Australia avoided the worst effects of the COVID-19 pandemic, but still experienced many negative impacts. Reflecting on lessons from Australia's public health response, an Australian expert panel ...composed of relevant discipline experts identified the following key lessons: 1) movement restrictions were effective, but their implementation requires careful consideration of adverse impacts, 2) disease modelling was valuable, but its limitations should be acknowledged, 3) the absence of timely national data requires re-assessment of national surveillance structures, 4) the utility of advanced pathogen genomics and novel vaccine technology was clearly demonstrated, 5) decision-making that is evidence informed and consultative is essential to maintain trust, 6) major system weaknesses in the residential aged-care sector require fixing, 7) adequate infection prevention and control frameworks are critically important, 8) the interests and needs of young people should not be compromised, 9) epidemics should be recognised as a ‘standing threat’, 10) regional and global solidarity is important. It should be acknowledged that we were unable to capture all relevant nuances and context specific differences. However, the intent of this review of Australia's public health response is to critically reflect on key lessons learnt and to encourage constructive national discussion in countries across the Western Pacific Region.
Genetic testing has the potential to guide the prevention and treatment of disease in a variety of settings, and recent technical advances have greatly increased our ability to acquire large amounts ...of genetic data. The interpretation of this data remains challenging, as the clinical significance of genetic variation detected in the laboratory is not always clear. Although regulatory agencies and professional societies provide some guidance regarding the classification, reporting, and long‐term follow‐up of variants, few protocols for the implementation of these guidelines have been described. Because the primary aim of clinical testing is to provide results to inform medical management, a variant classification program that offers timely, accurate, confident and cost‐effective interpretation of variants should be an integral component of the laboratory process. Here we describe the components of our laboratory's current variant classification program (VCP), based on 20 years of experience and over one million samples tested, using the BRCA1/2 genes as a model. Our VCP has lowered the percentage of tests in which one or more BRCA1/2 variants of uncertain significance (VUSs) are detected to 2.1% in the absence of a pathogenic mutation, demonstrating how the coordinated application of resources toward classification and reclassification significantly impacts the clinical utility of testing.
We previously demonstrated that the Alzheimer's disease (AD) associated risk allele, rs3865444C, results in a higher surface density of CD33 on monocytes. Here, we find alternative splicing of exon 2 ...to be the primary mechanism of the genetically driven differential expression of CD33 protein. We report that the risk allele, rs3865444C, is associated with greater cell surface expression of CD33 in both subjects of European and African–American ancestry and that there is a single haplotype influencing CD33 surface expression. A meta-analysis of the two populations narrowed the number of significant SNPs in high linkage disequilibrium (LD) (r2
> 0.8) with rs3865444 to just five putative causal variants associated with increased protein expression. Using gene expression data from flow-sorted CD14+CD16− monocytes from 398 healthy subjects of three populations, we show that the rs3865444C risk allele is strongly associated with greater expression of CD33 exon 2 (p
META = 2.36 × 10−60). Western blotting confirms increased protein expression of the full-length CD33 isoform containing exon 2 relative to the rs3865444C allele (P < 0.0001). Of the variants in strong LD with rs3865444, rs12459419, which is located in a putative SRSF2 splice site of exon 2, is the most likely candidate to mediate the altered alternative splicing of CD33's Immunoglobulin V-set domain 2 and ultimately influence AD susceptibility.
