Proof of concept of triple COMBI therapy to prohibit MPN progression to AML.

Patients with accelerated or blast phase myeloproliferative neoplasms have a dismal prognosis. The report by de Castro et al. provides important information on the rationale and prospect for a novel therapeutic approach combining interferon-alpha2 with 5-azacytidine and a JAK1-2 inhibitor (ruxolitinib) to be explored in well-designed clinical trials. Commentary on: Castro et al. Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia. Br J Haematol 2024;204:206-220.

The CALR mutations enhance the expression of the immunosuppressive proteins GARP and LAP on peripheral blood lymphocytes through increased binding of activated platelets.

Recently, an antibody which inhibits the glycoprotein A repetitions predominant (GARP)-mediated release of active transforming growth factor beta (TGFß) from the TGFß propeptide latency-associated peptide (LAP) showed preclinical activity in a murine model of the chronic myeloproliferative neoplasms (MPN). Consequently, we investigated the expression of the immunosuppressive molecules LAP and GARP on peripheral blood lymphocytes from 56 MPN patients and 11 healthy donors (HD). We found that lymphocytes from patients with MPN express higher levels of LAP and GARP with no strong differences found between the different MPN diagnoses. The impact of clinical parameters on the expression of LAP and GARP by lymphocytes showed that patients with calreticulin (CALR)mut MPN have increased expression compared with HD and patients with the Januskinase2 (JAK2) mutation. The fraction of lymphocytes bound to activated platelets (aPLT) strongly correlate to LAP and GARP expression suggesting that it is not the lymphocytes themselves but aPLT, which confer the increased expression of GARP and LAP on MPN patient lymphocytes. Notably, no differences in neither platelet counts nor anti-thrombotic therapy was identified between patients with JAK2- and CALRmut patients. Analysis of platelet gene expression failed to identify differences in expression of relevant genes between JAK2- and CALRmut patients.

COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study.

Patients with chronic lymphocytic leukemia (CLL) are at high risk of developing severe COVID-19. The present study was undertaken to elucidate COVID-19 related morbidity and mortality in CLL patients treated with venetoclax. We present a single-center study of 108 patients with small lymphocytic lymphoma or CLL treated with venetoclax. Primary outcome was 30-day COVID-19 mortality. Secondary outcomes included COVID-19 severity and hospitalization rate. Forty-eight (44%) patients had PCR-verified SARS-COV-2 between March 2020 and January 2023. Thirty-six patients (75%) presented with asymptomatic/mild COVID-19 and 12 (25%) with severe/critical disease. The hospitalization rate was 46% with a 30-day mortality rate of only 4% and severe comorbidities as the primary cause of death. COVID-19 severity and mortality were similar before and during the Omicron era. High CIRS-scores (P < 0.02) and thrombocytopenia (P < 0.01) were more frequent in patients with severe/critical disease. In real-world data, most venetoclax treated patients presented with mild COVID-19. Hospitalization and mortality rates were low compared to data of general CLL populations. Our data indicate that venetoclax was a safe treatment option for CLL patients during the pandemic.

JAK2V617F drives gut microbiota differences in patients with myeloproliferative neoplasms.

BACKGROUND: Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF) are myeloproliferative neoplasms (MPN). Inflammation is involved in the initiation, progression, and symptomology of the diseases. The gut microbiota impacts the immune system, infection control, and steady-state hematopoiesis. METHODS: We analyzed the gut microbiota of 227 MPN patients and healthy controls (HCs) using next-generation sequencing. We expanded our previous results in PV and ET patients with additional PV, pre-MF, and MF patients which allowed us to compare MPN patients collectively, MPN sub-diagnoses, and MPN mutations (separately and combined) vs. HCs (N = 42) and compare within MPN sub-diagnoses and MPN mutation. RESULTS: MPN patients had a higher observed richness (median, 245 [range, 49-659]) compared with HCs (191.5 [range, 111-300; p = .003]) and a lower relative abundance of taxa within the Firmicutes phylum; for example, Faecalibacterium (6% vs. 14%, p < .001). The microbiota of CALR-positive patients (N = 30) resembled that of HCs more than that of patients with JAK2V617F (N = 177). In JAK2V617F-positive patients, only minor differences in the gut microbiota were observed between MPN sub-diagnoses, illustrating the importance of this mutation. CONCLUSION: The gut microbiota in MPN patients differs from HCs and is driven by JAK2V617F, whereas the gut microbiota in CALR patients resembles HCs more.

