Comparative analysis of centrally mediated and inflammatory pain experiences amongst patients diagnosed with rheumatoid arthritis: A multimethods study.

BACKGROUND: The identification of pain originating from distinct biological processes may lead to individualised pain treatment. In this study, we aimed to explore the pain experiences of patients with rheumatoid arthritis (RA), differentiating between those predominantly exhibiting features of peripheral inflammatory versus centrally mediated pain. METHODS: Through a multimethods approach we (i) quantitatively analysed the differences in pain descriptors between patients diagnosed with RA experiencing peripheral inflammatory and centrally mediated pain, utilising the Short Form-McGill Pain Questionnaire which includes the pain visual analogue scale (VAS) and (ii) qualitatively explored their subjective pain experiences grounded in the biopsychosocial model, commonly applied in chronic pain. RESULTS: Participants with centrally mediated pain reported higher pain scores on the VAS, used a wider range of pain descriptors, and a higher proportion selected each descriptor compared to those with inflammatory pain (p < .001). The qualitative analysis revealed the centrally mediated pain group's experiences were overwhelming and relentless, struggling to precisely articulate the nature of their pain. In contrast, individuals with inflammatory pain expressed their pain in more tangible terms and shared their adaptive and coping strategies. Importantly, both groups revealed the substantial psychological, functional and social impacts of their pain, highlighting the often 'invisible' and misunderstood nature of their symptoms. CONCLUSION: This study has gained a deeper insight into the pain experiences of patients living with RA, particularly in differentiating between centrally mediated and inflammatory types of pain, potentially facilitating a more individualised approach to pain treatment. PATIENT CONTRIBUTION: Patients actively participated in the study conception and design. This engagement includes collaboration with key stakeholders, such as members of the National Rheumatoid Arthritis Society and Patient Research Partners (PRPs), who provided continuous feedback and guidance throughout the research process. Specifically, the qualitative element was coproduced with two PRPs, who were involved in co-leading the focus groups and data analysis.

Proteomic profiling of paired human liver homogenate and tissue derived extracellular vesicles.

Advances in technologies to isolate extracellular vesicles (EVs) and detect/quantify their cargo underpin the novel potential of these circulating particles as a liquid biopsy to understand physiology and disease. One organ of particular interest in terms of utilizing EVs as a liquid biopsy is the liver. The extent to which EVs originating from the liver reflect the functional status of this organ remains unknown. This is an important knowledge gap that underpins the utility of circulating liver derived EVs as a liquid biopsy. The primary objective of this study was to characterize the proteomic profile of EVs isolated from the extracellular space of liver tissue (LEV) and compare this profile to that of paired tissue (LH). LCMS analyses detected 2892 proteins in LEV and 2673 in LH. Of the 2673 proteins detected in LH, 1547 (58%) were also detected in LEV. Bioinformatic analyses demonstrated comparable representation of proteins in terms of biological functions and cellular compartments. Although, enriched representation of membrane proteins and associated functions was observed in LEV, while representation of nuclear proteins and associated functions was depleted in LEV. These data support the potential use of circulating liver derived EVs as a liquid biopsy for this organ.

Epigenetic cell memory: The gene's inner chromatin modification circuit.

Epigenetic cell memory allows distinct gene expression patterns to persist in different cell types despite a common genotype. Although different patterns can be maintained by the concerted action of transcription factors (TFs), it was proposed that long-term persistence hinges on chromatin state. Here, we study how the dynamics of chromatin state affect memory, and focus on a biologically motivated circuit motif, among histones and DNA modifications, that mediates the action of TFs on gene expression. Memory arises from time-scale separation among three circuit's constituent processes: basal erasure, auto and cross-catalysis, and recruited erasure of modifications. When the two latter processes are sufficiently faster than the former, the circuit exhibits bistability and hysteresis, allowing active and repressed gene states to coexist and persist after TF stimulus removal. The duration of memory is stochastic with a mean value that increases as time-scale separation increases, but more so for the repressed state. This asymmetry stems from the cross-catalysis between repressive histone modifications and DNA methylation and is enhanced by the relatively slower decay rate of the latter. Nevertheless, TF-mediated positive autoregulation can rebalance this asymmetry and even confers robustness of active states to repressive stimuli. More generally, by wiring positively autoregulated chromatin modification circuits under time scale separation, long-term distinct gene expression patterns arise, which are also robust to failure in the regulatory links.

