Effectiveness of Tofacitinib in Patients With Ulcerative Colitis: A Nationwide Veterans Administration Cohort Study.

INTRODUCTION: There is paucity of data on the effectiveness and safety of tofacitinib among elderly patients with ulcerative colitis (UC). METHODS: Through a retrospective cohort study among the US National Veterans Affairs Healthcare System, we evaluated effectiveness among the elderly (≥65) and young (<65) patients with UC initiated on tofacitinib. RESULTS: Among 158 patients (53 elderly, 105 young), effectiveness at 12 months was 50.94% in the elderly and 33.33% in the young ( P = 0.032). DISCUSSION: In a nationwide cohort of patients with UC initiating tofacitinib, effectiveness was seen in half of the elderly patients.

Lossless Encoding of Time-Aggregated Neuromorphic Vision Sensor Data Based on Point-Cloud Compression.

Neuromorphic Vision Sensors (NVSs) are emerging sensors that acquire visual information asynchronously when changes occur in the scene. Their advantages versus synchronous capturing (frame-based video) include a low power consumption, a high dynamic range, an extremely high temporal resolution, and lower data rates. Although the acquisition strategy already results in much lower data rates than conventional video, NVS data can be further compressed. For this purpose, we recently proposed Time Aggregation-based Lossless Video Encoding for Neuromorphic Vision Sensor Data (TALVEN), consisting in the time aggregation of NVS events in the form of pixel-based event histograms, arrangement of the data in a specific format, and lossless compression inspired by video encoding. In this paper, we still leverage time aggregation but, rather than performing encoding inspired by frame-based video coding, we encode an appropriate representation of the time-aggregated data via point-cloud compression (similar to another one of our previous works, where time aggregation was not used). The proposed strategy, Time-Aggregated Lossless Encoding of Events based on Point-Cloud Compression (TALEN-PCC), outperforms the originally proposed TALVEN encoding strategy for the content in the considered dataset. The gain in terms of the compression ratio is the highest for low-event rate and low-complexity scenes, whereas the improvement is minimal for high-complexity and high-event rate scenes. According to experiments on outdoor and indoor spike event data, TALEN-PCC achieves higher compression gains for time aggregation intervals of more than 5 ms. However, the compression gains are lower when compared to state-of-the-art approaches for time aggregation intervals of less than 5 ms.

In Silico and In Vitro Mapping of Receptor-Type Protein Tyrosine Phosphatase Receptor Type D in Health and Disease: Implications for Asprosin Signalling in Endometrial Cancer and Neuroblastoma.

BACKGROUND: Protein Tyrosine Phosphatase Receptor Type D (PTPRD) is involved in the regulation of cell growth, differentiation, and oncogenic transformation, as well as in brain development. PTPRD also mediates the effects of asprosin, which is a glucogenic hormone/adipokine derived following the cleavage of the C-terminal of fibrillin 1. Since the asprosin circulating levels are elevated in certain cancers, research is now focused on the potential role of this adipokine and its receptors in cancer. As such, in this study, we investigated the expression of PTPRD in endometrial cancer (EC) and the placenta, as well as in glioblastoma (GBM). METHODS: An array of in silico tools, in vitro models, tissue microarrays (TMAs), and liquid biopsies were employed to determine the gene and protein expression of PTPRD in healthy tissues/organs and in patients with EC and GBM. RESULTS: PTPRD exhibits high expression in the occipital lobe, parietal lobe, globus pallidus, ventral thalamus, and white matter, whereas in the human placenta, it is primarily localised around the tertiary villi. PTPRD is significantly upregulated at the mRNA and protein levels in patients with EC and GBM compared to healthy controls. In patients with EC, PTPRD is significantly downregulated with obesity, whilst it is also expressed in the peripheral leukocytes. The EC TMAs revealed abundant PTPRD expression in both low- and high-grade tumours. Asprosin treatment upregulated the expression of PTPRD only in syncytialised placental cells. CONCLUSIONS: Our data indicate that PTPRD may have potential as a biomarker for malignancies such as EC and GBM, further implicating asprosin as a potential metabolic regulator in these cancers. Future studies are needed to explore the potential molecular mechanisms/signalling pathways that link PTPRD and asprosin in cancer.

Incidence of Pneumonia, Related Hospitalization, and Mortality Among Younger Unvaccinated IBD Patients in a Nationwide Cohort.

