Dynamic cell tracking using time-lapse MRI with variable temporal resolution Cartesian sampling.

PURPOSE: Temporal resolution of time-lapse MRI to track individual iron-labeled cells is limited by the required data-acquisition time to fill k-space and to reach sufficient SNR. Although motion of slowly patrolling monocytes can be resolved, detection of fast-moving immune cells requires improved acquisition and reconstruction strategies. THEORY AND METHODS: For accelerated MRI cell tracking, a Cartesian sampling scheme was designed, in which the fully sampled and undersampled k-space data for different acceleration factors were acquired simultaneously, and multiple undersampling ratios could be chosen retrospectively. Compressed-sensing reconstruction was applied using dictionary learning and low-rank constraints. Detection of iron-labeled monocytes was evaluated with simulations, rotating phantom experiments and in vivo mouse brain measurements at 9.4 T. RESULTS: Fully sampled and 2.4-times and 4.8-times accelerated images were reconstructed and had sufficient contrast-to-noise ratio (CNR) for single cells to be resolved and followed dynamically. The phantom experiments showed an improvement in CNR of 6.1% per µm/s in the 4.8-times undersampled images. Geometric distortion of cells caused by motion was visibly reduced in the accelerated images, which enabled detection of moving cells with velocities of up to 7.0 µm/s. In vivo, additional cells were resolved in the accelerated images due to the improved temporal resolution. CONCLUSION: The easy-to-implement flexible Cartesian sampling scheme with compressed-sensing reconstruction permits simultaneous acquisition of both fully sampled and high temporal resolution images. The CNR of moving cells is effectively improved, enabling the recovery of high velocity cells with sufficient contrast at virtually no cost.

Antimicrobial stewardship in diabetic ketoacidosis: a single-centre experience.

BACKGROUND: Diabetic ketoacidosis (DKA) is a common and serious complication arising predominantly in patients with type 1 diabetes mellitus. International data demonstrate that infection is one of the most common precipitating causes of DKA. Currently there are limited data regarding the role of antimicrobial stewardship (AMS) in this setting. AIM: To provide epidemiologic data regarding infections precipitating DKA, microbiological aetiology and antimicrobial prescribing practices in order to inform AMS interventions. METHODS: Retrospective chart review of all type 1 diabetes mellitus DKA presentations from May 2015 to June 2018. RESULTS: In total, 249 DKA presentations occurred in 111 patients. Suspected infection accounted for 100/249 (40%) presentations, and only 36/249 (14.5%) were proven or probable infections. Skin and soft tissue infection was the most common (9/36, 25%), followed by urinary tract infection (8/36, 22%) and respiratory tract infection (7/36, 19%). A pathogen was identified in 24/100 presumed infections and included Staphylococcus aureus (24, 46%), Klebsiella pneumoniae (4/24, 17%) and Escherichia coli (3/24, 13%). No viral pathogens were identified. Of 80 empirical antimicrobial prescriptions, 75% were inappropriate based on guideline management of the documented suspected infection. Single agent ceftriaxone was appropriately prescribed in 7/23 (30%) cases, and was most frequently prescribed overall 23/80 (29%). CONCLUSION: This study demonstrates a lower incidence of infection compared to most previous publications, and suggests that infection-precipitated DKA may be over reported. Furthermore, our findings provide support for the role of AMS in the management of DKA.

Q fever vaccination of children in Australia: Limited experience to date.

AIM: Q fever is a zoonotic disease caused by the bacterium Coxiella burnetii and is associated with significant morbidity and mortality in both adults and children. Australia is the only country that has produced and registered a Q fever vaccine for human use, but this vaccine is licenced only for people aged over 15 years as data and experience in children are limited. This review describes the experience of Q fever vaccination of known paediatric cases in Australia to date. METHODS: Patients aged younger than 15 years who received the Q fever vaccination had data abstracted from medical records after consent was obtained from the relevant guardians. Data on risk factors for Q fever, skin testing procedure, dose of vaccination, adverse effects and follow-up assessment were obtained. RESULTS: Twelve children were identified as having received the Q fever vaccination. Vaccination was feasible, with empirical weight-based dose adjustment performed for younger children. There were no significant adverse effects. CONCLUSIONS: Q fever vaccine may be safe in children and should be considered in children who are at significant risk of Q fever infection. Safe vaccine protocols with proven efficacy will allow children of all ages to be protected. Prospective studies of vaccination in children are indicated. Expanding available Q fever registries to include children would allow outcomes to be systematically followed.