Spatiotemporal Trends Spanning Three Decades Show Toxic Levels of Chemical Contaminants in Marine Mammals.

Despite their ban and restriction under the 2001 Stockholm Convention, persistent organic pollutants (POPs) are still widespread and pervasive in the environment. Releases of these toxic and bioaccumulative chemicals are ongoing, and their contribution to population declines of marine mammals is of global concern. To safeguard their survival, it is of paramount importance to understand the effectiveness of mitigation measures. Using one of the world's largest marine mammals strandings data sets, we combine published and unpublished data to examine pollutant concentrations in 11 species that stranded along the coast of Great Britain to quantify spatiotemporal trends over three decades and identify species and regions where pollutants pose the greatest threat. We find that although levels of pollutants have decreased overall, there is significant spatial and taxonomic heterogeneity such that pollutants remain a threat to biodiversity in several species and regions. Of individuals sampled within the most recent five years (2014-2018), 48% of individuals exhibited a concentration known to exceed toxic thresholds. Notably, pollutant concentrations are highest in long-lived, apex odontocetes (e.g., killer whales (Orcinus orca), bottlenose dolphins (Tursiops truncatus), and white-beaked dolphins (Lagenorhynchus albirostris)) and were significantly higher in animals that stranded on more industrialized coastlines. At the present concentrations, POPs are likely to be significantly impacting marine mammal health. We conclude that more effective international elimination and mitigation strategies are urgently needed to address this critical issue for the global ocean health.

Comparison Theorems for Stochastic Chemical Reaction Networks.

Continuous-time Markov chains are frequently used as stochastic models for chemical reaction networks, especially in the growing field of systems biology. A fundamental problem for these Stochastic Chemical Reaction Networks (SCRNs) is to understand the dependence of the stochastic behavior of these systems on the chemical reaction rate parameters. Towards solving this problem, in this paper we develop theoretical tools called comparison theorems that provide stochastic ordering results for SCRNs. These theorems give sufficient conditions for monotonic dependence on parameters in these network models, which allow us to obtain, under suitable conditions, information about transient and steady-state behavior. These theorems exploit structural properties of SCRNs, beyond those of general continuous-time Markov chains. Furthermore, we derive two theorems to compare stationary distributions and mean first passage times for SCRNs with different parameter values, or with the same parameters and different initial conditions. These tools are developed for SCRNs taking values in a generic (finite or countably infinite) state space and can also be applied for non-mass-action kinetics models. When propensity functions are bounded, our method of proof gives an explicit method for coupling two comparable SCRNs, which can be used to simultaneously simulate their sample paths in a comparable manner. We illustrate our results with applications to models of enzymatic kinetics and epigenetic regulation by chromatin modifications.

Perspectives of family-centred care at the end of life during the COVID-19 pandemic: A qualitative descriptive study.

AIM: To explore nurses' and family members' perspectives of family care at the end of life, during restricted visitation associated with the COVID-19 pandemic. BACKGROUND: To minimise the transmission of COVID-19, stringent infection prevention and control measures resulted in restricted hospital access for non-essential workers and visitors, creating challenges for the provision of family-centred care at the end of life. DESIGN: Qualitative descriptive approach based on naturalistic inquiry. METHODS: At a large public hospital in Melbourne, Australia, individual semi-structured interviews were undertaken with 15 registered nurses who cared for patients who died during restricted visitation associated with the COVID-19 pandemic, and 21 bereaved family members. COREQ guidelines informed analysis and reporting. RESULTS: Five themes developed from the data: (i) impact of visitor restrictions, which describes uncertain, ambiguous and arbitrary rules, onerous and inconsistent requirements; (ii) nurse-family communication; (iii) family-centred care and interrupted connections; (iv) well-being and negative emotions; and (v) suggestions for a better way, such as moving away from the black and whiteness of the rules, prioritising communication, compassion and advocacy. CONCLUSIONS: Negative consequences for communication and the patient-family connection at the end of life were felt deeply. The evolving COVID-19 rules that were frequently revised and applied at short notice, and the subsequent consequences for clinical practices and care were felt deeply. RELEVANCE TO CLINICAL PRACTICE: Technology-facilitated communication, innovation and increased resources must be prioritised to overcome the challenges described in this study. A family-centred approach to care and emphasising the patient-family connection at the end of life is fundamental to minimising trauma and distress associated with future public health emergencies. PATIENT OR PUBLIC CONTRIBUTION: Bereaved family members contributed their first-hand experience. Members of the health service's patient experience team ensured the research was conducted in accordance with health service guidelines for patient and public contribution.

