A single-day polychemotherapy regimen with proteasome inhibitor combinations for relapsed/refractory myeloma in the era of novel therapies.

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37-80), with a median of four (1-8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5-6.7) and 7.4 months (95% CI 6.4-10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6-13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4-39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics.

Ro60-Roles in RNA Processing, Inflammation, and Rheumatic Autoimmune Diseases.

The Ro60/SSA2 autoantigen is an RNA-binding protein and a core component of nucleocytoplasmic ribonucleoprotein (RNP) complexes. Ro60 is essential in RNA metabolism, cell stress response pathways, and cellular homeostasis. It stabilises and mediates the quality control and cellular distribution of small RNAs, including YRNAs (for the 'y' in 'cytoplasmic'), retroelement transcripts, and misfolded RNAs. Ro60 transcriptional dysregulation or loss of function can result in the generation and release of RNA fragments from YRNAs and other small RNAs. Small RNA fragments can instigate an inflammatory cascade through endosomal toll-like receptors (TLRs) and cytoplasmic RNA sensors, which typically sense pathogen-associated molecular patterns, and mount the first line of defence against invading pathogens. However, the recognition of host-originating RNA moieties from Ro60 RNP complexes can activate inflammatory response pathways and compromise self-tolerance. Autoreactive B cells may produce antibodies targeting extracellular Ro60 RNP complexes. Ro60 autoantibodies serve as diagnostic markers for various autoimmune diseases, including Sjögren's disease (SjD) and systemic lupus erythematosus (SLE), and they may also act as predictive markers for anti-drug antibody responses among rheumatic patients. Understanding Ro60's structure, function, and role in self-tolerance can enhance our understanding of the underlying molecular mechanisms of autoimmune conditions.

Poor engagement and adherence predict neoplasia in inflammatory bowel disease: a case-control study.

BACKGROUND: Colorectal adenocarcinoma is an important and preventable complication of inflammatory bowel disease (IBD). A previous case series suggested mental health issues and poor engagement in care as novel risk factors. AIMS: To confirm the role of patient engagement in care in the development of neoplasia using a case-control methodology. METHODS: Patients in a single referral centre from 2007 to 2017 with colorectal adenocarcinoma, high-grade dysplasia or multifocal low-grade dysplasia were included as neoplasia cases. Each case was assigned up to three matched controls (matched for age, gender, underlying disease, IBD type and phenotype and disease duration). Novel and known risk factors were compared between groups. RESULTS: Thirty-two cases with 88 matched controls were included. Patients with neoplasia were more likely to have poor adherence to, or engagement with, care (odds ratio (OR) 4.79). They were also more likely to have chronic use of opioids (OR 3.86) and long-term prednisolone (OR 2.97). Of note, no difference was found in measures of socioeconomic disadvantage, reflecting equitable access to healthcare in the public institution where the care was studied. As previously shown, patients with neoplasia had multiple markers of increased cumulative burden of inflammation, including more IBD-related hospital admissions, elevated inflammatory markers and severe inflammation at colonoscopy. CONCLUSIONS: This study confirms poor adherence or engagement with care as a new risk factor for colorectal adenocarcinoma in patients with IBD; identifying a vulnerable group whom clinicians should endeavour to engage in order to avoid this catastrophic complication.

Impact of device length on electrogram sensing in miniaturized insertable cardiac monitors.

BACKGROUND: Little data exists on electrogram sensing in current generation of miniaturized insertable cardiac monitors (ICMs). OBJECTIVE: To compare the sensing capability of ICM with different vector length: Medtronic Reveal LINQ (~40 mm) vs. Biotronik Biomonitor III (BM-III, ~70 mm). METHODS: De-identified remote monitoring transmissions from n = 40 patients with BM-III were compared with n = 80 gender and body mass index (BMI)-matched patients with Reveal LINQ. Digital measurement of P- and R-wave amplitude from calibrated ICM electrograms was undertaken by 3 investigators independently. Further, we evaluated the impact of BMI and gender on P-wave visibility. RESULTS: Patients in both groups were well matched for gender and BMI (53% male, mean BMI 26.7 kg/m2, both p = NS). Median P- and R-wave amplitude were 97% & 56% larger in the BM-III vs. LINQ [0.065 (IQR 0.039-0.10) vs. 0.033 (IQR 0.022-0.050) mV, p < .0001; & 0.78 (IQR 0.52-1.10) vs. 0.50 (IQR 0.41-0.89) mV, p = .012 respectively). The P/R-wave ratio was 36% greater with the BM-III (p < .001). The 25th percentile of P-wave amplitude for all 120 patients was .026 mV. Logistic regression analysis showed BM-III was more likely than LINQ to have P-wave amplitude ≥.026 mV (OR 7.47, 95%CI 1.965-29.42, p = .003), and increasing BMI was negatively associated with P-wave amplitude ≥.026 mV (OR 0.84, 95%CI 0.75-0.95, p = .004). However, gender was not significantly associated with P-wave amplitude ≥.026 mV (p = .37). CONCLUSION: The longer ICM sensing vector of BM-III yielded larger overall P- and R- wave amplitude than LINQ. Both longer sensing vector and lower BMI were independently associated with greater P-wave visibility.

