Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now ...available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology.
•JNJ-7184 has an average in vitro EC50 of 13/72 nM on RSV-A/B strains.•JNJ-7184 targets the connector domain of the L polymerase.•It blocks early elongation of vRNA products and partly 1st dinucleotide formation.•Methyltransferase activity is barely impacted.•It is active in primary air-liquid interface cultures and the neonatal lamb model.
Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication, reverse liver inflammation and ...fibrosis, and decrease risks of cirrhosis and hepatocellular carcinoma, but hepatitis B surface antigen (HBsAg) loss is rare. Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. This requires suppression of HBV replication and viral protein production as well as restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. In parallel, immune modulatory therapies to stimulate HBV-specific immune response and to remove immune blockade are being tested. Clinical trials of direct-acting antivirals alone or immune modulatory therapies alone have not been successful in achieving HBV cure. Recent combinations of direct-acting antivirals and immune modulatory therapies have shown promising results particularly with combinations that included pegIFN-α. These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.
Background
The first-in-class approved BCMA CAR-T therapy was idecabtagene vicleucel (ide-cel), approved in March 2021, for RRMM patients who progressed after 4 or more lines of therapy. Despite the ...promising outcomes, there were limited apheresis/production slots for ide-cel. We report outcomes of patients at our institution who were on the “waitlist” to receive ide-cel in 2021 and who could not secure a slot.
Methods
We conducted a retrospective review of RRMM patients evaluated at the University of Kansas Cancer Center for ide-cel from 3/2021-7/2021. A retrospective chart review was performed to determine patient and disease characteristics. Descriptive statistics were reported using medians for continuous variables. Survival analysis from initial consult was performed using Kaplan-Meier Survival estimator.
Results
Forty patients were eligible and were on the “waitlist” for CAR-T. The median follow-up was 14 months (2-25mo). Twenty-four patients (60%) secured a production slot and 16 (40%) did not. The median time from consult to collection was 38 days (8-703). The median time from collection to infusion was 42 days (34-132 days). The median overall survival was higher in the CAR-T group (NR vs 9 mo, p<0.001).
Conclusion(s)
Many patients who were eligible for ide-cel were not able to secure a timely slot in 2021. Mortality was higher in this group, due to a lack of comparable alternatives. Increasing alternate options as well as improvement in manufacturing and access is an area of high importance to improve RRMM outcomes.
Wang Y., Ning L., Li J. and Prevezer M. Foreign direct investment spillovers and the geography of innovation in Chinese regions: the role of regional industrial specialization and diversity, Regional ...Studies. Foreign direct investment (FDI) brings technology spillovers, but little is known about the interactive effects of industrial structure at the regional level on how FDI works to bring spillovers. This paper brings together technological spillovers from FDI with impacts on regional innovation through industrial structure. This is important for China as a recipient of FDI which is both regionally skewed and unevenly distributed. Results indicate that inward FDI has positive effects on regional innovation, but that industrial specialization diminishes the positive effects of FDI whilst a more diversified industrial structure enhances spillovers from inward FDI.
•The remaining useful life (RUL) of bearing using signal processing method is studied.•Improved Distance Evaluation (IDE) method is used for feature dimensionality reduction.•K-Nearest Neighbors ...(KNN) algorithm is used for healthy and faulty bearing classification.•The results show that the IDE method enables natural fault detection in bearings accurately.•The results show that kurtosis, FM4, k factor, energy, and peak are the best features.
In this paper, the estimation of the remaining useful life (RUL) of angular contact ball bearing using time-domain signal processing method is discussed. An experimental setup based on acoustic emission (AE) signal is used to extract and collect the desired data. The residual life test is performed on the SKF 7202 BEP angular contact ball bearing. Sixty-time domain features have been introduced and used for fault detection. Improved Distance Evaluation (IDE) method has been used for feature dimensionality reduction and the best 10 features have been selected. K-Nearest Neighbors (KNN) algorithm has been used to investigate the classification accuracy of IDE based on selected features for classifying healthy and faulty bearings. The results show that the IDE method enables natural fault detection in bearings with high precision. To validate the performance of the KNN classifier, performance indices such as accuracy, precision, and specificity are applied. The results show that kurtosis, FM4, k factor, energy, and peak are the best features and kurtosis has the highest KNN rank with accuracy, precision, and specificity of 97%, 93%, and 94%, respectively.