To sell or not to sell: considerations when evaluating private equity acquisitions.

PURPOSE OF REVIEW: Many private practice ophthalmology groups are considering a partnership with private equity. When evaluating whether to remain independent or to engage an equity partner, practice leaders must analyze their existing practice, address issues of equity transitions, management, and governance, and determine strategic goals. This paper discusses the factors that need to be considered when evaluating the possibility of an acquisition model. SUMMARY: When considering a partnership with private equity, a thriving and mature private practice must conduct an in-depth analysis of four factors: how to transition the equity of a mature practice, how to continue growth, how to manage an increasingly complex organization, and the after-effects of a sale. These same issues must be addressed whether the group decides to pursue private equity or decides to remain independent.

The impact of the COVID-19 pandemic on Australian hospital-based nursing and midwifery educators.

Background: The COVID-19 pandemic significantly disrupted health services and their staff, including nursing and midwifery educators. Nursing and midwifery educators were tasked with meeting nurses' and midwives' rapidly-changing educational requirements, and supporting the nursing and midwifery workforce through the pandemic. Thus, nursing and midwifery educators were pivotal to the pandemic response. Aim: To assess the impact of the COVID-19 pandemic on nursing and midwifery educators across four large, multisite Australian health services. Methods: Qualitative descriptive study. All nursing and midwifery educators from public health services in Melbourne, Victoria (n = 3) and Adelaide, South Australia (n=1) were invited to participate in a semistructured interview (July - November 2020). Interviews were audio-recorded and transcribed verbatim. Data were analysed thematically. Findings: Forty-six nursing and midwifery educators participated in interviews. Across the health services, two similar themes and six sub-themes were identified. In the first theme, "Occupational impacts of COVID-19," participants described adjusting to providing education during the pandemic, managing increased workloads, concerns about not being able to carry out their usual education activities and the importance of support at work. The second theme, "Psychological impacts of COVID-19," included two sub-themes: the negative impact on participants' own mental health and difficulties supporting the mental health of other staff members. Participants from all health services identified unexpected positive impacts; online education, virtual meetings and working at home were perceived as practices to be continued postpandemic. Conclusions: Hospital-based nursing and midwifery educators demonstrated agility in adjusting to the fast-changing requirements of providing education during the pandemic. Educators would benefit from continued occupational and psychosocial support during the COVID-19 pandemic, and inclusion in discussions to inform hospitals' preparedness for managing the education of nurses and midwives during future pandemics.

Genome and epigenome engineering CRISPR toolkit for in vivo modulation of cis-regulatory interactions and gene expression in the chicken embryo.

CRISPR/Cas9 genome engineering has revolutionised all aspects of biological research, with epigenome engineering transforming gene regulation studies. Here, we present an optimised, adaptable toolkit enabling genome and epigenome engineering in the chicken embryo, and demonstrate its utility by probing gene regulatory interactions mediated by neural crest enhancers. First, we optimise novel efficient guide-RNA mini expression vectors utilising chick U6 promoters, provide a strategy for rapid somatic gene knockout and establish a protocol for evaluation of mutational penetrance by targeted next-generation sequencing. We show that CRISPR/Cas9-mediated disruption of transcription factors causes a reduction in their cognate enhancer-driven reporter activity. Next, we assess endogenous enhancer function using both enhancer deletion and nuclease-deficient Cas9 (dCas9) effector fusions to modulate enhancer chromatin landscape, thus providing the first report of epigenome engineering in a developing embryo. Finally, we use the synergistic activation mediator (SAM) system to activate an endogenous target promoter. The novel genome and epigenome engineering toolkit developed here enables manipulation of endogenous gene expression and enhancer activity in chicken embryos, facilitating high-resolution analysis of gene regulatory interactions in vivo.