Revisiting Conversion Reaction Mechanisms in Lithium Batteries: Lithiation-Driven Topotactic Transformation in FeF2.

Intercalation-type electrodes have now been commonly employed in today's batteries as such materials are capable of storing and releasing lithium reversibly via topotactic transformation, conducive to small structural change, but they have limited interstitial sites to hold Li. In contrast, conversion electrodes feature high Li-storage capacity, but often undergo large structural change during (de)lithiation, resulting in cycling instability. One exception is iron fluoride (FeF2), a conversion-type cathode that exhibits both high capacity and high cycling stability. Herein, we report a lithiation-driven topotactic transformation in a single crystal of FeF2, unveiled by in situ visualization of the spatial and crystallographic correlation between the parent and converted phases. Specifically, conversion in FeF2 resembles the intercalation process but involves transport of both Li+ and Fe2+ ions within the F-anion array, leading to formation of Fe preferentially along specific crystallographic orientations of FeF2. Throughout the process, the F-anion framework is retained, creating a checkerboard-like structure, within which the volume change is largely compensated, thereby enabling the high cyclability in FeF2. Findings from this study, with unique insights into conversion reaction mechanisms, may help to pave the way for designing conversion-type electrodes for the next-generation high energy lithium batteries.

Salmonella Weltevreden lung abscess and empyema without preceding gastrointestinal symptoms: an emerging pathogen in Australia?

Non-typhoidal Salmonella lung infections are rare and are usually confined to immunocompromised hosts. Previous case reports have found that usually patients have either gastroenteritis or bacteraemia in addition to pulmonary involvement. We present the first known reported case of a Salmonella Weltevreden lung abscess and empyema in an immunocompetent patient without gastroenteritis. Despite the use of antimicrobials active against the pathogen, the patient needed surgical intervention to achieve adequate source control. While S. Weltevreden has previously been associated with returned travellers, especially from Southeast Asia, its incidence in Queensland is now increasing. Therefore, it is important for clinicians to be aware of its potential severity as well as the range of presentations.

A sibling-controlled, prospective study of outcomes at home and school in children with severe congenital heart disease.

OBJECTIVES: The objectives of this study were to compare behaviour problems and competencies, at home and school, in 7-year-old children with congenital heart disease with a sibling control group, to examine the prospective determinants of outcome from infancy, and to explore whether any gains were maintained in our sub-group of children who had participated in a previous trial of psychological interventions in infancy. METHODS: A total of 40 children who had undergone surgery to correct or palliate a significant congenital heart defect in infancy were compared (Child Behavior Checklist) with a nearest-age sibling control group (18 participants). Comparisons were made between sub-groups of children and families who had and had not participated in an early intervention trial. RESULTS: Problems with attention, thought and social problems, and limitations in activity and school competencies, were found in comparison with siblings. Teacher reports were consistent with parents, although problems were of a lower magnitude. Disease, surgical, and neurodevelopmental functioning in infancy were related to competence outcomes but not behaviour problems. The latter were mediated by family and maternal mental health profiles from infancy. Limited, but encouraging, gains were maintained in the sub-group that had participated in the early intervention programme. CONCLUSIONS: The present study is strengthened by its longitudinal design, use of teacher informants, and sibling control group. The patterns of problems and limitations discerned, and differential determinants thereof, have clear implications for interventions. We consider these in the light of our previously reported intervention trial with this sample and current outcomes at the 7-year follow-up.

Comparison of Melioidosis Indirect Hemagglutination Assay between Three Testing Laboratories in Australia.

