The Association between Fat-Free Mass and Exercise Test Outcomes in People with Chronic Obstructive Pulmonary Disease: A Systematic Review.

People with chronic obstructive pulmonary disease (COPD) tend to have abnormally low levels of fat-free mass (FFM), which includes skeletal muscle mass as a central component. The purpose of this systematic review was to synthesise available evidence on the association between FFM and exercise test outcomes in COPD. MEDLINE, Cochrane Library, EMBASE, Web of Science, and Scopus were searched. Studies that evaluated exercise-related outcomes in relation to measures of FFM in COPD were included. Eighty-three studies, containing 18,770 (39% female) COPD participants, were included. Considerable heterogeneity was identified in the ways that FFM and exercise test outcomes were assessed; however, higher levels of FFM were generally associated with greater peak exercise capacity. This association was stronger for some exercise test outcomes (e.g. peak rate of oxygen consumption during incremental cycle exercise testing) than others (e.g. six-minute walking distance). This review identified heterogeneity in the methods used for measuring FFM and exercise capacity. There was, in general, a positive association between FFM and exercise capacity in COPD. There was also an identified lack of studies investigating associations between FFM and temporal physiological and perceptual responses to exercise. This review highlights the significance of FFM as a determinant of exercise capacity in COPD.

CyTOF: An Emerging Technology for Single-Cell Proteomics in the Mouse.

The ability to analyze the proteome of single cells is critical for the advancement of studies of steady-state and pathological processes. Mass cytometry, or CyTOF, combines principles of mass spectrometry and flow cytometry to enable single-cell analysis of protein expression. CyTOF can simultaneously assess DNA content and proteins and has the capacity to measure 40 to 100 parameters in each cell. Applying this technology to tissues or cells on slides, termed imaging mass cytometry (IMC), allows for visualization of normal and diseased tissues in situ. The high-dimensional proteomic analysis that can be undertaken with CyTOF and IMC has the potential to enhance our understanding of complex and heterogeneous developmental and disease pathways. This article will describe the CyTOF experimental workflow, including reagent selection, sample preparation, and data analysis. CyTOF is compared to flow cytometry, focusing on the strengths and weaknesses of these powerful techniques. Importantly, we review key studies in mouse models of human disease that highlight the strength of CyTOF and IMC to drive discovery research and therapeutic advancement. © 2021 Wiley Periodicals LLC.

Relieving exertional dyspnea during the 3-min constant speed shuttle test in patients with COPD with indacaterol/glycopyrronium versus tiotropium: the RED trial.

BACKGROUND: Exertional dyspnea is a cardinal feature of chronic obstructive pulmonary disease (COPD) and a major cause of activity limitation. Although dual bronchodilation is more effective than bronchodilator monotherapy at improving resting pulmonary function, it is unclear to which extent this translates into superior relief of exertional dyspnea. METHODS: We conducted a randomized controlled, double-blind, cross-over trial comparing indacaterol 110 µg/glycopyrronium 50 µg once daily (OD) with tiotropium 50 µg OD in patients with moderate to severe COPD and resting hyperinflation (functional residual capacity >120% of predicted value). The primary outcome was Borg dyspnea score at the end of a 3-min constant speed shuttle test after 3 weeks of treatment. Secondary outcomes included changes in Borg dyspnea score after the first dose of study medication, expiratory flows and lung volumes. Statistical analysis was conducted using a cross-over analysis of variance model with repeated measurements. RESULTS: A total of 50 patients with COPD and a mean forced expiratory volume in 1 s of 54 ± 11% (mean ± SEM) predicted participated in the cross-over phase of the trial. Compared with baseline, there was a decrease in dyspnea after the first dose of medication with indacaterol/glycopyrronium [mean -1.00, 95% confidence interval (CI) -1.49 to -0.52] but not with tiotropium alone (mean -0.36, 95% CI -0.81 to 0.08). The reduction in dyspnea after the first dose was statistically significant between the two treatments (mean difference of -0.64, 95% CI -1.11 to -0.17). Despite indacaterol/glycopyrronium providing further bronchodilation and lung deflation throughout the trial, the reduction in dyspnea was not sustained at 3 weeks of treatment (mean between-treatment difference at 3 weeks of 0.09, 95% CI -0.44 to 0.61). CONCLUSION: In comparison with bronchodilator monotherapy, indacaterol/glycopyrronium provided greater immediate exertional dyspnea relief, although this difference was not sustained after 3 weeks of therapy despite evidence of further bronchodilation and lung deflation.The reviews of this paper are available via the supplemental material section.

