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(C, D) Patient OS and PFS according to the R2ISS scoring in the R-ISS II cohort only. Keywords: cancer cytogenetics; myeloma; prognostic factors EN cancer cytogenetics myeloma prognostic factors e17 e21 5 01/16/23 20230115 NES 230115 To evaluate the performance of the second revision of the International Staging System 2 (R2ISS)[1] in a real-world cohort, we applied the scoring system to patients with newly-diagnosed multiple myeloma (NDMM) in the Myeloma and Related Diseases Registry (MRDR). The second revision of the International Staging System (R2-ISS) stratifies progression-free and overall survival in multiple myeloma: Real world data results in an Australian and New Zealand Population. [Extracted from the article]

A response by Joby Taylor and colleagues to a letter to the editor regarding their article "British Association of Urological Surgeons' suprapubic catheter practice guidelines" in the 2011 issue is presented.

Reports the case of a boy with red cell agglutination and erythrophagocytosis. Background on the subject's health; Results of a blood count; Fluctuations in hemoglobin levels.

The first record of the Asian/yellow-legged hornet (Vespa velutina) in Ireland was reported in April 2021, when a single female individual was discovered in Dublin. Vespa velutina has been present in mainland Europe since 2004 and in the UK since 2016 and poses an enormous threat to European apiculture and bee-mediated pollination services. Three mitochondrial genes were sequenced from the Irish specimen to determine whether the specimen originated from the established European population or signified a new point of entry from its native range in China. Additionally, specimens from Portugal, Spain, France, Germany, and the Channel Islands were sequenced at these three genes to build on previous studies which have asserted, based solely on Cytochrome Oxidase 1 (COI) analysis, that the entire range of V. velutina in Europe represents a single invasion which has proliferated since the first record in France. Further data were retrieved from GenBank for comparison. Results reveal that the mtDNA lineage observed in Dublin is the same as that seen throughout Europe, and therefore the arrival of this species in Ireland likely represents a further spread of the ongoing European invasion. [ABSTRACT FROM AUTHOR]

Summary: The frequency and causes of early mortality in patients with newly diagnosed multiple myeloma (NDMM) have not been well described in the era of novel agents. We investigated early mortality in a prospective cohort study of all patients with NDMM registered on the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) at 36 institutions between July 2011 and March 2020. Early mortality was defined as death from any cause within the first 12 months after diagnosis. A total of 2377 patients with NDMM were included in the analysis, with a median (interquartile range) age of 67.4 (58.9–74.60 years, and 60% were male. Overall, 216 (9.1%) patients died within 12 months, with 119 (4.5%) having died within 6 months. Variables that were independent predictors of early mortality after adjustment in multivariable regression included age (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.05–1.08; p < 0.001), Eastern Cooperative Oncology Group performance status (OR 1.50, 95% CI 1.26–1.79; p < 0.001), serum albumin (OR 0.95, 95% CI 0.93–0.98; p < 0.001), cardiac disease (OR 1.96, 95% CI 1.35–2.86; p < 0.001) and International Staging System (OR 1.40, 95% CI 1.07–1.82; p = 0.01). For those with a primary cause of death available, it was reported as disease‐related in 151 (78%), infection 13 (7%), other 29 (15%). Infection was listed as a contributing factor for death in 38% of patients. [ABSTRACT FROM AUTHOR]

The article presents comments of the author and social scientist Brigitta Hauser-SchÄublin on the article "The New Guinea High Lands: Region, Culture Area, or Fuzzy Set?" by Terence E. Hays. Brigitta praises the analysis made by Hays regarding the "New Guinea Highlands." He acknowledges that Hays has identified his perspective for structuring complex reality. The author rejected the suggestion of Hays that one should try to stop thinking in categories.

Introduction: Infections are a leading cause of morbidity and mortality in patients with multiple myeloma. The epidemiology, risk factors and outcomes of viral respiratory tract infections (vRTI) are not well described in patients with multiple myeloma managed with novel agents, the current standard of care. Methods: Patients with myeloma from 2009 to 2012 who tested positive on respiratory virus multiplex polymerase chain reaction had clinical, radiological and microbiological records reviewed. The Fourth European Conference on Infections in Leukaemia (ECIL-4) definitions of RTI were applied. Univariate and multivariate regression analysis of risk factors was performed using vRTI as the evaluable outcome. Results: Of 330 patients, 75 (22.7 %) tested positive for a total of 100 vRTI episodes. All patients received thalidomide, lenalidomide or bortezomib in combination with myeloma therapies (median of three treatment regimens). vRTI occurred most commonly in patients with progressive disease, and receipt of more than three lines of myeloma therapy was associated with an increased risk of vRTI ( p < 0.01). Amongst key respiratory pathogens, influenza was associated with the highest hospital admission rate (66.7 %), ICU admission rate (41.6 %) and mortality (33.3 %) whilst RSV was associated with prolonged hospital stay. Conclusion: Patients with multiple myeloma and advanced disease managed with multiple lines of therapy are at risk for vRTI, and targeted interventions for prevention/treatment are required. [ABSTRACT FROM AUTHOR]

