computed tomography of the thorax was performed and used for segmentation. Further analyses provided lobe volume, airway volume, and airway resistance, giving an overall functional description of the separate airways and lobes. Ventilation perfusion (VQ) was calculated. Patient-reported outcomes were evaluated.ResultsPaCO2 significantly improved from 50.03 mmHg at baseline to 44.75 mmHg after 1 month and 43.37 mmHg after 6 months (P=0.006). Subjects showed improvement in the 6-minute walk tests (6MWTs) by an average of 51 m (from 332 m at baseline to 359 m at 1 month and 383 m at 6 months). Patients demonstrated improvement in self-reported anxiety (P=0.018). The improvement in image-based VQ was positively associated with the 6MWT and the anxiety domain of the Severe Respiratory Insufficiency Questionnaire.ConclusionThough previous studies of long-term NIV have shown conflicting results, this study demonstrates that patients can benefit from long-term NIV treatment, resulting in improved VQ, gas exchange, and exercise tolerance.