This paper presents a method to find the optimum maintenance policy for a component. Random failures and failures due to deterioration are considered. Using Markov processes, the state probabilities ...are calculated and the optimal value of the mean time to preventive maintenance is determined by maximizing the availability of single component with respect to mean time to minimal preventive maintenance. Using the state probabilities, the problem is set up as Markov decision processes and an optimum maintenance policy using the policy iteration algorithm is determined. An example is used to illustrate the method. Maple V and Matlab software have been used to solve the equations.
Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary ...dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis.
This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK.
Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing.
PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.
Several strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down the maternal line, most recently in three families where several individuals harbored ...a 'heteroplasmic haplotype' consistent with biparental transmission. Here we report a similar genetic signature in 7 of 11,035 trios, with allelic fractions of 5-25%, implying biparental inheritance of mtDNA in 0.06% of offspring. However, analysing the nuclear whole genome sequence, we observe likely large rare or unique nuclear-mitochondrial DNA segments (mega-NUMTs) transmitted from the father in all 7 families. Independently detecting mega-NUMTs in 0.13% of fathers, we see autosomal transmission of the haplotype. Finally, we show the haplotype allele fraction can be explained by complex concatenated mtDNA-derived sequences rearranged within the nuclear genome. We conclude that rare cryptic mega-NUMTs can resemble paternally mtDNA heteroplasmy, but find no evidence of paternal transmission of mtDNA in humans.
The pathogenesis of spotted fever group (SFG) Rickettsia species, including R. conorii and R. rickettsii, is acutely dependent on adherence to and invasion of host cells, including cells of the ...mammalian endothelial system. Bioinformatic analyses of several rickettsia genomes revealed the presence of a cohort of genes designated sca genes that are predicted to encode proteins with homology to autotransporter proteins of Gram-negative bacteria. Previous work demonstrated that three members of this family, rOmpA (Sca0), Sca2, and rOmpB (Sca5) are involved in the interaction with mammalian cells; however, very little was known about the function of other conserved rickettsial Sca proteins. Here we demonstrate that sca1, a gene present in nearly all SFG rickettsia genomes, is actively transcribed and expressed in R. conorii cells. Alignment of Sca1 sequences from geographically diverse SFG Rickettsia species showed that there are high degrees of sequence identity and conservation of these sequences, suggesting that Sca1 may have a conserved function. Using a heterologous expression system, we demonstrated that production of R. conorii Sca1 in the Escherichia coli outer membrane is sufficient to mediate attachment to but not invasion of a panel of cultured mammalian epithelial and endothelial cells. Furthermore, preincubation of a recombinant Sca1 peptide with host cells blocked R. conorii cell association. Together, these results demonstrate that attachment to mammalian cells can be uncoupled from the entry process and that Sca1 is involved in the adherence of R. conorii to host cells.
Background
A significant improvement in clinical signs was demonstrated with abrocitinib relative to placebo in adolescents with moderate‐to‐severe atopic dermatitis (AD) in three phase 3, ...randomized, double‐blinded, placebo‐controlled studies (JADE TEEN ClinicalTrials.gov, NCT03796676, JADE MONO‐1 NCT03349060 and JADE MONO‐2 NCT03575871).
Objectives
To evaluate the impact of abrocitinib on patient‐reported signs/symptoms, including sleep loss and quality of life among adolescents with moderate‐to‐severe AD.
Methods
JADE TEEN, JADE MONO‐1 and JADE MONO‐2 were conducted in the Asia‐Pacific region, Europe and North America and included patients aged 12–17 years with moderate‐to‐severe AD and inadequate response to ≥ 4 consecutive weeks of topical medication or treatment with systemic therapy for AD. Patients were randomly assigned (1 : 1 : 1, JADE TEEN; 2 : 2 : 1, JADE MONO‐1/‐2) to receive once‐daily oral abrocitinib (200 or 100 mg) or placebo for 12 weeks in combination with topical therapy (JADE TEEN) or as monotherapy (JADE MONO‐1/‐2). Data from adolescent patients in JADE MONO‐1/‐2 were pooled for these analyses.
Results
At week 12, more adolescents treated with abrocitinib (200 or 100 mg) vs. placebo achieved a ≥ 4‐point improvement from baseline in the Patient‐Oriented Eczema Measure in JADE TEEN (83.9% and 77.0% vs. 60.2%) and JADE MONO‐1/‐2 (83.0% and 69.4% vs. 43.5%) and a ≥ 6‐point improvement from baseline in the Children’s Dermatology Life Quality Index in JADE TEEN (73.8% and 67.5% vs. 56.5%) and JADE MONO‐1/‐2 (70.0% and 57.1% vs. 19.0%). Significant improvements in SCORing Atopic Dermatitis Visual Analog Scale for sleep loss scores were demonstrated with abrocitinib vs. placebo at weeks 2‐12 in JADE TEEN and JADE MONO‐1/‐2.
Conclusions
Patient‐reported signs/symptoms, including reduction of sleep loss and quality of life, were substantially improved with abrocitinib monotherapy or combination therapy relative to placebo in adolescents with moderate‐to‐severe AD.
Trust is an important cornerstone of patient-provider communication. Accurate reporting of pre-exposure prophylaxis (PrEP) adherence is vital for providers to determine who needs adherence support, ...especially adolescent girls and young women (AGYW) disproportionately affected by newly diagnosed HIV.