Anammox bacteria drive fixed nitrogen loss in hadal trench sediments.

Benthic N2 production by microbial denitrification and anammox is the largest sink for fixed nitrogen in the oceans. Most N2 production occurs on the continental shelves, where a high flux of reactive organic matter fuels the depletion of nitrate close to the sediment surface. By contrast, N2 production rates in abyssal sediments are low due to low inputs of reactive organics, and nitrogen transformations are dominated by aerobic nitrification and the release of nitrate to the bottom water. Here, we demonstrate that this trend is reversed in the deepest parts of the oceans, the hadal trenches, where focusing of reactive organic matter enhances benthic microbial activity. Thus, at ∼8-km depth in the Atacama Trench, underlying productive surface waters, nitrate is depleted within a few centimeters of the sediment surface, N2 production rates reach those reported from some continental margin sites, and fixed nitrogen loss is mainly conveyed by anammox bacteria. These bacteria are closely related to those known from shallow oxygen minimum zone waters, and comparison of activities measured in the laboratory and in situ suggest they are piezotolerant. Even the Kermadec Trench, underlying oligotrophic surface waters, exhibits substantial fixed N removal. Our results underline the role of hadal sediments as hot spots of deep-sea biological activity, revealing a fully functional benthic nitrogen cycle at high hydrostatic pressure and pointing to hadal sediments as a previously unexplored niche for anaerobic microbial ecology and diagenesis.

Interferon alpha-2 treatment reduces circulating neutrophil extracellular trap levels in myeloproliferative neoplasms.

Neutrophil extracellular traps (NETs) may play a pathogenic role in the thrombosis associated with myeloproliferative neoplasms (MPNs). We measured serum NET levels in 128 pretreatment samples from patients with MPNs and in 85 samples taken after 12 months of treatment with interferon alpha-2 (PEG-IFNα-2) formulations or hydroxyurea (HU). No differences in NET levels were observed across subdiagnoses or phenotypic driver mutations. In PV, a JAK2V617F+ allele burden ≥50% associated with increased NET levels (p = 0.006). Baseline NET levels correlated with neutrophil count (r = 0.29, p = 0.001), neutrophil-to-lymphocyte ratio (r = 0.26, p = 0.004) and JAK2V617F allele burden (r = 0.22, p = 0.03), particularly in patients with PV and with allele burden ≥50% (r = 0.50, p = 0.01, r = 0.56, p = 0.002 and r = 0.45, p = 0.03 respectively). In PV, after 12 months of treatment, NET levels decreased on average by 60% in patients with allele burden ≥50%, compared to only 36% in patients with an allele burden <50%. Overall, treatment with PEG-IFNα-2a or PEG-IFNα-2b reduced NETs levels in 77% and 73% of patients, respectively, versus only 53% of HU-treated patients (average decrease across treatments: 48%). Normalization of blood counts did not per se account for these reductions. In conclusion, baseline NET levels correlated with neutrophil count, NLR and JAK2V617F allele burden, and IFNα was more effective at reducing prothrombotic NET levels than HU.

Faecal haemoglobin concentrations are associated with all-cause mortality and cause of death in colorectal cancer screening.