33rd international mammalian genome conference: meeting highlights.

Scientists from 12 countries met at the International Mammalian Genome Conference (IMGC) to share advances in mammalian genetics and genomics research. The event was held in Strasbourg, France and represents the city's second time hosting the IMGC. A diverse attendance of pre-doctoral and post-doctoral trainees, young investigators, established researchers, clinicians, bioinformaticians, and computational biologists enjoyed a rich scientific program of 63 oral presentations, 65 posters, and 5 workshops in the fields of epigenetics, system genetics, developmental biology, cancer, human disease modeling, technical advances, and bioinformatics. This report presents selected highlights of this meeting which illustrate how recent advances in mammalian genetic approaches have improved our ability to decipher complex biological mechanisms.

Physiological and perceptual responses to exercise according to locus of symptom limitation in COPD.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, with pulmonary and extra-pulmonary factors contributing to exercise intolerance. The primary self-reported exercise-limiting symptom may reflect the primary pathophysiological factor contributing to exercise intolerance. We compared physiological and perceptual responses at the symptom-limited peak of incremental cardiopulmonary cycle exercise testing between people with COPD reporting breathlessness (B, n = 34), leg discomfort (LD, n = 16), or a combination of B and LD (BOTH, n = 42) as their main exercise-limiting symptom(s). Despite similarly impaired health status, symptomology and peak exercise capacity, the B group had greater restrictive constraints on tidal volume expansion at end-exercise and was more likely to report unpleasant qualities of exertional breathlessness than LD and BOTH groups. In conclusion, reporting breathlessness as the primary exercise-limiting symptom indicated the presence of distinct lung pathophysiology and symptom perception during exercise in people with COPD.

Standardized measurement of breathlessness during exercise.

PURPOSE OF REVIEW: Exertional breathlessness is common and pervasive across various chronic disease populations. To accurately assess response to intervention and optimize clinical (symptom) management, detailed assessment of exertional breathlessness is imperative. This review provides an update on current approaches to assess exertional breathlessness and presents the need for individualized assessment of breathlessness standardized for the level of exertion. RECENT FINDINGS: Breathlessness assessment tools commonly invite people to recall their breathlessness while at rest with reference to activities of daily living. To directly quantify breathlessness, however, requires assessment of the dimensions of breathlessness (e.g., sensory intensity, quality, and unpleasantness) in response to a standardized exercise stimulus. Different exercise stimuli (e.g., self-paced, incremental, and constant work rate exercise tests) have been used to elicit a breathlessness response. Self-paced (e.g., 6-min walk test) and incremental exercise tests assess exercise tolerance or endurance, and are not recommended for assessment of exertional breathlessness. Constant work rate tests, however, including recently validated 3-min constant-rate stair stepping and walking tests, standardize the exercise stimulus to enable the breathlessness response to be directly quantified and monitored over time. SUMMARY: To adequately guide symptom management and assess intervention efficacy, clinicians and researchers should assess breathlessness with multidimensional assessment tools in response to a standardized and individualized exercise stimulus.

Off to a Bad Start: Cancer Initiation by Pluripotency Regulator PRDM14.

Despite advances in chemotherapies that improve cancer survival, most patients who relapse succumb to the disease due to the presence of cancer stem cells (CSCs), which are highly chemoresistant. The pluripotency factor PR domain 14 (PRDM14) has a key role in initiating many types of cancer. Normally, PRDM14 uses epigenetic mechanisms to establish and maintain the pluripotency of embryonic cells, and its role in cancer is similar. This important link between cancer and induced pluripotency is a key revelation for how CSCs may form: pluripotency genes, such as PRDM14, can expand stem-like cells as they promote ongoing DNA damage. PRDM14 and its protein-binding partners, the ETO/CBFA2T family, are ideal candidates for eliminating CSCs from relevant cancers, preventing relapse and improving long-term survival.