Summary Hepatitis B flare, defined as an event with abrupt rise of alanine aminotransferase (ALT) levels to >5 times the upper limit of normal during chronic hepatitis B virus (HBV) infection, is ...considered to be the result of a human leukocyte antigen-I restricted, cytotoxic T lymphocyte mediated immune response against HBV and its downstream mechanisms. It may occur spontaneously, during or after antiviral therapy and in the setting of immunosuppression and/or chemotherapy. The clinical spectrum of hepatitis B flares varies from asymptomatic to symptomatic and typical overt acute hepatitis, even with hepatic decompensation or failure. Flares may also occur in viraemic patients with cirrhosis with higher incidence of decompensation/mortality, hence requiring immediate antiviral therapy. An upsurge of serum HBV DNA and hepatitis B surface antigen levels usually precedes the abrupt rise of ALT levels. Rising or stable and high HBV DNA during flares represent ineffective immune clearance and further hepatocytolysis, even hepatic decompensation, may occur. Such patients require immediate antiviral therapy. In contrast, bridging hepatic necrosis and/or alpha-fetoprotein levels >100 ng/ml or decreasing HBV DNA during flares represent a more effective immune clearance and frequently leads to seroclearance of HBV DNA and/or hepatitis B e antigen with remission. If patients are non-cirrhotic and there is no concern of developing decompensation, patients may be observed for 3–6 months before deciding on the need of antiviral therapy. Severe and repeated flares are prone to develop into decompensation or lead to the development of cirrhosis, thus a timely treatment to prevent the hepatitis B flare is better than to cope with the flare. Screening, monitoring and prophylactic or pre-emptive antiviral therapy is mandatory for patients who are going to receive immunosuppressants or chemotherapy.
Abstract
Background
Whether serum hepatitis B virus (HBV) RNA associates with hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients has not been fully elucidated.
Methods
...We enrolled 2974 patients receiving nucleos(t)ide analogues (NAs) from a prospective, observational CHB cohort to investigate the effect of serum HBV RNA, measured at study entry (baseline), on HCC development, using Cox regression analyses.
Results
During median follow-up of 4.4 years, 90 patients developed HCC. Patients with detectable baseline HBV RNA (n = 2072) exhibited significantly higher HCC risk than those with undetectable level (5-year HCC incidence estimated by Kaplan-Meier method: 4.1% versus 1.8%, P = .009; adjusted hazard ratio aHR = 2.21, P = .005). HBV RNA levels of 609–99 999 and ≥100 000 copies/mL were associated with incrementally increasing HCC risk (aHR = 2.15 and 3.05, respectively; P for trend = .003), compared to undetectable level (<609 copies/mL). Moreover, patients with single-detectable either HBV DNA or RNA and double-detectable DNA and RNA had 1.57- and 4.02-fold higher HCC risk, respectively, than those with double-undetectable DNA and RNA (P for trend = .001).
Conclusions
High-level HBV RNA is associated with increased HCC risk in NAs-treated patients. Achieving undetectable HBV RNA may contribute to better clinical outcomes, indicating it could be a valuable endpoint of anti-HBV treatment.
High level of serum HBV RNA, a surrogate marker of intrahepatic cccDNA, is associated with increased risk of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide analogues. Achieving undetectable HBV RNA could be a valuable endpoint of antiviral treatment.
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•Discontinuation of NA therapy leads to higher HBsAg loss rates in HBeAg-negative CHB patients.•T cells from patients with subsequent HBsAg loss show a less exhausted phenotype.•These ...T cells also express higher levels of activation and proliferation markers at week 12 after discontinuation of therapy.•Relapse of active HBV replication may trigger immunological environment that enhances responsiveness of HBV-specific T cells in vitro.
Treatment with nucleos(t)ide analogues (NA) leads to hepatitis B virus (HBV) DNA suppression in most patients with chronic hepatitis B (CHB), but HBV surface antigen (HBsAg) loss rates are low. Upon NA discontinuation, HBV DNA can return rapidly with ensuing alanine aminotransferase flares and induction of cytokines. Several studies reported higher HBsAg loss rates after stopping therapy, but at present it is unclear if cell-mediated immune responses are altered after treatment discontinuation. The aim of this study was to characterise T cell responses during the early phase of virological relapse, following discontinuation of NA therapy in HBeAg-negative patients.