BACKGROUND: Colorectal cancer (CRC) screening reduces all-cause and CRC-related mortality. New research demonstrates that the faecal haemoglobin concentration (f-Hb) may indicate the presence of other serious diseases not related to CRC. We investigated the association between f-Hb, measured by a faecal immunochemical test (FIT), and both all-cause mortality and cause of death in a population-wide cohort of screening participants. METHODS: Between 2014 and 2018, 1,262,165 participants submitted a FIT for the Danish CRC screening programme. We followed these participants, using the Danish CRC Screening Database and several other national registers on health and population, until December 31, 2018. We stratified participants by f-Hb and compared them using a Cox proportional hazards regression on all-cause mortality and cause of death reported as adjusted hazard ratios (aHRs). We adjusted for several covariates, including comorbidity, socioeconomic factors, demography and prescription medication. RESULTS: We observed 21,847 deaths in the study period. Our multivariate analyses indicated an association relationship between increasing f-Hb and the risk of dying in the study period. This risk increased steadily from aHR 1.38 (95% CI: 1.32, 1.44) in those with a f-Hb of 7.1-11.9 µg Hb/g faeces to 2.20 (95% CI: 2.10, 2.30) in those with a f-Hb ≥60.0 µg Hb/g faeces, when compared to those with a f-Hb ≤7.0 µg Hb/g faeces. The pattern remained when excluding CRC from the analysis. Similar patterns were observed between incrementally increasing f-Hb and the risk of dying from respiratory disease, cardiovascular disease and cancers other than CRC. Furthermore, we observed an increased risk of dying from CRC with increasing f-Hb. CONCLUSIONS: Our findings support the hypothesis that f-Hb may indicate an elevated risk of having chronic conditions if causes for the bleeding have not been identified. The mechanisms still need to be established, but f-Hb may be a potential biomarker for several non-CRC diseases.

Whole blood transcriptional profiling reveals highly deregulated atherosclerosis genes in Philadelphia-chromosome negative myeloproliferative neoplasms.

BACKGROUND: The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are associated with a huge comorbidity burden, including an increased risk of cardiovascular diseases. Recently, chronic inflammation has been suggested to be the driving force for clonal evolution and disease progression in MPN but also potentially having an impact upon the development of accelerated (premature) atherosclerosis. OBJECTIVES: Since chronic inflammation, atherosclerosis, and atherothrombosis are prevalent in MPNs and we have previously shown oxidative stress genes to be markedly upregulated in MPNs, we hypothesized that genes linked to development of atherosclerosis might be highly deregulated as well. METHODS: Using whole blood gene expression profiling in patients with essential thrombocythemia (ET; n = 19), polycythemia vera (PV; n = 41), or primary myelofibrosis (PMF; n = 9), we herein for the first time report aberrant expression of several atherosclerosis genes. RESULTS: Of 84 atherosclerosis genes, 45, 56, and 46 genes were deregulated in patients with ET, PV, or PMF, respectively. Furthermore, BCL2L1, MMP1, PDGFA, PTGS1, and THBS4 were progressively significantly upregulated and BCL2 progressively significantly downregulated from ET over PV to PMF (all FDR <0.05). CONCLUSIONS: We have for the first time shown massive deregulation of atherosclerosis genes in MPNs, likely reflecting the inflammatory state in MPNs in association with in vivo activation of leukocytes, platelets, and endothelial cells being deeply involved in the atherosclerotic process.

Socioeconomic differences in expected discomfort from colonoscopy and colon capsule endoscopy.