BACKGROUND AND GOALS: Community Acquired Pneumonia (CAP) is among the most common infections among Inflammatory Bowel Disease (IBD) patients. Our aim was to determine the absolute and relative risk of CAP, related hospitalization, and death among younger (age < 65) unvaccinated IBD patients exposed and unexposed to immunosuppressive medications. MATERIALS AND METHODS: We conducted a retrospective cohort study among a nationwide cohort of younger IBD unvaccinated patients in the VAHS. Exposure was administration of any immunosuppressive medication. The primary outcome was the first occurrence of pneumonia; secondary outcomes being pneumonia related hospitalization and mortality. We reported event rate per 1000 person-years, hazard ratio, and 95% confidence intervals (CIs) for each outcome. RESULTS: Among a total of 26,707 patients, 513 patients developed pneumonia. Mean age in years (SD) was 51.67 (11.34) for the exposed and 45.91 (12.34) for the unexposed group. The overall crude incidence rate was 3.2 per 1000 patient-years (PYs) [4.04/1000 PYs in the exposed versus 1.45/1000 PYs in the unexposed]. The overall crude incidence rates for pneumonia-related-hospitalization and mortality 1.12 and 0.09 per 1000 PYs, respectively. In Cox regression, the exposed group was associated with an increased risk of pneumonia (AHR 2.85; 95% CI: 2.21 to 3.66, P < 0.001) and pneumonia-related-hospitalization (AHR 3.46; 95% CI: 2.20 to 5.43, P < 0.001). CONCLUSIONS: Overall incidence of CAP among younger unvaccinated IBD patients was 3.2 per 1000 PYs. The overall associated hospitalization rates were low, however, higher amongst those exposed to immunosuppressive medications. This data will help patients and physicians make informed decisions regarding pneumococcal vaccine recommendations.

Open-source Artificial Pancreas Systems Are Safe and Effective When Supported In-clinic: Outcomes in 248 Consecutive Type 1 Diabetes Clients.

OBJECTIVE: Our aim in this study was to determine the safety, glycemia, and quality of life (QoL) associated with in-clinic installation and management of supported open-source artificial pancreas systems (SOSAPS) in type 1 diabetes (T1D). METHODS: This investigation is a retrospective cohort study of consecutive SOSAPS users at a Canadian diabetes centre. SOSAPS were offered to all moderately tech-savvy T1D clients on sensor-augmented multiple daily injection or pump, able to pay for hardware, and willing to sign a consent and waiver document. SOSAPS were installed and maintained by clinic staff at no cost to clients. iPhone users were assigned to either Loop (n=108) or iPhone artificial pancreas systems (iAPS; n=114) and Android users to Android-type APS (n=24). Outcomes included severe hypoglycemia and diabetic ketoacidosis (DKA), time in range (TIR) 4.0 to 10.0 mmol/L, time below range (TBR) <4 mmol/L, glucose management indicator (GMI), mean sensor glucose (MSG), change in glycated hemoglobin (A1C), and QoL. RESULTS: Two hundred forty-eight subjects (131 males, 117 females), with a mean age of 36 years and diabetes duration of 21 years, experienced 3 episodes of severe hypoglycemia and no DKA over a follow-up of 17 months. TIR rose by 16%, from 64% to 80% (p<0.0001); TBR fell by 1.0%, from 3.5% to 2.5% (p=0.001); MSG fell from 9.0 to 8.1 mmol/L (p<0.001); GMI fell from 7.3% to 6.7% (p<0.001); and A1C fell from 7.2% to 6.7% (p<0.0001). QoL scores were healthy before and improved after SOSAPS. CONCLUSIONS: Clients with T1D using SOSAPS and supported with no-cost care to the client (software, technology, and physician/physician assistant) safely achieved improved TIR, GMI, A1C, and QoL.

Experience with Tofacitinib in Patients with Ulcerative Colitis: Data from a United States Claims Database.