Microbes colonize the apical surfaces of polarized epithelia in nearly all animal taxa. In one example, the luminous bacterium Vibrio fischeri enters, grows to a dense population within, and persists ...for months inside, the light-emitting organ of the squid Euprymna scolopes. Crucial to the symbiont's success after entry is the ability to trigger the constriction of a host tissue region (the "bottleneck") at the entrance to the colonization site. Bottleneck constriction begins at about the same time as bioluminescence, which is induced in V. fischeri through an autoinduction process called quorum sensing. Here, we asked the following questions: (i) Are the quorum signals that induce symbiont bioluminescence also involved in triggering the constriction? (ii) Does improper signaling of constriction affect the normal maintenance of the symbiont population? We manipulated the presence of three factors, the two V. fischeri quorum signal synthases, AinS and LuxI, the transcriptional regulator LuxR, and light emission itself, and found that the major factor triggering and maintaining bottleneck constriction is an as yet unknown effector(s) regulated by LuxIR. Treating the animal with chemical inhibitors of actin polymerization reopened the bottlenecks, recapitulating the host's response to quorum-sensing defective symbionts, as well as suggesting that actin polymerization is the primary mechanism underlying constriction. Finally, we found that these host responses to the presence of symbionts changed as a function of tissue maturation. Taken together, this work broadens our concept of how quorum sensing can regulate host development, thereby allowing bacteria to maintain long-term tissue associations.
Interbacterial signaling within a host-associated population can have profound effects on the behavior of the bacteria, for instance, in their production of virulence/colonization factors; in addition, such signaling can dictate the nature of the outcome for the host, in both pathogenic and beneficial associations. Using the monospecific squid-vibrio model of symbiosis, we examined how quorum-sensing regulation by the Vibrio fischeri population induces a biogeographic tissue phenotype that promotes the retention of this extracellular symbiont within the light organ of its host, Euprymna scolopes. Understanding the influence of bacterial symbionts on key sites of tissue architecture has implications for all horizontally transmitted symbioses, especially those that colonize an epithelial surface within the host.
The COVID-19 pandemic has had a negative impact on the mental health of people globally. Significant concerns about health and access to services among women of reproductive age considering pregnancy ...may cause psychological distress, and in turn increase health risks during and after pregnancy for mothers and offspring. To examine the association between pregnancy intention and psychological distress during the COVID-19 pandemic in Australia, and explore if this association differed based on local viral transmission rates and corresponding levels of pandemic restrictions. A nationwide online survey was completed by 849 non-pregnant women aged 18-50 years between 15 October and 7 November 2020. Women were asked about their intention to become pregnant, and psychological distress was assessed using the Kessler Psychological Distress Scale (K10). Multivariable regression analysis examined associations between pregnancy intention and psychological distress. An interaction term was added to the model to examine differences in associations by level of viral transmission rates and lockdown restrictions which was determined based on postcode. Pregnancy intention was not associated with experiencing (very) high psychological distress in the overall study population (odds ratio (OR) 1.42, 95% CI 0.94, 2.11). The interaction term (p = 0.09) suggested potential differences by level of restrictions and viral transmission rates. In stratified analysis among women living in a location with strict lockdown restrictions and high viral transmission rates leading up to and during the study, those planning to become pregnant were more likely to experience (very) high psychological distress (OR 3.39, 2.04, 5.65) compared with women not planning to become pregnant. Pregnancy intention was not associated with psychological distress among women exposed to lower levels of pandemic restrictions and viral transmission rates (OR 1.17, 0.74, 1.85). Our findings highlight the need to identify and support women planning pregnancy during a public health crisis to mitigate potential short- and long-term intergenerational negative health outcomes associated with psychological distress.
The AUX1 and PIN auxin influx and efflux facilitators are key regulators of root growth and development. For root gravitropism to occur, AUX1 and PIN2 must transport auxin via the lateral root cap to ...elongating epidermal cells. Genetic studies suggest that AXR4 functions in the same pathway as AUX1. Here we show that AXR4 is a previously unidentified accessory protein of the endoplasmic reticulum (ER) that regulates localization of AUX1 but not of PIN proteins. Loss of AXR4 resulted in abnormal accumulation of AUX1 in the ER of epidermal cells, indicating that the axr4 agravitropic phenotype is caused by defective AUX1 trafficking in the root epidermis.