Meeting report: 32nd international mammalian genome conference.

Over 150 scientists from more than 50 research institutions and eight countries attended the 32nd annual meeting of the International Mammalian Genome Society (IMGS) held in Rio Mar, Puerto Rico. Attendees included predoctoral and postdoctoral trainees, junior investigators, clinicians, industry professionals, and established leaders in mammalian genetics and genomics. From November 11-14, major scientific advances in the fields of systems genetics, developmental biology, cancer, human disease modeling, and bioinformatics were showcased in a series of 66 poster and 54 platform presentations. Here we provide an overview of the meeting's proceedings and summarize the exciting, novel research findings communicated by conference participants that, collectively, are advancing the frontiers of mammalian genetics and genomics.

The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice.

PR domain-containing 14 (Prdm14) is a pluripotency regulator central to embryonic stem cell identity and primordial germ cell specification. Genomic regions containing PRDM14 are often amplified leading to misexpression in human cancer. Prdm14 expression in mouse hematopoietic stem cells (HSC) leads to progenitor cell expansion prior to the development of T-cell acute lymphoblastic leukemia (T-ALL), consistent with PRDM14's role in cancer initiation. Here, we demonstrate mechanistic insight into PRDM14-driven leukemias in vivo. Mass spectrometry revealed novel PRDM14-protein interactions including histone H1, RNA-binding proteins, and the master hematopoietic regulator CBFA2T3. In mouse leukemic cells, CBFA2T3 and PRDM14 associate independently of the related ETO family member CBFA2T2, PRDM14's primary protein partner in pluripotent cells. CBFA2T3 plays crucial roles in HSC self-renewal and lineage commitment, and participates in oncogenic translocations in acute myeloid leukemia. These results suggest a model whereby PRDM14 recruits CBFA2T3 to DNA, leading to gene misregulation causing progenitor cell expansion and lineage perturbations preceding T-ALL development. Strikingly, Prdm14-induced T-ALL does not occur in mice deficient for Cbfa2t3, demonstrating that Cbfa2t3 is required for leukemogenesis. Moreover, T-ALL develops in Cbfa2t3 heterozygotes with a significantly longer latency, suggesting that PRDM14-associated T-ALL is sensitive to Cbfa2t3 levels. Our study highlights how an oncogenic protein uses a native protein in progenitor cells to initiate leukemia, providing insight into PRDM14-driven oncogenesis in other cell types. IMPLICATIONS: The pluripotency regulator PRDM14 requires the master hematopoietic regulator CBFA2T3 to initiate leukemia in progenitor cells, demonstrating an oncogenic role for CBFA2T3 and providing an avenue for targeting cancer-initiating cells.

A prospective cohort study assessing the reactogenicity of pertussis and influenza vaccines administered during pregnancy.

BACKGROUND: Pertussis vaccination during pregnancy can prevent 91% of infant infections. In 2015, antenatal pertussis vaccination programs were introduced across Australia. METHODS: To monitor the safety of this program, pregnant women who received trivalent influenza vaccine (TIV) and/or diphtheria-tetanus-acellular pertussis vaccine (dTpa) were surveyed by text message seven days post-vaccination about possible adverse events following immunization (AEFI). Univariate logistic regression models were used to calculate the odds of reporting an AEFI following dTpa compared to TIV. Similar analyses were used to compare AEFI reported by women who received a previous dose of dTpa in 2011/2012 as part of a state-wide cocooning program. RESULTS: Of 5155 women, 4347 (84.3%) replied; 10.8% indicated they experienced an AEFI. There was no difference in the proportion of women who reported any reaction by vaccine; however, women who received dTpa were more likely to report a local reaction than women who received TIV (7.1% and 3.2%, respectively; OR: 2.29; 95% CI: 1.61-3.26). There was evidence suggesting local reactions were more common among women with a previous dose of dTpa (11.4%) compared to women with no previous dose (6.0%; OR: 2.00; 95% CI: 0.95-4.25); 11 (0.3%) women reported attending a hospital emergency department. Subsequent follow-up indicated symptoms resolved and mother and infant were healthy. There was no difference in the proportion of women attending hospital by vaccine (p > 0.05). DISCUSSION: Data on systemic and local reactions following receipt of TIV and dTpa during pregnancy support the safety of antenatal vaccination.