BACKGROUND: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). AIMS: To evaluate real-world data in US patients with UC receiving tofacitinib. METHODS: Characteristics and outcomes of patients with UC initiating tofacitinib between 2018 and 2019 were assessed using data from the IBM® MarketScan® claims database. The index date was the first tofacitinib claim; pre- and post-index periods were 12 months. Outcomes included tofacitinib adherence/persistence, oral corticosteroid (OCS) use, and healthcare resource utilization (HCRU) and costs. RESULTS: Of 276 patients with UC who initiated tofacitinib, 68 (24.6%) were bio-naïve, and 208 (75.4%) bio-experienced. At month 12, overall median tofacitinib adherence (proportion of days covered) was 0.82 (mean 0.68); 43.8% of patients discontinued tofacitinib (90-day gap). Of patients receiving OCS during the post-index 16-week tapering period, 40.4% discontinued OCS up to 12 months post-index. OCS use decreased in patients continuing tofacitinib versus those discontinuing tofacitinib (29.7% vs 59.5%, respectively). Reductions in all-cause and UC-related outpatient visits were observed for bio-naïve (- 1.34 and - 0.88, respectively) and bio-experienced (- 4.72 and - 5.16, respectively) patients, post-index. Decreased UC-related costs per year were observed for bio-experienced patients (difference in post-index vs pre-index, - US$12,448; driven by changes in pharmacy costs), but not for bio-naïve patients (US$47,152). CONCLUSIONS: In this real-world analysis in a mostly bio-experienced population, the majority of US patients with UC initiating tofacitinib remained on therapy at 12 months, and OCS use was reduced with tofacitinib treatment. HCRU (all patients) and UC-related costs were reduced in bio-experienced patients. The majority of patients with ulcerative colitis starting tofacitinib in this real-world study continued therapy at 12 months; there was a reduction in the use of steroids, and a decrease in healthcare resournce utilization and costs.

Financial burden associated with discordance to intravenous iron therapies in US patients with iron deficiency anemia.

BACKGROUND: Iron deficiency anemia (IDA) affects approximately 5 million people in the United States and has a significant impact on human health. Intravenous (IV) iron is indicated for treatment of IDA when oral iron is not effective or not tolerated. Several IV iron products are available, including oldergeneration and newer-generation products. Newer agents have certain benefits, including the ability to administer high iron doses in fewer infusions; despite the benefits, some payors require failure on older iron products before use of newer iron products in prior authorization processes. IV iron replacement regimens requiring multiple infusions may lead to patients not receiving recommended IV iron treatment per label; potential costs of this discordance may outweigh the difference in price between the older and newer products. OBJECTIVE: To quantify the burden of discordance to IV iron therapy and associated economic consequences. METHODS: This is a retrospective study using administrative claims data between January 2016 and December 2019 from adult patients who are enrolled in a commercial insurance program with a regional health plan. A course of IV iron therapy is defined as all infusions that occur within 6 weeks of the initial infusion. Discordance to therapy is defined as having received less than 1,000 mg of iron over a course of therapy. RESULTS: There were 24,736 patients included in the study. Baseline demographics were similar between the patients who received older- vs newer-generation products and patients who were concordant vs discordant. Discordance to IV iron therapy overall was 33%. Patients who received newer-generation products were less discordant to therapy (16%) than patients who received older-generation products (55%). In general, patients who received newer-generation products had a lower total cost of care than patients who received older-generation products. CONCLUSIONS: Discordance to the older-generation products was significantly higher than that to the newer-generation products. Patients who were concordant to therapy and on a newer-generation product had the lowest total cost of care, suggesting that overall cost of care is not necessarily proportional to the purchase price of the chosen IV iron replacement therapy. Optimizing concordance to IV iron therapy may lead to lower total cost of care in the IDA population. DISCLOSURES: Magellan Rx Management received funding for this study from Pharmacosmos Therapeutics Inc. AESARA contributed to study design and data analysis. Magellan Rx Management contributed to the study design, data analysis, and interpretation of results. Pharmacosmos Therapeutics Inc. participated in the study design and interpretation of results.

Mechanism of secretion of TcpF by the Vibrio cholerae toxin-coregulated pilus.

Many bacteria possess dynamic filaments called Type IV pili (T4P) that perform diverse functions in colonization and dissemination, including host cell adhesion, DNA uptake, and secretion of protein substrates-exoproteins-from the periplasm to the extracellular space. The Vibrio cholerae toxin-coregulated pilus (TCP) and the enterotoxigenic Escherichia coli CFA/III pilus each mediates export of a single exoprotein, TcpF and CofJ, respectively. Here, we show that the disordered N-terminal segment of mature TcpF is the export signal (ES) recognized by TCP. Deletion of the ES disrupts secretion and causes TcpF to accumulate in the V. cholerae periplasm. The ES alone can mediate export of Neisseria gonorrhoeae FbpA by V. cholerae in a T4P-dependent manner. The ES is specific for its autologous T4P machinery as CofJ bearing the TcpF ES is exported by V. cholerae, whereas TcpF bearing the CofJ ES is not. Specificity is mediated by binding of the ES to TcpB, a minor pilin that primes pilus assembly and forms a trimer at the pilus tip. Finally, the ES is proteolyzed from the mature TcpF protein upon secretion. Together, these results provide a mechanism for delivery of TcpF across the outer membrane and release into the extracellular space.

