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Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate-activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)-FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and estrogen-related receptor alpha (ERRα) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1-dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis.

AMP-activated protein kinase (AMPK) is a master regulator of cellular energetics which coordinates metabolism by phosphorylating a plethora of substrates throughout the cell. But how AMPK activity is regulated at different subcellular locations for precise spatiotemporal control over metabolism is unclear. Here we present a sensitive, single-fluorophore AMPK activity reporter (ExRai AMPKAR), which reveals distinct kinetic profiles of AMPK activity at the mitochondria, lysosome, and cytoplasm. Genetic deletion of the canonical upstream kinase liver kinase B1 (LKB1) results in slower AMPK activity at lysosomes but does not affect the response amplitude at lysosomes or mitochondria, in sharp contrast to the necessity of LKB1 for maximal cytoplasmic AMPK activity. We further identify a mechanism for AMPK activity in the nucleus, which results from cytoplasmic to nuclear shuttling of AMPK. Thus, ExRai AMPKAR enables illumination of the complex subcellular regulation of AMPK signaling.

: Objective: To describe the operationalisation of a novel outdoor quarantine facility managed by the Australian Medical Assistance Team, the Howard Springs International Quarantine Facility (HSIQF) at the Centre for National Resilience in the Northern Territory, Australia. Methods: We collated documentation and data from HSIQF to describe policies and procedures implemented and performed a descriptive analysis of key procedures and outcomes. Results: From 23 October 2020 to 31 March 2021, 2.2% (129/5,987) of residents were confirmed COVD‐19 cases. On average per day, 82 [Interquartile Range (IQR): 29‐95] staff completed personal protective equipment (PPE) training, 94 [IQR: 90‐104] staff completed antigen testing and 51 [IQR: 32‐136] staff completed polymerase chain reaction testing. The operation focused on building a safe environment with infection prevention and control adherence and workforce sustainability. There was no leakage of SARS‐CoV‐2 to staff or the community and no PPE compromises requiring staff to quarantine for 14 days. Conclusion: HSIQF demonstrates the operationalisation of an effective, safe and replicable quarantine system. Implications for public health: Quarantine is a critical public health tool for pandemic control. The HSIQF operations may be useful to inform the establishment and management of quarantine facilities for future and current disease outbreaks., International travel has driven global transmission of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Travel‐related control measures, including mandatory quarantine for returned travellers, were implemented early in the pandemic in [...]

In Fiji, the SARS-CoV-2 Delta variant wave occurred in a largely unvaccinated and nonimmune population during April-November 2021 (1). A risk-based COVID-19 vaccine rollout strategy commenced in March 2021, and, [...]

The aim of this document is to provide guidance for the management of women and birthing people with a permanent pacemaker (PPM) or implantable cardioverter defibrillator (ICD). Cardiac devices are becoming more common in obstetric practice and a reference document for contemporary evidence‐based practice is required. Where evidence is limited, expert consensus has established recommendations. The purpose is to improve safety and reduce the risk of adverse events relating to implanted cardiac devices during pregnancy, birth and the postnatal period. [ABSTRACT FROM AUTHOR]

We investigated whether injecting drug use was a risk factor for methicillin resistance among inpatients with Staphylococcus aureus bloodstream infections (SABSIs) at an Australian health service. In 273 inpatients, 46 (16.9%) of SABSIs were methicillin‐resistant S. aureus (MRSA). MRSA was more frequent in those who had injected drugs in the past 6 months (20.6%) compared with other inpatients (15.7%). Injecting drug use was associated with a 4.82‐fold (95% confidence interval = 1.54–16.29) increased odds of MRSA after accounting for confounders. [ABSTRACT FROM AUTHOR]

People who inject drugs are at risk of acute bacterial and fungal injecting-related infections. There is evidence that incidence of hospitalizations for injecting-related infections are increasing in several countries, but little is known at an individual level. We aimed to examine injecting-related infections in a linked longitudinal cohort of people who inject drugs in Melbourne, Australia. A retrospective descriptive analysis was conducted to estimate the prevalence and incidence of injecting-related infections using administrative emergency department and hospital separation datasets linked to the SuperMIX cohort, from 2008 to 2018. Over the study period, 33% (95%CI: 31–36%) of participants presented to emergency department with any injecting-related infections and 27% (95%CI: 25–30%) were admitted to hospital. Of 1,044 emergency department presentations and 740 hospital separations, skin and soft tissue infections were most common, 88% and 76%, respectively. From 2008 to 2018, there was a substantial increase in emergency department presentations and hospital separations with any injecting-related infections, 48 to 135 per 1,000 person-years, and 18 to 102 per 1,000 person-years, respectively. The results emphasize that injecting-related infections are increasing, and that new models of care are needed to help prevent and facilitate early detection of superficial infection to avoid potentially life-threatening severe infections. [ABSTRACT FROM AUTHOR]

