Cardiac Substrate Utilization and Relationship to Invasive Exercise Hemodynamic Parameters in HFpEF.

The authors conducted transcardiac blood sampling in healthy subjects and subjects with heart failure with preserved ejection fraction (HFpEF) to compare cardiac metabolite and lipid substrate use. We demonstrate that fatty acids are less used by HFpEF hearts and that lipid extraction is influenced by hemodynamic factors including pulmonary pressures and cardiac index. The release of many products of protein catabolism is apparent in HFpEF compared to healthy myocardium. In subgroup analyses, differences in energy substrate use between female and male hearts were identified.

Agricultural and urban practices are correlated to changes in the resistome of riverine systems.

The objective of this study was to comprehensively characterise the resistome, the collective set of antimicrobial resistance genes in a given environment, of two rivers, from their source to discharge into the sea, as these flow through areas of different land use. Our findings reveal significant differences in the riverine resistome composition in areas of different land uses, with increased abundance and diversity of AMR in downstream agricultural and urban locations, with the resistome in urban areas more similar to the resistome in wastewater. The changes in resistome were accompanied by changes in microbial communities, with a reduction in microbial diversity in downstream agricultural and urban affected areas, driven mostly by increased relative abundance in the phyla, Bacteroidetes and Proteobacteria. These results provide insight into how pollution associated with agricultural and urban activities affects microbial communities and influences AMR in aquatic water bodies. These results add valuable insights to form effective strategies for mitigating and preserving aquatic ecosystems. Overall, our study highlights the critical role of the environment in the development and dissemination of AMR and underscores the importance of adopting a One Health approach to address this global public health threat.

Hippocampal resting-state connectivity is associated with posterior-cortical cognitive impairment in Parkinson's disease.

AIM: Frontal and posterior-cortical cognitive subtypes in Parkinson's disease (PD) present with executive/attention and memory/visuospatial deficits, respectively. As the posterior-cortical subtype is predicted to progress rapidly toward dementia, the present study aimed to explore biological markers of this group using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: K-means cluster analysis delineated subtypes (cognitively intact, frontal, posterior-cortical, and globally impaired) among 85 people with PD. A subset of PD participants (N = 42) and 20 healthy controls (HCs) underwent rs-fMRI. Connectivity of bilateral hippocampi with regions of interest was compared between posterior-cortical, cognitively intact, and HC participants using seed-based analysis, controlling for age. Exploratory correlations were performed between areas of interest from the group analysis and a series of cognitive tests. RESULTS: The posterior-cortical subtype (N = 19) showed weaker connectivity between the left hippocampus and right anterior temporal fusiform cortex compared to the cognitively intact (N = 11) group, p-false discovery rate (FDR) = .01, and weaker connectivity between bilateral hippocampi and most fusiform regions compared to HCs (N = 20). No differences were found between HCs and cognitively intact PD. Exploratory analyses revealed strongest associations between connectivity of the right anterior temporal fusiform cortex and left hippocampus with category fluency (p-FDR = .01). CONCLUSION: Results suggest that weakened connectivity between the hippocampus and fusiform region is a unique characteristic of posterior-cortical cognitive deficits in PD. Further exploration of hippocampal and fusiform functional integrity as a marker of cognitive decline in PD is warranted.

Bacterial proximity effects on the transfer of antibiotic resistance genes within the alimentary tract of yellow mealworm larvae.