A total of 15 HBeAg-negative patients with CHB on long-term NA treatment were included in a prospective study and subjected to structured NA discontinuation. T cell responses were studied at the end of NA therapy and 4, 8 and 12 weeks thereafter.
The T cell phenotype of patients with CHB on long-term NA therapy was markedly different compared to healthy individuals, but was only slightly altered after discontinuation of therapy. T cells from patients with HBsAg loss expressed low levels of KLRG1 and PD-1 at all time-points and high levels of Ki-67 and CD38 at week 12 after treatment cessation. In vitro peptide stimulated HBV-specific T cell responses were increased in several patients after NA cessation. Blocking of PD-L1 further enhanced HBV-specific T cell responses, especially after discontinuation of therapy.
Relapse of active HBV replication after stopping therapy may trigger an immunological environment that enhances the responsiveness of HBV-specific T cells in vitro. Together with other immune interventions, this approach might be of interest for the development of novel therapeutic options to induce HBsAg loss in CHB.
Relapse of hepatitis B virus replication after discontinuation of nucleos(t)ide analogue therapy in certain patients with chronic hepatitis B may alter the phenotype of T cells and enhance the responsiveness of hepatitis B virus-specific T cells to in vitro peptide stimulation. Blocking PD-L1 can further augment these hepatitis B virus-specific T cell responses. Interestingly, T cells of patients that subsequently achieve hepatitis B surface antigen loss are less exhausted at all time-points after stopping treatment and display a higher proliferative capacity 12-weeks after treatment discontinuation. These findings contribute to the understanding of the immunological events that occur during discontinuation of nucleos(t)ide analogue therapy.
Although most patients with chronic hepatitis B (CHB) reach effective virological suppression with long-term nucleos(t)ide analogues (NA) therapy, some might not need to continue treatment for life. ...In this randomised, controlled, phase IV trial, we evaluated off-therapy outcomes in patients after discontinuing long-term NA therapy.
Patients who had received NA therapy for ≥1 year and achieved virological suppression (hepatitis B e antigen (HBeAg) seroconversion combined with undetectable hepatitis B virus (HBV) DNA ≥12 months in HBeAg-positive patients or undetectable HBV DNA ≥36 months in HBeAg-negative patients) were randomised 2:1 to stop or continue NA therapy for 72 weeks. Sustained disease remission (HBeAg negative, HBV DNA <2000 IU/mL and normal alanine aminotransferase (ALT)) was evaluated at 72 weeks after stopping NA therapy.
Among 67 enrolled patients, sustained disease remission was observed in 13/45 (29%) stop versus 18/22 (82%) continue patients. Hepatitis B surface antigen (HBsAg) loss occurred in two patients (one in each group). The median HBsAg decline from randomisation to week 72 was similar in both groups (0.2 (0.0-0.4) vs 0.1 (0.0-0.2) log IU/mL in stop vs continue patients). Among patients who stopped, 15/45 (33%) had virological or biochemical relapse and 17/45 (38%) were retreated according to predefined criteria. A total of 11/18 (61%) pretreatment HBeAg-positive versus 6/27 (22%) HBeAg-negative patients required retreatment (p=0.01). Fourteen (31%) patients developed ALT >10× upper limit of normal (ULN) and another 7 (16%) had ALT >5× ULN. No patients experienced liver decompensation or died.
The findings of this prospective study suggest limited benefit of stopping NA therapy in chronic hepatitis B.
NCT01911156.
The OPC Foundation defines standards for online data exchange between automation systems. They address access to current data (OPC DA), alarms and events (OPC AE) and historical data (OPC HDA). Those ...standards are successfully applied in industrial automation. The new OPC Unified Architecture (OPC UA) unifies the existing standards and brings them to state-of-the-art technology using service-oriented architecture (SOA). Main advantages of the new standard are: Platform-independent technology allows the deployment of OPC UA beyond current OPC applications only running on Windows-based PC systems. OPC UA can also run on embedded systems as well as Linux / UNIX based enterprise systems. The provided information can be generically modeled and therefore arbitrary information models can be provided using OPC UA. This book gives an easy to understand introduction into OPC UA and explains the concepts of the standard and other relevant topics that are not directly addressed by the standard.
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