Aortic dissection is one of the most common causes of death in pregnancy. Most cases are caused by hereditary thoracic aortopathy (HTA), and women are often unaware they are at risk. Awareness, early recognition and involvement of senior clinicians from the expert cardio-obstetric team are essential to facilitate early diagnosis and carefully planned and coordinated antenatal and postnatal care. Frequent imaging antenatally and good blood pressure control are key. Delivery needs particular attention with optimal pain control and techniques to minimise maternal effort. Dissection is most common post partum and a period of close surveillance with meticulous blood pressure control after delivery is crucial, as well as follow-up of the baby in paediatric services. All women with a family history of aortic dissection or sudden death should be investigated. Women with known HTA should be offered specialist individualised pre-pregnancy counselling, including advice about genetics and inheritance, before starting a family. Future research is directed towards more individualised risk assessment, pre-pregnancy advice and pharmacological options to reduce dissection risk. [ABSTRACT FROM AUTHOR]

Introduction: People who inject drugs are at risk of hospitalisation with injection‐related infections (IRI). We audited the clinical features, microbiology and management of IRI at a tertiary service in Melbourne to describe the burden and identify quality improvement opportunities. Methods: We performed retrospective review of IRI admissions from January 2017 to April 2019. We extracted admissions where ICD‐10 codes or triage text suggested injecting drug use, and the diagnosis suggested IRI. We reviewed these for eligibility and extracted data using a standardised form. We performed mixed‐effects logistic regression to determine predictors of unplanned discharge. Results: From 574 extracted candidate admissions, 226 were eligible, representing 178 patients. Median age was 41 years (interquartile range 36–47), 66% (117/178) male and 49% (111/226) had unstable housing. Over 50% (96/178) had a psychiatric diagnosis and 35% (62/178) were on opioid agonist therapy (OAT) on admission. Skin and soft tissue infection was the most common IRI (119/205, 58%), followed by bacteraemia (36/205, 18%) and endocarditis (26/205, 13%). Management included addictions review (143/226, 63%), blood‐borne virus screening (115/226, 51%), surgery (77/226, 34%) and OAT commencement (68/226, 30%). Aggression events (54/226, 15%) and unplanned discharge (69/226, 30%) complicated some admissions. Opioid use without OAT was associated with almost 3‐fold increased odds of unplanned discharge compared to no opioid use (odds ratio 2.90, 95% confidence interval 1.23, 6.85, p = 0.015). Discussion and Conclusion: Comorbidities associated with IRI may be amenable to opportunistic intervention during hospitalisation. Further research is needed to develop optimal models of care for this vulnerable patient group. [ABSTRACT FROM AUTHOR]

Introduction: Injection‐related infections (IRI) cause morbidity and mortality in people who inject drugs. Hospital administrative datasets can be used to describe hospitalisation trends, but there are no validated algorithms to identify injecting drug use and IRIs. We aimed to validate International Classification of Diseases (ICD) codes to identify admissions with IRIs and use these codes to describe IRIs within our hospital. Methods: We developed a candidate set of ICD codes to identify current injecting drug use and IRI and extracted admissions satisfying both criteria. We then used manual chart review data from 1 January 2017 to 30 April 2019 to evaluate the performance of these codes and refine our algorithm by selecting codes with a high‐positive predictive value (PPV). We used the refined algorithm to describe trends and outcomes of people who inject drugs with an IRI at Alfred Hospital, Melbourne from 2008 to 2020. Results: Current injecting drug use was best predicted by opioid‐related disorders (F11), 80% (95% confidence interval [CI] 74–85%), and other stimulant‐related disorders (F15), 82% (95% CI 70–90%). All PPVs were ≥67% to identify specific IRIs, and ≥84% for identifying any IRI. Using these codes over 12 years, IRIs increased from 138 to 249 per 100 000 admissions, and skin and soft tissues infections (SSTI) were the most common (797/1751, 46%). Discussion and Conclusion: Validated ICD‐based algorithms can inform passive surveillance systems. Strategies to reduce hospitalisation with IRIs should be supported by early intervention and prevention, particularly for SSTIs which may represent delayed access to care. [ABSTRACT FROM AUTHOR]

