Of autoregressive continuous time model parameters estimation

This article revisits a sequential approach to the estimation of the parameter in a first-order autoregressive model (AR(1)) with continuous time. There is provided a numerical study to get a results of sequential estimations of the parameter in first-order autoregressive model with continuous time and is computed a stopping rule and the optimal time of observations. Also there is provided a comparing analysis of estimation results with using the sequential approach both the optimal time of observations

Improved inflammatory bowel disease, wound healing and normal oxidative burst under treatment with empagliflozin in glycogen storage disease type Ib

BACKGROUND: Glycogen storage disease type Ib (GSD Ib) is a rare inborn error of glycogen metabolism due to mutations in SLC37A4. Besides a severe form of fasting intolerance, the disorder is usually associated with neutropenia and neutrophil dysfunction causing serious infections, inflammatory bowel disease, oral, urogenital and perianal lesions as well as impaired wound healing. Recently, SGLT2 inhibitors such as empagliflozin that reduce the plasma levels of 1,5-anhydroglucitol have been described as a new treatment option for the neutropenia and neutrophil dysfunction in patients with GSD Ib. RESULTS: We report on a 35-year-old female patient with GSD Ib who had been treated with G-CSF for neutropenia since the age of 9. She had a large chronic abdominal wound as a consequence of recurrent operations due to complications of her inflammatory bowel disease. Treatment with 20 mg empagliflozin per day resulted in normalisation of the neutrophil count and neutrophil function even after termination of G-CSF. The chronic abdominal wound that had been unchanged for 2 years before the start of empagliflozin nearly closed within 12 weeks. No side effects of empagliflozin were observed. CONCLUSION: SGLT2 inhibitors are a new and probably safe treatment option for GSD Ib-associated neutropenia and neutrophil dysfunction. We hypothesize that restoration of neutrophil function and normalisation of neutrophil apoptosis leads to improvement of wound healing and ameliorates symptoms of inflammatory bowel disease

Intra-season variations in distribution and abundance of humpback whales in the West Antarctic Peninsula using cruise vessels as opportunistic platforms

Fine-scale knowledge of spatiotemporal dynamics in cetacean distribution and abundance throughout the Western Antarctic Peninsula (WAP) is sparse yet essential for effective ecosystem-based management (EBM). Cruise vessels were used as platforms of opportunity to collect data on the distribution and abundance of humpback whales (Megaptera novaeangliae) during the austral summer of 2019/2020 in a region that is also important for the Antarctic krill (Euphausia superba) fishery, to assess potential spatiotemporal interactions for future use in EBM. Data were analyzed using traditional design-based line transect methodology and spatial density surface hurdle models fitted using a set of physical environmental covariates to estimate the abundance and distribution of whales in the area, and to describe their temporal dynamics. Our results indicate a rapid increase in humpback whale abundance in the Bransfield and Gerlache Straits through December, reaching a stable abundance by mid-January. The distribution of humpback whales appeared to change from a patchier distribution in the northern Gerlache Strait to a significantly concentrated presence in the central Gerlache and southern Bransfield Straits, followed by a subsequent dispersion throughout the area. Abundance estimates agreed well with previous literature, increasing from approximately 7000 individuals in 2000 to a peak of 19,107 in 2020. Based on these estimates, we project a total krill consumption of between 1.4 and 3.7 million tons based on traditional and contemporary literature on per capita krill consumption of whales, respectively. When taken in the context of krill fishery catch data in the study area, we conclude that there is minimal spatiotemporal overlap between humpback whales and fishery activity during our study period of November-January. However, there is potential for significant interaction between the two later in the feeding season, but cetacean survey efforts need to be extended into late season in order to fully characterize this potential overlap.Publisher PDFPeer reviewe

Multi-omic studies on missense PLG variants in families with otitis media

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial a-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.Peer reviewe

A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation [preprint]

