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Loss-of-function heterozygous mutations in GRN, the gene encoding progranulin (PGRN), were identified in patients with frontotemporal lobar degeneration (FTLD) almost two decades ago and are generally linked to reduced PGRN protein expression levels. Although initial characterization of PGRN function primarily focused on its role in extracellular signaling as a secreted protein, more recent studies revealed critical roles of PGRN in regulating lysosome function, including proteolysis and lipid degradation, consistent with its lysosomal localization. Emerging from these studies is the notion that PGRN regulates glucocerebrosidase activity via direct chaperone activities and via interaction with prosaposin (i.e., a key regulator of lysosomal sphingolipid-metabolizing enzymes), as well as with the anionic phospholipid bis(monoacylglycero)phosphate. This emerging lysosomal biology of PGRN identified novel and promising opportunities in therapeutic discovery as well as biomarker development.

Prescription opioid use in Australia has increased over the last 3 decades. The majority of opioids are prescribed and dispensed in primary care, however, there are few studies that are specific to opioid prescribing in this setting. Evidence about the impact of key government policy strategies to optimize opioid prescribing in primary care is limited. The aim of this study is to examine the impact of recent policy changes and clinical guidelines on opioid prescribing in primary care.Longitudinal analysis of people prescribed opioid analgesics using Population Level Analysis and Reporting (POLAR) data. POLAR is a primary care dataset comprising 464 primary health care practices in Victoria, Australia. People prescribed opioid analgesics between 2015 and 2020 will be included. The impact of opioid policies and guideline recommendations will be evaluated using interrupted time series models. Group- based trajectory modelling and multivariate regression will be used to identify patterns of opioid cessation and the provision of corresponding non-opioid interventions.The study has received Monash University Human Research Ethics Committee approval (ID 24139). Permission to access, collate and use POLAR data is granted from Outcome Health as the data custodians. The results of this study will be disseminated through publication in international journals, presented at national and international scientific conferences, and disseminated to consumers, policy makers, primary care providers and primary health networks.EU PAS Register (EUPAS43218).

BACKGROUND: In pulmonary arterial hypertension (PAH), there are no data comparing initial triple oral therapy with initial double oral therapy. OBJECTIVES: TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension; NCT02558231), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH. METHODS: Efficacy was assessed until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week26. RESULTS: Patients were assigned to initial triple (n=123) or initial double therapy (n=124). At week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval: 0.86-1.07; P=0.42). Six-minute walk distance and N-terminal pro-brain natriuretic peptide improved by week 26, with no difference between groups. Risk for disease progression (to end of main observation period) was reduced with initial triple versus initial double therapy (hazard ratio: 0.59; 95% confidence interval: 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, 2 patients in the initial triple and 9 in the initial double therapy groups had died. CONCLUSIONS: In patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). Exploratory analyses suggested a possible signal for improved long-term outcomes with initial triple versus initial double oral therapy.

Background: Little is known about changes in pro re nata (PRN) medication prescribing and administration in residential aged care facilities (RACFs) over time. Objective: To determine the prevalence and factors associated with PRN medication administration in RACFs and examine changes over 12-months. Methods: Secondary analyses utilizing data from the SIMPLER randomized controlled trial (n = 242 residents, 8 RACFs) was undertaken. PRN medication data were extracted from RACF medication charts. Factors associated with PRN medication administration in the preceding week were explored using multivariable logistic regression. Results: At baseline, 211 residents (87.2%) were prescribed ≥1 PRN medication, with 77 (36.5%) administered PRN medication in the preceding week. PRN administration was more likely in non-metropolitan areas, and less likely among residents with more severe dementia symptoms and greater dependence with activities of daily living. No significant differences in overall PRN prescribing or administration in 162 residents alive at 12-month follow-up were observed. Conclusions: Despite being frequently prescribed, the contribution of PRNs to overall medication use in RACFs is small. PRN prescribing and administration was relatively static over 12-months despite likely changes in resident health status over this period, suggesting further exploration of PRN prescribing in relation to resident care needs may be warranted. Refereed/Peer-reviewed