The PI3K/AKT pathway is constitutively active in hematologic malignancies, providing proliferative and antiapoptotic signals and possibly contributing to drug resistance. We conducted an open-label phase 1 study to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of afuresertib-an oral AKT inhibitor-in patients with advanced hematologic malignancies. Seventy-three patients were treated at doses ranging from 25 to 150 mg per day. The MTD was established at 125 mg per day because of 2 dose-limiting toxicities in the 150-mg cohort (liver function test abnormalities). The most frequent adverse events were nausea (35.6%), diarrhea (32.9%), and dyspepsia (24.7%). Maximum plasma concentrations and area under the plasma concentration-time curves from time 0 to 24 hours were generally dose proportional at >75-mg doses; the median time to peak plasma concentrations was 1.5 to 2.5 hours post dose, with a half-life of approximately 1.7 days. Three multiple myeloma patients attained partial responses; an additional 3 attained minimal responses. Clinical activity was also observed in non-Hodgkin lymphoma, Langerhan's cell histiocytosis, and Hodgkin disease. Single-agent afuresertib showed a favorable safety profile and demonstrated clinical activity against hematologic malignancies, including multiple myeloma. [ABSTRACT FROM AUTHOR]

Objectives: To investigate volume–outcome relationships in robot‐assisted radical prostatectomy (RARP) for cancer using data from the Hospital Episodes Statistics (HES) database for England. Materials and Methods: Data for all adult, elective RPs for cancer during the period January 2013–December 2018 (inclusive) were extracted from the HES database. The HES database records data on all National Health Service (NHS) hospital admissions in England. Data were extracted for the NHS trust and surgeon undertaking the procedure, the surgical technique used (laparoscopic, open or robot‐assisted), hospital length of stay (LOS), emergency readmissions, and deaths. Multilevel modelling was used to adjust for hierarchy and covariates. Results: Data were available for 35 629 RPs (27 945 RARPs). The proportion of procedures conducted as RARPs increased from 53.2% in 2013 to 92.6% in 2018. For RARP, there was a significant relationship between 90‐day emergency hospital readmission (primary outcome) and trust volume (odds ratio [OR] for volume decrease of 10 procedures: 0.99, 95% confidence interval [CI] 0.99–1.00; P = 0.037) and surgeon volume (OR for volume decrease of 10 procedures: 0.99, 95% CI 0.99–1.00; P = 0.013) in the previous year. From lowest to highest volume category there was a decline in the adjusted proportion of patients readmitted as an emergency at 90 days from 10.6% (0–49 procedures) to 7.0% (≥300 procedures) for trusts and from 9.4% (0–9 procedures) to 8.3% (≥100 procedures) for surgeons. LOS was also significantly associated with surgeon and trust volume, although 1‐year mortality was associated with neither. Conclusions: There is evidence of a volume–outcome relationship for RARP in England and minimising low‐volume RARP will improve patient outcomes. Nevertheless, the observed effect size was relatively modest, and stakeholders should be realistic when evaluating the likely impact of further centralisation at a population level. [ABSTRACT FROM AUTHOR]