Cytokine-mediated activation of host immunity is central to the control of pathogens. A key cytokine in protective immunity is interferon-gamma (IFNγ), which is a potent activator of antimicrobial and immunomodulatory effectors within the host. A major role of IFNγ is to induce major histocompatibility complex class II molecules (MHCII) on the surface of cells, which is required for CD4+ T cell activation. Despite its central role in host immunity, the complex and dynamic regulation of IFNγ-induced MHCII is not well understood. Here, we integrated functional genomics and transcriptomics to comprehensively define the genetic control of IFNγ-mediated MHCII surface expression in macrophages. Using a genome-wide CRISPR-Cas9 library we identified genes that control MHCII surface expression, many of which have yet to be associated with MHCII. Mechanistic studies uncovered two parallel pathways of IFNγ-mediated MHCII control that require the multifunctional glycogen synthase kinase 3 beta (GSK3β) or the mediator complex subunit MED16. Both pathways are necessary for IFNγ-mediated induction of the MHCII transactivator CIITA, MHCII expression, and CD4+ T cell activation. Using transcriptomic analysis, we defined the regulons controlled by GSK3β and MED16 in the presence and absence of IFNγ and identified unique networks of the IFNγ-mediated transcriptional landscape that are controlled by each gene. Our analysis suggests GSK3β and MED16 control distinct aspects of the IFNγ-response and are critical for macrophages to respond appropriately to IFNγ. Our results define previously unappreciated regulation of MHCII expression that is required to control CD4+ T cell responses by macrophages. These discoveries will aid in our basic understanding of macrophage-mediated immunity and will shed light on mechanisms of failed adaptive responses pervasive in infectious disease, autoimmunity, and cancer

Structural barriers to knowledge transfer and exchange among men and women in low-, middle- and high-income countries: an international cross-sectional study with vaccine researchers in 44 countries

Background: Globally, women constitute 30% of researchers. Despite an increasing proportion of women in research, they are still less likely to have international collaborations. Literature on barriers to knowledge transfer and exchange (KTE) between men and women remains limited. This study aimed to assess perceived gender barriers to KTE activities in vaccination-related research in low-, middle- and high-income countries. Methods: This was a cross-sectional data assessment from a self-administered questionnaire distributed to researchers in the field of vaccination research. The administered questionnaire was developed and validated by WHO and McMaster University. Descriptive statistics were carried out. Structural factors of KTE were assessed using 12 statements measured with a five-point Likert scale, ranging from 1 (strongly disagree) to 5 (strongly agree). An index ranging from 12 to 60 points was created to assess structural factors of KTE, with higher score indicating fewer perceived barriers. Multivariable linear regression modelling was applied to examine the association between KTE barriers and gender. Results: A total of 158 researchers were included in the analysis. Regardless of gender and country of affiliation, researchers experienced challenges with respect to KTE activities; particularly factors related to the availability of human and financial resources and level of technical expertise among their target audience. We were also able to identify perceived facilitators among men and women, such as the presence of structures that link researchers and target audiences, the investment of target audiences in KTE efforts and the presence of stable contacts among target audiences. Our linear regression analysis showed that women perceived more barriers than men (R2 = 0.014; B = −1.069; 95% CI −4.035; 1.897). Conclusions: Men and women shared common perspectives on barriers to KTE. KTE activities could be strengthened by improving structural efforts to reduce gender differences and increase collaborations between researchers and their target audience

Changes in beverage consumption from pre-pregnancy to early pregnancy in the Norwegian Fit for Delivery study

Objective: To describe changes in consumption of different types of beverages from pre-pregnancy to early pregnancy, and to examine associations with maternal age, educational level and BMI. Design: Cross-sectional design. Participants answered an FFQ at inclusion into a randomized controlled trial, the Fit for Delivery (FFD) trial, in median gestational week 15 (range: 9–20), reporting current consumption and in retrospect how often they drank the different beverages pre-pregnancy. Setting: Eight local antenatal clinics in southern Norway from September 2009 to February 2013. Subjects: Five hundred and seventy-five healthy pregnant nulliparous women. Results: Pre-pregnancy, 27% reported drinking alcohol at least once weekly, compared with none in early pregnancy (P<0·001). The percentage of women drinking coffee (38 % v. 10 %, P < 0·001), sugar-sweetened beverages (10 % v. 6 %, P=0·011) and artificially sweetened beverages (12% v. 9%, P=0·001) at least daily decreased significantly from pre-pregnancy to early pregnancy, while the percentage of women who reported to drink water (85% v. 92%, P<0·001), fruit juice (14% v. 20%, P=0·001) and milk (37% v. 42%, P=0·001) at least daily increased significantly. From pre-pregnancy to early pregnancy higher educated women reduced their consumption frequency of coffee significantly more than women with lower education. Older women reduced their consump- tion frequency of coffee and artificially sweetened beverages and increased their consumption frequency of fruit juice and milk significantly more than younger women. Conclusions: There is a significant change in beverage consumption from pre-pregnancy to early pregnancy among Norwegian nulliparous women. Keywords Beverage consumption Dietary change Pregnant womenpublishedVersio