Discrimination reported by older adults living with mental health conditions: types, contexts and association with healthcare barriers.

OBJECTIVE: Australian policy-making needs better information on the prevalence, context and types of discrimination reported by people living with mental health conditions and the association of exposure to discrimination with experiencing a barrier to accessing healthcare. METHODS: Secondary data analysis using the national representative General Social Survey 2014 to examine discrimination and healthcare barriers. Multivariable logistic regression was used to examine the association between discrimination and barriers to healthcare. RESULTS: Around 10% of older adults without mental health conditions reported an instance of discrimination in the last 12 months, compared to 22-25% of those with mental health conditions. Approximately 20% with mental health conditions attributed discrimination to their health conditions, along with other characteristics including age. Discrimination was reported in settings important to human capital (e.g., healthcare, workplace), but also in general social and public contexts. Everyday discrimination (OR = 2.11 p < 0.001), discrimination in healthcare (OR = 2.92 p < 0.001), and discrimination attributed to the person's health condition (OR = 1.99 p < 0.05) increased the odds of experiencing a barrier to care two-to-three-fold. For each type of discrimination reported (e.g., racism, ageism etc.), the odds of experiencing a barrier to care increased 1.3 times (OR = 1.29 p < 0.01). CONCLUSION: This new population-level evidence shows older adults with mental health conditions are experiencing discrimination at more than twofold compared to those without mental health conditions. Discrimination was associated with preventing or delaying healthcare access. These findings indicate that future strategies to promote mental healthcare in underserved groups of older people will need to be multidimensional and consideration given to address discrimination.

Insights into olfactory ensheathing cell development from a laser-microdissection and transcriptome-profiling approach.

Olfactory ensheathing cells (OECs) are neural crest-derived glia that ensheath bundles of olfactory axons from their peripheral origins in the olfactory epithelium to their central targets in the olfactory bulb. We took an unbiased laser microdissection and differential RNA-seq approach, validated by in situ hybridization, to identify candidate molecular mechanisms underlying mouse OEC development and differences with the neural crest-derived Schwann cells developing on other peripheral nerves. We identified 25 novel markers for developing OECs in the olfactory mucosa and/or the olfactory nerve layer surrounding the olfactory bulb, of which 15 were OEC-specific (that is, not expressed by Schwann cells). One pan-OEC-specific gene, Ptprz1, encodes a receptor-like tyrosine phosphatase that blocks oligodendrocyte differentiation. Mutant analysis suggests Ptprz1 may also act as a brake on OEC differentiation, and that its loss disrupts olfactory axon targeting. Overall, our results provide new insights into OEC development and the diversification of neural crest-derived glia.

Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures.

OBJECTIVE: We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAE). METHODS: We deeply phenotyped MAE patients for epilepsy features, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to identify genetic etiologies. RESULTS: We analyzed 101 patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including five previously published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three new candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each. SIGNIFICANCE: MAE is associated with significant neurodevelopmental impairment. MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity.

Disability discrimination and avoidance in later life: prevalence, disability differentials and association with mental health.

BACKGROUND: Later life is a period of increased risk of disability, but there is little quantitative evidence regarding the exclusion of older people (through discrimination and avoidance) due to their health conditions. This study aims to (1) measure the prevalence of disability exclusion in later life, (2) examine how experiences of exclusion differ by disability type, and (3) investigate the association of exposure to exclusion with psychological distress. METHODS: Using data from the 2015 ABS Survey of Disability, Ageing and Carers, we calculated the prevalence of people aged 55 years and over with a disability experiencing discrimination and engaging in avoidance behaviors, disaggregated by 18 detailed disability types. Modified Log-Poisson models were fitted to estimate Prevalence Ratios to measure the association between exclusion and psychological distress, stratified by disability type. RESULTS: In 2015, about 5% of Australians aged 55 years and over with a disability reported experiencing an instance of disability discrimination, and one in four reported avoiding a situation or context due to their disability. Accounting for psychosocial comorbidities and with extensive demographic controls, exposure to disability avoidance (PR = 1.9, 95% CI 1.7, 2.1) or discrimination (PR = 1.7, 95% CI 1.4, 2.1) almost doubled the probability of experiencing psychological distress. Effects were heightened for individuals reporting specific disabilities including sensory and speech and physical disabilities as well as those reporting a head injury, stroke, or acquired brain injury. CONCLUSIONS: Despite protections against disability discrimination in legislation, discrimination and avoidance due to disability is prevalent and is associated with poor mental health outcomes.

