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Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.

Little research has focused on the accuracy of gonad shield placement, especially by students. While studies have investigated the presence of gonad shields they do not aim to measure accuracy but only look at repeatability. This study aimed to establish students' knowledge of gonad shields and their accuracy in placing it.Following an invitation email and informed consent, students completed a 7-question questionnaire and placed a gonad shield on a Pixi full body adult phantom (male configuration). The phantom was x-rayed and images were assessed for gonad shield positioning in terms of obscuring bony anatomy, correct orientation and distance from a "gold standard" position.36% of images displayed shields covering bony anatomy while 16% of shields were incorrectly orientated. All shields incorrectly orientated also covered bony anatomy. Statistical significance was seen between incorrect shield orientation and the obscuring of bony anatomy (p = 0.01). Dispersion of positioning error measurements ranged from -6.80 mm (better placed than the "gold standard") to 62.35 mm inferiorly, with an average 28.22 mm inferiorly.The average misplacement of 28.22 mm suggests participants placed the gonad shielding lower than necessary to avoid obscuring bony anatomy. The 36% of misplaced shields, while lower than in previous studies, is still a significant number of radiographs that would require repeats.Given the associated difficulties surrounding gonad shields and their placement, this study supports previous research suggesting that the benefit of using gonad shielding is questionable.

Neurons throughout the brain modulate their firing rate lawfully in response to changes in sensory input. Theories of neural computation posit that these modulations reflect the outcome of a constrained optimization: neurons aim to efficiently and robustly represent sensory information under resource limitations. Our understanding of how this optimization varies across the brain, however, is still in its infancy. Here, we show that neural responses transform along the dorsal stream of the visual system in a manner consistent with a transition from optimizing for information preservation to optimizing for perceptual discrimination. Focusing on binocular disparity – the slight differences in how objects project to the two eyes – we re-analyze measurements from neurons characterizing tuning curves in macaque monkey brain regions V1, V2, and MT, and compare these to measurements of the natural visual statistics of binocular disparity. The changes in tuning curve characteristics are computationally consistent with a shift in optimization goals from maximizing the information encoded about naturally occurring binocular disparities to maximizing the ability to support fine disparity discrimination. We find that a change towards tuning curves preferring larger disparities is a key driver of this shift. These results provide new insight into previously-identified differences between disparity-selective regions of cortex and suggest these differences play an important role in supporting visually-guided behavior. Our findings support a key re-framing of optimal coding in regions of the brain that contain sensory information, emphasizing the need to consider not just information preservation and neural resources, but also relevance to behavior.SignificanceA major role of the brain is to transform information from the sensory organs into signals that can be used to guide behavior. Neural activity is noisy and can consume large amount of energy, so sensory neurons must optimize their information processing so as to limit energy consumption while maintaining key behaviorally-relevant information. In this report, we re-examine classically-defined brain areas in the visual processing hierarchy, and ask whether neurons in these areas vary lawfully in how they represent sensory information. Our results suggest that neurons in these brain areas shift from being an optimal conduit of sensory information to optimally supporting perceptual discrimination during natural tasks.

Osmosis is an important force in all living organisms, yet the molecular basis of osmosis is widely misunderstood as arising from differences in water concentration in solutions of differing osmolarities. In 1923 Debye proposed a physical model for a semipermeable membrane that was hardly noticed at the time and slipped out of view. We show that Debye’s analysis of van’t Hoff’s law for osmotic equilibrium provides a consistent and plausible explanation for osmotic flow. A difference in osmolyte concentrations in solutions separated by a semipermeable membrane generates different pressures at the two water-membrane interfaces. Water is therefore driven through the membrane for exactly the same reason that pure water flows in response to an imposed hydrostatic pressure difference. In this paper we present the Debye model in both equilibrium and flow conditions. We point out its applicability regardless of the nature of the membrane with examples ranging from predominantly convective flow of water through synthetic membranes to purely diffusive flow of independent water molecules through a lipid bilayer and the flow of strongly interacting water molecules in single file across narrow protein channels.

Molecular profiling to characterize the effects of environmental exposures is important from the human health and performance as well as the occupational medicine perspective in space exploration. We have developed a novel exosome-based platform that allows profiling of biological processes in the body from a variety of body fluids. The technology is suitable for diagnostic applications as well as studying the pathophysiology of the Space Associated Neuro-Ocular Syndrome in astronauts and monitoring patients with chronically impaired cerebrospinal fluid drainage or elevated intracranial pressure. In this proof-of-concept, we demonstrate that: (a) exosomes from different biofluids contain a specific population of RNA transcripts; (b) urine collection hardware aboard the ISS is compatible with exosome gene expression technology; (c) cDNA libraries from exosomal RNA can be stored in dry form and at room temperature, representing an interesting option for the creation of longitudinal molecular catalogs that can be stored as a repository for retrospective analysis.

