Growing a provincial patient and family engagement network to optimize kidney care.

Patient and family engagement is crucial for a responsive health system and improves patient outcomes. However, few practical resources for purposeful engagement are available to health leaders. Over the past 5 years, BC Renal, the provincial kidney care network in British Columbia, developed, operationalized, and implemented a framework to enable meaningful patient and family engagement. An advisory committee, comprising patient partners and representatives from health authorities and the community, directs the outreach, resource development, and evaluation of patient and family engagement at BC Renal. Here, we describe how our network-wide patient engagement strategy was developed and expanded upon, and the progress so far. A 2022 survey reports that 95% were satisfied with the engagement opportunities, and narrative feedback suggests network members continue to adopt practical ways to collaborate more effectively. Health leaders, patient partners, and others continue to align operational and strategic activities to advance culture change in kidney care provincially.

Weight as an indicator of enclosure suitability in Livingstone's fruit bats (Pteropus livingstonii).

Obesity is common in zoo animals, and both dietary management and the provision of adequate opportunities for exercise are needed to tackle it. We used 30 years of records from Jersey Zoo to compare the weight and forearm length of wild and captive-born Livingstone's fruit bats (Pteropus livingstonii), and to assess the impact on weight of enclosure space. The mean capture weight of wild-caught male Livingstone's bats was 657 g, significantly higher than that of females (544 g). In both wild and captive-born bats, males had significantly longer forearms than females, but there was no effect of birth location. Males weighed more in the mating season than at other times of year. Both sexes gained more weight during development if born in enclosures that restricted flight rather than a large aviary; this was particularly noticeable in females. After reaching maturity at 3 years, weights of bats born in restricted enclosures continued to increase, reached a peak of over 1000 g at 8-10 years, and then declined in both sexes. The weight of bats born in the aviary remained more stable after the age of three. Like wild bats, adult females born in the aviary weighed less than males. However, females born in restricted enclosures weighed more than males born in the same enclosures. Enclosure designs that maximize opportunities for flight can limit excessive weight gain in captive fruit bats and may therefore improve fitness and health, essential in planning for future reintroduction programs.

Embryonic temporal-spatial delineation of excitatory spinal V3 interneuron diversity.

Spinal neural circuits that execute movement are composed of cardinal classes of neurons that emerged from distinct progenitor lineages. Each cardinal class contains multiple neuronal subtypes characterized by distinct molecular, anatomical, and physiological characteristics. Through a focus on the excitatory V3 interneuron class, here we demonstrate that interneuron subtype diversity is delineated through a combination of neurogenesis timing and final laminar settling position. We have revealed that early-born and late-born embryonic V3 temporal classes further diversify into subclasses with spatially and molecularly discrete identities. While neurogenesis timing accounts for V3 morphological diversification, laminar settling position accounts for electrophysiological profiles distinguishing V3 subtypes within the same temporal classes. Furthermore, V3 interneuron subtypes display independent behavioral recruitment patterns demonstrating a functional modularity underlying V3 interneuron diversity. These studies provide a framework for how early embryonic temporal and spatial mechanisms combine to delineate spinal interneuron classes into molecularly, anatomically, and functionally relevant subtypes in adults.

CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence.

Abnormal increases in cell size are associated with senescence and cell cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the cell cycle remain unknown. We address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2- breast cancer. We demonstrate that CDK4/6-inhibited cells overgrow during G0/G1, causing p38/p53/p21-dependent cell cycle withdrawal. Cell cycle withdrawal is triggered by biphasic p21 induction. The first p21 wave is caused by osmotic stress, leading to p38- and size-dependent accumulation of p21. CDK4/6 inhibitor washout results in some cells entering S-phase. Overgrown cells experience replication stress, resulting in a second p21 wave that promotes cell cycle withdrawal from G2 or the subsequent G1. We propose that the levels of p21 integrate signals from overgrowth-triggered stresses to determine cell fate. This model explains how hypertrophy can drive senescence and why CDK4/6 inhibitors have long-lasting effects in patients.