Validating hidden Markov models for seabird behavioural inference.

Understanding animal movement and behaviour can aid spatial planning and inform conservation management. However, it is difficult to directly observe behaviours in remote and hostile terrain such as the marine environment. Different underlying states can be identified from telemetry data using hidden Markov models (HMMs). The inferred states are subsequently associated with different behaviours, using ecological knowledge of the species. However, the inferred behaviours are not typically validated due to difficulty obtaining 'ground truth' behavioural information. We investigate the accuracy of inferred behaviours by considering a unique data set provided by Joint Nature Conservation Committee. The data consist of simultaneous proxy movement tracks of the boat (defined as visual tracks as birds are followed by eye) and seabird behaviour obtained by observers on the boat. We demonstrate that visual tracking data is suitable for our study. Accuracy of HMMs ranging from 71% to 87% during chick-rearing and 54% to 70% during incubation was generally insensitive to model choice, even when AIC values varied substantially across different models. Finally, we show that for foraging, a state of primary interest for conservation purposes, identified missed foraging bouts lasted for only a few seconds. We conclude that HMMs fitted to tracking data have the potential to accurately identify important conservation-relevant behaviours, demonstrated by a comparison in which visual tracking data provide a 'gold standard' of manually classified behaviours to validate against. Confidence in using HMMs for behavioural inference should increase as a result of these findings, but future work is needed to assess the generalisability of the results, and we recommend that, wherever feasible, validation data be collected alongside GPS tracking data to validate model performance. This work has important implications for animal conservation, where the size and location of protected areas are often informed by behaviours identified using HMMs fitted to movement data.

TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease.

TRIM21 (Ro52/SSA1) is an E3 ubiquitin ligase with key roles in immune host defence, signal transduction, and possibly cell cycle regulation. It is also an autoantibody target in Sjögren's syndrome, systemic lupus erythematosus, and other rheumatic autoimmune diseases. Here, we summarise the structure and function of this enzyme, its roles in innate immunity, adaptive immunity and cellular homeostasis, the pathogenesis of autoimmunity against TRIM21, and the potential impacts of autoantibodies to this intracellular protein.

Ginkgolic Acid Inhibits Herpes Simplex Virus Type 1 Skin Infection and Prevents Zosteriform Spread in Mice.

Herpes simplex virus type 1 (HSV-1) causes a lifelong latent infection with an estimated global prevalence of 66%. Primary and recurrent HSV infections are characterized by a tingling sensation, followed by an eruption of vesicles, which can cause painful erosions. Commonly used antiviral drugs against HSV infection are nucleoside analogues including acyclovir (ACV), famciclovir, and valacyclovir. Although these nucleoside analogues reduce morbidity and mortality in immunocompetent individuals, ACV-resistant HSV strains (ACVR-HSV) have been isolated from immunocompromised patients. Thus, ACVR-HSV infection poses a critical emerging public health concern. Recently, we reported that ginkgolic acid (GA) inhibits HSV-1 by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis. Additionally, we showed GA affords a broad spectrum of fusion inhibition of all three classes of fusion proteins, including those of HIV, Ebola, influenza A and Epstein Barr viruses. Here we report GA's antiviral activity against HSV-1 skin infection in BALB/cJ mice. GA-treated mice demonstrated a significantly reduced mortality rate and decreased infection scores compared to controls treated with dimethylsulfoxide (DMSO)-vehicle. Furthermore, GA efficiently inhibited ACVR-HSV-1 strain 17+ in vitro and in vivo. Since GA's mechanism of action includes virucidal activity and fusion inhibition, it is expected to work alone or synergistically with other anti-viral drugs, and we anticipate it to be effective against additional cutaneous and potentially systemic viral infections.

Being here with you: An examination of the relational field in dementia care.

Underpinning the provision and receipt of care is the involvement of two parties: carer and cared-for. This paper seeks to understand how the National Dementia Strategy constructs the relational field in professional dementia care, and how this writes itself (or not) into the actual realities of daily care practice in a dementia care home. The paper will explore the connections between (i) the ways the needs of those who receive care are constituted in dementia care discourse; (ii) the ideological frames, around policies, said to respond to such needs; and (iii) the incidences of tension between policy and the realities of the embodied and psychic experiences of those involved in dementia care.

Fine-scale harbour seal usage for informed marine spatial planning.