DNS Tunnelling, Exfiltration and Detection over Cloud Environments.

The domain name system (DNS) protocol is fundamental to the operation of the internet, however, in recent years various methodologies have been developed that enable DNS attacks on organisations. In the last few years, the increased use of cloud services by organisations has created further security challenges as cyber criminals use numerous methodologies to exploit cloud services, configurations and the DNS protocol. In this paper, two different DNS tunnelling methods, Iodine and DNScat, have been conducted in the cloud environment (Google and AWS) and positive results of exfiltration have been achieved under different firewall configurations. Detection of malicious use of DNS protocol can be a challenge for organisations with limited cybersecurity support and expertise. In this study, various DNS tunnelling detection techniques were utilised in a cloud environment to create an effective monitoring system with a reliable detection rate, low implementation cost, and ease of use for organisations with limited detection capabilities. The Elastic stack (an open-source framework) was used to configure a DNS monitoring system and to analyse the collected DNS logs. Furthermore, payload and traffic analysis techniques were implemented to identify different tunnelling methods. This cloud-based monitoring system offers various detection techniques that can be used for monitoring DNS activities of any network especially accessible to small organisations. Moreover, the Elastic stack is open-source and it has no limitation with regards to the data that can be uploaded daily.

COVID-19 Vaccine Effectiveness Against the Omicron Variant in a Veterans Affairs Cohort of Patients With Inflammatory Bowel Disease.

INTRODUCTION: With the advent of the Omicron variant, there are concerns about the efficacy of current vaccinations, especially among immunocompromised/immunosuppressed patients. Our aim was to determine the efficacy of the first booster dose against Omicron. METHODS: This was a retrospective cohort study using a well-established inflammatory bowel disease (IBD) cohort in the Veterans Health Administration. We followed patients on baseline IBD medications through the month of January 2022 during the Omicron COVID-19 wave and created adjusted models for vaccination and boosting effectiveness in reducing SARS-CoV-2 infection, hospitalization, and all-cause mortality. RESULTS: A total of 22,756 patients with IBD were included, of whom 34.9% had received a booster dose. During follow-up, 622 patients (2.7%) were diagnosed with SARS-CoV-2 infection. In adjusted models, booster status was associated with a 30% reduced hazard of SARS-CoV-2 infection (hazard ratio 0.70 vs unvaccinated status, 95% confidence interval 0.56-0.88, P = 0.002), translating to 25.05% effectiveness. Boosted status was also significantly associated with reduced COVID-19 hospitalization (hazard ratio 0.35, 95% confidence interval 0.16-0.74, P = 0.006), demonstrating a 65.06% effectiveness in adjusted models. There was no significant association between vaccination status and all-cause mortality in adjusted models. DISCUSSION: The boosted state was associated with a lower risk of SARS-CoV-2 infections and COVID-19-related hospitalization. Efficacy was lower than what has been seen against previous variants and decreased with prolonged duration from the booster. These findings suggest that patients with IBD, especially those who are immunosuppressed, should consider getting a second booster as per Centers for Disease Control and Prevention recommendations.

Risk of severe and opportunistic infections and the impact of SARS-COV-2 on this risk in a nationwide cohort of patients with inflammatory bowel disease.

BACKGROUND: The Inflammatory Bowel Disease (IBD) patients have adopted lifestyle modifications to prevent infection via SARS COV-2. AIMS: This study aims to examine rate of serious infections and opportunistic infections in the pre-pandemic and pandemic period, and to analyse if the risk associated with medications used to treat IBD were potentially modified by associated change in lifestyle. METHODS: We conducted a retrospective cohort study of patients from the US national Veteran Affairs Healthcare System (VAHS). Patients were stratified into two groups: pre-pandemic (prior to SARS COV-2 pandemic) and pandemic (during SARS COV-2 pandemic) and outcomes were measured in these groups. Primary outcome was occurrence of any serious infection. Secondary outcome was occurrence of any opportunistic infection. RESULTS: There were 17,202 IBD patients in the pre-pandemic era and 15,903 patients in the pandemic era. The pre-pandemic era had a significantly higher proportion of serious infections relative to the pandemic era (5.1% vs. 4.4%, p = 0.002). The proportion of opportunistic infections were similar between pre-pandemic and pandemic eras (0.3% vs. 0.3%, p = 0.82). Relative to 5-ASA, patients taking anti-TNF (HR = 1.50 (1.31-1.72)), anti-TNF+TP (HR = 1.56 (1.24-1.95)) or vedolizumab (HR = 1.81 (1.49-2.20)) had an increased hazard of serious infection (p > 0.001). CONCLUSION: In a nationwide cohort of IBD patients, we found that risk of serious infections could possibly be affected by behavioural modifications due to SARS-COV-2 pandemic.