The arthropod intestinal tract and other anatomical parts naturally carry microorganisms. Some of which are pathogens, secrete toxins, or carry transferable antibiotic-resistance genes. The risks associated with the production and consumption of edible arthropods are dependent on indigenous microbes, as well as microbes introduced during the processes of rearing. This mass arthropod production puts individual arthropods in close proximity, which increases the possibility of their exposure to antibiotic-resistant bacteria carried by bacteria from fellow insects, industry workers, or rearing hardware and substrates. The purpose of this study was to determine if the alimentary tract of the yellow mealworm provided an environment permitting horizontal gene transfer between bacteria. The effect of the concentration of bacterial exposure was also assessed. Antibiotic resistance gene transfer between marker Salmonella Lignières (Enterobacterales: Enterobacteriaceae) and Escherichia coli (Migula) (Enterobacterales: Enterobacteriaceae) introduced into the larval gut demonstrated that the nutrient-rich environment of the yellow mealworm gut provided favorable conditions for the transfer of antibiotic resistance genes. Conjugation frequencies were similar across inoculum concentrations; however, transconjugant production correlated positively to increased exposure concentration. The lowest concentration of bacterial exposure required enrichment to detect and thus may have been approaching a threshold level for the 2 bacteria to colocate within the expanse of the larval gut. While many factors can affect this transfer, the simple factor of the proximity of donor and recipient bacteria, as defined by the concentration of bacteria within the volume of the insect gut, likely primarily contributed to the efficiency of antibiotic gene transfer.

A biologging database of mobulid rays from the Gulf of California, Mexico.

We initiated a tagging program in 2004 to determine the large-scale and long-term movement patterns of three species of Mobulid Ray (Mobula mobular, M. munkiana, M. thurstoni). Between 2004 and 2014 we deployed 48 pop-up archival (PAT) tags that recorded temperature, pressure, and light level. Pressure and light level records were then used to calculate animal depth and geolocation. Transmitted and when available recovered raw data files from successful deployments (n = 45) were auto-ingested from the manufacturer into the United States Animal Telemetry Network's (ATN) Data Assembly Center (DAC). Through the ATN DAC, all necessary metadata were compiled, dataset was prepped for release, and derived geolocation trajectories (n = 43) were visualized within their public facing data portal. These data and the full metadata records are available for download from the ATN portal as well as permanently archived under the DataONE Research Workspace member node.

Feasibility and Acceptability of a Videoconferencing CBT Intervention for Anxiety in People with Parkinson's Disease.

OBJECTIVES: In people with Parkinson's disease (PwPD), non-motor symptoms such as anxiety are common and have negative impacts on their quality of life. There are currently few interventions that address anxiety in PwPD, and access to diagnosis and treatment is often limited for those living in rural areas. The aim of this study was to evaluate the feasibility and acceptability of a telehealth videoconferencing CBT intervention for anxiety in PwPD. METHODS: A pre- and post-test feasibility study (N = 10) was conducted and evaluated utilizing the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, and Maintenance). RESULTS: Lack of access to the internet and videoconferencing technology were identified as barriers to participation. Physical health issues also impacted recruitment and retention. Non-completers were significantly older and less likely to have a carer involved in the intervention. Clinician adoption of the intervention was low while participant acceptability of videoconferencing technology varied and required carer support. CONCLUSIONS: Providing access to technology and support to overcome technological issues, as well as telehealth training for clinicians, are recommended in future studies to improve recruitment, retention, and implementation. CLINICAL IMPLICATIONS: Identification of barriers and facilitators provides future studies with the knowledge to tailorize their program to better suit PwPD.

A physiotherapy group exercise and self-management approach to improve physical activity in people with mild-moderate Parkinson's disease: a randomized controlled trial.

BACKGROUND: Physical activity levels are low in people with Parkinson's disease (PD) and have proved difficult to increase with exercise programs alone. Intervention approaches that address both the capacity to engage in physical activity and self-management strategies to change and maintain exercise behaviours are needed to address this intractable issue. METHODS: This will be an assessor-blinded, randomized controlled trial performed in Brisbane, Australia. Ninety-two people with mild-moderate PD will be randomly allocated to two groups: usual care, and a physiotherapy-led group exercise program combined with self-management strategies. In the intervention group, twelve, 80-min sessions will be conducted over 4 weeks in groups of up to 4 participants. The intervention will consist of circuit training including treadmill walking to target aerobic fitness, and activities targeting strength, balance, and gait performance. In addition, each session will also incorporate strategies focusing on self-management and behaviour change, augmented by the provision of a fitness activity tracker. Outcome measures will be collected at baseline (T1), immediately post intervention (T2) and at 6 months follow-up (T3). The primary outcome measure is free-living physical activity (average daily step count over 7 days) at pre (T1) and post (T2) intervention measured using an activPAL™ device. Secondary outcome measures captured at all time points include time spent walking, sedentary and in moderate intensity exercise over 7 days; spatiotemporal gait performance (step length, gait speed, endurance); health-related quality of life; and outcome expectations and self-efficacy for exercise. DISCUSSION: Sustainability of gains in physical activity following exercise interventions is a challenge for most populations. Our incorporation of a chronic disease self-management approach into the exercise program including fitness tracking extends previous trials and has potential to significantly improve free-living physical activity in people with PD. TRIAL REGISTRATION: This study has been prospectively registered in Australian and New Zealand Clinical Trial Registry (ACTRN12617001057370), registered on 19/07/2017. Available from www.anzctr.org.au/ACTRN12617001057370.aspx .

Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult. METHODS: Metabolomic analyses in a mouse model of HFpEF showed that levels of indole-3-propionic acid (IPA), a metabolite produced by gut bacteria from tryptophan, were reduced in the plasma and heart tissue of HFpEF mice as compared with controls. We then examined the role of IPA in mouse models of HFpEF as well as 2 human HFpEF cohorts. RESULTS: The protective role and therapeutic effects of IPA were confirmed in mouse models of HFpEF using IPA dietary supplementation. IPA attenuated diastolic dysfunction, metabolic remodeling, oxidative stress, inflammation, gut microbiota dysbiosis, and intestinal epithelial barrier damage. In the heart, IPA suppressed the expression of NNMT (nicotinamide N-methyl transferase), restored nicotinamide, NAD+/NADH, and SIRT3 (sirtuin 3) levels. IPA mediates the protective effects on diastolic dysfunction, at least in part, by promoting the expression of SIRT3. SIRT3 regulation was mediated by IPA binding to the aryl hydrocarbon receptor, as Sirt3 knockdown diminished the effects of IPA on diastolic dysfunction in vivo. The role of the nicotinamide adenine dinucleotide circuit in HFpEF was further confirmed by nicotinamide supplementation, Nnmt knockdown, and Nnmt overexpression in vivo. IPA levels were significantly reduced in patients with HFpEF in 2 independent human cohorts, consistent with a protective function in humans, as well as mice. CONCLUSIONS: Our findings reveal that IPA protects against diastolic dysfunction in HFpEF by enhancing the nicotinamide adenine dinucleotide salvage pathway, suggesting the possibility of therapeutic management by either altering the gut microbiome composition or supplementing the diet with IPA.

Factors affecting successful prosthetic use after hemipelvectomy and hip disarticulation amputations: Five-year experience from a tertiary prosthetic rehabilitation center.

BACKGROUND: Rehabilitation after hip disarticulation and hemipelvectomy amputations can be challenging, and many opt to forego prosthetic limb use. There is limited evidence on characteristics that result in successful prosthetic use; therefore, our study aimed to identify these to help guide patient expectations. METHODS: A retrospective review was performed on patients seen at a UK tertiary prosthetic center in the past 5 years with hip disarticulation or hemipelvectomy amputations. Details and etiology of amputation, length between assessment and delivery of prosthesis, goals, reasons for abandonment, and outcomes were recorded. Successful prosthetic use was defined as the use of a prosthesis at least 3 times a week. Characteristics were compared using odds ratios and Fisher exact test. RESULTS: Twenty-seven patient notes were analyzed: 42% female, 58% male, and age range 14-90. Thirty percent had a hemipelvectomy, and 70% had a hip disarticulation. Neoplasia accounted for 78% of etiologies followed by trauma 15% and infected endoprosthesis 7%. Sixty-seven percent trialed a walking prosthesis; 33% of these stopped eventually. There were no statistically significant findings of factors increasing odds of successful prosthetic use. However, age significantly increased the odds of being given a trial of a prosthesis. CONCLUSION: Although younger patients are more likely to be given the opportunity to trial a walking prosthesis, age does not seem to affect the overall outcome alone. In cases of neoplasia, there is often a delayed start to rehabilitation and prosthetic use, which may affect eventual success. Further studies are required to define the optimum characteristics for successful prosthetic use at higher amputation levels.