Background Seroprotection and seroconversion rates are not well understood for 2-dose inactivated influenza vaccination (IIV) schedules in autologous hematopoietic stem cell transplantation (autoHCT) patients. Methods A randomized, single-blind, controlled trial of IIV in autoHCT patients in their first year post-transplant was conducted. Patients were randomized 1:1 to high-dose (HD) IIV followed by standard dose (SD) vaccine (HD-SD arm) or 2 SD vaccines (SD-SD arm) 4 weeks apart. Hemagglutination inhibition (HI) assay for IIV strains was performed at baseline, 1, 2, and 6 months post–first dose. Evaluable primary outcomes were seroprotection (HI titer ≥40) and seroconversion (4-fold titer increase) rates and secondary outcomes were geometric mean titers (GMTs), GMT ratios (GMRs), adverse events, influenza-like illness (ILI), and laboratory-confirmed influenza (LCI) rates and factors associated with seroconversion. Results Sixty-eight patients were enrolled (34/arm) with median age of 61.5 years, majority male (68%) with myeloma (68%). Median time from autoHCT to vaccination was 2.3 months. For HD-SD and SD-SD arms, percentages of patients achieving seroprotection were 75.8% and 79.4% for H1N1, 84.9% and 88.2% for H3N2 (all P  > .05), and 78.8% and 97.1% for influenza-B/Yamagata (P  = .03), respectively. Seroconversion rates, GMTs and GMRs, and number of ILI or LCIs were not significantly different between arms. Adverse event rates were similar. Receipt of concurrent cancer therapy was independently associated with higher odds of seroconversion (OR, 4.3; 95% CI, 1.2–14.9; P  = .02). Conclusions High seroprotection and seroconversion rates against all influenza strains can be achieved with vaccination as early as 2 months post-autoHCT with either 2-dose vaccine schedules. Clinical Trials Registration Australian New Zealand Clinical Trials Registry: ACTRN12619000617167. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Platelet Glycoprotein (GP)VI is a member of the immunoglobulin superfamily expressed only on platelets, and is the major signalling receptor for collagen. Histone deacetylase inhibitors (HDACi) are anti-cancer agents used for the treatment of haematological malignancies, and we examined the effects of administration of HDACi to mice on platelet function including responses to agonists including collagen related peptide (CRP). Materials and Methods: C57BL/6 mice were injected with two structurally different HDACi, panobinostat and romidepsin, for three days and platelet receptor levels and responses to agonists were assessed by flow cytometry and western blot. Results: Platelets from mice treated with either HDACi were impaired in their ability to respond to CRP, but not thrombin or adenosine diphosphate (ADP). HDACi treatment increased acetylation of megakaryocytic GPVI, resulting in loss of intact (~60-65-kDa) GPVI and formation of ~10-kDa remnant GPVI. Circulating platelets had reduced surface and total expression of GPVI. Platelets from mice treated with HDACi had impaired GPVI signalling following treatment with CRP, resulting in inhibition of Syk phosphorylation and activation, and the final common pathways of platelet activation. Conclusions: Administration of HDACi in vivo may ablate platelet responses to agonists and platelet function. [Copyright &y& Elsevier]

Purpose – The purpose of this paper is to show how simulation of the flow of particulates and fluids using discrete element modelling (DEM) and smoothed particle dynamics (SPH) particle methods, offer opportunities for better understanding the dynamics of flow processes. Design/methodology/approach – DEM and SPH methods are demonstrated in a broad range of computationally-demanding applications including comminution, biomedical, geophysical extreme flow events (risk/disaster modelling), eating of food by humans and elite water-based sports. Findings – DEM is ideally suited to predicting industrial and geophysical applications where collisions between particles are the dominant physics. SPH is highly suited to multi-physics fluid flow applications in industrial, biophysical and geophysical applications. The advantages and disadvantages of these particle methods are discussed. Research limitations/implications – Research results are limited by the numerical resolution that can currently be afforded. Practical implications – The paper demonstrates the use of particle-based computational methods in a series of high value applications. Enterprises that share interests in these applications will benefit in their product and service development by adopting these methods. Social implications – The ability to model disasters provides governments and companies with the opportunity and obligation to use these to render knowable disasters which were previously considered unknowable. The ability to predict the breakdown of food during eating opens up opportunities for the design of superior performing foods with lower salt, sugar and fat that can directly contribute to improved health outcomes and can influence government food regulatory policy. Originality/value – The paper extends the scale and range of modelling of particle methods for demanding leading-edge problems, of practical interest in engineering and applied sciences. [ABSTRACT FROM AUTHOR]

Aims: Primary gastric extramedullary plasmacytoma is an extremely rare condition and there is scant information in the literature concerning its natural history or therapy. There have been anecdotal reports of surgical resection, with or without Helicobacter pylori eradication, but there are no useful reports of the role of radiotherapy. We report the clinicopathologic outcome of radical radiotherapy as a primary treatment modality. Methods: We identified two patients with biopsy-proven primary gastric extramedullary plasmacytoma. Routine staging investigations were performed and H. pylori status was determined. Radical radiotherapy to 41.4 Gy in 23 fractions was delivered using conformal techniques. The target volume was the stomach with a 1-cm margin. Prophylactic anti-emetic was administered prior to each fraction. Post-treatment endoscopies and biopsies were performed at 3-monthly intervals to assess clinicopathological response. Treatment-related toxicities were documented. Results: Both patients achieved durable (>12 months) pathologically confirmed complete remissions without significant toxicities. Conclusion: Radical radiotherapy offers the potential for cure and organ preservation with low toxicity. It should be considered a favourable alternative to surgery in the management of this rare disease entity. [ABSTRACT FROM AUTHOR]