PRDM14 promotes RAG-dependent Notch1 driver mutations in mouse T-ALL.

PRDM14 is an epigenetic regulator known for maintaining embryonic stem cell identity and resetting potency in primordial germ cells. However, hematopoietic expression of Prdm14 at supraphysiological levels results in fully penetrant and rapid-onset T-cell acute lymphoblastic leukemia (T-ALL) in the mouse. Here, we show that PRDM14-induced T-ALLs are driven by NOTCH1, a frequently mutated driver of human T-ALL. Notch1 is activated in this murine model via RAG-dependent promoter deletions and subsequent production of truncated, ligand-independent protein from downstream regions of the Notch1 locus. These T-ALLs also have focal changes in H3K4me3 deposition at the Notch1 locus and global increases in both H3K4me1 and H3K4me3. Using a PRDM14-FLAG mouse model, we show that PRDM14 binds within an intron of Notch1 prior to leukemia development. Our data support the idea that PRDM14 binding promotes a chromatin state that allows access of the RAG recombinase complex to cryptic RAG signal sequences embedded at the Notch1 locus. Indeed, breeding into a RAG recombination-deficient background abrogates T-ALL development and prevents Notch1 deletions, while allowing for transient hematopoietic stem cell (HSC)-like pre-leukemia cell expansion. Together, our data suggest that PRDM14 expands a progenitor cell population while promoting a permissive epigenetic state for the creation of driver mutations (here, in Notch1), enabling cancer development through the misappropriation of endogenous cellular DNA recombination machinery.

Trends in seasonal influenza vaccine uptake during pregnancy in Western Australia: Implications for midwives.

BACKGROUND: Antenatal influenza vaccination is an important public health intervention for preventing serious illness in mothers and newborns, yet uptake remains low. AIM: To evaluate trends in seasonal influenza vaccine coverage and identify determinants for vaccination among pregnant women in Western Australia. METHODS: We conducted an annual telephone survey in a random sample of post-partum women who delivered a baby in Western Australia between 2012 and 2014. Women were asked whether influenza vaccination was recommended and/or received during their most recent pregnancy; women were also asked why or why they were not immunised. FINDINGS: Between 2012 and 2014, influenza vaccine coverage increased from 22.9% to 41.4%. Women who reported receiving the majority of their antenatal care from a private obstetrician were significantly more likely to have influenza vaccination recommended to them than those receiving the majority of their care from a public antenatal hospital or general practitioner (p<0.001). In 2014, the most common reason women reported for accepting influenza vaccination was to protect the baby (92.8%) and the most common reason for being unimmunised was lack of a healthcare provider recommendation (48.5%). DISCUSSION: Antenatal influenza vaccination uptake is increasing, but coverage remains below 50%. A recommendation from the principal care provider is an important predictor of maternal influenza vaccination. CONCLUSION: Antenatal care providers, including midwives, have a key role in providing appropriate information and evidence-based recommendations to pregnant women to ensure they are making informed decisions. Consistent recommendations from antenatal care providers are critical to improving influenza vaccine coverage in pregnant women.

Surveillance of antenatal influenza vaccination: validity of current systems and recommendations for improvement.