Individual income and educational level are associated with participation rates in colorectal cancer screening. We aimed to investigate the expected discomfort from the endoscopic diagnostic modalities of colonoscopy and colon capsule endoscopy in different socioeconomic groups as a potential barrier for participation. In a randomized clinical trial within the Danish colorectal cancer screening program, we distributed questionnaires to 2031 individuals between August 2020 and December 2022 to investigate the expected procedural and overall discomfort from investigations using visual analogue scales. Socioeconomic status was determined by household income and educational level. Multivariate continuous ordinal regressions were performed to estimate the odds of higher expected discomfort. The expected procedural and overall discomfort from both modalities were significantly higher with increasing educational levels and income, except for procedural discomfort from colon capsule endoscopy between income quartiles. The odds ratios for higher expected discomfort increased significantly with increasing educational level, whereas the differences between income groups were less substantial. Bowel preparation contributed most to expected discomfort in colon capsule endoscopy, whereas in colonoscopy, the procedure itself was the largest contributor. Individuals with prior experiences of colonoscopy reported significantly lower expected overall but not procedural discomfort from colonoscopy. The threshold for acceptable discomfort between subgroups is unknown, but the expected discomfort in colon capsule endoscopy and colonoscopy was higher in higher socioeconomic subgroups, suggesting that expected discomfort is not a significant contributor to the inequalities in screening uptake.

Long-term stability of thyroid peroxidase antibody (anti-TPO) in serum in the Danish General Suburban Population Study.

OBJECTIVES: We evaluated the long-term stability of thyroid peroxidase antibody (anti-TPO). METHODS: In the Danish General Suburban Population Study (GESUS), serum samples were biobanked at -80 °C during 2010-2013. In a paired design with 70 subjects, we compared anti-TPO (30-198 U/mL) measured on fresh serum on Kryptor Classic in 2010-2011 (anti-TPOfresh) with anti-TPO remeasured on frozen serum (anti-TPOfrozen) on Kryptor Compact Plus in 2022. Both instruments used the same reagents and the anti-TPOn automated immunofluorescent assay, which was calibrated against the international standard NIBSC 66/387, based on the Time Resolved Amplified Cryptate Emission (TRACE) technology from BRAHMS. Values greater than 60 U/mL are regarded as positive in Denmark with this assay. Statistical comparisons included Bland-Altman, Passing-Bablok regression, and Kappa statistic. RESULTS: The mean follow-up time was 11.9 years (SD: 0.43). For anti-TPOfrozen vs. anti-TPOfresh, the line of equality was within the confidence interval of the absolute mean difference [5.71 (-0.32; 11.7) U/mL] and the average percentage deviation [+2.22% (-3.89%; +8.34%)]. The average percentage deviation of 2.22% did not exceed analytical variability. Passing-Bablok regression revealed both a statistically significant systematic and proportional difference: Anti-TPOfrozen=-22.6 + 1.22*(anti-TPOfresh). Frozen samples were correctly classified as positive in 64/70 (91.4%; Kappa=71.8%). CONCLUSIONS: Anti-TPO serum samples in the range 30-198 U/mL were stable after 12-years of storage at -80 °C with an estimated nonsignificant average percentage deviation of +2.22%. This comparison is based on Kryptor Classic and Kryptor Compact Plus, which used identical assays, reagents, and calibrator, but for which the agreement in the range 30-198 U/mL is unclarified.

Projected future European power sector water usage across power scenarios and corresponding trends in water availability.

The current transition toward added renewables into the power mix is essential to mitigate climate change effects, but the energy transition has environmental impacts outside the scope of greenhouse gas emissions that also need attention. One such impact is the water-energy dependency nexus, where water dependencies are also seen for non-fossil technologies such as concentrated solar power (CSP), bioenergy and hydropower and mitigation technologies such as carbon capture and storage (CCS). In this light, the selection of power production technologies can potentially affect long-term water resource renewability and dry summer conditions, causing, e.g., power plant shutdowns. In this study, we employ an established and validated scheme of water consumption and withdrawal rates across energy conversion technologies at the European scale to project corresponding water usage rates towards 2050 for EU30 countries. We further use the entire range of global- and regional climate model ensembles for low-, medium- and high-emission scenarios to project trends and robustness estimates of freshwater resources and availability at the distributed level for corresponding countries and years towards 2100. The results show a high sensitivity of water usage rates to the implementation of energy technologies such as CSP and CCS, as well as the decommissioning rates of fossil technologies and some scenarios generally show unaltered or even vastly increasing water consumption and withdrawal rates. Further, the assumptions on using CCS technologies, an evolving field, show a high impact. The assessment of hydro-climatic projections showed some degree of overlaps between decreasing water availabilities and increasing power sector water usage, especially for one power production scenario with a high share of CCS implementation. Further, a vast climate model spread in water availability was seen for both yearly means and summer minima, emphasising the need to include extremes in water management, and the water availability was highly dependent on the emission scenario in some regions.