Tropomyosin 1 deficiency facilitates cell state transitions to enhance hemogenic endothelial cell specification during hematopoiesis.

Tropomyosins coat actin filaments and impact actin-related signaling and cell morphogenesis. Genome-wide association studies have linked Tropomyosin 1 (TPM1) with human blood trait variation. Prior work suggested that TPM1 regulated blood cell formation in vitro, but it was unclear how or when TPM1 affected hematopoiesis. Using gene-edited induced pluripotent stem cell (iPSC) model systems, TPM1 knockout was found to augment developmental cell state transitions, as well as TNFα and GTPase signaling pathways, to promote hemogenic endothelial (HE) cell specification and hematopoietic progenitor cell (HPC) production. Single-cell analyses showed decreased TPM1 expression during human HE specification, suggesting that TPM1 regulated in vivo hematopoiesis via similar mechanisms. Indeed, analyses of a TPM1 gene trap mouse model showed that TPM1 deficiency enhanced the formation of HE during embryogenesis. These findings illuminate novel effects of TPM1 on developmental hematopoiesis.

Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.

INTRODUCTION: BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa. OBJECTIVE: This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period. METHODS: Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated. RESULTS: Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed. CONCLUSIONS: The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required. CLINICAL TRIAL REGISTRATION: NCT03373422 (date registered: November 23, 2017).

PETRA: A pencil beam trimming algorithm for analytical proton therapy dose calculations with the dynamic collimation system.

BACKGROUND: The Dynamic Collimation System (DCS) has been shown to produce superior treatment plans to uncollimated pencil beam scanning (PBS) proton therapy using an in-house treatment planning system (TPS) designed for research. Clinical implementation of the DCS requires the development and benchmarking of a rigorous dose calculation algorithm that accounts for pencil beam trimming, performs monitor unit calculations to produce deliverable plans at all beam energies, and is ideally implemented with a commercially available TPS. PURPOSE: To present an analytical Pencil bEam TRimming Algorithm (PETRA) for the DCS, with and without its range shifter, implemented in the Astroid TPS (.decimal, Sanford, Florida, USA). MATERIALS: PETRA was derived by generalizing an existing pencil beam dose calculation model to account for the DCS-specific effects of lateral penumbra blurring due to the nickel trimmers in two different planes, integral depth dose variation due to the trimming process, and the presence and absence of the range shifter. Tuning parameters were introduced to enable agreement between PETRA and a measurement-validated Dynamic Collimation Monte Carlo (DCMC) model of the Miami Cancer Institute's IBA Proteus Plus system equipped with the DCS. Trimmer position, spot position, beam energy, and the presence or absence of a range shifter were all used as variables for the characterization of the model. The model was calibrated for pencil beam monitor unit calculations using procedures specified by International Atomic Energy Agency Technical Report Series 398 (IAEA TRS-398). RESULTS: The integral depth dose curves (IDDs) for energies between 70 MeV and 160 MeV among all simulated trimmer combinations, with and without the ranger shifter, agreed between PETRA and DCMC at the 1%/1 mm 1-D gamma criteria for 99.99% of points. For lateral dose profiles, the median 2-D gamma pass rate for all profiles at 1.5%/1.5 mm was 99.99% at the water phantom surface, plateau, and Bragg peak depths without the range shifter and at the surface and Bragg peak depths with the range shifter. The minimum 1.5%/1.5 mm gamma pass rates for the 2-D profiles at the water phantom surface without and with the range shifter were 98.02% and 97.91%, respectively, and, at the Bragg peak, the minimum pass rates were 97.80% and 97.5%, respectively. CONCLUSION: The PETRA model for DCS dose calculations was successfully defined and benchmarked for use in a commercially available TPS.

Acute Colonic Pseudo-obstruction Following Spinal Fixation for Trauma.