This is a secondary analysis of the HPTN 082 open-label PrEP demonstration trial. From 2016-2018, 451 AGYW aged 16-25 years were enrolled in South Africa (Cape Town and Johannesburg) and Zimbabwe (Harare). PrEP was initiated by 427, and 354 (83%) had month three patient-reported adherence responses and intracellular tenofovir diphosphate (TFV-DP) measurements. The patient-reported adherence response to 'In the past month, how often did you take the tablet?' was dichotomized as 'high' if the response was every day or most days, and 'low' if some days or not many days or never. The biomarker marker evidence of adherence in dried blood spots was defined as 'high' if TFV-DP ≥ 700, and 'low' if < 350 fmol/punch. We used multinomial logistic regression to examine if trust in the PrEP provider was associated with concordance between patient-reported adherence and intracellular tenofovir-diphosphate (TFV-DP).
AGYW who reported trust in their providers were almost four-fold (aOR 3.72, 95% CI 1.20-11.51) more likely to have concordant adherence (high self-reported adherence and high TFV-DP concentrations) compared to discordant non-adherence (high self-reported adherence and low TFV-DP concentrations).
Education and training of providers to build trusting relationships with AGYW may lead to more accurate reporting of PrEP adherence. With accurate reporting, adequate support can be provided to bolster adherence.
ClinicalTrials.gov Identifier: NCT02732730.
To retrospectively compare the computed tomographic (CT) features of liver abscesses caused by Klebsiella pneumoniae with those caused by other bacterial pathogens.
This retrospective study was ...approved by the institutional review board, with waiver of informed consent. Hospital records of all patients with a diagnosis of liver abscess between July 2003 and July 2010 were retrieved from an electronic hospital database. One hundred and thirty-one consecutive patients with confirmed pyogenic liver abscesses were studied. Data on clinical presentation, comorbid conditions, septic hematogenous complications, hospitalization duration, and abscess-related mortality were obtained. CT characteristics of abscesses including number, distribution, unilocular or multilocular appearance, cystic or solid appearance, gas in cavity, pylephlebitis, thrombophlebitis, and pneumobilia were reviewed. Etiology was established by pus and/or blood culture. Patients were placed into a monomicrobial K pneumoniae liver abscess group and a comparison group. A comparison of the CT features and clinical findings between the two groups was performed. The χ(2) analysis or Fisher exact test was used for categorical variables, and Student t and log-rank tests were used for continuous variables. A P value of less than .05 was considered to indicate a significant difference.
Monomicrobial K pneumoniae liver abscesses were present in 92 cases (70.2%). On CT images, characteristics more likely to be associated with monomicrobial K pneumoniae liver abscesses than other pyogenic liver abscesses were a single abscess (79.3% vs 56.4%, P = .01), unilobar involvement (82.6% vs 61.5%, P = .01), solid appearance (57.6% vs 35.9%, P = .03), multilocular (94.6% vs 71.8%, P = .01), association with thrombophlebitis (30.4% vs 5.1%, P < .01), and hematogenous complications (28.3% vs 7.7%, P < .01). Thrombophlebitis was associated with higher incidence of hematogenous septic complications (50.0% vs 13.9%, P < .001). Monomicrobial K pneumoniae liver abscesses were associated with significantly shorter duration of antibiotic treatment (P = .018) and hospital stay (P = .005), but there was no significant difference in incidence of septic shock and abscess-related mortality as compared with other pyogenic liver abscesses.
Monomicrobial K pneumoniae liver abscesses appear as single, solid, or multiloculated liver abscesses and are associated with thrombophlebitis and septic hematogenous complications.
Cognitively Guided Instruction (CGI) researchers have found that while teachers readily ask initial questions to elicit students’ mathematical thinking, they struggle with how to follow up on student ...ideas. This study examines the classrooms of three teachers who had engaged in algebraic reasoning CGI professional development. We detail teachers’ questions and how they relate to students’ making explicit their complete and correct explanations. We found that after the initial “How did you get that?” question, a great deal of variability existed among teachers’ questions and students’ responses.
Recent improvements in the speed and sensitivity of liquid chromatography-mass spectrometry systems have driven significant progress toward system-wide characterization of the proteome of many ...species. These efforts create large proteomic datasets that provide insight into biological processes and identify diagnostic proteins whose abundance changes significantly under different experimental conditions. Yet, these system-wide experiments are typically the starting point for hypothesis-driven, follow-up experiments to elucidate the extent of the phenomenon or the utility of the diagnostic marker, wherein many samples must be analyzed. Transitioning from a few discovery experiments to quantitative analyses on hundreds of samples requires significant resources both to develop sensitive and specific methods as well as analyze them in a high-throughput manner. To aid these efforts, we developed a workflow using data acquired from discovery proteomic experiments, retention time prediction, and standard-flow chromatography to rapidly develop targeted proteomic assays. We demonstrated this workflow by developing MRM assays to quantify proteins of multiple metabolic pathways from multiple microbes under different experimental conditions. With this workflow, one can also target peptides in scheduled/dynamic acquisition methods from a shotgun proteomic dataset downloaded from online repositories, validate with appropriate control samples or standard peptides, and begin analyzing hundreds of samples in only a few minutes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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