Background & Aims: Necrotizing enterocolitis (NEC) is a life-threatening disease, and the most common gastrointestinal emergency in premature infants. Accurate early diagnosis is challenging. Modified Bell’s staging is routinely used to guide diagnosis, but early diagnostic signs are non-specific, potentially leading to unobserved disease progression, which is problematic given the often rapid deterioration observed. We investigated faecal cytokine levels, coupled with gut microbiota profiles, as a non-invasive method to discover specific NEC-associated signatures that can be applied as potential diagnostic markers. Methods: Premature babies born below 32 weeks of gestation were admitted to the 2-site neonatal intensive care unit (NICU) of Imperial College hospitals (St. Mary’s or Queen Charlotte’s & Chelsea) between January 2011 and December 2012. During the NICU stay, expert neonatologist grouped individuals by modified Bell’s staging (healthy, NEC1, NEC2/3) and faecal samples from diapers were collected consecutively. Microbiota profiles were assessed by 16S rRNA gene amplicon sequencing and cytokine concentrations were measured by V-Plex multiplex assays. Results: Early evaluation of microbiota profiles revealed only minor differences. However, at later time points, significant changes in microbiota structure were observed for Bacillota (adj. p=0.0396), with Enterococcus being the least abundant in Bell stage 2/3 NEC. Evaluation of faecal cytokine levels revealed significantly higher concentrations of IL-1α (p=0.045), IL-5 (p=0.0074), and IL-10 (p=0.032) in Bell stage 1 NEC compared to healthy individuals. Conclusions: Differences in certain faecal cytokine profiles in patients with NEC indicate their potential use as diagnostic biomarkers to facilitate earlier diagnosis. Additionally, associations between microbial and cytokine profiles contribute to improving knowledge about NEC pathogenesis.

Inflammation is closely associated with many neurodegenerative disorders. Yet whether inflammation causes or exacerbates neurodegeneration has been challenging to define because the two processes are so closely linked. Here we disentangle inflammation from the axon damage it causes by individually blocking cytotoxic T cell function and axon degeneration. We model inflammatory damage in mouse skin, a barrier tissue that, despite frequent inflammation, must maintain proper functioning of a dense array of axon terminals. We show that sympathetic axons control skin inflammation through release of norepinephrine, which suppresses activation of gamma delta T cells via the β2 adrenergic receptor. Strong inflammatory stimulation in the form of the toll like receptor 7 (TLR7) agonist imiquimod (IMQ) causes progressive gamma delta T cell-mediated, Sarm-1-dependent loss of these immunosuppressive sympathetic axons, a positive feedback loop that removes a physiological brake on T cells, resulting in enhanced inflammation and inflammatory axon damage.

Frailty is a geriatric condition associated with increased vulnerability to adverse drug events and medication-related harm. Existing clinical practice guidelines rarely provide medication management recommendations specific to frail older people. This report presents international consensus principles, generated by the Optimizing Geriatric Pharmacotherapy through Pharmacoepidemiology Network, related to medication management in frail older people. This consensus comprises 7 principles for clinical practice, 6 principles for research, and 4 principles for education. Principles for clinical practice include (1) perform medication reconciliation and maintain an up-to-date medication list; (2) assess and plan based on individual's capacity to self-manage medications; (3) ensure appropriate prescribing and deprescribing; (4) simplify medication regimens when appropriate to reduce unnecessary burden; (5) be alert to the contribution of medications to geriatric syndromes; (6) regularly review medication regimens to align with changing goals of care; and (7) facilitate multidisciplinary communication among patients, caregivers, and healthcare teams. Principles for research include (1) include frail older people in randomized controlled trials; (2) consider frailty status as an effect modifier; (3) ensure collection and reporting of outcome measures important in frailty; (4) assess impact of frailty on pharmacokinetics and pharmacodynamics; (5) encourage frailty research in under-researched settings; and (6) utilize routinely collected linked health data. Principles for education include (1) provide undergraduate and postgraduate education on frailty; (2) minimize low-value care related to medication management; (3) improve health and medication literacy; and (4) incorporate evidence in relation to frailty into clinical practice guidelines. These principles for clinical practice, research and education highlight different considerations for optimizing medication management in frail older people. These principles can be used in conjunction with existing best practice guidelines to help achieve optimal health outcomes for this vulnerable population. Implementation of the principles will require multidisciplinary collaboration between healthcare professionals, researchers, educators, organizational leaders, and policymakers Refereed/Peer-reviewed

Background Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. Research Question Which factors determine the outcome of PH in COPD? Study Design and Methods We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). Results The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. Interpretation Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. Trial Registry ClinicalTrials.gov; No.: NCT01347216 ; URL: www.clinicaltrials.gov