Exploring association between pseudoexfoliation syndrome and ocular aging.

PURPOSE: Within a population-based follow-up study, to examine the 10-year incidence of pseudoexfoliation syndrome (PEX), possible risk factors for PEX and its association with ocular aging of the cornea, lens and retina. METHODS: The baseline examination was conducted in 2006 on a random sample of 1,033 adult participants from Kaunas city (Lithuania) population of whom 631 had ophthalmic examination data at attendance of the 10-year follow-up in 2016. Detailed examination of the anterior and posterior segment of the eye was carried out. After diagnostic mydriasis PEX was diagnosed by the presence of typical grayish-white exfoliation material on the anterior capsule surface of the lens. The participants were divided to PEX and non-PEX groups. RESULTS: PEX prevalence increased from 9.8 to 34.2% from baseline to 10-year follow-up. Nuclear cataract was common both in the PEX group (66.7%) and in those without PEX (72.2%), but this difference did not reach statistically significantly increased risk of developing cataract in those with PEX (OR 1.2; p = 0.61). Central corneal thickness (CCT) was thinner in the PEX group (529 ± 34 µm) and in the oldest group (525 ± 36 µm) (p < 0.001). Compared to baseline, corneal curvature (CC) became flatter in both groups (7.6 ± 0.27 vs 7.7 ± 0.26 mm; p < 0.001) during the follow-up, but the difference did not reach significance between groups. Corneal astigmatism was most commonly with-the-rule in both groups (37 (50.0%) vs 148 (68.5%); p > 0.05). Age, sex and PEX had no influence on age-related macular degeneration distribution. CONCLUSION: The prevalence of PEX increased significantly with age in our population, with those with PEX having thinner and flatter corneae, but no difference in cataract and age-related macular degeneration characteristics.

Clonal haematopoiesis of indeterminate potential and impaired kidney function-A Danish general population study with 11 years follow-up.

The myeloproliferative neoplasms are associated with chronic kidney disease but whether clonal haematopoiesis of indeterminate potential (CHIP) is associated with impaired kidney function is unknown. In the Danish General Suburban Population Study (N = 19 958) from 2010 to 2013, 645 individuals were positive for JAK2V617F (N = 613) or CALR (N = 32) mutations. Mutation-positive individuals without haematological malignancy were defined as having CHIP (N = 629). We used multiple and inverse probability weighted (IPW)-adjusted linear regression analysis to estimate adjusted mean (95% confidence interval) differences in estimated glomerular filtration rate (eGFR; ml/min/1.73 m2 ) by mutation status, variant allele frequency (VAF%), blood cell counts, and neutrophil-to-lymphocyte ratio (NLR). We performed 11-year longitudinal follow-up of eGFR in all individuals. Compared to CHIP-negative individuals, the mean differences in eGFR were -5.6 (-10.3, -0.8, p = .02) for CALR, -11.9 (-21.4, -2.4, p = 0.01) for CALR type 2, and -10.1 (-18.1, -2.2, p = .01) for CALR with VAF ≥ 1%. The IPW-adjusted linear regression analyses showed similar results. NLR was negatively associated with eGFR. Individuals with CALR type 2 had a worse 11-year longitudinal follow-up on eGFR compared to CHIP-negative individuals (p = .004). In conclusion, individuals with CALR mutations, especially CALR type 2, had impaired kidney function compared to CHIP-negative individuals as measured by a lower eGFR at baseline and during 11-year follow-up.