BACKGROUND: Although influenza vaccination is recommended during pregnancy as standard of care, limited surveillance data are available for monitoring uptake. Our aim was to evaluate the validity of existing surveillance in Western Australia for measuring antenatal influenza immunisations. METHODS: The self-reported vaccination status of 563 women who delivered between April and October 2013 was compared against three passive data collection sources: a state-wide antenatal influenza vaccination database maintained by the Department of Health, a public maternity hospital database, and a private health service database. Sensitivity, specificity, and positive and negative predictive values were calculated for each system using self-report as the "gold standard." RESULTS: The state-wide antenatal vaccination database detected 45.7 % (95 % CI: 40.1-51.4 %) of influenza vaccinations, the public maternity hospital database detected 66.7 % (95 % CI: 55.1-76.9 %), and the private health service database detected 29.1 % (95 % CI: 20.5-39.4 %). Specificity exceeded 90 % and positive predictive values exceeded 80 % for each system. Sensitivity was lowest for women whose antenatal care was provided by a private obstetrician. CONCLUSIONS: Existing resources for surveillance of antenatal influenza vaccinations detect 29-67 % of vaccinations. Considering the importance of influenza immunisation as a public health intervention, particularly in pregnant women, improvements to routine monitoring of influenza vaccination is warranted.

From the hospital to the home--the rise and rise of Clostridium difficile infection.

BACKGROUND: Clostridium difficile infection (CDI) has emerged as a serious worldwide public health threat. Although C. difficile has always been a cause of diarrhoeal disease in patients presenting to general practice, the rates of community-associated CDI (CA CDI) have increased. OBJECTIVE: This article provides a summary of what is currently known about CA CDI and the implications for Australian general practitioners (GPs). DISCUSSION: Changes in the colonic flora (most often because of antibiotic use) and exposure to C. difficile are both required for the disease to develop. Potential sources of C. difficile in the community include the home environment, food and water, workplace and environment. Identification of risk factors for CDI may help in the early diagnosis and subsequent management of infection, and these are being explored further. GPs have a role in understanding and managing CA CDI through prudent prescribing, patient education and adequate testing.

Post-marketing surveillance of adverse events following immunization with inactivated quadrivalent and trivalent influenza vaccine in health care providers in Western Australia.

In 2015, inactivated quadrivalent influenza vaccine (QIV) was first introduced into the Australian market. A routine vaccine safety surveillance system in Western Australia was used to conduct post-licensure surveillance of adverse events following immunization with inactivated QIV and trivalent influenza vaccines (TIV) in a sample of 1685 healthcare providers (HCPs). A similar percentage of HCPs who received QIV reported having any reaction seven days post-vaccination as HCPs who received TIV (13.6 vs. 12.8%, respectively; p=0.66). However, a slightly higher percentage of HCPs who received QIV reported pain or swelling at the injection site as compared to HCPs who received TIV (6.9% vs. 4.2%, respectively; p=0.02). No serious vaccine-associated adverse events were detected during follow-up of either vaccine. Acknowledging the study limitations, the results of this post-marketing surveillance support the safety of QIV, suggesting there is little difference in the reactogenicity of QIV as compared to TIV.

The impact of parental postpartum pertussis vaccination on infection in infants: A population-based study of cocooning in Western Australia.

During a pertussis epidemic in 2011-2012 the Western Australian (WA) Department of Health implemented a 'cocooning' programme, offering free pertussis-containing vaccine (dTpa) to new parents. We assessed the impact of vaccinating parents with dTpa on the incidence of pertussis infection in newborns. Births in WA during 2011-2012 were linked to a register of parental pertussis vaccinations and to notified reports of laboratory-proven pertussis in children <6 months of age. Parents who received dTpa during the four weeks after their child's birth were defined as 'vaccinated postpartum.' Cox proportional-hazards methods were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of pertussis infection among infants born to parents vaccinated postpartum vs. unvaccinated parents, adjusted for maternal age, geographic region, timing of birth, and number of siblings. Of 64,364 live-births, 43,480 (68%) infants had at least one vaccinated parent (60% of mothers and 36% of fathers). After excluding records where parent(s) were either vaccinated prior to the birth, vaccinated >28 days after the birth, the vaccination date was uncertain, or the child died at birth (n=42), the final cohort contained 53,149 children, 118 of whom developed pertussis. There was no difference in the incidence of pertussis among infants whose parents were both vaccinated postpartum compared to those with unvaccinated parents (1.9 vs 2.2 infections per 1000 infants; adjusted HR 0.91; 95%CI 0.55-1.53). Similarly, when assessed independently, maternal postpartum vaccination was not protective (adjusted HR 1.19; 95%CI 0.82-1.72). Supplemental sensitivity analyses which varied the time period for parental vaccination and accounted for under-reporting of vaccination status did not significantly alter these findings. In our setting, vaccinating parents with dTpa during the four weeks following delivery did not reduce pertussis diagnoses in infants. WA now provides dTpa vaccine to pregnant women during the third trimester.