Melioidosis caused by Burkholderia pseudomallei causes significant morbidity and mortality in Southeast Asia and northern Australia. Clinical manifestations remain diverse, including localized skin infection, pneumonia, and chronic abscess formation. Culture remains the gold standard of diagnosis, with serology and antigen detection tests playing a role if culture is unfeasible. Serologic diagnosis remains challenging, with limited standardization across different assays. In areas of endemicity, high rates of seropositivity have been documented. The indirect hemagglutination assay (IHA) is one of the more widely used serologic tests in these areas. In Australia, only three centers perform the test. Annually, laboratory A, laboratory B, and laboratory C perform approximately 1,000, 4,500, and 500 tests, respectively. A comparison of a total of 132 sera was analyzed from the routine quality exchange program between these centers from 2010 until 2019. Overall, 18.9% of sera tested had an interpretative discrepancy between laboratories. IMPORTANCE This study found significant discrepant results between three Australian centers offering the melioidosis indirect hemagglutination assay (IHA), despite testing the same samples. We have highlighted that the IHA is a nonstandardized test, which had different source antigens at each of the different laboratories. Melioidosis is a global disease, is associated with significant mortality, and is perhaps under recognized. It is likely to have increasing impact with changing weather patterns. The IHA has been used frequently as an adjunct to the diagnosis of clinical disease and is the mainstay of determining seroprevalence within populations. Despite its relative ease of use, especially in low resource settings, our study highlights the significant limitations of the melioidosis IHA. It has wide ranging implications, serving as an impetus for developing better diagnostic tests. This study is of interest to practitioners and researchers working in the various geographic regions affected by melioidosis.

Characterisation of PfCZIF1 and PfCZIF2 in Plasmodium falciparum asexual stages.

Plasmodium falciparum exerts strong temporal control of gene expression across its lifecycle. Proteins expressed exclusively during late schizogony of blood stages, for example, often have a role in facilitating merozoite invasion of the host red blood cell (RBC), through merozoite development, egress, invasion or early establishment of infection in the RBC. Here, we characterise P. falciparum C3H1 zinc finger 1 (PfCZIF1, Pf3D7_1468400) and P. falciparum C3H1 zinc finger 2 (PfCZIF2, Pf3D7_0818100) which we identified as the only C3H1-type zinc finger proteins with peak expression at schizogony. Previous studies reported that antibodies against PfCZIF1 inhibit merozoite invasion, suggesting this protein may have a potential role during RBC invasion. We show using C-terminal truncations and gene knockouts of each of Pfczif1 and Pfczif2 that neither are essential for blood stage growth. However, they could not both be knocked out simultaneously, suggesting that at least one is needed for parasite growth in vitro. Immunofluorescence localisation of PfCZIF1 and PfCZIF2 indicated that both proteins occur in discrete foci on the periphery of the parasite's cytosol and biochemical assays suggest they are peripherally associated to a membrane. Transcriptomic analyses for the C-terminal truncation mutants reveal no significant expression perturbations with PfCZIF1 truncation. However, modification of PfCZIF2 appears to modify the expression for some exported proteins including PfKAHRP. This study does not support a role for PfCZIF1 or PfCZIF2 in merozoite invasion of the RBC and suggests that these proteins may help regulate the expression of proteins exported into the RBC cytosol after merozoite invasion.

Determination of Tr1 cell populations correlating with distinct activation states in acute IAV infection.

Type I regulatory (Tr1) cells are defined as FOXP3-IL-10-secreting clusters of differentiation (CD4+) T cells that contribute to immune suppression and typically express the markers LAG-3 and CD49b and other co-inhibitory receptors. These cells have not been studied in detail in the context of the resolution of acute infection in the lung. Here, we identify FOXP3- interleukin (IL)-10+ CD4+ T cells transiently accumulating in the lung parenchyma during resolution of the response to sublethal influenza A virus (IAV) infection in mice. These cells were dependent on IL-27Rα, which was required for timely recovery from IAV-induced weight loss. LAG-3 and CD49b were not generally co-expressed by FOXP3- IL-10+ CD4+ T cells in this model and four populations of these cells based on LAG-3 and CD49b co-expression were apparent [LAG-3-CD49b- (double negative), LAG-3+CD49b+ (double positive), LAG-3+CD49b- (LAG-3+), LAG-3-CD49b+ (CD49b+)]. However, each population exhibited suppressive potential consistent with the definition of Tr1 cells. Notably, differences between these populations of Tr1 cells were apparent including differential dependence on IL-10 to mediate suppression and expression of markers indicative of different activation states and terminal differentiation. Sort-transfer experiments indicated that LAG-3+ Tr1 cells exhibited the capacity to convert to double negative and double positive Tr1 cells, indicative of plasticity between these populations. Together, these data determine the features and suppressive potential of Tr1 cells in the resolution of IAV infection and identify four populations delineated by LAG-3 and CD49b, which likely correspond to different Tr1 cell activation states.