BACKGROUND: Acute colonic pseudo-obstruction (ACPO) is a potentially highly morbid surgical complication. The incidence of ACPO following spinal trauma is unknown, but is likely higher than after elective spinal fusion. The purpose of this study was to establish the incidence of ACPO in patients with major trauma undergoing spinal fusion for unstable thoracic and lumbar fracture, and secondly, to characterize the nature of ACPO in this group, including treatment and complications. METHODS: A metropolitan hospital prospective trauma database was utilized to identify all patients from November 2015 to December 2021 meeting major trauma criteria and undergoing thoracic or lumbar spinal fusion for fracture. Individual records were then evaluated for occurrence of ACPO. ACPO was defined as radiologic evidence of colonic dilation without mechanical obstruction in symptomatic patients undergoing dedicated abdominal imaging. RESULTS: After exclusions, 456 patients with major trauma undergoing thoracic or lumbar spinal fusion were identified. ACPO occurred in 34-an incidence rate of 7.5%. There was no evidence of difference in terms of the spinal fracture type, level, surgical approach, or number of segments fused. There were no perforations; only 2 patients required colonoscopic decompression and none required surgical resection. CONCLUSIONS: ACPO occurred at a high frequency in this group of patients, although it required relatively simple treatment. High vigilance for ACPO should be maintained in trauma patients requiring thoracic or lumbar fixation, with a view to early intervention. The etiology driving the high rates of ACPO in this cohort is not understood and would benefit from further investigation.

Nociceptor activity induces nonionotropic NMDA receptor signaling to enable spinal reconsolidation and reverse pathological pain.

Chronic, pathological pain is a highly debilitating condition that can arise and be maintained through central sensitization. Central sensitization shares mechanistic and phenotypic parallels with memory formation. In a sensory model of memory reconsolidation, plastic changes underlying pain hypersensitivity can be dynamically regulated and reversed following the reactivation of sensitized sensory pathways. However, the mechanisms by which synaptic reactivation induces destabilization of the spinal "pain engram" are unclear. We identified nonionotropic N-methyl-d-aspartate receptor (NI-NMDAR) signaling as necessary and sufficient for the reactive destabilization of dorsal horn long-term potentiation and the reversal of mechanical sensitization associated with central sensitization. NI-NMDAR signaling engaged directly or through the reactivation of sensitized sensory networks was associated with the degradation of excitatory postsynaptic proteins. Our findings identify NI-NMDAR signaling as a putative synaptic mechanism by which engrams are destabilized in reconsolidation and as a potential means of treating underlying causes of chronic pain.

The Colonoscopy Cookbook: Analysis of effect of a recipe resource on quality and experience of bowel preparation in colonoscopy.

Background High-quality bowel preparation for a colonoscopy improves identification of early lesions in the large bowel, decreases procedure time and increases intervals between colonoscopies. Current recommendations advise a low-residue diet in the days leading up to colonoscopy to improve quality of preparation. This study prepared and provided a recipe resource to patients undergoing colonoscopy and assessed the quality of bowel preparation and patient experience. Patients and methods A "Colonoscopy Cookbook" resource of recipes that comply with the preoperative diet recommendations was created and added to routine preoperative information given to patients undergoing elective colonoscopies at a regional Australian hospital over a 12-month period. Endoscopic reports were reviewed for each case and quality of bowel preparation was classified as "adequate'' or "inadequate". Data collected were compared to a representative local cohort from 2019. Results Procedure reports from 96 patients who were provided with the resource were compared with 96 patients who were not. Adequate bowel preparation was nine times as likely when the resource was available (odds ratio 8.54, 95 % confidence interval: 2.85 to 25.60, P  < 0.001) compared to when it was not. The patient experience was assessed using a post-procedure survey, which demonstrated a positive experience in recipe preparation. Most patients would use the resource prior to future colonoscopies. Conclusions Further randomized controlled trials are required to validate this scoping review. Pre-procedure recipe resources may improve quality of bowel preparation in patients undergoing colonoscopy.

Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation.

The development of K-Ras independence may explain the failure of targeted therapy for pancreatic cancer (PC). In this paper, active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was shown that depleting K-Ras reduced total Ras activity, while cell lines described as independent had no significant decline in total Ras activity. The knockdown of N-Ras showed it had an important role in controlling the relative level of oxidative metabolism, but only K-Ras depletion caused a decrease in G2 cyclins. Proteasome inhibition reversed this, and other targets of APC/c were also decreased by K-Ras depletion. K-Ras depletion did not cause an increase in ubiquitinated G2 cyclins but instead caused exit from the G2 phase to slow relative to completion of the S-phase, suggesting that the mutant K-Ras may inhibit APC/c prior to anaphase and stabilise G2 cyclins independently of this. We propose that, during tumorigenesis, cancer cells expressing wild-type N-Ras protein are selected because the protein protects cancer cells from the deleterious effects of the cell cycle-independent induction of cyclins by mutant K-Ras. Mutation independence results when N-Ras activity becomes adequate to drive cell division, even in cells where K-Ras is inhibited.

Necrotising fasciitis: a case series set in rural Australia.

Necrotising fasciitis (NF) is a rapidly progressive infection of soft tissue and fascia. Early diagnosis and prompt extensive surgical debridement decrease mortality. This remains a challenge for rural surgeons who have limited experience with the disease, in a setting where patient transfers to tertiary centres are lengthy and often delayed. To assist clinical decision making in this setting, a case series of five NF presentations in a rural Australian hospital were retrospectively analysed for presentation, investigation, treatment and clinical outcomes. Three underwent abdominal wall debridement and two underwent below knee amputation. Results demonstrate early recognition of NF and the extent of surgical intervention prior to acute transfer are key to successful outcomes. Expedient diagnosis and early extensive debridement at the initial contact reduce mortality and should be the goal of management in this setting.

Ruthenium(II) Polypyridyl Complexes as FRET Donors: Structure- and Sequence-Selective DNA-Binding and Anticancer Properties.

Ruthenium(II) polypyridyl complexes (RPCs) that emit from metal-to-ligand charge transfer (MLCT) states have been developed as DNA probes and are being examined as potential anticancer agents. Here, we report that MLCT-emissive RPCs that bind DNA undergo Förster resonance energy transfer (FRET) with Cy5.5-labeled DNA, forming mega-Stokes shift FRET pairs. Based on this discovery, we developed a simple and rapid FRET binding assay to examine DNA-binding interactions of RPCs with diverse photophysical properties, including non-"light switch" complexes [Ru(dppz)2(5,5'dmb)]2+ and [Ru(PIP)2(5,5'dmb)]2+ (dppz = dipyridophenazine, 5,5'dmb = 5,5'-dimethyl-2,2'-bipyridine, PIP = 2-phenyl-imidazo[4,5-f][1,10]phenanthroline). Binding affinities toward duplex, G-quadruplex, three-way junction, and mismatch DNA were determined, and derived FRET donor-acceptor proximities provide information on potential binding sites. Molecules characterized by this method demonstrate encouraging anticancer properties, including synergy with the PARP inhibitor Olaparib, and mechanistic studies indicate that [Ru(PIP)2(5,5'dmb)]2+ acts to block DNA replication fork progression.

A rare case of oesophageal and gastric fundus necrosis following traumatic splenectomy.

Oesophageal and gastric fundus necrosis are rare clinical entities and have not previously been reported concurrently. This case study describes oesophageal and gastric fundus necrosis in a 71-year-old female who developed chest pain post-splenectomy for infected splenic haematoma in the context of a fall. Upper gastrointestinal endoscopy demonstrated oesophageal and gastric fundus necrosis. This was likely due to multiple factors including comorbidities, hypoperfusion, post-splenectomy state and herpes simplex virus oesophagitis. This finding is an important differential in the unwell patient with chest pain post-splenectomy and investigation with upper gastrointestinal endoscopy could be considered in the absence of another cause.