Summary 1. Algal growth in lotic systems is controlled either from the bottom-up (e.g. nutrients and light, which determine growth rates) or from the top-down (e.g. grazing pressure, which reduces accumulated biomass). Nutrient-enriched streams that support large and diverse grazing macroinvertebrate populations and those with shaded riparian corridors rarely suffer from excessive algal growth. 2. In this study, the density of benthic algivorous macroinvertebrates was experimentally manipulated in shaded and open nutrient-enriched stream habitats of the Owennagearagh River, south-west Ireland. The ability of macroinvertebrate grazers and riparian shade to control benthic algal growth [particularly the nuisance alga, Cladophora glomerata (L. Kütz)] was investigated. Three sites with markedly different concentrations of plant nutrients (one site upstream and two sites downstream of the sewage outfall) were selected. The density of grazing invertebrates colonising ceramic tiles was reduced using high-voltage localised electric pulses. Replicates of treatment (grazer-excluded) and control (grazed) tiles were deployed in open and shaded (<25 and >80% canopy cover, respectively) patches of stream bed, in each site. 3. After 2-week Cladophora cover, periphytic chlorophyll a and biofilm ash-free dry mass (AFDM) were quantified for all experimental tiles. Values for all three parameters were highest on grazer-excluded tiles from open patches. Grazed tiles from open patches accrued little Cladophora and had significantly lower levels of chlorophyll a and AFDM. Nutrient inputs were found to have an impact on the density of grazing invertebrates, with higher densities of Baetis nymphs at the most nutrient-enriched site. 4. Our results demonstrate that in eutrophic, high-light streams, filamentous algae can quickly accumulate to nuisance levels in the absence of invertebrate grazers. In future, greater attention should be paid to the role of grazing invertebrates in controlling nuisance algae in streams, in addition to algal-nutrient relationships. [ABSTRACT FROM AUTHOR]

OBJECTIVE To report a large, single-centre experience with a continent, catheterizable abdominal conduit in adult patients. PATIENTS AND METHODS We retrospectively reviewed the case notes of all 65 patients who had surgery to create a continent catheterizable conduit based on the Mitrofanoff principle. Operations were carried out over a 13-year period. Data on surgical procedure, complications and final outcome were collected and analysed. RESULTS The mean age of the patients was 38.4 years and mean follow-up interval was 75.2 months. Patients with neuropathic lower urinary tracts accounted for the largest single indication for reconstruction (36 patients). The appendix was the conduit of choice and was available and suitable for use in 37 patients. There were 57 patients who continued to use their native bladder or had undergone an augmentation or substitution cystoplasty; 24.5% of these 57 individuals had also undergone closure of the bladder neck or urethra. There were postoperative complications requiring laparotomy in five (8%) patients. In all, 30 patients (46%) had catheterization problems, but most of these were easy to treat. Five patients (8%) had an incontinent conduit which was a more difficult problem to deal with. Two patients have died of unrelated cause and five patients have been converted to an ileal conduit. In all, 58 patients (92%) now have a Mitrofanoff conduit, of which 97% are catheterizable and 95% are continent. CONCLUSIONS Continent urinary diversion, based on the Mitrofanoff principle, has similar outcomes in adult urological practice to those described in published paediatric case series. There is good evidence to suggest that Mitrofanoff conduits are durable. However, patients should be aware of complications and the need for long-term follow-up. [ABSTRACT FROM AUTHOR]

Background Although responsible for significant mortality and morbidity, our knowledge of modifiable causes of multiple myeloma (MM) remains limited. This analysis of an Australian population-based case-control family study investigated associations between smoking and alcohol consumption and MM risk. Methods Incident cases (n = 789) of MM were recruited mainly via cancer registries in Victoria and NSW. The controls included in the analysis (n = 1,113) were either family members of cases (n = 696) or recruited as part of a similarly designed case-control family study of renal cancer (n = 417). Unconditional multivariable logistic regression was used to estimate ORs, 95% CIs and p-values for associations between alcohol- and tobacco-related exposures and risk of MM. Results Heavy drinkers of alcohol had lower MM risk compared with non-drinkers (OR = 0.68, 95% CI = 0.50 – 0.93), and there was an inverse dose-response relationship for alcohol intake (OR per 10g ethanol per day = 0.92, 95% CI: 0.86 – 0.99); there was no evidence of interaction with sex (p = 0.27). There was no evidence of association between smoking-related exposures and MM risk. Conclusions These findings extend the knowledge of MM risk factor epidemiology. Further research into the causality of the association of alcohol with MM risk and potential underlying mechanisms is recommended. Key messages We found alcohol consumption to be inversely associated with risk of multiple myeloma. [ABSTRACT FROM AUTHOR]

