Cortical and subcortical functional connectivity and cognitive impairment in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease with cognitive as well as motor impairments. While much is known about the brain networks leading to motor impairments in PD, less is known about the brain networks contributing to cognitive impairments. Here, we leveraged resting-state functional magnetic resonance imaging (rs-fMRI) data from the Parkinson's Progression Marker Initiative (PPMI) to examine network dysfunction in PD patients with cognitive impairment. We focus on canonical cortical networks linked to cognition, including the salience network (SAL), frontoparietal network (FPN), and default mode network (DMN), as well as a subcortical basal ganglia network (BGN). We used the Montreal Cognitive Assessment (MoCA) as a continuous index of coarse cognitive function in PD. In 82 PD patients, we found that lower MoCA scores were linked with lower intra-network connectivity of the FPN. We also found that lower MoCA scores were linked with lower inter-network connectivity between the SAL and the BGN, the SAL and the DMN, as well as the FPN and the DMN. These data elucidate the relationship of cortical and subcortical functional connectivity with cognitive impairments in PD.

Salience network and cognitive impairment in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease with cognitive as well as motor impairments. While much is known about the brain networks leading to motor impairments in PD, less is known about the brain networks contributing to cognitive impairments. Here, we leveraged resting-state functional magnetic resonance imaging (rs-fMRI) data from the Parkinson's Progression Marker Initiative (PPMI) to examine network dysfunction in PD patients with cognitive impairment. We tested the hypothesis that cognitive impairments in PD involve altered connectivity of the salience network (SN), a key cortical network that detects and integrates responses to salient stimuli. We used the Montreal Cognitive Assessment (MoCA) as a continuous index of coarse cognitive function in PD. We report two major results. First, in 82 PD patients we found significant relationships between lower intra-network connectivity of the frontoparietal network (FPN; comprising the dorsolateral prefrontal and posterior parietal cortices bilaterally) with lower MoCA scores. Second, we found significant relationships between lower inter-network connectivity between the SN and the basal ganglia network (BGN) and the default mode network (DMN) with lower MoCA scores. These data support our hypothesis about the SN and provide new insights into the brain networks contributing to cognitive impairments in PD.

What is the impact of a pre-hospital geriatrician led telephone 'Silver Triage' for older people living with frailty?

PURPOSE: Most older people are conveyed to hospital via ambulance, therefore presenting a focus to reduce hospitalisation. North Central London has introduced 'Silver Triage', a pre-hospital telephone support scheme where geriatricians support the London Ambulance Service with clinical decision-making. METHODS: Data from the first 14 months was analysed descriptively. RESULTS: There have been 452 Silver Triage cases (November 2021 to January 2023). 80% resulted in a decision to not convey. The mode clinical frailty scale (CFS) was 6. CFS did not influence conveyance rates. Prior to triage, paramedics thought hospitalisation was not required in 44% of cases (n = 72/165). All paramedics surveyed (n = 176) would use the service again. Most (66%, n = 108/164) felt they learnt something and 16% (n = 27/164) reported it changed their decision-making process. CONCLUSION: Silver Triage has the potential to improve the care of older people by preventing unnecessary hospitalisation and has been well received by paramedics.

Comparing methods to deposit Pd-In catalysts on hydrogen-permeable hollow-fiber membranes for nitrate reduction.

Catalytic hydrogenation of nitrate in water has been studied primarily using nanoparticle slurries with constant hydrogen-gas (H2) bubbling. Such slurry reactors are impractical in full-scale water treatment applications because 1) unattached catalysts are difficult to be recycled/reused and 2) gas bubbling is inefficient for delivering H2. Membrane Catalyst-film Reactors (MCfR) resolve these limitations by depositing nanocatalysts on the exterior of gas-permeable hollow-fiber membranes that deliver H2 directly to the catalyst-film. The goal of this study was to compare the technical feasibility and benefits of various methods for attaching bimetallic palladium/indium (Pd/In) nanocatalysts for nitrate reduction in water, and subsequently select the most effective method. Four Pd/In deposition methods were evaluated for effectiveness in achieving durable nanocatalyst immobilization on the membranes and repeatable nitrate-reduction activity: (1) In-Situ MCfR-H2, (2) In-Situ Flask-Synthesis, (3) Ex-Situ Aerosol Impaction-Driven Assembly, and (4) Ex-Situ Electrostatic. Although all four deposition methods achieved catalyst-films that reduced nitrate in solution (≥ 1.1 min-1gPd-1), three deposition methods resulted in significant palladium loss (>29%) and an accompanying decline in nitrate reactivity over time. In contrast, the In-Situ MCfR-H2 deposition method had negligible Pd loss and remained active for nitrate reduction over multiple operational cycles. Therefore, In-Situ MCfR-H2 emerged as the superior deposition method and can be utilized to optimize catalyst attachment, nitrate-reduction, and N2 selectivity in future studies with more complex water matrices, longer treatment cycles, and larger reactors.