Genome-wide association study: Exploring the genetic basis for responsiveness to ketogenic dietary therapies for drug-resistant epilepsy.

OBJECTIVE: With the exception of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDTs) are unknown. We aimed to determine whether common variation across the genome influences the response to KDT for epilepsy. METHODS: We genotyped individuals who were negative for glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Genotyping was performed with the Infinium HumanOmniExpressExome Beadchip. Hospital records were used to obtain demographic and clinical data. KDT response (≥50% seizure reduction) at 3-month follow-up was used to dissect out nonresponders and responders. We then performed a genome-wide association study (GWAS) in nonresponders vs responders, using a linear mixed model and correcting for population stratification. Variants with minor allele frequency <0.05 and those that did not pass quality control filtering were excluded. RESULTS: After quality control filtering, the GWAS of 112 nonresponders vs 123 responders revealed an association locus at 6p25.1, 61 kb upstream of CDYL (rs12204701, P = 3.83 × 10-8 , odds ratio [A] = 13.5, 95% confidence interval [CI] 4.07-44.8). Although analysis of regional linkage disequilibrium around rs12204701 did not strengthen the likelihood of CDYL being the candidate gene, additional bioinformatic analyses suggest it is the most likely candidate. SIGNIFICANCE: CDYL deficiency has been shown to disrupt neuronal migration and to influence susceptibility to epilepsy in mice. Further exploration with a larger replication cohort is warranted to clarify whether CDYL is the causal gene underlying the association signal.

Discrimination and avoidance due to disability in Australia: evidence from a National Cross Sectional Survey.

BACKGROUND: Across most high-income countries, populations are ageing. With this demographic change is an increase in the number of people living with disabilities. In this context, we sought to examine the prevalence of disability discrimination and disability avoidance in Australia, the demographic and health correlates of exclusion and the contexts in which disability discrimination and avoidance are experienced. METHODS: Utilising newly released measures from the 2015 ABS Survey of Disability, Ageing and Carers, we calculate the prevalence of people living with a disability who have experienced discrimination and engage in avoidance behaviours, and the contexts in which they occur. Logistic regression models were fitted to examine the correlates of discrimination and avoidance behaviours, once controls and complex survey design were accounted for. RESULTS: Approximately 9% (95% CI = 8.1, 9.2) of people with a disability experienced disability discrimination in 2015 and 31% (95% CI = 30.9, 32.9) engaged in avoidance behaviours because of their disability. With controls included, the prevalence of avoidance and discrimination declined with age, was higher for divorced people (versus married), the unemployed (versus employed) and was lower for people with lower levels of education (versus a degree) and those born overseas. Having a psychosocial or physical disability significantly increased the odds of experiencing discrimination or avoidance, as did having an increasing number of long-term health conditions. We further find that disability discrimination and avoidance occurs in contexts critical to human capital, such as the workforce, education and healthcare. CONCLUSIONS: Despite protections in legislation and international accords, significant proportions of Australians with a disability experience discrimination or engage in avoidance behaviours in various settings with potentially important human capital implications. Recently, sectoral responses (eg., in education and the workplace) have been offered by Government reports, providing direction for future research and evaluation.

Multiple health conditions and barriers to healthcare among older Australians: prevalence, reasons and types of barriers.