Lessons learnt in the first year of an Australian pediatric cardio oncology clinic.

BACKGROUND: Modern oncological therapies together with chemotherapy and radiotherapy have broadened the agents that can cause cardiac sequelae, which can manifest for pediatric oncology patients while on active treatment. Recommendations for high-risk patients who should be monitored in a pediatric cardio-oncology clinic have previously been developed by expert Delphi consensus by our group. In 2022 we opened our first multidisciplinary pediatric cardio-oncology clinic adhering to these recommendations in surveillance and management. OBJECTIVES: Our pediatric cardio-oncology clinic aimed to: (i) Document cardiovascular toxicities observed within a pediatric cardio-oncology clinic and. (ii) Evaluate the applicability of the Australian and New Zealand Pediatric Cardio-Oncology recommendations. METHODS: Monthly multidisciplinary cardio-oncology clinics were conducted in an Australian tertiary pediatric hospital. Structured standardised approaches to assessment were built into the electronic medical record (EMR). All patients underwent baseline echocardiogram and electrocardiogram assessment together with vital signs in conjunction with standard history and examination. RESULTS: Nineteen (54%) individuals had a documented cardiovascular toxicity or pre-existing risk factor prior to referral. The two most common cardiovascular toxicities documented during clinic review included Left Ventricular Dysfunction (LVD) and hypertension. Of note 3 (8.1%) patients had CTCAE grade III LVD. An additional 10 (27%) patients reviewed in clinic had CTCAE grade I hypertension. None of these patients had hypertension noted within their referral. Cascade testing for cardiac history was warranted in 2 (5.4%) of patients. CONCLUSIONS: Pediatric cardio-oncology clinics are likely beneficial to documenting previously unrecognised cardiotoxicity and relevant cardiac family histories, whilst providing an opportunity to address lifestyle risk factors.

The first human normative ranges and biomarker performance of dimethylguanidino valeric acid isoforms in fatty liver disease.

We have recently determined dimethylguanidino valeric acid (DMGV) to be a novel biomarker of liver injury in non-alcoholic fatty liver disease (NAFLD) and an independent predictor of incident diabetes over a decade in advance. DMGV consists of two stereo-isomers, asymmetric dimethylguanidino valeric acid (ADGV) and symmetric dimethylguanidino valeric acid (SDGV). Here we report, for the first time, the upper limits of normal of both isomers in humans at the accepted 5.56% liver fat threshold for NAFLD, determined using in vivo magnetic resonance spectroscopy. We performed independent and blinded comparative analyses of ADGV and SDGV levels using two different liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods in (A) our laboratory, and (B) the New South Wales Chemical Pathology state laboratory, using unique columns, LC-MS/MS equipment, extraction protocols and normalisation approaches. Despite these differences, each laboratory reported consistent absolute concentrations across a range of liver fat percentages. We next determined the diagnostic performance of SDGV compared to ADGV in a cohort of 268 individuals with liver fat measurements. In derivation-validation analyses we determined rule-in/rule-out thresholds and the concentration of SDGV that provides optimal performance across sensitivity and specificity for the identification of NAFLD. In conclusion, we have herein determined for the first time the true human plasma reference range of both isoforms of an emerging novel biomarker of NAFLD, at the accepted upper normal threshold of liver fat. We have also identified that SDGV is the isoform with the best diagnostic performance and determined the optimal cut-point for its detection of NAFLD.

Subacute Ulnar Nerve Compression Neuropathy Following Hand Crush Injury in the Setting of Intracanal Accessory Abductor Digiti Minimi: A Double Crush Phenomenon.