SAR11 bacteria linked to ocean anoxia and nitrogen loss.

Bacteria of the SAR11 clade constitute up to one half of all microbial cells in the oxygen-rich surface ocean. SAR11 bacteria are also abundant in oxygen minimum zones (OMZs), where oxygen falls below detection and anaerobic microbes have vital roles in converting bioavailable nitrogen to N2 gas. Anaerobic metabolism has not yet been observed in SAR11, and it remains unknown how these bacteria contribute to OMZ biogeochemical cycling. Here, genomic analysis of single cells from the world's largest OMZ revealed previously uncharacterized SAR11 lineages with adaptations for life without oxygen, including genes for respiratory nitrate reductases (Nar). SAR11 nar genes were experimentally verified to encode proteins catalysing the nitrite-producing first step of denitrification and constituted ~40% of OMZ nar transcripts, with transcription peaking in the anoxic zone of maximum nitrate reduction activity. These results link SAR11 to pathways of ocean nitrogen loss, redefining the ecological niche of Earth's most abundant organismal group.

Spatial variability of prokaryotic and viral abundances in the Kermadec and Atacama Trench regions.

Hadal trenches represent the deepest part of the ocean and are dynamic depocenters with intensified prokaryotic activity. Here, we explored the distribution and drivers of prokaryotic and viral abundance from the ocean surface and 40 cm into sediments in two hadal trench regions with contrasting surface productivity. In the water column, prokaryotic and viral abundance decreased with water depth before reaching a rather stable level at ~ 4000 m depth at both trench systems, while virus to prokaryote ratios were increasing with depth, presumably reflecting the declining availability of organic material. Prokaryotic and viral abundances in sediments were lower at the adjacent abyssal sites than at the hadal sites and declined exponentially with sediment depth, closely tracking the attenuation of total organic carbon (TOC) content. In contrast, hadal sediment exhibited erratic depth profiles of prokaryotes and viruses with many subsurface peaks. The prokaryotic abundance correlated well to extensive fluctuations in TOC content at centimeter scale, which were likely caused by recurring mass wasting events. Yet while prokaryotic and viral abundances cross correlated well in the abyssal sediments, there was no clear correlation in the hadal sites. The results suggested that dynamic depositional conditions and higher substrate availability result in a high spatial heterogeneity in viral and prokaryotic abundances in hadal sediments in comparison to more stable abyssal settings. We argue that these conditions enhance the relatively importance of viruses for prokaryotic mortality and carbon recycling in hadal settings.

Smoking, blood cells and myeloproliferative neoplasms: meta-analysis and Mendelian randomization of 2·3 million people.

Meta-analyses and Mendelian randomization (MR) may clarify the associations of smoking, blood cells and myeloproliferative neoplasms (MPN). We investigated the association of smoking with blood cells in the Danish General Suburban Population Study (GESUS, n = 11 083), by meta-analyses (including GESUS) of 92 studies (n = 531 741) and MR of smoking variant CHRNA3 (rs1051730[A]) in UK Biobank, and with MPN in a meta-analysis of six studies (n (total/cases):1 425 529/2187), totalling 2 307 745 participants. In the meta-analysis the random-effects standardized mean difference (SMD) in current smokers versus non-smokers was 0·82 (0·75-0·89, P = 2·0 * 10-108 ) for leukocytes, 0·09 (-0·02 to 0·21, P = 0·12) for erythrocytes, 0·53 (0·42-0·64, P = 8·0 * 10-22 ) for haematocrit, 0·42 (0·34-0·51, P = 7·1 * 10-21 ) for haemoglobin, 0·19 (0·08-0·31, P = 1·2 * 10-3 ) for mean corpuscular haemoglobin (MCH), 0·29 (0·19-0·39, P = 1·6 * 10-8 ) for mean corpuscular volume (MCV), and 0·04 (-0·04 to 0·13, P = 0·34) for platelets with trends for ever/ex-/current smokers, light/heavy smokers and female/male smokers. Analyses presented high heterogeneity but low publication bias. Per allele in CHRNA3, cigarettes per day in current smokers was associated with increased blood cell counts (leukocytes, neutrophils), MCH, red cell distribution width (RDW) and MCV. The pooled fixed-effects odds ratio for MPN was 1·44 [95% confidence interval (CI): 1·33-1·56; P = 1·8 * 10-19 ; I2  = 0%] in current smokers, 1·29 (1·15-1·44; P = 8·0 * 10-6 ; I2  = 0%) in ex-smokers, 1·49 (1·26-1·77; P = 4·4 * 10-6 ; I2  = 0%) in light smokers and 2·04 (1·74-2·39, P = 2·3 * 10-18 ; I2  = 51%) in heavy smokers compared with non-smokers. Smoking is observationally and genetically associated with increased leukocyte counts and red blood cell indices (MCH, MCV, RDW) and observationally with risk of MPN in current and ex-smokers versus non/never-smokers.