In human heart failure the role of wave generation by the ventricle and wave reflection by the vasculature is contentious. The aim of this study was to compare wave generation and reflection in normal subjects with patients with stable compensated heart failure. Twenty-nine normal subjects and 67 patients with heart failure (New York Heart Association class II or III) were studied by noninvasive techniques applied to the common carotid artery. Data were analyzed by wave intensity analysis to determine the nature and direction of waves during the cardiac cycle. The energy carried by an early systolic forward compression wave (S wave) generated by the left ventricle and responsible for acceleration of flow in systole was significantly reduced in subjects with heart failure (P < 0.001), and the timing of the peak of this wave was delayed. In contrast, reflection of this wave was increased in subjects with heart failure (P < 0.001), but the timing of reflections with respect to the S wave was unchanged. The energy of an expansion wave generated by the heart in protodiastole was unaffected by heart failure. The carotid artery wave speed and the augmentation index did not significantly differ between subjects with heart failure compared with normal individuals. The ability of the left ventricle to generate a forward compression wave is markedly impaired in heart failure. Increased wave reflection serves to maintain systolic blood pressure but also places an additional load on cardiac function in heart failure. cardiac function; blood pressure doi:10.1152/ajpheart.01095.2006

In response to deprivation for fixed nitrogen, the filamentous cyanobacterium Anabaena sp. strain PCC 7120 provides a microoxic intracellular environment for nitrogen fixation through the differentiation of semiregularly spaced vegetative cells into specialized cells called heterocysts. The devH gene is induced during heterocyst development and encodes a product with characteristics of a trans-acting regulatory protein. A devH mutant forms morphologically distinguishable heterocysts but is [Fox.sup.-], incapable of nitrogen fixation in the presence of oxygen. We demonstrate that rearrangements of nitrogen fixation genes take place normally in the devH mutant and that it is [Fix.sup.+], i.e., has nitrogenase activity under anoxic conditions. The [Fox.sup.-] phenotype was shown by ultrastructural studies to be associated with the absence of the glycolipid layer of the heterocyst envelope. The expression of glycolipid biosynthetic genes in the mutant is greatly reduced, and heterocyst glycolipids are undetectable.

Research has been conducted on the devH gene in Anabaena sp. strain PCC 7120. Results indicate that devH mutant nitrogen starvation can induce wild-type morphology heterocysts.

Objective: Children with attention-deficit/hyperactivity disorder (ADHD) commonly exhibit impairments in their executive functions. Caregivers are primarily responsible for the daily management of their children's ADHD and executive functioning difficulties. Psychoeducation, a cornerstone of ADHD treatment, can empower caregivers by providing them the knowledge and resources they require to support their child with ADHD. This study examined the efficacy of a suite of six caregiver psychoeducation sessions delivered by a specialised ADHD service. Two of these sessions pertained to (i) Understanding ADHD and (ii) Executive Functioning in ADHD. The other four covered information around Family Self-Care and Stress Management, Social Connectedness and Communication, Sensory Processing and Self-Regulation in ADHD and, Medication. Participants and Methods: All sessions were delivered between May 2016 and July 2022, in 2 to 3-hour sessions each. Caregivers completed pre and post-session questionnaires, rating (i) their understanding of each of the topics, (ii) whether they identified effective strategies to help their child with ADHD meet their needs, and (iii) whether they improved their knowledge of resources they can access to assist with ADHD management. Altogether, 666 caregiver responses were collected across all sessions, 35% (n=234) of which were from the Understanding ADHD sessions and 4.2% (n = 28) from the Executive Functioning sessions. Results: Wilcoxon signed-rank tests with Bonferroni adjusted alpha level of 0.016 were conducted to examine each session's pre- and post-session responses. Results showed that the Understanding ADHD workshops impelled significant improvements in attendee-rated levels of topic understanding (z = -8.79, p <.001, r = -.41), strategies gained (z = -8.54, p <.001, r = -.40) and perceived resource accessibility (z = -6.40, p <.001, r = -.30). Attendees reported moderate to large improvements following the Executive Functioning in ADHD sessions, including in their topic understanding (z = -4.18, p <.001, r = -.57), strategies gained (z = -3.93, p <.001, r = -.54) and perceived resource accessibility (z = -4.23, p <.001, r = -.61). Improvements across all three areas were also noted across the other four caregiver sessions, except for the medication session where no significant changes in strategies gained and perceived access to resources were noted. Conclusions: This study provides evidence that caregiver sessions within a Tier-4 service are efficacious and can (i) meet caregivers' needs to better understand ADHD, executive functioning difficulties as well as of other ADHD-related issues, and (ii) may equip caregivers with the knowledge to access resources to appropriately manage their children with ADHD - a possible precursor to improved clinical and functional outcomes in children. That the session on ADHD medications only led to improved understanding of the topic but not to perceived gains in strategies or perceived access to strategies could be attributed to low pre-and post-session questionnaire response rates as well as to the nature of those sessions which were purely informative and did not discuss strategies and resources. Nonetheless, longitudinal studies, with control groups, should determine whether any post-intervention improvements are sustained over time and should establish whether these are associated with improved outcomes in children. [ABSTRACT FROM AUTHOR]