BACKGROUND: Statins are associated with muscle-related adverse events, but few studies have investigated the association with fall-related hospitalizations among residents of long-term care facilities(LTCFs). OBJECTIVE: The objective of the study is to investigate whether statin use is associated with fall related hospitalizations from LTCFs. METHODS: A case-control study was conducted among residents aged $65 years admitted to hospital from 2013 to 2015. Cases (n 5 332) were residents admitted for falls and fall-related injuries.Controls (n 5 332) were selected from patients admitted for reasons other than cardiovascular and diabetes.Cases and controls were matched 1:1 by age (62 years), index date of admission (66 months),and sex. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression, after considering for history of falls, hypertension, dementia, functional comorbidity index, polypharmacy ($9 regular preadmission medications), and fall-risk medications. Subanalyses were performed for individual statins, dementia, and statin intensity. RESULTS: Overall, 43.1% of cases and 27.1% of controls used statins. Statins were associated with fall-related hospitalizations (aOR 5 2.24, 95% CI 1.56–3.23), in particular simvastatin (aOR 5 2.26, 95% CI 1.22–4.20) and atorvastatin (aOR 5 2.08, 95% CI 1.33–3.24). Statins were associated with fall-related hospitalizations in residents with (aOR 5 2.34, 95% CI 1.33–4.11) and without dementia (aOR 5 2.30, 95% CI 1.46–3.63). There was no association between statin intensity and fall-related hospitalizations (aOR 5 0.78, 95% CI 0.43–1.40). CONCLUSION: This study suggests a possible association between statin use and fall-related hospitalizations among residents living in LTCFs. However, there was minimal evidence for a relationship between statin intensity and fall-related hospitalizations. Further research is required to substantiate these hypothesis-generating findings. Refereed/Peer-reviewed

COVID-19 restrictions may have an unintended consequence of limiting access to cardiovascular care. Australia implemented adaptive interventions (e.g. telehealth consultations, digital image prescriptions, continued dispensing, medication delivery) to maintain medication access. This study investigated whether COVID-19 restrictions in different jurisdictions coincided with changes in statin incidence, prevalence and adherence.Analysis of a 10% random sample of national medication claims data from January 2018 to December 2020 was conducted across three Australian jurisdictions. Weekly incidence and prevalence were estimated by dividing the number statin initiations and any statin dispensing by the Australian population aged 18-99 years. Statin adherence was analysed across the jurisdictions and years, with adherence categorised as40%, 40-79% and ≥80% based on dispensings per calendar year.Overall, 309,123, 315,703 and 324,906 people were dispensed and 39029, 39816, and 44979 initiated statins in 2018, 2019 and 2020 respectively. Two waves of COVID-19 restrictions in 2020 coincided with no meaningful change in statin incidence or prevalence per week when compared to 2018 and 2019. Incidence increased 0.3% from 23.7 to 26.2 per 1000 people across jurisdictions in 2020 compared to 2019. Prevalence increased 0.14% from 158.5 to 159.9 per 1000 people across jurisdictions in 2020 compared to 2019. The proportion of adults with ≥80% adherence increased by 3.3% in Victoria, 1.4% in NSW and 1.8% in other states and territories between 2019 and 2020.COVID-19 restrictions did not coincide with meaningful changes in the incidence, prevalence or adherence to statins suggesting adaptive interventions succeeded in maintaining access to cardiovascular medications.

Background After a dementia diagnosis, goals of care are often reassessed, including the use of preventive medications like statins. Objective To examine changes in statin use after initiating medication for managing dementia. Methods A case-crossover study utilizing medication dispensing data from the Australian Pharmaceutical Benefits Scheme (PBS) 10% random sample was conducted. Use of statins was compared in the 12 months pre- and post-initiation (pre-period and post-period) of anti-dementia medications or risperidone for behavioural symptoms of dementia. Individuals aged ≥65 years who had their first dispensing of anti-dementia medication or risperidone between July 2006 and June 2017 and survived ≥12 months after their first supply were included. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for change in statin use in the discordant pairs. Results The cohort (n = 19,809) had a median age of 81 years and 61% were female. Statins were less likely to be used after initiating anti-dementia medication or risperidone (OR 0.50; 95%CI 0.45–0.55). The OR for statin use in the post-period versus the pre-period decreased annually over the 11 years from 1.21; 95%CI 0.84–1.75 in 2006–7 to 0.31; 95%CI 0.24–0.41 in 2016–17 (p for interaction Conclusion Statins are more likely to be ceased than started after initiating medication for dementia. This may reflect changes in goals of care, or changes in the interpretation of the available evidence for the safety and efficacy of statins in older people living with dementia.

Trauma to the neck poses a unique set of challenges owing to the presence of multiple important structures lying in close proximity to each other. A thorough understanding of the anatomy of the neck as well as having a step wise approach for timely evaluation and management, are crucial in identifying and managing neck injuries. Trauma to the neck can occur due to blunt or penetrating mechanisms. Though the injury patterns may differ, the initial management is similar and follows an algorithm based approach based on anatomic landmarks as well as patient stability. Various imaging and diagnostic modalities are available and are utilized in the prompt diagnosis of cerebrovascular and aerodigestive neck injuries.

PPARγ is a critical transcriptional regulator of adipogenesis and type 2 immune responses, however until recently its role in type 2 innate lymphoid cells had not been characterised. In two papers in this issue of Mucosal Immunology, PPARγ is shown to have a dominant role in ILC2 responses, mediating IL-33-responsiveness and activation.