Changes in cellular calcium (Ca2+) handling are thought to underlie the altered contraction that occurs during cardiac hypertrophy and failure. Recent work has highlighted the importance of t-tubules in the control of intracellular Ca2+. The present study was performed to investigate whether changes in the distribution of I Ca between the surface and t-tubule membranes might contribute to the altered Ca2+ handling observed during compensated hypertrophy in the spontaneously hypertensive rat (SHR). Experiments were performed on ventricular myocytes isolated from 5-month-old SHR and normotensive Wistar-Kyoto (WKY) control rats. Osmotic shock using formamide was used to disrupt the t-tubular system and the whole-cell patch clamp technique used to monitor I Ca in the presence and absence of t-tubules. Membrane capacitance and I Ca were greater in control SHR than WKY myocytes; following detubulation, cell capacitance and I Ca both decreased and were no longer significantly different in the two cell types. The density of I Ca was not significantly different in control SHR and WKY cells or in detubulated myocytes from the two species. These data suggest that the distribution of I Ca is unchanged in SHR myocytes compared to WKY controls; I Ca density in the t-tubules was 1.2-fold greater than in the sarcolemma in both strains. These data also imply that the increase in surface area in SHR myocytes is due principally to an increase in t-tubular area, which is accompanied by an approximately equivalent increase in I Ca, so that the density of I Ca at the cell surface and in the t-tubules remains the same. These changes would be expected to retain cell function and synchronicity of Ca2+ release in the SHR at this stage of compensated hypertrophy. [ABSTRACT FROM AUTHOR]

OBJECTIVE To describe the pattern and prevalence of lower urinary tract symptoms (LUTS) and related help-seeking behaviour in men of South Asian origin living in the UK, and to compare this to the white population. SUBJECTS AND METHODS Data were obtained as part of the Leicestershire MRC Incontinence Study. Community-dwelling men aged >40 years were sent a postal questionnaire addressing urinary symptoms, bother and help-seeking. Prevalence rates of self-reported LUTS were compared on the basis of the Office of Population Censuses and Surveys ethnic classifications. Logistic regression was used to estimate the relative risk of symptoms between groups. Data from 7810 men were included in the analysis. RESULTS In all, 409 (5.3%) of the population sample described themselves as Asian; 36.5% of these men described at least one significant LUTS, vs 29.0% of white men. The overall prevalence rates for all storage symptoms were significantly higher in Asian men. Straining to void was the only voiding symptom to show a difference in prevalence between the groups. However, when controlling for age, Asian men were at greater risk for all symptoms except a weak urinary stream. Reported levels of bother and felt need were the same in both population groups, but actual help-seeking was significantly less in the Asian group. Only 25.0% of Asian men had actively sought help, compared to 53.1% of white men. CONCLUSION South Asian men in the UK have a higher risk of experiencing LUTS than white men from the same population. This increase in risk is greatest for storage symptoms. Although levels of bother are the same, South Asian men are less likely to seek help for their symptoms. [ABSTRACT FROM AUTHOR]

Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18–24 months. Cross‐sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website. [ABSTRACT FROM AUTHOR]

Rationale, aims, and objectives: The Getting It Right First Time programme aims to reduce variation in clinical practice that unduly impacts on outcomes for patients in the National Health Service (NHS) in England; often termed "unwarranted variation." However, there is no "gold standard" method for detecting unwarranted variation. The aim of this study was to describe a method to allow such variation in recorded practice or patient outcomes between NHS trusts to be detected using data over multiple time periods. By looking at variation over time, it was hoped that patterns that could be missed by looking at data at a single time point, or averaged over a longer time period, could be identified. Methods: This was a retrospective time‐series analysis of observational administrative data. Data were extracted from the Hospital Episodes Statistics database for two exemplar aspects of clinical practice within the field of urology: (a) use of ureteric stents on first emergency admission to treat urinary tract stones and (b) waiting times for definitive surgery for urinary retention. Data were categorized into 3‐month time periods and three rules were used to detect unwarranted variation in the outcome metric relative to the national average: (a) two of any three consecutive values greater than two standard deviations above the mean, (b) four of any five consecutive values greater than one standard deviation above the mean, and (c) eight consecutive values above the mean. Results: For the urinary tract stones dataset, 24 trusts were identified as having unwarranted variation in the outcomes using funnel plots and 23 trusts using the time‐series method. For the urinary retention data, 18 trusted were identified as having unwarranted variation in the outcomes using funnel plots and 22 trusts using the time‐series method. Conclusions: The time‐series method may complement other methods to help identify unwarranted variation. [ABSTRACT FROM AUTHOR]

Abstract: We measured the contractile response of left ventricular cardiac myocytes from female rats to selective β1-adrenoceptor stimulation (isoprenaline, 10−8 M and 10−7 M in the presence of 10−7 M ICI 118,551 a β2-adrenoceptor inverse agonist). A heterogenic response to stimulation, inversely related to the extent of cell shortening prior to adrenergic stimulation, was observed. Challenge of cardiac myocytes with a selective β1-antagonist, atenolol (10−7 M), suggests the heterogenic response is not caused by basal β1-adrenoceptor activity. Thus, basal myocyte contractility determines the response to β1-adrenoceptor stimulation, this should be taken into account when experimental conditions are designed. [Copyright &y& Elsevier]