We analyzed the safety and efficacy of Mylotarg (gemtuzumab ozogamicin, an antibody-targeted chemotherapy consisting of a humanized anti-CD33 antibody linked to calicheamicin, a potent antitumor ...antibiotic) in the treatment of 101 patients > or =60 years of age with acute myeloid leukemia (AML) in untreated first relapse in three open-label trials. Mylotarg is administered as a 2-h intravenous infusion at 9 mg/m(2) for two doses with 14 days between doses. The overall remission rate was 28%, with complete remission (CR) in 13% of patients and complete remission with incomplete platelet recovery (CRp) in 15%. Median survival was 5.4 months for all patients and 14.5 months and 11.8 months for patients achieving CR and CRp, respectively. CD33 antigen is present on normal hematopoietic progenitor cells; thus, an expected high incidence of grade 3 or 4 neutropenia (99%) and thrombocytopenia (99%) was observed. The incidences of grade 3 or 4 elevations of bilirubin and hepatic transaminases were 24% and 15%, respectively. There was a low incidence of grade 3 or 4 mucositis (4%) and infections (27%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Mylotarg is an effective treatment for older patients with CD33-positive AML in first relapse and has acceptable toxicity.
•Hippocampal subfields were automatically segmented with FreeSurfer.•Reliability of subfield measurements was assessed using three timepoints.•FreeSurfer preprocessing pipeline had excellent ...reliability.•Hippocampal subfields were not related to prospective PTSD symptoms.
The hippocampus plays a central role in post-traumatic stress disorder (PTSD) pathogenesis, and the majority of neuroimaging research on PTSD has studied the hippocampus in its entirety. Although extensive literature demonstrates changes in hippocampal volume are associated with PTSD, fewer studies have probed the relationship between symptoms and the hippocampus’ functionally and structurally distinct subfields. We utilized data from a longitudinal study examining post-trauma outcomes to determine whether hippocampal subfield volumes change post-trauma and whether specific subfields are significantly associated with, or prospectively related to, PTSD symptom severity. As a secondary aim, we leveraged our unique study design sample to also investigate reliability of hippocampal subfield volumes using both cross-sectional and longitudinal pipelines available in FreeSurfer v6.0.
Two-hundred and fifteen traumatically injured individuals were recruited from an urban Emergency Department. Two-weeks post-injury, participants underwent two consecutive days of neuroimaging (time 1: T1, and time 2: T2) with magnetic resonance imaging (MRI) and completed self-report assessments. Six-months later (time 3: T3), participants underwent an additional scan and were administered a structured interview assessing PTSD symptoms. First, we calculated reliability of hippocampal measurements at T1 and T2 (automatically segmented with FreeSurfer v6.0). We then examined the prospective (T1 subfields) and cross-sectional (T3 subfields) relationship between volumes and PTSD. Finally, we tested whether change in subfield volumes between T1 and T3 explained PTSD symptom variability.
After controlling for sex, age, and total brain volume, none of the subfield volumes (T1) were prospectively related to T3 PTSD symptoms nor were subfield volumes (T3) associated with current PTSD symptoms (T3). Tl – T2 reliability of all hippocampal subfields ranged from good to excellent (intraclass correlation coefficient (ICC) values > 0.83), with poorer reliability in the hippocampal fissure.
Our study was a novel examination of the prospective relationship between hippocampal subfield volumes in relation to PTSD in a large trauma-exposed urban sample. There was no significant relationship between subfield volumes and PTSD symptoms, however, we confirmed FreeSurfer v6.0 hippocampal subfield segmentation is reliable when applied to a traumatically-injured sample, using both cross-sectional and longitudinal analysis pipelines. Although hippocampal subfield volumes may be an important marker of individual variability in PTSD, findings are likely conditional on the timing of the measurements (e.g. acute or chronic post-trauma periods) and analysis strategy (e.g. cross-sectional or prospective).
Climate change is shifting the distribution of species, and may have a profound impact on the ecology and evolution of species interactions. However, we know little about the impact of increasing ...temperature and changing rainfall patterns on the interactions between plants and their beneficial and antagonistic root symbionts.