Impact of Biologics on SARS-COV-2 Disease Course When Infused Within 2 Weeks of Acquiring the Infection Among IBD Patients.

SARS-CoV-2 was first identified in Wuhan in December 2019 and since then it has progressed into a pandemic that evolves continuously.1 As of May 5, 2022, there have been more than 81 million cases and 994,187 deaths in the United States.2 Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract consisting of ulcerative colitis and Crohn's disease treated with immunosuppressive/immunomodulatory agents. Over the course of the pandemic different aspects of the interaction between SARS-COV-2 and IBD medications have been studied.3,4 At the onset of the pandemic there was decreased use of infusible biologics.5 Despite the passage of time an area that has not been explored is the impact of biologics on the clinical course of SARS-COV-2 when given soon after the detection of infection. Our aim was to determine the impact of biologics on the clinical course of SARS-COV-2 among patients with IBD, when given 1-2 weeks postinfection among stable patients. This is of critical importance because patients may delay getting their scheduled treatment, which in turn could adversely affect their clinical condition.

Adverse Events Related to SARS-CoV-2 Vaccine in a Nationwide Cohort of Patients With Inflammatory Bowel Disease.

INTRODUCTION: There are limited data on the safety profile of the severe acute respiratory syndrome coronavirus-2 vaccine among patients taking immunosuppressive medications. Our aim was to evaluate the adverse events related to the vaccines in a nationwide cohort of patients with inflammatory bowel disease on diverse immunosuppressive medications. METHODS: This was a retrospective cohort study using data from the Veterans Health Administration. The primary outcome was any adverse event of special interest (cerebrovascular accident, venous thromboembolism, acute myocardial infarction, Bell palsy) within 90 days of vaccination. RESULTS: A total of 17,201 patients were included, and 12,351 patients (71.8%) received at least 1 vaccine dose. The most common adverse events were acute myocardial infarction and venous thromboembolism. In inverse probability treatment weighting-adjusted logistic regression, full vaccination was not significantly associated with increased adverse events through 90 days, relative to unvaccinated patients. DISCUSSION: Full severe acute respiratory syndrome coronavirus-2 vaccination was not associated with an increased rate of key adverse events relative to unvaccinated individuals among patients with inflammatory bowel disease.

Dynamic phase separation of the androgen receptor and its coactivators key to regulate gene expression.

Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa.

Differential Regulation of Genes by the Glucogenic Hormone Asprosin in Ovarian Cancer.

Background: Ovarian cancer (OvCa) is one of the most lethal forms of gynaecological malignancy. Altered energy metabolism and increased aerobic glycolysis in OvCa are hallmarks that demand attention. The glucogenic hormone asprosin is often dysregulated in metabolic disorders such as insulin resistance, diabetes (type 2 and gestational), and preeclampsia. Despite association with metabolic disorders, its role in energy metabolism within the tumour microenvironment is yet to be explored. Here, we study the role of asprosin in OvCa using transcriptomics and expand on functional studies with clinical samples. Methods: RNA sequencing, functional gene enrichment analysis, Western blotting and ImageStream. Results: Following treatment with 100 nM of asprosin, the serous OvCa cell line, SKOV-3, displayed 160 and 173 gene regulatory changes, at 4 and 12 h respectively, when compared with control samples (p < 0.05 and Log2FC > 1). In addition to energy metabolism and glucose-related pathways, asprosin was shown to alter pathways associated with cell communication, TGF-ß signalling, and cell proliferation. Moreover, asprosin was shown to induce phosphorylation of ERK1/2 in the same in vitro model. Using liquid biopsies, we also report for novel expression of asprosin's predicted receptors OR4M1 and TLR4 in cancer-associated circulating cells; with significant reduction seen between pre-chemotherapy and end of first line chemotherapy, in addition to patients under maintenance with bevacizumab +/− olaparib for OR4M1. Conclusions: In relation to OvCa, asprosin appears to regulate numerous signalling pathways in-vitro. The prognostic potential of OR4M1 in liquid biopsies should also be explored further.