Expert Consensus Panel Recommendations for Selection of the Optimal Supraglottic Airway Device for Inclusion to the Medic's Aid Bag.

INTRODUCTION: Airway obstruction is the second leading cause of potentially survivable death on the battlefield. The Committee on Tactical Combat Casualty Care (CoTCCC) has evolving recommendations for the optimal supraglottic airway (SGA) device for inclusion to the medics' aid bag. METHODS: We convened an expert consensus panel consisting of a mix of 8 prehospital specialists, emergency medicine experts, and experienced combat medics, with the intent to offer recommendations for optimal SGA selection. Prior to meeting, we independently reviewed previously published studies conducted by our study team, conducted a virtual meeting, and summarized the findings to the panel. The studies included an analysis of end-user after action reviews, a market analysis, engineering testing, and prospective feedback from combat medics. The panel members then made recommendations regarding their top 3 choices of devices including the options of military custom design. Simple descriptive statistics were used to analyze panel recommendations. RESULTS: The preponderance (7/8, 88%) of panel members recommended the gel-cuffed SGA, followed by the self-inflating-cuff SGA (5/8, 62%) and laryngeal tube SGA (5/8, 62%). Panel members expressed concerns primarily related to the (1) devices' tolerance for the military environment, and (2) ability to effectively secure the gel-cuffed SGA and the self-inflating-cuff SGA during transport. CONCLUSIONS: A preponderance of panel members selected the gel-cuff SGA with substantial feedback highlighting the need for military-specific customizations to support the combat environment needs.

Trust as a key measure of quality and safety after the restriction of family contact in Canadian long-term care settings during the COVID-19 pandemic.

Family caregivers in Canadian long-term care homes are estimated to provide 10 h per week of direct care to approximately 30% of residents through roles including mobility support, mealtime assistance, personal care, social interaction, psychological care, care coordination, and advocacy. Despite these contributions, they continue to be viewed as visitors rather than as key participants in the interdependent relationships that support the long-term care sector. Their marginalization was evident during the COVID-19 pandemic, as Canadian public health policy focused on preventing them from entering long-term care, rather than supporting personal risk management, symptom screening, personal protective equipment, and other mechanisms for safe involvement in care. Several iatrogenic resident outcomes have been attributed to this, including decreased cognitive function, decreased mobility, increased incontinence, weight loss, increased depression and anxiety, increased responsive behaviours amongst those living with dementia, and increased delirium. In this commentary article, we argue that family caregiver presence was conflated as a risk when instead, it contributed to unintended harm. We identify nine well-known human social cognitive predispositions that may have contributed to this. We then examine their implications for trust in long-term care, and consider how quality and safety can be further fostered in long-term care by working in partnership with family caregivers to rebuild trust through enquiry and collaboration. We advocate incorporating trust as an essential measure of quality health service.

Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy.

General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound 39 engages GCN2 at levels ≥80% with an oral dose of 15 mg/kg BID. We also demonstrate the ability of compound 39 to alleviate MDSC-related T cell suppression and restore T cell proliferation, similar to the effect seen in MDSCs from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI) as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced by treatment with compound 39 demonstrating the complementarity of these two mechanisms.

Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors.

The C-C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (Treg) as well as other circulating and tissue-resident T cells. Treg can be recruited to the tumor microenvironment (TME) through the C-C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the Treg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of Treg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein.

Survey of National Surgical Site Infection Surveillance Programs in Low- and Middle-Income Countries.

Background: Surgical site infection (SSI) surveillance programs are strongly recommended as a core component of effective national infection prevention and control (IPC) programs. Participation in national SSI surveillance (nSSIS) programs has been shown to decrease reported SSIs among high-income countries (HICs), and it is expected that the same is possible among low- and middle-income countries (LMICs). We sought to determine what, if any nSSIS programs exist among LMICs. Methods: A cross-sectional survey was performed to evaluate existence of nSSIS of World Bank-defined LMICs. A digital survey assessment for presence of national IPC and nSSIS programs was delivered to persons capable of identifying the presence of such a program. Statistical analysis was performed using STATA. Institutional Review Board approval was obtained for this study. Results: Of the 137 countries identified, 55 (40%) were upper middle income (UMI), 47 (34%) were lower middle income (LMI), and 34 (25%) were low income. Representatives from 39 (28%) LMICs completed the survey. Of these respondent countries, 13 (33%) reported the presence of a national IPC program. There was no difference between countries with IPC programs and those without with respect to country income designation, population size, World Health Organization region, or conflict status. Only five (13% of all respondents) reported presence of a nSSIS program. Conclusions: National surgical site infection surveillance programs are an integral component of a country's ability to provide safe surgical procedures. Presence of nSSIS was reported infrequently in LMICs. International governing bodies should be encouraged to guide LMIC leadership in establishing a nSSIS infrastructure that will help enable safe surgical procedures.