Winter oceanographic conditions predict summer bull kelp canopy cover in northern California.

Bull kelp, Nereocystis luetkeana, is an iconic kelp forest species of the Northeast Pacific that provides a wide range of ecosystem services to coastal marine species and society. In northern California, U.S.A., Nereocystis abundance declined sharply in 2014 and has yet to recover. While abiotic and biotic stressors were present prior to 2014, the population collapse highlights the need for a better understanding of how environmental conditions impact Nereocystis. In this study, we used a newly-developed, satellite-based dataset of bull kelp abundance, proxied by canopy cover over 20 years, to test the hypothesis that winter oceanographic conditions determine summer Nereocystis canopy cover. For the years before the collapse (1991 through 2013), wintertime ocean conditions, synthesized in a Multivariate Ocean Climate Indicator (MOCI), were indeed a good predictor of summer Nereocystis canopy cover (R2 = 0.40 to 0.87). We attribute this relationship to the effects of upwelling and/or temperature on nutrient availability. South of Point Arena, California, winter ocean conditions had slightly lower explanatory power than north of Point Arena, also reflective of spring upwelling-driven nutrient entrainment. Results suggest that the Nereocystis gametophytes and/or early sporophytes are sensitive to winter oceanographic conditions. Furthermore, environmental conditions in winter 2014 could have been used to predict the Nereocystis collapse in summer 2014, and for kelp north of Point Arena, a further decline in 2015. Importantly, environmental models do not predict changes in kelp after 2015, suggesting biotic factors suppressed kelp recovery, most likely extreme sea urchin herbivory. Conditions during winter, a season that is often overlooked in studies of biophysical interactions, are useful for predicting summer Nereocystis kelp forest canopy cover, and will be useful in supporting kelp restoration actions in California and perhaps elsewhere in the world.

Interventions that support unpaid carers of adult mental health inpatients: a scoping review.

BACKGROUND: Unpaid carers of adult mental health inpatients often lack support for their well-being and feel excluded from decisions about patient care. AIMS: This scoping review aimed to: synthesise the peer-reviewed literature evaluating the outcomes of brief interventions for unpaid carers of adult mental health inpatients, identify transferable lessons for evidenced-informed practice, and establish future research priorities. METHODS: PRISMA scoping review guidelines were followed to search 12 databases using predefined search terms. Two reviewers independently screened papers and applied exclusion/inclusion criteria. Studies were included if they evaluated the impact or outcomes of interventions. Two reviewers extracted data and assessed study quality. Data were synthesised to categorise types of interventions and evidence for their outcomes. RESULTS: 16 papers met the inclusion criteria, and five types of interventions were identified: those that aimed to (1) increase carer involvement in inpatient care; (2) facilitate organisational change to increase carer support and involvement; (3) provide carers with support; (4) deliver psychoeducation and offer support; and (5) reduce carer stress and improve coping skills. CONCLUSIONS: Whilst evidence of intervention effectiveness was promising, the quality of studies was generally weak. More research is needed to develop an evidence-informed approach to supporting carers during inpatient stays.

Endothelial MEKK3-KLF2/4 signaling integrates inflammatory and hemodynamic signals during definitive hematopoiesis.