Anatomical variations within Guyon's canal such as an accessory abductor digiti minimi are described as causes of ulnar nerve compression. Here we present a unique case of delayed ulnar neuropathy following treatment of left fourth metacarpal base fracture with percutaneous pinning fixation and an uncomplicated two month postoperative course. He returned with new ulnar sensory loss and motor weakness. EMG demonstrated nerve compression with CT identifying an accessory abductor digiti minimi in Guyon's canal. Following Guyon's canal release with partial accessory muscle resection, there was immediate sensory and progressive motor recovery with resolution of clawing. Delayed compression by an accessory abductor digiti minimi following trauma has not been described, suggestive of double-crush phenomenon. The accessory muscle was an asymptomatic variable (first "crush") and with the second "crush" of post-surgical changes resulting in pathological nerve compression. With delayed onset ulnar neuropathy after trauma, surgeons should consider possible accessory structures.

Levetiracetam for the treatment of mild cognitive impairment in Parkinson's disease: a double-blind controlled proof-of-concept trial protocol.

BACKGROUND: Mild memory impairment, termed amnestic mild cognitive impairment (aMCI), is associated with rapid progression towards dementia in Parkinson's disease (PD). Studies have shown hyperactivation of hippocampal DG/CA3 subfields during an episodic memory task as a biomarker of aMCI related to Alzheimer's disease. This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target DG/CA3 hyperactivation and improve episodic memory deficits in aMCI in PD. Based on previous work, it is hypothesized that levetiracetam will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance. METHODS: Twenty-eight PD-aMCI participants, 28 PD participants without memory impairment (PD-nMI), and 28 healthy controls will be recruited. PD-aMCI participants will undertake a 12-week randomized, placebo-controlled, double-blind cross-over trial with a 14-day treatment of 125 mg levetiracetam or placebo twice daily, separated by a 4-week washout period. After each treatment period, participants will complete an episodic memory task designed to tax hippocampal subregion-specific function during high-resolution functional magnetic resonance imaging (fMRI). PD-nMI and healthy controls will undergo the fMRI protocol only, to compare baseline DG/CA3 subfield activity. RESULTS: Episodic memory task performance and functional activation in the DG/CA3 subfield during the fMRI task will be primary outcome measures. Global cognition, PD severity, and adverse events will be measured as secondary outcomes. Recruitment, eligibility, and study completion rates will be explored as feasibility outcomes. CONCLUSIONS: This study, the first of its kind, will establish hippocampal subregion functional impairment and proof of concept of levetiracetam as an early therapeutic option to reduce dementia risk in PD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04643327 . Registered on 25 November 2020.

Pareidolias are a function of visuoperceptual impairment.

Pareidolias, or the misperception of ambiguous stimuli as meaningful objects, are complex visual illusions thought to be phenomenologically similar to Visual Hallucination (VH). VH are a major predictor of dementia in Parkinson's Disease (PD) and are included as a core clinical feature in Dementia with Lewy Bodies (DLB). A newly developed Noise Pareidolia Test (NPT) was proposed as a possible surrogate marker for VH in DLB patients as increased pareidolic responses correlated with informant-corroborated accounts of VH. This association could, however, be mediated by visuoperceptual impairment. To understand the drivers of performance on the NPT, we contrasted performances in patient groups that varied both in terms of visuoperceptual ability and rates of VH. N = 43 patients were studied of whom n = 13 had DLB or PD with Dementia (PDD); n = 13 had PD; n = 12 had typical, memory-onset Alzheimer's Disease (tAD); and n = 5 had Posterior Cortical Atrophy (PCA) due to Alzheimer's disease. All patient groups reported pareidolias. Within the Lewy body disorders (PD, DLB, PDD), there was no significant difference in pareidolic response rates between hallucinating and non-hallucinating patients. Visuoperceptual deficits and pareidolic responses were most frequent in the PCA group-none of whom reported VH. Regression analyses in the entire patient cohort indicated that pareidolias were strongly predicted by visuoperceptual impairment but not by the presence of VH. These findings suggest that pareidolias reflect the underlying visuoperceptual impairment of Lewy body disorders, rather than being a direct marker for VH.

Evaluation of probiotic growth stimulation using prebiotic ingredients to optimize compounds for in ovo delivery.