Automatic Bone Marrow Cellularity Estimation in H&E Stained Whole Slide Images.

Bone marrow cellularity is an important measure in diagnostic hematopathology. Currently, the gold standard for bone marrow cellularity estimation is manual inspection of hematoxylin and eosin stained whole slide images (H&E WSI) by hematopathologists. However, these assessments are subjective and subject to interobserver and intraobserver variability. This may be reduced by using a computer-assisted estimate of bone marrow cellularity. The aim of this study was to develop a fully automated algorithm to estimate bone marrow cellularity in H&E WSI stains using bone marrow segmentation. Data consisted of eight bone marrow H&E WSIs extracted from eight subjects. An algorithm was developed to estimate the bone marrow cellularity consisting of biopsy segmentation, tissue classification, and bone marrow segmentation. Segmentations of the red and yellow bone marrow (YBM) were used to estimate the bone marrow cellularity within the WSI H&E stains. The DICE coefficient between automatic tissue segmentations and ground truth segmentations conducted by an experienced hematopathologist were used for validation. Furthermore, the agreement between the automatic and two manual cellularity estimates was assessed using Bland-Altman plots and intraclass correlation coefficients (ICC). The validation of the bone marrow segmentation demonstrated an average DICE of 0.901 and 0.920 for the red and YBM, respectively. A mean cellularity estimate difference of -0.552 and - 7.816 was obtained between the automatic cellularity estimates and two manual cellularity estimates, respectively. An ICC of 0.980 (95%CI: 0.925-0.995, P-value: 5.51 × 10-7 ) was obtained between the automatic and manual cellularity estimates based on manual annotations. The study demonstrated that it was possible to obtain bone marrow cellularity estimates with a good agreement with bone marrow cellularity estimates obtained from an experienced hematopathologist. © 2019 International Society for Advancement of Cytometry.

Screening individuals' experiences of colonoscopy and colon capsule endoscopy; a mixed methods study.

BACKGROUND: The standard investigation in colorectal cancer screening (optical colonoscopy [OC]) has a less invasive alternative with the colon capsule endoscopy (CCE). The experiences of screening individuals are needed to support a decision aid (DA) and to provide a patient view in future health technology assessments (HTA). We aimed to explore the experiences of CCE at home and OC in an outpatient clinic by screening participants who experienced both investigations on the same bowel preparation. METHODS: In a mixed methods study, Danish screening individuals with a positive immunological fecal occult blood test (FIT) were consecutively included and underwent both CCE and OC in the same bowel preparation. They answered questionnaires about discomfort during CCE, delivered at home, and during a following OC in the outpatient clinic. Data were calculated in percentages and Wilcoxon signed rank test was used for comparisons. Among the 253 included patients, 10 participants were selected for a semi-structured interview about their experiences of the two examinations. The analysis and interpretation of the transcribed data were inspired by Ricoeur. RESULTS: Questionnaire data were received from 239 participants and revealed significant less discomfort during the CCE than the OC. Interview data included explained discomfort elements in two categories: 'The examination' and 'The setting'. Compared to OC, the CCE was experienced with less pain, embarrassment and invasiveness, but presented challenges and disadvantages as well, i.e., a large camera capsule to swallow, a longer waiting time for test results after CCE and an additional OC, if pathologies were found. The home setting for CCE delivery made the participants feel less like they were ill or patients less restricted and that they received more personal care, but could induce technical challenges. CONCLUSION: In screening individuals, CCE at home was associated with significantly less discomfort compared to OC at a hospital, and multiple reasons for this was identified.