The hematopoietic stem cells (HSCs) that produce blood for the lifetime of an animal arise from RUNX1+ hemogenic endothelial cells (HECs) in the embryonic vasculature through a process of endothelial-to-hematopoietic transition (EHT). Studies have identified inflammatory mediators and fluid shear forces as critical environmental stimuli for EHT, raising the question of how such diverse inputs are integrated to drive HEC specification. Endothelial cell MEKK3-KLF2/4 signaling can be activated by both fluid shear forces and inflammatory mediators, and it plays roles in cardiovascular development and disease that have been linked to both stimuli. Here we demonstrate that MEKK3 and KLF2/4 are required in endothelial cells for the specification of RUNX1+ HECs in both the yolk sac and dorsal aorta of the mouse embryo and for their transition to intraaortic hematopoietic cluster (IAHC) cells. The inflammatory mediators lipopolysaccharide and interferon-γ increase RUNX1+ HECs in an MEKK3-dependent manner. Maternal administration of catecholamines that stimulate embryo cardiac function and accelerate yolk sac vascular remodeling increases EHT by wild-type but not MEKK3-deficient endothelium. These findings identify MEKK-KLF2/4 signaling as an essential pathway for EHT and provide a molecular basis for the integration of diverse environmental inputs, such as inflammatory mediators and hemodynamic forces, during definitive hematopoiesis.

MyD88-dependent TLR signaling oppositely regulates hematopoietic progenitor and stem cell formation in the embryo.

Hemogenic endothelial (HE) cells in the dorsal aorta undergo an endothelial-to-hematopoietic transition (EHT) to form multipotent progenitors, lympho-myeloid biased progenitors (LMPs), pre-hematopoietic stem cells (pre-HSCs) and adult-repopulating HSCs. These briefly accumulate in intra-arterial hematopoietic clusters (IAHCs) before being released into the circulation. It is generally assumed that the number of IAHC cells correlates with the number of HSCs. Here, we show that changes in the number of IAHC cells, LMPs and HSCs can be uncoupled. Mutations impairing MyD88-dependent toll-like receptor (TLR) signaling decreased the number of IAHC cells and LMPs, but increased the number of HSCs in the aorta-gonad-mesonephros region of mouse embryos. TLR4-deficient embryos generated normal numbers of HE cells, but IAHC cell proliferation decreased. Loss of MyD88-dependent TLR signaling in innate immune myeloid cells had no effect on IAHC cell numbers. Instead, TLR4 deletion in endothelial cells (ECs) recapitulated the phenotype observed with germline deletion, demonstrating that MyD88-dependent TLR signaling in ECs and/or in IAHCs regulates the numbers of LMPs and HSCs.

Innovations and the Use of Collimators in the Delivery of Pencil Beam Scanning Proton Therapy.

PURPOSE: The development of collimating technologies has become a recent focus in pencil beam scanning (PBS) proton therapy to improve the target conformity and healthy tissue sparing through field-specific or energy-layer-specific collimation. Given the growing popularity of collimators for low-energy treatments, the purpose of this work was to summarize the recent literature that has focused on the efficacy of collimators for PBS and highlight the development of clinical and preclinical collimators. MATERIALS AND METHODS: The collimators presented in this work were organized into 3 categories: per-field apertures, multileaf collimators (MLCs), and sliding-bar collimators. For each case, the system design and planning methodologies are summarized and intercompared from their existing literature. Energy-specific collimation is still a new paradigm in PBS and the 2 specific collimators tailored toward PBS are presented including the dynamic collimation system (DCS) and the Mevion Adaptive Aperture. RESULTS: Collimation during PBS can improve the target conformity and associated healthy tissue and critical structure avoidance. Between energy-specific collimators and static apertures, static apertures have the poorest dose conformity owing to collimating only the largest projection of a target in the beam's eye view but still provide an improvement over uncollimated treatments. While an external collimator increases secondary neutron production, the benefit of collimating the primary beam appears to outweigh the risk. The greatest benefit has been observed for low- energy treatment sites. CONCLUSION: The consensus from current literature supports the use of external collimators in PBS under certain conditions, namely low-energy treatments or where the nominal spot size is large. While many recent studies paint a supportive picture, it is also important to understand the limitations of collimation in PBS that are specific to each collimator type. The emergence and paradigm of energy-specific collimation holds many promises for PBS proton therapy.