Here, we used a reciprocal multifactorial growth chamber experiment with seeds and soil microbial communities from three origins to investigate the impact of temperature and soil moisture on the growth, arbuscular mycorrhizal (AM) fungal colonization and root‐associated fungal community of a perennial herb. Moreover, we tested whether plants and AM fungi performed better or worse when plants were grown with their local soil biota, for example, due to plant adaptation or changes in the genetic or species composition of the soil microbial community.
Temperature and soil moisture generally increased plant growth, whereas temperature but not soil moisture increased AM fungal colonization. The strength and direction of the plants' response to temperature were dependent on soil moisture and differed among plant populations, and AM fungal colonization was further affected by the origin of the soil microbial community. The root‐associated fungal community structure was impacted by temperature, soil moisture and the soil microbial origin, with interactive effects between the microbial origin and the abiotic environment. Plant biomass was lower when plants were grown with their local soil microbes, potentially due to intraspecific negative plant–soil feedbacks.
Synthesis. Our findings indicate that, beyond a relatively uniform increase of plant growth and arbuscular mycorrhizal (AM) fungal colonization with increasing temperature, plants and root‐associated fungi of different origins will vary in their response to climate change (i.e. elevated temperature and shifts in rainfall). This may create pronounced, but difficult to predict, spatial and temporal variation in the ecology and evolution of plant–microbe interactions with a changing climate.
Foreign Language
(in Swedish)
Klimatförändringar påverkar arters utbredningar och kan ha djupgående inverkan på ekologin och evolutionen av arters interaktioner. Vi vet emellertid lite om hur ökande temperaturer och förändrade regnmönster påverkar växelverkan mellan växter och deras fördelaktiga och antagonistiska rotsymbionter.
Vi använde här ett multifaktoriellt tillväxtkammarexperiment med frön och samhällen av jordmikrober från tre ursprung för att undersöka påverkan av temperatur och markfuktighet på tillväxten, svampkoloniseringen av arbuskulär mykorrhiza (AM) och det rot‐associerade svampsamhället hos en flerårig ört. Dessutom testade vi om växter och AM‐svampar fungerade bättre eller sämre när växterna odlades med sina lokala jordmikrober, t.ex. på grund av växtens anpassning, genetiska förändringar eller artsammansättningen i jordens mikrobiella samhälle.
Temperatur och markfuktighet ökade i allmänhet växttillväxten, medan temperaturen, men inte markfuktigheten, ökade AM‐svampkoloniseringen. Styrkan och riktningen för växternas respons på temperaturen var beroende av markfuktighet och skiljde sig åt bland växtpopulationerna, och AM‐svampkolonisering påverkades även av ursprunget hos jordens mikrobiella samhälle. Den rot‐associerade svampsamhällsstrukturen påverkades av temperatur, markfuktighet och jordens mikrobiella ursprung, med interaktiva effekter mellan det mikrobiella ursprunget och den abiotiska miljön. Växtbiomassan var lägre när växter odlades med sina lokala jordmikrober, potentiellt på grund av intraspecifika negativa återkopplingar mellan växt och mark.
Syntes. Studien visar att utöver en ökning av växttillväxt och AM‐svampkolonisering med ökande temperatur, kommer växter och rot‐associerade svampar av olika ursprung att variera som svar på klimatförändringar (dvs förhöjd temperatur och skifte i nederbörd). Ett förändrat klimat kan därför skapa uttalade, men svårförutsägbara, rumsliga och temporära variationer i ekologin och utvecklingen av växt och mikrob‐interaktioner.
This study shows that, beyond a relatively uniform increase of plant growth and arbuscular mycorrhizal fungal colonization with increasing temperature, plants and root‐associated fungi of different origins will vary in their response to climate change. This may create pronounced, but difficult to predict, spatial and temporal variation in the ecology and evolution of plant–microbe interactions with a changing climate.
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