Repair of transposition of the great arteries usually involves an atrial switch or arterial switch operation, which can complicate physiological adaptation to the demands of pregnancy and adversely affect the fetus. We retrospectively compared outcomes of 48 completed pregnancies in 23 women with surgically corrected transposition of the great arteries (38 atrial switch/10 arterial switch operation) under joint cardiac-obstetric care in our tertiary referral clinic between 1997 and 2017. Most women delivered vaginally (85%). The pre-term delivery rate was high (atrial switch 39%; arterial switch operation 40%). Small for gestational age occurred in 56% of babies, significantly more in the atrial switch group (66%) than arterial switch operation (20%), p = 0.013. Women with surgically corrected transposition of the great arteries wishing to become pregnant are at high risk of obstetric complications, primarily pre-term delivery and small for gestational age baby. They require more careful ultrasound surveillance beyond 36 weeks' gestation and/or may benefit from early induction of labour. Trial registration : Text/Not applicable. [ABSTRACT FROM AUTHOR]

Background Ebstein's anomaly (EA) is mainly thought of as a right heart condition, however, congenital left-sided lesions can co-exist. Therefore, it is paramount to include the left side of the heart as part of a routine investigation in these patients. We present a 57-year-old symptomatic patient with EA and progressive tricuspid regurgitation (TR) associated with acquired left ventricular outflow obstruction (LVOTO). Case summary A 57-year-old women, known to have severe EA presented with shortness of breath and chest pain on exertion secondary to progression of the tricuspid valve regurgitation and right ventricle dilatation leading to a dynamic compression of the left outflow tract requiring surgical intervention. Discussion Left ventricular obstruction secondary to severe TR and dilation of the right ventricle can present and remain silent at rest but becoming significant on exertion. Therefore, we recommend that all patients with EA and significant TR undergo exercise echocardiography at regular intervals to specifically look for acquired dynamic LVOTO. [ABSTRACT FROM AUTHOR]

Background: Pregnancy outcomes in women with pre-existing coronary artery disease (CAD) are poorly described. There is a paucity of data therefore on which to base clinical management to counsel women, with regard to both maternal and neonatal outcomes.Method: We conducted a retrospective multicentre study of women with established CAD delivering at 16 UK specialised cardiac obstetric clinics. We included pregnancies of 24 weeks' gestation or more, delivered between January 1998 and October 2018. Data were collected on maternal cardiovascular, obstetric and neonatal events.Results: 79 women who had 92 pregnancies (94 babies including two sets of twins) were identified. 35.9% had body mass index >30% and 24.3% were current smokers. 18/79 (22.8%) had prior diabetes, 27/79 (34.2%) had dyslipidaemia and 21/79 (26.2%) had hypertension. The underlying CAD was due to atherosclerosis in 52/79 (65.8%), spontaneous coronary artery dissection (SCAD) in 11/79 (13.9%), coronary artery spasm in 7/79 (8.9%) and thrombus in 9/79 (11.4%).There were six adverse cardiac events (6.6% event rate), one non-ST elevation myocardial infarction at 23 weeks' gestation, two SCAD recurrences (one at 26 weeks' gestation and one at 9 weeks' postpartum), one symptomatic deterioration in left ventricular function and two women with worsening angina. 14% of women developed pre-eclampsia, 25% delivered preterm and 25% of infants were born small for gestational age.Conclusion: Women with established CAD have relatively low rates of adverse cardiac events in pregnancy. Rates of adverse obstetric and neonatal events are greater, highlighting the importance of multidisciplinary care. [ABSTRACT FROM AUTHOR]

The distributions of genetic and phenotypic variation for two Yellowstone National Park populations of the heterocyst-forming cyanobacterium Mastigocladus laminosus that exhibit dramatic phenotypic differences as a result of environmental differences in nitrogen availability are investigated. Population genetic model suggest that local adaptation is mutation limited but also that the populations are expected to continue to diverge due to low migratory gene flow.