High-resolution distribution maps can help inform conservation measures for protected species; including where any impacts of proposed commercial developments overlap the range of focal species. Around Orkney, northern Scotland, UK, the harbour seal (Phoca vitulina) population has decreased by 78% over 20 years. Concern for the declining harbour seal population has led to constraints being placed on tidal energy generation developments. For this study area, telemetry data from 54 animals tagged between 2003 and 2015 were used to produce density estimation maps. Predictive habitat models using GAM-GEEs provided robust predictions in areas where telemetry data were absent, and were combined with density estimation maps, and then scaled to population levels using August terrestrial counts between 2008 and 2015, to produce harbour seal usage maps with confidence intervals around Orkney and the North coast of Scotland. The selected habitat model showed that distance from haul out, proportion of sand in seabed sediment, and annual mean power were important predictors of space use. Fine-scale usage maps can be used in consenting and licensing of anthropogenic developments to determine local abundance. When quantifying commercial impacts through changes to species distributions, usage maps can be spatially explicitly linked to individual-based models to inform predicted movement and behaviour.

Preparatory planning framework for Created Out of Mind: Shaping perceptions of dementia through art and science.

Created Out of Mind is an interdisciplinary project, comprised of individuals from arts, social sciences, music, biomedical sciences, humanities and operational disciplines. Collaboratively we are working to shape perceptions of dementias through the arts and sciences, from a position within the Wellcome Collection. The Collection is a public building, above objects and archives, with a porous relationship between research, museum artefacts, and the public.  This pre-planning framework will act as an introduction to Created Out of Mind. The framework explains the rationale and aims of the project, outlines our focus for the project, and explores a number of challenges we have encountered by virtue of working in this way.

Avoidance of wind farms by harbour seals is limited to pile driving activities.

As part of global efforts to reduce dependence on carbon-based energy sources there has been a rapid increase in the installation of renewable energy devices. The installation and operation of these devices can result in conflicts with wildlife. In the marine environment, mammals may avoid wind farms that are under construction or operating. Such avoidance may lead to more time spent travelling or displacement from key habitats. A paucity of data on at-sea movements of marine mammals around wind farms limits our understanding of the nature of their potential impacts.Here, we present the results of a telemetry study on harbour seals Phoca vitulina in The Wash, south-east England, an area where wind farms are being constructed using impact pile driving. We investigated whether seals avoid wind farms during operation, construction in its entirety, or during piling activity. The study was carried out using historical telemetry data collected prior to any wind farm development and telemetry data collected in 2012 during the construction of one wind farm and the operation of another.Within an operational wind farm, there was a close-to-significant increase in seal usage compared to prior to wind farm development. However, the wind farm was at the edge of a large area of increased usage, so the presence of the wind farm was unlikely to be the cause.There was no significant displacement during construction as a whole. However, during piling, seal usage (abundance) was significantly reduced up to 25 km from the piling activity; within 25 km of the centre of the wind farm, there was a 19 to 83% (95% confidence intervals) decrease in usage compared to during breaks in piling, equating to a mean estimated displacement of 440 individuals. This amounts to significant displacement starting from predicted received levels of between 166 and 178 dB re 1 µPa(p-p). Displacement was limited to piling activity; within 2 h of cessation of pile driving, seals were distributed as per the non-piling scenario. Synthesis and applications. Our spatial and temporal quantification of avoidance of wind farms by harbour seals is critical to reduce uncertainty and increase robustness in environmental impact assessments of future developments. Specifically, the results will allow policymakers to produce industry guidance on the likelihood of displacement of seals in response to pile driving; the relationship between sound levels and avoidance rates; and the duration of any avoidance, thus allowing far more accurate environmental assessments to be carried out during the consenting process. Further, our results can be used to inform mitigation strategies in terms of both the sound levels likely to cause displacement and what temporal patterns of piling would minimize the magnitude of the energetic impacts of displacement.

Activated platelets and monocytes generate four hydroxyphosphatidylethanolamines via lipoxygenase.

12/15-Lipoxygenase (LOX) mediates immune-regulatory activities not accounted for by its known free acid eicosanoids, suggesting that additional lipids may be generated by activated cells. To characterize novel LOX-derived lipids, a lipidomic approach was utilized. Ionophore-activated interleukin-4-treated human peripheral monocytes generated up to 10-fold more esterified 15-hydroxyeicosatetraenoic acid (15-HETE) than free in a phosphatidylinositol 3-kinase- and protein kinase C-sensitive manner. Precursor scanning electrospray ionization/tandem spectroscopy for m/z 319 (HETE, [M-H](-)) showed 4 ions at m/z 738, 764, 766, and 782 that were identified using tandem spectroscopy and MS3 as specific diacyl and plasmalogen 15-HETE phosphatidylethanolamines. Using H (18)(2)O water, the compounds were shown to form by direct oxidation of endogenous phosphatidylethanolamine (PE) by 15-LOX, with PE being the preferred phospholipid pool containing 15-HETE. Similarly, human platelets generated 4 analogous PE lipids that contained 12-HETE and increased significantly in response to ionophore, collagen, or convulxin. These products were retained in the cells, in contrast to free acids, which are primarily secreted. Precursor scanning of platelet extracts for the major platelet-derived prostanoid, thromboxane B2 (m/z 369.2), did not reveal PE esters, indicating that this modification is restricted to the LOX pathway. In summary, we show formation of PE-esterified HETEs in immune cells that may contribute to LOX signaling in inflammation.