Recent studies have proposed that release of calcium from the sarcoplasmic reticulum (SR) modulates the spontaneous activity of the sinoatrial node (SAN). Previously we have shown that several calcium regulatory proteins are expressed at a lower level in the centre of the SAN compared with the periphery. Such differences may produce heterogeneity of intracellular calcium handling and pacemaker activity across the SAN. Selective isolations showed that the centre of the SAN is composed of smaller cells than the periphery. Measurements of cytosolic calcium in spontaneously beating cells showed that diastolic calcium, systolic calcium, the calcium transient amplitude and spontaneous rate were greater in larger (likely to be peripheral) cells compared with smaller (likely to be central) SAN cells. The SR calcium content was greater in larger cells, although SR recruitment was more efficient in smaller cells. The sodium-calcium exchanger and sarcolemmal calcium ATPase had a lower activity and the exchanger was responsible for a larger proportion of sarcolemmal calcium extrusion in smaller cells compared with larger cells. Ryanodine had a greater effect on the spontaneous calcium transient in larger cells compared with smaller cells, and slowed pacemaker activity in larger cells but not smaller cells, thus abolishing the difference in cycle length. This study shows heterogeneity of intracellular calcium regulation within the SAN and this contributes to differences in pacemaker activity between cells from across the SAN. The smallest central cells of the leading pacemaker region of the SAN do not require SR calcium for spontaneous activity nor does disruption of the SR alter pacemaking in these primary pacemaker cells. [ABSTRACT FROM AUTHOR]

In previous studies, regional variations in the expression of the Na+-Ca2+ exchanger (NCX) have been examined qualitatively in human heart using the C2C12 monoclonal antibody [Wang, J., Schwinger, R.H., Frank, K., Muller-Ehmsen, J., Martin-Vasallo, P., Pressley, T.A., Xiang, A., Erdmann, E. & McDonough, A.A. (1996) J. Clin. Invest. 98, 1650–1658]. Although NCX expression was found to be significantly lower in the atria compared to the septum, no significant differences were found between atrial and ventricular tissue. NCX has been located in the general sarcolemma and t-tubules of ventricular muscle and as t-tubules are sparse in atrial tissue compared to ventricular tissue, it is surprising that NCX expression was found to be similar in both atria and ventricles [Wang et al. (1996)]. To reinvestigate this, we have used SDS/PAGE and a quantitative Western blotting technique to determine the pattern of expression of NCX in guinea-pig heart in tissue samples from left atrium, right atrium, septum, left ventricle and right ventricle. NCX protein expression was 17.5 ± 3.9 pmol·mg-1 of protein in the left atrium and 29.2 ± 6.1 pmol·mg-1 of protein in the right atrium, which were both significantly lower (P < 0.05) than NCX expression in the septum, left ventricle and right ventricle (64.7 ± 15.2, 76.8 ± 19.5 and 69.4 ± 14.1 pmol·mg-1 of protein, respectively, n = 7). These differences in NCX expression may reflect variations in the cellular location of NCX protein in these regions. To study this, we used confocal immunofluorescence of single isolated myocytes to examine differences in the proportion of fluorescent staining on the general surface membrane compared with the interior of the cell (which presumably reflects a t-tubular location). We found that the general membrane staining was 79.0 ± 1.2% in cells from the atria which was significantly higher (P <... [ABSTRACT FROM AUTHOR]

There are currently limited Australian data on the outcomes of autologous stem cell transplantation (ASCT) in elderly multiple myeloma (MM) patients. We present the largest cohort of elderly MM patients aged ≥65 years undergoing ASCT in Australia and report their outcomes based on our two‐centre experience. Our study affirms that ASCT is well tolerated, safe and effective in elderly MM patients aged ≥65 years and should be considered an important component of treatment in patients who are fit enough for the procedure. [ABSTRACT FROM AUTHOR]

The article presents two case studies of patients who were diagnosed with myeloma or had a relapse during pregnancy, including one of a 30 year old woman who presented with persistent hemorrhage after a spontaneous abortion in a pregnancy following in vitro fertilization and one of a 32 year old woman who was diagnosed with kappa light-chain myeloma while she was 14 weeks pregnant with her fourth child. A discussion of medical treatment which was given to both patients is presented.