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41.

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.

ACKR4 restrains antitumor immunity by regulating CCL21.

Current immunotherapies involving CD8+ T cell responses show remarkable promise, but their efficacy in many solid tumors is limited, in part due to the low frequency of tumor-specific T cells in the tumor microenvironment (TME). Here, we identified a role for host atypical chemokine receptor 4 (ACKR4) in controlling intratumor T cell accumulation and activation. In the absence of ACKR4, an increase in intratumor CD8+ T cells inhibited tumor growth, and nonhematopoietic ACKR4 expression was critical. We show that ACKR4 inhibited CD103+ dendritic cell retention in tumors through regulation of the intratumor abundance of CCL21. In addition, preclinical studies indicate that ACKR4 and CCL21 are potential therapeutic targets to enhance responsiveness to immune checkpoint blockade or T cell costimulation.

Prevalence of scabies in Sanma Province, Vanuatu.

BACKGROUND: Scabies is a common, under-reported condition in the Pacific with acute and chronic complications. In this study we explored the prevalence of scabies in Sanma Province, Vanuatu. METHODS: We randomly selected 30 villages from nine government zones across three islands and examined residents present within these villages for scabies. Bivariate analysis and multilevel models were conducted to investigate associated demographic and household factors. RESULTS: Of 1879 participants examined, 563 had scabies (30%, 95% CI 27.9 to 32.1) with the highest prevalence in children aged 6-10 y (38.8%, 95% CI 33.9 to 44). CONCLUSIONS: Scabies is a significant issue in Sanma with very high prevalence in children.

A contemporary 16-year review of Coxiella burnetii infective endocarditis in a tertiary cardiac center in Queensland, Australia.

BACKGROUND: Coxiella burnetii endocarditis can be difficult to diagnose leading to delays in treatment. This retrospective case series study was undertaken to understand the epidemiologic trends and clinical features of Q fever endocarditis in Southeast Queensland, Australia. METHODS: Clinical records of patients from a single center with coding diagnosis of C. burnetii, or serology consistent with chronic Q fever, were reviewed from 1999 to 2015. Data from patients with probable or confirmed Q fever endocarditis was abstracted. RESULTS: Thirteen patients had confirmed and 5 had probable Q fever endocarditis. Median age at diagnosis in confirmed cases was 60 years. In confirmed cases, 92% (12/13) of patients had an underlying valvular defect. Two patients in the confirmed cases had serology not consistent with a diagnosis of Q fever endocarditis. Eight patient records noted retrospective diagnosis of Q fever endocarditis after surgery. CONCLUSIONS: As pre-existing valve pathology is a major risk for developing endocarditis, prophylactic strategies such as targeted echocardiography and Q fever vaccination could be considered to reduce the incidence of Q fever endocarditis.

Successful outpatient management of Campylobacter fetus bacteremia in an immunocompetent patient with endovascular involvement.

We describe a case of Campylobacter fetus bacteremia with endovascular involvement in an immunocompetent female patient. The patient was treated with high dose ciprofloxacin as an outpatient and recovered well.

Correlation between serum cryptococcal antigen titre and meningitis in immunocompetent patients.