The use of probiotics, prebiotics and synbiotics in poultry diets beneficially stimulates the gut microbiome thus promoting the health and welfare of the animals. In this study, we analyzed 7 poultry probiotics (Lactobacillus plantarum - B1 and B4, Lactobacillus rhamnosus - B3, Bifidobacterium lactis - B2, Carnobacterium divergens - B5, Propionibacterium thoenii - B6, Clostridium butyricum - B7) and 12 prebiotics, differing in chemical composition and source of origin (fungi, algae, animal, etc.). The main goal of our research was to select the most promising candidates to develop synbiotic combinations. We determined the growth kinetics of all probiotics in the presence of prebiotics in a series of in vitro studies to select optimal combinations. Five out of seven investigated probiotics were significantly stimulated by astragalus polysaccharide, and this prebiotic was characterized in our work as the most effective. Moreover, in the case of three probiotics, B2, B3 and B4, significant growth stimulation has been found when beta-glucan, vegetable protein hydrolysate and liquid seaweed extract were supplied. Strain B1 (L. plantarum) was stimulated by 6 out of 12 prebiotics. The growth of B4 (L. plantarum) and B2 (B. lactis) was enhanced by prebiotics after 2 h of incubation. A high growth rate of 3.13% was observed in the case of L. plantarum (B4) and a 3.37% higher rate for B. lactis (B3), compared to the growth of probiotics in the control medium with glucose but no prebiotics. The best candidates for synbiotic combinations based on this in vitro work are the strains belonging to L. plantarum (B4), L. rhamnosus (B3) and B. lactis (B2), consistent with prebiotics such as astragalus polysaccharides and vegetable protein hydrolysate. These combinations will be subject to future in vivo poultry trials involving the in ovo microbiome modulation.

Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors: JACC State-of-the-Art Review.

Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed.

An Evolutionarily Conserved Strategy for Ribosome Binding and Host Translation Inhibition by ß-coronavirus Non-structural Protein 1.

An important pathogenicity factor of SARS-CoV-2 and related coronaviruses is Non-structural protein 1 (Nsp1), which suppresses host gene expression and stunts antiviral signaling. SARS-CoV-2 Nsp1 binds the ribosome to inhibit translation through mRNA displacement and induces degradation of host mRNAs. Here we show that Nsp1-dependent host shutoff is conserved in diverse coronaviruses, but only Nsp1 from ß-Coronaviruses (ß-CoV) inhibits translation through ribosome binding. The C-terminal domain (CTD) of all ß-CoV Nsp1s confers high-affinity ribosome binding despite low sequence conservation. Modeling of interactions of four Nsp1s with the ribosome identified the few absolutely conserved amino acids that, together with an overall conservation in surface charge, form the ß-CoV Nsp1 ribosome-binding domain. Contrary to previous models, the Nsp1 ribosome-binding domain is an inefficient translation inhibitor. Instead, the Nsp1-CTD likely functions by recruiting Nsp1's N-terminal "effector" domain. Finally, we show that a cis-acting viral RNA element has co-evolved to fine-tune SARS-CoV-2 Nsp1 function, but does not provide similar protection against Nsp1 from related viruses. Together, our work provides new insight into the diversity and conservation of ribosome-dependent host-shutoff functions of Nsp1, knowledge that could aid future efforts in pharmacological targeting of Nsp1 from SARS-CoV-2 and related human-pathogenic ß-CoVs. Our study also exemplifies how comparing highly divergent Nsp1 variants can help to dissect the different modalities of this multi-functional viral protein.

Real-world treatment persistence of four commonly prescribed biologic therapies for moderate to severe psoriasis in Australia.