Reproducibility and accuracy of visual estimation of polyp size in large colorectal polyps.

BACKGROUND: Previous studies indicate that visual size estimation (in situ) of polyp size tends to differ from postfixation measurements, which effects allocation to surveillance intervals. Little is known about interobserver variation of in-situ measurements of large polyps. The primary objective was to assess interobserver variation of in situ measurements of large colorectal polyps. Secondary objectives were the agreement of in situ measurements with postfixation measurements, and the agreement on detection of ≥20 mm polyps between these measurements. MATERIAL AND METHODS: Interobserver variability of in situ polyp size measurements was assessed between a diagnostic colonoscopy and the secondary therapeutic colonoscopy by dedicated endoscopists, in patients that were referred for an advanced polypectomy. After excision pre- and postfixation polyp sizes were measured with a ruler in three dimensions. RESULTS: A total of 40 patients, with 45 polyps, were included in the study. The average difference between the two in situ measurements was 2.4 mm (95% confidence interval (CI): -0.4-5.2). The differences between the first in situ, second in situ and pre-fixation measurement in comparison to postfixation measurements were 1.8 mm (95% CI: -1.2-4.9), 0.1 mm (95% CI: -1.5-1.8) and 1.0 mm (95% CI: -0.2-2.2). Cohen's Kappa on detection of ≥20 mm polyps in agreement with postfixation measurements was 0.65 in the primary and 0.88 in the secondary in situ measurements. CONCLUSION: This study shows a variation between in situ size measurements of large polyps. Improvements in daily clinical routines can be made by using an instrument to compare polyp size with and refraining from rounding sizes up or down. A randomized controlled trial assessing which instruments should be used for in-situ measurements of large polyps is warranted, in order to optimize size measurements of large colorectal polyps.

Necrotizing fasciitis and meningitis due to Streptococcus pneumoniae serotype 9 N: a case report.

BACKGROUND: Necrotizing fasciitis is a deep infection of the fascia and subcutaneous tissue with a high mortality rate. Meningitis is an infection of the membranes surrounding the brain with a likewise high mortality rate. Streptococcus pneumoniae is the most frequent cause of bacterial meningitis and it is an extremely rare cause of necrotizing fasciitis. Different subcapsular serotypes of S. pneumoniae are known to have diverse virulence. The serotype 9 N is associated with a high risk of death. CASE PRESENTATION: We report a case of a previously healthy 68-year-old female who presented at our clinic with complaints of pain in her left calf since having experienced a very painful leg cramp 3 weeks prior. Within a few hours after admission, she developed fever, neck stiffness and an altered mental state. Concurrently, the pain in her leg worsened. Upon further examination it was found that she suffered from both meningitis and necrotizing fasciitis due to S. pneumoniae, serotype 9 N. The patient survived and avoided leg amputation. CONCLUSIONS: The patient suffered from two very lethal infections simultaneously. Both of them were caused by S. pneumoniae. We believe that her favorable outcome was, a result of prompt surgical intervention and appropriate antibiotic treatment. Our case underlines the importance of continuous reevaluation of the symptoms and clinical findings in patients with unclear causes of severe illness, especially if the patient's condition changes.