Sortie-based aircraft component demand rate to predict requirements

PurposeForecasting techniques improve supply chain resilience by ensuring that the correct parts are available when required. In addition, accurate forecasts conserve precious resources and money by avoiding new start contracts to produce unforeseen part requests, reducing labor intensive cannibalization actions and ensuring consistent transportation modality streams where changes incur cost. This study explores the effectiveness of the United States Air Force’s current flying hour-based demand forecast by comparing it with a sortie-based demand forecast to predict future spare part needs.Design/methodology/approachThis study employs a correlation analysis to show that demand for reparable parts on certain aircraft has a stronger correlation to the number of sorties flown than the number of flying hours. The effect of using the number of sorties flown instead of flying hours is analyzed by employing sorties in the United States Air Force (USAF)’s current reparable parts forecasting model. A comparative analysis on D200 forecasting error is conducted across F-16 and B-52 fleets.FindingsThis study finds that the USAF could improve its reparable parts forecast, and subsequently part availability, by employing a sortie-based demand rate for particular aircraft such as the F-16. Additionally, our findings indicate that forecasts for reparable parts on aircraft with low sortie count flying profiles, such as the B-52 fleet, perform better modeling demand as a function of flying hours. Thus, evidence is provided that the Air Force should employ multiple forecasting techniques across its possessed, organically supported aircraft fleets. The improvement of the forecast and subsequent decrease in forecast error will be presented in the Results and Discussion section.Research limitations/implicationsThis study is limited by the data-collection environment, which is only reported on an annual basis and is limited to 14 years of historical data. Furthermore, some observations were not included because significant data entry errors resulted in unusable observations.Originality/valueThere are few studies addressing the time measure of USAF reparable component failures. To the best of the authors’ knowledge, there are no studies that analyze spare component demand as a function of sortie numbers and compare the results of forecasts made on a sortie-based demand signal to the current flying hour-based approach to spare parts forecasting. The sortie-based forecast is a novel methodology and is shown to outperform the current flying hour-based method for some aircraft fleets.

A susceptibility locus in the IL12B but not LILRA3 region is associated with vascular damage in Takayasu arteritis

HLA-B*52 is an established genetic factor in Takayasu arteritis (TAK). Recently, single nucleotide polymorphisms (SNPs) in IL12B (rs6871626) and LILRA3 (rs103294) were newly identified as non-HLA susceptibility loci in TAK. Here, we examined how these SNPs contribute to clinical characteristics and vascular damage in TAK. We retrospectively reviewed the medical records of 99 TAK patients enrolled in our previous genome-wide association study, and whose genotypes for IL12B rs6871626, LILRA3 rs103294, and HLA-B*52 were available. Incidence of aortic regurgitation (AR) was significantly associated with the A allele (risk allele) of IL12B rs6871626 (CC 42%, AC 61%, AA 81%; p = 0.0052; odds ratio [OR] 2.45), as well as with the incidence of hypertension (p = 0.049; OR 1.82) and the proportion of patients who underwent aortic valve replacement (p = 0.023; OR 3.64). Regarding vascular damage, there was positive correlation between the Takayasu Arteritis Damage Score and the A allele of IL12B rs6871626 (CC 3.42 ± 2.71, AC 4.06 ± 3.25, AA 6.00 ± 2.81; p = 0.0035; β = 1.35) and between the Vasculitis Damage Index and the A allele (CC 3.47 ± 1.98, AC 4.33 ± 2.40, AA 5.37 ± 2.22; p = 0.0054; β = 0.96). Contrarily, no correlation was found between LILRA3 rs103294 and vascular damage. In the present study, IL12B rs6871626 was associated with vascular damage in TAK, whereas LILRA3 rs103294 was not. Genotyping of IL12B rs6871626 may help to identify patients at risk of disease progression.

STING ligand-mediated priming of functional CD8 + T-cells specific for HIV-1 protective epitopes from naïve T-cells