Objectives: Patients with multiple myeloma (MM) are at increased risk for infection. Clinical assessment of infection risk is increasingly challenging in the era of immune‐based therapy. A pilot systems‐level immune analysis study to identify predictive markers for infection was conducted. Methods: Patients with relapsed and/or refractory MM (RRMM) who participated in a treatment trial of lenalidomide and dexamethasone were evaluated. Data on patient demographics, disease and episodes of infection were extracted from clinical records. Peripheral blood mononuclear cells (PBMCs) collected at defined intervals were analysed, with or without mitogen re‐stimulation, using RNA sequencing and mass cytometry (CyTOF). CyTOF‐derived cell subsets and RNAseq gene expression profiles were compared between patients that did and did not develop infection to identify immune signatures that predict infection over a 3‐month period. Results: Twenty‐three patients participated in the original treatment trial, and we were able to access samples from 17 RRMM patients for further evaluation in our study. Nearly half the patients developed an infection (8/17) within 3 months of sample collection. Infections were mostly clinically diagnosed (62.5%), and the majority involved the respiratory tract (87.5%). We did not detect phenotypic or numerical differences in immune cell populations between patients that did and did not develop infections. Transcriptional profiling of stimulated PBMCs revealed distinct Th2 immune pathway signatures in patients that developed infection. Conclusion: Immune cell counts were not useful predictors of infection risk. Functional assessment of stimulated PBMCs has identified potential immune profiles that may predict future infection risk in patients with RRMM. [ABSTRACT FROM AUTHOR]

Survival following lung transplantation (LTx) is limited by the development of chronic lung allograft dysfunction (CLAD), for which there are few effective therapies and no standardized management. Several small studies have demonstrated the effectiveness of extracorporeal photopheresis (ECP) as a therapeutic option for CLAD. A retrospective descriptive audit of 12 LTx recipients who received rescue ECP for CLAD over 5 years (2013-2018) at the Alfred Hospital, Melbourne, Australia, was completed. Nonresponders to ECP were defined as patients who experienced a 20% decrease in forced expiratory volume (FEV 1) within 6 weeks of commencing therapy. Mean time since LTx was 849 days and mean time since diagnosis of CLAD was 131 days. Fifty-eight percent of patients were male (n = 7) and 67% responded to ECP therapy (n = 8). Among responders, the mean (95% confidence interval) decline in FEV 1 pre-ECP was 9.0 mL/day (5-12 mL/day), compared to 1.4 mL/day (0-4 mL/day) post-ECP (P =.01). Among nonresponders, mean (95% confidence interval) decline in FEV 1 was 7.2 mL/day (4-10 mL/day) pre-ECP and 5.0 mL/day (3-7 mL/day) post ECP (P =.2). Nonresponders were more likely to be female (P =.01) and neutropenic (P =.005). Patients with prior exposure to anti-thymocyte globulin had a lowered response to ECP. Rescue ECP arrested the decline of lung function in 67% of patients with CLAD. Sex, pre-ECP neutrophil count, and exposure to anti-thymocyte globulin may help determine response to ECP. Future clinical trials are needed to confirm this effect, help predict response to therapy, and ultimately guide the placement of ECP in the treatment algorithm for CLAD. • Extracorporeal photopheresis can slow decline in lung function from chronic lung allograft dysfunction. • Not all patients with chronic lung allograft dysfunction respond to extracorporeal photopheresis. • Female sex, low neutrophil count, and prior treatment with anti-thymocyte globulin appear to limit response to extracorporeal photopheresis. [ABSTRACT FROM AUTHOR]

The article presents a commentary on the development of novel immunotherapeutic approaches in multiple myeloma. The authors comment a study conducted by M. Witzens-Harig and colleagues on whether an immune response can be generated against three different peptides including a modified heteroclitic peptide that derived from the antigen SPAN-XB. They suggest improving the study design and the availability of antigens and peptides to develop the next generation of immunotherapeutic studies.

Preclinical evidence supports the investigation of histone deacetylase inhibitors for the treatment of myeloma. Results from early studies demonstrate clinical activity and further studies investigating combination strategies should be explored. [ABSTRACT FROM AUTHOR]

Receiving four or fewer cycles of therapy predicts poor survival in newly diagnosed transplant-ineligible patients with myeloma who are treated with bortezomib-based induction SIGNIFICANCE STATEMENT Our study highlights that for patients with myeloma treated with the chemotherapy drug bortezomib, the number of cycles of treatment received is an important predictor of survival. We read with interest the study from Rampotas et al1 where they evaluated 158 transplant-non-eligible newly diagnosed myeloma patients treated with bortezomib (Velcade), cyclophosphamide and dexamethasone (VCD) chemotherapy. [Extracted from the article]