Regional differences in presence of Shiga toxin-producing Escherichia coli virulence-associated genes in the environment in the North West and East Anglian regions of England.

Shiga toxin-producing Escherichia coli is carried in the intestine of ruminant animals, and outbreaks have occurred after contact with ruminant animals or their environment. The presence of STEC virulence genes in the environment was investigated along recreational walking paths in the North West and East Anglia regions of England. In all, 720 boot sock samples from walkers' shoes were collected between April 2013 and July 2014. Multiplex PCR was used to detect E. coli based on the amplification of the uidA gene and investigate STEC-associated virulence genes eaeA, stx1 and stx2. The eaeA virulence gene was detected in 45·5% of the samples, where stx1 and/or stx2 was detected in 12·4% of samples. There was a difference between the two regions sampled, with the North West exhibiting a higher proportion of positive boot socks for stx compared to East Anglia. In univariate analysis, ground conditions, river flow and temperature were associated with positive boot socks. The detection of stx genes in the soil samples suggests that STEC is present in the English countryside and individuals may be at risk for infection after outdoor activities even if there is no direct contact with animals. SIGNIFICANCE AND IMPACT OF THE STUDY: Several outbreaks within the UK have highlighted the danger of contracting Shiga toxin-producing Escherichia coli from contact with areas recently vacated by livestock. This is more likely to occur for STEC infections compared to other zoonotic bacteria given the low infectious dose required. While studies have determined the prevalence of STEC within farms and petting zoos, determining the risk to individuals enjoying recreational outdoor activities that occur near where livestock may be present is less researched. This study describes the prevalence with which stx genes, indicative of STEC bacteria, were found in the environment in the English countryside.

Effects of a brief interpersonal conflict cognitive reappraisal intervention on improvements in access to emotion regulation strategies and depressive symptoms in college students.

Objective: Research has demonstrated relative success with brief interventions that utilize social psychological theory to target the root cause of unwanted behaviours. Given the intersections among anxious attachment, depression, and emotion dysregulation, the current research utilises an interpersonal conflict cognitive reappraisal intervention to evaluate improvements in depressive symptoms. We also evaluated mediation via improvements in emotion regulation and moderation by attachment anxiety. Design: Undergraduates (N = 260) completed a baseline assessment and were randomised to one of four writing conditions: An interpersonal conflict from (a) their own perspective; (b) the other party's perspective; or (c) a neutral, third-party perspective (primary experimental condition) or about their day (control condition). They also completed a follow-up survey online two weeks later. Main outcome measures included limited access to emotion regulation strategies and depressive symptoms. Results: Consistent with hypotheses, compared to control, participants who adopted the perspective of neutral third party reported improvements in access to emotion regulation strategies. There was also a significant indirect effect on depressive symptoms through changes in strategies. Finally, improving strategies led to a reduction in depressive symptoms, especially for those higher in attachment anxiety. Conclusion: We present promising emerging results for a single-session, conflict-focused, brief cognitive reappraisal intervention on changes in emotion regulation and depressive symptoms.

An agent-based model about the effects of fake news on a norovirus outbreak.

BACKGROUND: Concern about health misinformation is longstanding, especially on the Internet. METHODS: Using agent-based models, we considered the effects of such misinformation on a norovirus outbreak, and some methods for countering the possible impacts of "good" and "bad" health advice. The work explicitly models spread of physical disease and information (both online and offline) as two separate but interacting processes. The models have multiple stochastic elements; repeat model runs were made to identify parameter values that most consistently produced the desired target baseline scenario. Next, parameters were found that most consistently led to a scenario when outbreak severity was clearly made worse by circulating poor quality disease prevention advice. Strategies to counter "fake" health news were tested. RESULTS: Reducing bad advice to 30% of total information or making at least 30% of people fully resistant to believing in and sharing bad health advice were effective thresholds to counteract the negative impacts of bad advice during a norovirus outbreak. CONCLUSION: How feasible it is to achieve these targets within communication networks (online and offline) should be explored.