Functional HIV-1-specific CD8 + T-cells primed from naïve T-cells are expected to act as effector T-cells in a ‘‘shock and kill’’ therapeutic strategy for an HIV-1 cure since less functional HIV-1-specific CD8 + T-cells are elicited from memory T-cells in HIV-1-infected individuals on cART. CD8 + T-cells specific for HIV-1 conserved and protective epitopes are candidates of such T-cells. We here investigated the priming with STING ligand of CD8 + T-cells specific for HLA-B*52:01 or HLA-C*12:02-restricted protective epitopes from naïve T-cells. STING ligand 3’3’-cGAMP effectively primed CD8 + T-cells specific for 3 of 4 HLA-B*52:01-restricted epitopes but failed to prime those specific for all 3 HLA-C*12:02-restricted epitopes from the naïve T-cells of HIV-1-uninfected individuals having an HLA-B*52:01-C*12:02 protective haplotype. These HLA-B*52:01-restricted CD8 + T-cells had a strong ability to suppress HIV-1 replication and expressed a high level of cytolytic effector molecules. The viral suppression ability of these T-cells was significantly correlated with the expression level of perforin and showed a trend for a positive correlation with the expression level of CD107a. The present study highlighted the priming with STING ligand of functional CD8 + T-cells specific for protective epitopes, which T-cells would contribute as effector T-cells to a ‘‘shock and kill’’ therapy. Importance Current therapeutic strategy ‘‘shock and kill’’ for HIV cure has been directed towards eliminating latent viral reservoirs by reactivation of latent reservoirs with latency-reversing agents followed by eradication of these cells by immune-mediated responses. Although HIV-1-specific T-cells are expected to eradicate viral reservoirs, the function of these T-cells is reduced in HIV-1-infected individuals with long-term cART. Therefore, priming of HIV-1-specific T-cells with high function from naïve T-cells are to be expected in these individuals. We here demonstrated the priming with STING ligand 3’3’-cGAMP of CD8 + T-cells specific for HIV-1 protective epitopes from naïve T cells. cGAMP primed CD8 + T-cells specific for 3 HLA-B*52:01-restricted protective epitopes, which cells expressed a high level of cytolytic effector molecules and effectively suppressed HIV-1 replication. The present study suggested that the priming with STING ligand of functional CD8 + T-cells specific for protective epitopes would be useful in a therapy for an HIV-1 cure.

HLA-A*11:01:01:01, HLA-C*12:02:02:01-HLA-B*52:01:02:02, Age and Sex Are Associated With Severity of Japanese COVID-19 With Respiratory Failure

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February–August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27–3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24–3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50–7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01–1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31–6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.

Heráclito, B 52 DK: contribuição à semântica do jogo

Resumo: O fragmento B 52 DK de Heráclito define aiṓn (“tempo”, “vida”, ou “duração da vida”) como uma criança brincando/jogando. Qual é, no entanto, o jogo/a brincadeira dessa criança? A interpretação mais comum desqualifica o jogo heraclítico, elencando esse fragmento dentre aqueles nos quais o filósofo critica o conhecimento falho dos homens. Na contramão dessas, propõe-se neste texto uma análise filológica que pode oferecer algumas sugestões para melhor identificar e compreender o jogo de B 52, acreditando que não se trate de uma brincadeira infantil, mas, de fato, de um jogo sério que ressoa com metáforas cósmicas e cívicas.

HLA-A*11:01:01:01, HLA*C*12:02:02:01-HLA-B*52:01:02:02, age and sex are associated with severity of Japanese COVID-19 with respiratory failure

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February–August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27–3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24–3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50–7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01–1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31–6.54)] remained significant. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.

T-cell responses to sequentially emerging viral escape mutants shape long-term HIV-1 population dynamics

HIV-1 strains harboring immune escape mutations can persist in circulation, but the impact of selection by multiple HLA alleles on population HIV-1 dynamics remains unclear. In Japan, HIV-1 Reverse Transcriptase codon 135 (RT135) is under strong immune pressure by HLA-B*51:01-restricted and HLA-B*52:01-restricted T cells that target a key epitope in this region (TI8; spanning RT codons 128–135). Major population-level shifts have occurred at HIV-1 RT135 during the Japanese epidemic, which first affected hemophiliacs (via imported contaminated blood products) and subsequently non-hemophiliacs (via domestic transmission). Specifically, threonine accumulated at RT135 (RT135T) in hemophiliac and non-hemophiliac HLA-B*51:01+ individuals diagnosed before 1997, but since then RT135T has markedly declined while RT135L has increased among non-hemophiliac individuals. We demonstrated that RT135V selection by HLA-B*52:01-restricted TI8-specific T-cells led to the creation of a new HLA-C*12:02-restricted epitope TN9-8V. We further showed that TN9-8V-specific HLA-C*12:02-restricted T cells selected RT135L while TN9-8T-specific HLA-C*12:02-restricted T cells suppressed replication of the RT135T variant. Thus, population-level accumulation of the RT135L mutation over time in Japan can be explained by initial targeting of the TI8 epitope by HLA-B*52:01-restricted T-cells, followed by targeting of the resulting escape mutant by HLA-C*12:02-restricted T-cells. We further demonstrate that this phenomenon is particular to Japan, where the HLA-B*52:01-C*12:02 haplotype is common: RT135L did not accumulate over a 15-year longitudinal analysis of HIV sequences in British Columbia, Canada, where this haplotype is rare. Together, our observations reveal that T-cell responses to sequentially emerging viral escape mutants can shape long-term HIV-1 population dynamics in a host population-specific manner.