Concurrent acute myeloid leukemia and T lymphoblastic lymphoma in a patient with rearranged PDGFRB genes

Concurrent hematologic malignancies are relatively rare. We encountered a case of concurrent acute myeloid leukemia (AML) and T lymphoblastic lymphoma. The bone marrow chromosome analysis showed the karyotype 46, XY, t(5;12)(q33;p13), which indicated presence of PDGFRB gene translocations. Therefore, this disease belongs to the new WHO category of myeloid and lymphoid neoplasms with abnormalities in PDGFRA, PDGFRB and FGFR1 genes. Although such genetic mutations are prone to multi-lineage differentiation, the present case is in fact the first report of concurrent AML and T lymphoblastic lymphoma involving PDGFRB mutations. The patient was treated with cytarabine and daunomycin in combination with high dose dexamethasone. Allogeneic stem cell transplantation was performed after successful remission induction for both entities. The patient eventually died of chronic graft-versus-host-disease related infection. Based on such an experience, we suggest the decision of stem cell transplantation should be weighed carefully against the risks, especially when tyrosine kinase inhibitors are safe and potentially effective in dealing with such entities

Multiple evidence for methylotrophic methanogenesis as the dominant methanogenic pathway in hypersaline sediments from the Orca Basin, Gulf of Mexico

Among the most extreme habitats on Earth, dark, deep, anoxic brines host unique microbial ecosystems that remain largely unexplored. As the terminal step of anaerobic degradation of organic matter, methanogenesis is a potentially significant but poorly constrained process in deep-sea hypersaline environments. We combined biogeochemical and phylogenetic analyses with incubation experiments to unravel the origin of methane in the hypersaline sediments of Orca Basin in the northern Gulf of Mexico. Substantial concentrations of methane, up to 3.4 mM, coexisted with high concentrations of sulfate from 16 to 43 mM in two sediment cores retrieved from the northern and southern parts of Orca Basin. The strong depletion of 13C in methane (-77‰ to -89‰) points towards a biological source. While low concentrations of competitive substrates limited the significance of hydrogenotrophic and acetoclastic methanogenesis, the presence of non-competitive methylated substrates (methanol, trimethylamine, dimethyl sulfide, dimethylsulfoniopropionate) supported the potential for methane generation through methylotrophic methanogenesis. Thermodynamic calculations demonstrated that hydrogenotrophic and acetoclastic methanogenesis were unlikely to occur under in situ conditions, while methylotrophic methanogenesis from a variety of substrates was highly favorable. Likewise, carbon isotope relationships between methylated substrates and methane suggested methylotrophic methanogenesis was the major source of methane. Stable and radio-isotope tracer experiments with 13C-labeled bicarbonate, acetate and methanol and 14C-labeled methylamine indicated that methylotrophic methanogenesis was the predominant methanogenic pathway. Based on 16S rRNA gene sequences, halophilic methylotrophic methanogens related to the genus Methanohalophilus dominated the benthic archaeal community in the northern basin and also occurred in the southern basin. High abundances of methanogen lipid biomarkers such as intact polar and polyunsaturated hydroxyarchaeols were detected in sediments from the northern basin, with lower abundances in the southern basin. Strong 13C-depletion of saturated and monounsaturated hydroxyarchaeol were consistent with methylotrophic methanogenesis as the major methanogenic pathway. Collectively, the availability of methylated substrates, thermodynamic calculations, experimentally determined methanogenic activity as well as lipid and gene biomarkers support the hypothesis that methylotrophic methanogenesis is the predominant pathway of methane formation in the presence of sulfate in Orca Basin sediments