A prospective cohort study comparing the reactogenicity of trivalent influenza vaccine in pregnant and non-pregnant women.

BACKGROUND: Influenza vaccination during pregnancy can prevent serious illness in expectant mothers and provide protection to newborns; however, historically uptake has been limited due to a number of factors, including safety concerns. Symptomatic complaints are common during pregnancy and may be mistakenly associated with reactions to trivalent influenza vaccine (TIV). To investigate this, we compared post-vaccination events self-reported by pregnant women to events reported by non-pregnant women receiving TIV. METHODS: A prospective cohort of 1,086 pregnant women and 314 non-pregnant female healthcare workers (HCWs) who received TIV between March-May 2014 were followed-up seven days post-vaccination to assess local and systemic adverse events following immunisation (AEFIs). Women were surveyed by text message regarding perceived reactions to TIV. Those reporting an AEFI completed an interview by telephone or mobile phone to ascertain details. Logistic regression models adjusting for age and residence were used to compare reactions reported by pregnant women and non-pregnant HCWs. RESULTS: Similar proportions of pregnant women and non-pregnant, female HCWs reported ≥1 reaction following vaccination with TIV (13.0% and 17.3%, respectively; OR = 1.2 [95% CI: 0.8-1.8]). Non-pregnant, female HCWs were more likely to report fever or headache compared to pregnant women (OR: 4.6 [95% CI 2.1-10.3] and OR: 2.2 [95% CI 1.0-4.6], respectively). No other significant differences in reported symptoms were observed. No serious vaccine-associated adverse events were reported, and less than 2% of each group sought medical advice for a reaction. CONCLUSIONS: We found no evidence suggesting pregnant women are more likely to report adverse events following influenza vaccination when compared to non-pregnant female HCWs of similar age, and in some cases, pregnant women reported significantly fewer adverse events. These results further support the safety of TIV administered in pregnant women.

Increasing incidence of Clostridium difficile infection, Australia, 2011-2012.

OBJECTIVES: To report the quarterly incidence of hospital-identified Clostridium difficile infection (HI-CDI) in Australia, and to estimate the burden ascribed to hospital-associated (HA) and community-associated (CA) infections. DESIGN, SETTING AND PATIENTS: Prospective surveillance of all cases of CDI diagnosed in hospital patients from 1 January 2011 to 31 December 2012 in 450 public hospitals in all Australian states and the Australian Capital Territory. All patients admitted to inpatient wards or units in acute public hospitals, including psychiatry, rehabilitation and aged care, were included, as well as those attending emergency departments and outpatient clinics. MAIN OUTCOME MEASURES: Incidence of HI-CDI (primary outcome); proportion and incidence of HA-CDI and CA-CDI (secondary outcomes). RESULTS: The annual incidence of HI-CDI increased from 3.25/10 000 patient-days (PD) in 2011 to 4.03/10 000 PD in 2012. Poisson regression modelling demonstrated a 29% increase (95% CI, 25% to 34%) per quarter between April and December 2011, with a peak of 4.49/10 000 PD in the October-December quarter. The incidence plateaued in January-March 2012 and then declined by 8% (95% CI, - 11% to - 5%) per quarter to 3.76/10 000 PD in July-September 2012, after which the rate rose again by 11% (95% CI, 4% to 19%) per quarter to 4.09/10 000 PD in October-December 2012. Trends were similar for HA-CDI and CA-CDI. A subgroup analysis determined that 26% of cases were CA-CDI. CONCLUSIONS: A significant increase in both HA-CDI and CA-CDI identified through hospital surveillance occurred in Australia during 2011-2012. Studies are required to further characterise the epidemiology of CDI in Australia.