Accompanying population ageing is an increase in the number of older Australians living with multiple health conditions and disabilities (Australian Institute of Health and Welfare 2014). This study sought to examine the barriers to accessing healthcare faced by older Australians. Utilising the 2014 Australian Bureau of Statistics General Social Survey, it was found that 6% of respondents aged 50 years and over reported experiencing a barrier to accessing healthcare within the previous 12 months. Those with multiple health conditions are at a considerably higher risk of experiencing a barrier to healthcare (21% with four or more disabilities) compared with people with no or fewer health conditions, and this risk persists once wide-ranging control variables are included. Long waiting times or unavailability of appointments (43%) were the main type of barriers to accessing healthcare, followed by cost (23%). Points-of-care barriers experienced included accessing GPs, specialists and hospital sector care. Respondents who experienced a barrier were more likely to have low levels of trust in the healthcare system compared with people who had no experience of barriers to healthcare, and were more likely to have a perception of experiencing discrimination or unfair treatment in a healthcare setting.

Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5.

AIM: To characterize the phenotypic profile of a cohort of children affected with CLN5, a rare form of neuronal ceroid-lipofuscinosis (NCL), and to trace the features of the natural history of the disease. METHOD: Records of 15 children (nine males, six females) were obtained from the data sets of the DEM-CHILD International NCL Registry. Disease progression was measured by rating six functional domains at different time points along the disease course. All patients underwent mutation analysis of the CLN5 gene and ultrastructural investigations of peripheral tissues. Expression of the gene product, pCLN5, was characterized in vitro in six patients. RESULTS: Disease onset was at 2 to 7 years 6 months of age: impaired learning and cognition were the most common early symptoms. Seizures occurred relatively late (median age 8y) and were the presenting symptoms in two children. Nine mutations were detected in 30 alleles, including six mutations predicting a truncated protein. Mixed cytosomes were observed by electron microscopy. Differences of disease progression were observed in two groups of patients and could be related to their genetic profile. INTERPRETATION: Clinical features in a multicentre cohort of patients with CLN5 confirm that cognitive difficulties are early clinical markers of this condition. Severe mutations were associated with a more rapid decline of neurological function.

Reducing recurrence of bacterial skin infections in Aboriginal children in rural communities: new ways of thinking, new ways of working.

Reports from health workers, school staff and community members in rural NSW suggested that bacterial skin infections are a significant health issue for Aboriginal children and their families, affecting quality of life and contributing to poor school attendance. Current NSW treatment guidelines do not incorporate important sociocultural factors or ways of living in Aboriginal communities. The aim of this qualitative study was to gain a deeper understanding of the experience of parents and carers of Aboriginal children affected by skin infections and of other community members, health workers and school staff, and what actions have been considered successful or unsuccessful in reducing the recurrence of infection. This study used a Participatory Action Research methodology. Interviews and focus groups were conducted with 38 health workers and managers, school staff, community members and parents and carers. Themes that emerged included: (i) skin infections have become normalised; (ii) skin infections are, in part, a consequence of transgenerational trauma; (iii) skin infections are interwoven with social determinants; (iv) families have survived but more could thrive; and (v) something can and should be done about the problem. The findings of this study will inform the development of more effective and acceptable options to reduce skin infections in Aboriginal children.

Criticality and Adaptivity in Enzymatic Networks.

The contrast between the stochasticity of biochemical networks and the regularity of cellular behavior suggests that biological networks generate robust behavior from noisy constituents. Identifying the mechanisms that confer this ability on biological networks is essential to understanding cells. Here we show that queueing for a limited shared resource in broad classes of enzymatic networks in certain conditions leads to a critical state characterized by strong and long-ranged correlations between molecular species. An enzymatic network reaches this critical state when the input flux of its substrate is balanced by the maximum processing capacity of the network. We then consider enzymatic networks with adaptation, when the limiting resource (enzyme or cofactor) is produced in proportion to the demand for it. We show that the critical state becomes an attractor for these networks, which points toward the onset of self-organized criticality. We suggest that the adaptive queueing motif that leads to significant correlations between multiple species may be widespread in biological systems.

Creation of the American Board of Ophthalmology: The Role of the American Medical Association.

In the early 20th century, the American Medical Association (AMA), specifically its Section on Ophthalmology, played a central role in the founding of America's first medical specialty board, the American Board of Ophthalmology. With the American Ophthalmological Society and the American Academy of Ophthalmology and Otolaryngology, the AMA's contributions to the formation of the American Board of Ophthalmology led to the establishment of sound educational standards for practicing ophthalmologists and helped to advance the culture of medical excellence within the profession that is synonymous with board certification today.