The aim of this paper was to determine the correlation between serum cryptococcal antigen and a diagnosis of cryptococcal meningitis in the immunocompetent cohort. A retrospective multicentre analysis of immunocompetent patients diagnosed and treated for cryptococcal meningitis between January 2000 and December 2017 was performed. Sixty-seven of the 143 cases of cryptococcosis occurred in immunocompetent patients. The serum cryptococcal antigen titre was significantly higher in the meningitis group [1 : 256 (IQR: 64-1024)] compared with that for non-meningitis patients [1 : 64 (IQR: 8-256)], P=0.012. The relative risk of meningitis with a serum cryptococcal antigen (CRAG) >1 : 64 was 1.8 (95 % CI: 1.15-2.82). This study demonstrates a clear correlation between serum cryptococcal antigen titre and meningitis. While the serum titre is not definitive for meningitis, in resource-limited settings or cases where lumbar puncture may be contraindicated, this evidence may aid diagnosis and subsequent therapeutic decisions.

Rickettsia australis and Queensland Tick Typhus: A Rickettsial Spotted Fever Group Infection in Australia.

Rickettsia australis, the etiologic agent of Queensland tick typhus (QTT), is increasingly being recognized as a cause of community-acquired acute febrile illness in eastern Australia. Changing human population demographics, climate change, and increased understanding of expanding vector distribution indicate QTT is an emerging public health threat. This review summarizes the epidemiology, pathogenesis, clinical features, treatment principles, and future directions of this disease. Increased recognition of QTT will enable consideration of and prompt treatment of R. australis infection by clinicians in Australia.

Epidemiology and Characteristics of Rickettsia australis (Queensland Tick Typhus) Infection in Hospitalized Patients in North Brisbane, Australia.

Queensland Tick Typhus (QTT; Rickettsia australis) is a Spotted Fever Group (SFG) rickettsial infection endemic to Australia. It is an underreported and often unrecognized illness with poorly defined epidemiology. This article describes epidemiological features and the geographical distribution of QTT in hospitalized patients. Cases of QTT were identified retrospectively from 2000⁻2015 at five sites in Northern Brisbane through a pathology database. Included cases had a four-fold rise in SFG-specific serology, a single SFG-specific serology ≥256 or an SFG-specific serology ≥128 with a clinically consistent illness. Of the fifty cases identified by serology, 36 were included. Age ranged from 3⁻72 years (with a mean of 39.5 years) with a male-to-female ratio of 1:1.1. Fifteen of 36 (42%) study participants had hobbies and/or occupations linked with the acquisition of the disease. Seventeen of 36 (47%) identified a tick bite in the days preceding presentation to hospital, and reported exposure to a known animal host was minimal (25%). QTT infection occurred throughout the year, with half reported between April and July. Recent ecological and sociocultural changes have redefined the epidemiology of this zoonotic illness, with areas of heightened infection identified. Heightened public health awareness is required to monitor QTT disease activity.

Clinical Manifestations and Outcomes of Rickettsia australis Infection: A 15-Year Retrospective Study of Hospitalized Patients.

Queensland tick typhus (QTT; Rickettsia australis) is an important cause of community-acquired acute febrile illness in eastern Australia. Cases of QTT were identified retrospectively from 2000 to 2015 at five sites in Northern Brisbane through a pathology database. Those included had a fourfold rise in spotted fever group (SFG)-specific serology, a single SFG-specific serology ≥ 256 or SFG-specific serology ≥ 128 with a clinically consistent illness. Cases were excluded on the basis of clinical unlikelihood of QTT infection. Thirty-six cases were included. Fever was found in 34/36 (94%) patients. Rash occurred in 83% of patients with maculopapular being the dominant morphology (70%). Thrombocytopenia, lymphopenia, and raised transaminases were common and occurred in 58%, 69%, and 89% of patients, respectively. Thirty-one of 36 (86%) patients received antibiotic therapy (usually doxycycline) and the time to correct antibiotic (from admission) ranged from 3 to 120 h (mean 45.5 h). Four of 36 (11%) required intensive care unit (ICU) admission for severe sepsis and end-organ support. There were no deaths. QTT has a wide range of clinical and laboratory features. Early and appropriate antimicrobial therapy is important and may prevent severe disease. Further prospective studies are required to identify factors associated with severe infection and sepsis.