An in silico pipeline for subject-specific hemodynamics analysis in liver surgery planning.

The progresses in fast simulations of the hepatic flow in subject-specific vascular tree have created new toolkits for pre-surgical planning. The aim of this short communication is to introduce a computational pipeline that integrates several recently developed in silico liver models and algorithms. Firstly, a semi-automatic segmentation pipeline is used to digitise hepatic vessels. Then, a constructive constraint optimisation (CCO) algorithm is used to extend the digitised vascular tree, and also to compute the blood pressure and flow velocity in the tree. Couinaud segments are simulated from the diffusion zones of the portal venous tree. The constructed surgical planning model is then deployed cross-platform for use in various scenarios.

Computational simulations for the hepatic arterial buffer response after liver graft transplantation from an adult to a child.

Live donor liver transplantation (LDLT) is an important surgical technique for treating children with end-stage liver diseases. Surgical complications may occur, e.g., due to thrombosis formed in hepatic arteries (HAs) or portal veins (PVs). From the hepatic circulation point of view, a hepatic arterial buffer response (HABR) mechanism, where the HA flow counteracts the changes in the PV flow, could play a role in graft dysfunction, yet this intricate mechanism has not been elucidated in LDLT procedures. In this short communication we simulate the HABR which may occur in an adult-to-child LDLT, where the left lateral lobe of an adult donor is transplanted to a child. Using an electrical analog model we show that the HABR could be triggered in both portal hyper-perfusion and venous obstruction scenarios, and this may be associated with arterial and/or venous thrombosis in the liver graft as reported in clinical studies. In conclusion, HABR could be important in adult-to-child LDLT and it should be considered in pre-surgical planning.

Discovery of a Potent and Selective CCR4 Antagonist That Inhibits Treg Trafficking into the Tumor Microenvironment.

Recruitment of suppressive CD4+ FOXP3+ regulatory T cells (Treg) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human Treg express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, Treg accumulation correlates with poor patient prognosis. Preclinical data suggests that preventing the recruitment of Treg and increasing the population of activated effector T cells (Teff) in the TME can potentiate antitumor immune responses. We developed a novel series of potent, orally bioavailable small molecule antagonists of CCR4. From this series, several compounds exhibited high potency in distinct functional assays in addition to good in vitro and in vivo ADME properties. The design, synthesis, and SAR of this series and confirmation of its in vivo activity are reported.

Meeting the multiscale challenge: representing physiology processes over ApiNATOMY circuits using bond graphs.

We introduce, and provide examples of, the application of the bond graph formalism to explicitly represent biophysical processes between and within modular biological compartments in ApiNATOMY. In particular, we focus on modelling scenarios from acid-base physiology to link distinct process modalities as bond graphs over an ApiNATOMY circuit of multiscale compartments. The embedding of bond graphs onto ApiNATOMY compartments provides a semantically and mathematically explicit basis for the coherent representation, integration and visualisation of multiscale physiology processes together with the compartmental topology of those biological structures that convey these processes.

Facile Conversion of Bis-Silylene to Cyclic Silylene Isomers: Unexpected C-N and C-H Bond Cleavage.

Reaction of thiolate 1 with carbene-stabilized diiodo-bis-silylene (2) (in a 2:1 ratio) in THF unexpectedly gives both the first five-membered, sulfur-containing, zwitterionic silylene ring (3) via insertion of the "SiI2" unit of 2 into the olefinic C-H bond of the imidazole ring of 1 and four-membered cyclic silylene (4) via insertion of a silicon(I) atom of 2 into the Cphenyl-N bond of the carbene ligand. The parallel reaction in toluene only gives 3 as the major product. The nature of the bonding in isomeric 3 and 4 was probed by experimental and theoretical methods.

1,3,2-Diazaborole-derived carbene complexes of boron.

Reaction of 2-bromo-1,3,2-diazaborole (1) with excess BBr3 induces 1,2-hydrogen migration, giving 1,3,2-diazaborole-derived carbene complexes of boron bromide (2). Compound 2 exists in a dynamic solution equilibrium with 1. The 1H NMR study shows that the equilibrium lies to the right side of the dissociation reaction of 2. Parallel reaction of 1 with excess BI3 gives the corresponding 1,3,2-diazaborole-derived carbene boron iodide complex (3). Notably, in contrast to 2, the dissociation reaction of 3 largely lies to the left side, favouring the formation of 3. The dynamic solution equilibrium behaviours of 2 and 3 are probed by both experimental and theoretical methods.