BACKGROUND/OBJECTIVES: Australian data comparing biologic treatments for moderate to severe chronic plaque psoriasis are lacking. We compared persistence on therapy across four biologic therapies (adalimumab, guselkumab, secukinumab and ustekinumab) used to treat chronic plaque psoriasis. The impact of prior biologic use on persistence was also investigated. METHODS: This retrospective cohort analysis of the Pharmaceutical Benefits Scheme (PBS) 10% sample included data from adult patients prescribed ≥1 biologic of interest by a dermatologist from 1 September 2015 to 31 December 2021. Persistence was defined as continued use until 180 days without a prescription. The index date was the date of the first claim of the biologic. Persistence was evaluated using Kaplan-Meier methods, log-rank tests, adjusted analyses using Cox's regressions, and propensity score matching. RESULTS: In total, 878 patients, with 1131 index prescriptions, were included. Guselkumab median persistence was not reached in the study period (PBS listed from February 2019). In the adjusted analysis, persistence to guselkumab was significantly greater than to adalimumab (n = 105; median 16 months, HR 2.71 (95% CI 1.94-3.8), p < 0.001), ustekinumab (n = 336; median 19 months, HR 2.91 (95% CI 2.22-3.82), p < 0.001) and secukinumab (n = 305; median 30 months, HR 1.8 (95% CI 1.36-2.38), p < 0.001). Bio-naïve patients had longer persistence on treatment than bio-experienced patients. CONCLUSIONS: The nationally representative PBS dataset can provide real-world insights into the persistence on biologic therapies for psoriasis in Australia, where eligibility criteria for reimbursed treatment are stringent. Persistence is an indirect marker of sustained treatment effectiveness and tolerability. Both unadjusted and adjusted analyses found longer persistence for guselkumab compared to adalimumab, secukinumab or ustekinumab.

Hemocyte-like cells in larvae of the freshwater snail Biomphalaria glabrata (Mollusca: Panpulmonata).

Despite undergoing development within a germfree egg capsule, embryos and larvae of the freshwater snail Biomphalaria glabrata possess passive immune protection in the form of parentally-derived antimicrobial proteins in the perivitelline fluid. However, the point at which larvae begin to form their own internal defense system (IDS), which consists of both plasma proteins and hemocytes, is not known. In this study, hemocyte-like cells were observed in mechanically-disrupted late trochophores and veligers of the BS-90 strain of B. glabrata. These cells showed the properties of glass adherence, spreading, motility, and binding and phagocytosing polystyrene microspheres. No hemocyte-like cells were recovered from the early trochophore stage, and therefore their formation first occurs during subsequent maturation. Numbers of hemocyte-like cells increased during larval development. Although the functional significance of these cells is not known, they may represent the initial cellular component of the IDS.

Longitudinal follow up of data-driven cognitive subtypes in Parkinson's disease.

AIM: The dual syndrome hypothesis proposes that there are two cognitive subtypes in Parkinson's disease (PD): a frontal subtype with executive/attention impairment and gradual cognitive decline, and a posterior-cortical subtype with memory/visuospatial deficits and rapid cognitive decline. We aimed to compare the rate of global cognitive decline between subtypes derived using data-driven methods and explore their longitudinal performance within specific cognitive domains to better understand the prognosis of each subtype. METHOD: Frontal, posterior-cortical, globally impaired, and cognitively intact PD subtypes were identified at baseline using k-means clustering (N = 85), and 29 participants (34%) returned for follow-up assessments on average 4.87 years from baseline. Linear mixed effects models compared progression of subtypes on global cognition; psychological symptoms; parkinsonism; and the memory, attention, executive, language, and visuospatial cognitive domains. RESULTS: The frontal subtype was lost to attrition. While rate of change in parkinsonism, anxiety, and apathy differed between subtypes, there was no difference in the rate of global cognitive decline. However, the posterior-cortical subtype declined most rapidly in verbal memory, card sorting, trail making, and judgement of line orientation (JLO), while the cognitively intact group declined most rapidly on verbal memory and semantic fluency. The globally impaired subtype declined most rapidly in JLO, although this should be interpreted with caution due to high attrition. CONCLUSION: Despite limited sample size, the present study supports the differential progression of the posterior-cortical subtype compared to cognitively intact and globally impaired PD. These results encourage further, large-scale longitudinal investigations of cognitive subtypes in PD.