Australia and New Zealand have achieved excellent community control of COVID‐19 infection. In light of the imminent COVID‐19 vaccination roll out in both countries, representatives of all adult and paediatric allogeneic bone marrow transplant and cellular therapy (TCT) centres as well as representatives from autologous transplant only centres in Australia and New Zealand collaborated with infectious diseases specialists with expertise in TCT on this consensus position statement regarding COVID‐19 vaccination in TCT patients in Australia and New Zealand. It is our recommendation that TCT patients, should have expedited access to high‐efficacy COVID‐19 vaccines given that these patients are at high risk of morbidity and mortality from COVID‐19 infection. We also recommend prioritising vaccination of TCT healthcare workers and household members of TCT patients. Vaccination should not replace other public health measures in TCT patients given the effectiveness of COVID‐19 vaccination in TCT patients is unknown. Furthermore, given the limited available data, prospective collection of safety and efficacy data of COVID‐19 vaccination in this patient group is a priority. [ABSTRACT FROM AUTHOR]

Ireland, being an island situated on Europe's western seaboard, has a fewer number of native species than mainland European Union Member States (MS). Increased numbers of vectors and pathways have reduced the island's biotic isolation, increasing the risk of new introductions and their associated impacts on native biodiversity. It is likely that these risks are greater here than they are in continental MSs, where the native biodiversity is richer. A horizon scanning approach was used to identify the most likely invasive alien species (IAS) (with the potential to impact biodiversity) to arrive on the island of Ireland within the next ten years. To achieve this, we used a consensus-based approach, whereby expert opinion and discussion groups were utilised to establish and rank a list of 40 species of the most likely terrestrial, freshwater and marine IAS to arrive on the island of Ireland within the decade 2017-2027. The list of 40 included 18 freshwater, 15 terrestrial and seven marine IAS. Crustacean species (freshwater and marine) were taxonomically dominant (11 out of 40); this reflects their multiple pathways of introduction, their ability to act as ecosystem engineers and their resulting high impacts on biodiversity. Freshwater species dominated the top ten IAS (seven species out of ten), with the signal crayfish (Pacifastacus leniusculus) highlighted as the most likely species to arrive and establish in freshwaters, while roe deer (Capreolus capreolus) (second) and the warm-water barnacle (Hesperibalanus fallax) (fifth), were the most likely terrestrial and marine invaders. This evidence-based list provides important information to the relevant statutory agencies in both the Republic of Ireland and Northern Ireland to prioritise the prevention of the most likely invaders and aid in compliance with legislation, in particular the EU Regulation on Invasive Alien Species (EU 1143/2014). Targeted biosecurity in both jurisdictions is urgently required in order to manage the pathways and vectors of arrival, and is vital to maintaining native biodiversity on the island of Ireland. [ABSTRACT FROM AUTHOR]

Objectives: To investigate volume–outcome relationships in nephrectomy and cystectomy for cancer. Materials and Methods: Data were extracted from the UK Hospital Episodes Statistics database, which records data on all National Health Service (NHS) hospital admissions in the England. Data were included for a 5‐year period (April 2013–March 2018 inclusive) and data on emergency and paediatric admissions were excluded. Data were extracted on the NHS trust and surgeon undertaking the procedure, the surgical technique used (open, laparoscopic or robot‐assisted) and length of hospital stay during the procedure. This dataset was supplemented by data on mortality from the UK Office for National Statistics. A number of volume thresholds and volume measures were investigated. Multilevel modelling was used to adjust for hierarchy and confounding factors. Results: Data were available for 18 107 nephrectomy and 6762 cystectomy procedures for cancer. There was little evidence of trust or surgeon volume influencing readmission rates or mortality. There was some evidence of shorter length of hospital stay for high‐volume surgeons, although the volume measure and threshold used were important. Conclusions: We found little evidence that further centralization of nephrectomy or cystectomy for cancer surgery will improve the patient outcomes investigated. It may be that length of stay can be optimized though training and support for lower‐volume centres, rather than further centralization. [ABSTRACT FROM AUTHOR]

PET/CT is useful for investigation of neutropenic fever (NF) and potential invasive fungal infection (IFI) in those with hematological malignancies (HM). An online survey evaluating the utility and current practices regarding PET/CT scanning for investigation of NF was distributed to infectious diseases (ID) clinicians and hematologists via email lists hosted by key professional bodies. One-hundred and forty-five clinicians responded (120 ID; 25 hematologists). Access to PET/CT was fair but timeliness of investigation was limited (within 3 days in 35% and 46% of ID and hematology respondents, respectively). Among those with experience with PET/CT for infection (n = 109), 40% had utilized PET/CT for prolonged NF and 20% for diagnosing IFI. The majority of respondents indicated the desire to utilize PET/CT more frequently for infection indications. There is a strong desire among surveyed Australian clinicians to use PET/CT for prolonged NF and potential IFI. However, access to PET/CT is a current barrier to uptake. [ABSTRACT FROM AUTHOR]