The aim was to explore the feasibility and safety of performing common surgical steps in epiretinal membrane (ERM) peeling using the Preceyes Surgical System (PSS).In a tertiary centre, 15 pseudophakic patients with an idiopathic ERM were randomised to robot-assistance or manual surgery in a 2:1 ratio. In the robot-assisted group, the following steps were performed using PSS: (1) staining the internal limiting membrane (ILM), (2) removal of the dye, (3) creating an ILM flap, (4) completing the peeling, (5) holding a light pipe and (6) fluid-air exchange. Primary outcome measures were feasibility and safety. Secondary outcome measures were duration, best-corrected visual acuity (BCVA) and central retinal thickness (CRT). Moreover, the distance travelled by the instrument during peeling was assessed using motion tracking software.All steps performed with PSS were feasible with no clinical adverse events or complications. The surgical time was longer in the robot-assisted group (mean 56 min, SD = 12 vs. 24 min, SD = 5). During the study, the duration of robot-assisted surgeries decreased from 72 to 46 min. The distance travelled by the forceps was shorter in the robot-assisted group (mean 403 mm, SD = 186 vs. 550 mm, SD = 134). BCVA and CRT improved equally in both groups.This is the world's first randomised controlled trial on robotic surgery for ERM. Although more time-consuming, we found that several surgical steps were feasible with assistance of the PSS.

Persons living with mental health challenges are at increased risk of stigma, social isolation, and social exclusion. Due to its emphasis on member participation and community, the clubhouse model of mental health may help address these issues. In this study, we examined experiences of social belonging and of various social determinants of mental health among members attending a psychosocial clubhouse. Twelve members of a large psychosocial clubhouse were interviewed regarding their experiences of community life and belonging. Phenomenological qualitative methods were utilized to examine the meaning and structure of these experiences. Members overwhelmingly experienced the clubhouse as a central site of belonging ("an oasis"), but members also recounted devastating portraits of life in the outside world ("a desert"). This world presented fundamental restrictions on their movement and speech and held deeply sedimented norms pertaining to who is considered valuable, productive, and even human, which they were reminded of through an endless tyranny of questions ("what do you do," "where do you live," etc.). Life in the clubhouse presented an alternative world for members to experience nourishment, dignity, reaffirmed personhood, and a sense of beauty. And yet, the desert outside remained. Implications of these findings for clubhouses, mental health practice, and sociopolitical and community engagement are discussed, including the need to address profound deprivations and power imbalances within the wider world, beyond the walls of humane spaces such as these. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

This study was conducted to assess the utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting radiographic sacroiliitis and active disease in axial spondyloarthritis (SpA) and to explore the association between use of a tumor necrosis factor inhibitor (TNFi) and these laboratory values compared with traditional inflammatory markers.Observational data from the Program to Understand the Longterm Outcomes in Spondyloarthritis (PULSAR) registry were analyzed. We generated receiver operating characteristic curves to calculate laboratory cutoff values; we used these values in multivariable logistic regression models to identify associations with radiographically confirmed sacroiliitis and active disease. We also used logistic regression to determine the likelihood of elevated laboratory values after initiation of TNFi.Most study participants (n = 354) were White, male, and HLA-B27 positive. NLR (odds ratio [OR] 1.459, P = 0.034), PLR (OR 4.842, P 0.001), erythrocyte sedimentation rate (OR 4.397, P 0.001), and C-reactive protein (CRP) level (OR 2.911, P = 0.001) were independent predictors of radiographic sacroiliitis. Models that included PLR with traditional biomarkers performed better than those with traditional biomarkers alone. NLR (OR 6.931, P = 0.002) and CRP (OR 2.678, P = 0.004) were predictors of active disease, but the model that included both NLR and CRP performed better than CRP alone. TNFi use reduced the odds of elevated NLR (OR 0.172, P 0.001), PLR (OR 0.073, P 0.001), erythrocyte sedimentation rate (OR 0.319, P 0.001), and CRP (OR 0.407, P 0.001), but models that included NLR or PLR and traditional biomarkers performed best.These findings demonstrate an association between NLR and PLR and sacroiliitis and disease activity, with NLR and PLR showing response after TNFi treatment and adding useful clinical information to established biomarkers, thus perhaps assisting in management of axial SpA.

The Special Issue of gels titled “Advancements in Gel Science” has been published from MDPI in 2019 [...]

PurposeTo examine perceptual adaptation when people wear spectacles that produce unequal retinal image magnification.MethodsTwo groups of 15 participants (10 male; mean age 25.6 ± 4.9 years) wore spectacles with a 3.8% horizontal magnifier over one eye. The continuous-wear group wore the spectacles for 5 hours straight. The intermittent-wear group wore them for five 1-hour intervals. To measure slant and shape distortions produced by the spectacles, participants adjusted visual stimuli until they appeared frontoparallel or equiangular, respectively. Adaptation was quantified as the difference in responses at the beginning and end of wearing the spectacles. Aftereffects were quantified as the difference before and after removing the spectacles. We hypothesized that intermittent wear may lead to visual cue reweighting, so we fit a cue combination model to the data and examined changes in weights given to perspective and binocular disparity slant cues.ResultsBoth groups experienced significant shape adaptation and aftereffects. The continuous-wear group underwent significant slant adaptation and the intermittent group did not, but there was no significant difference between groups, suggesting that the difference in adaptation was negligible. There was no evidence for cue reweighting in the intermittent wear group, but unexpectedly, the weight given to binocular disparity cues for slant increased significantly in the continuous-wear group.ConclusionsWe did not find strong evidence that adaptation to spatial distortions differed between the two groups. However, there may be differences in the cue weighting strategies employed when spectacles are worn intermittently or continuously.

Present political climate and an increase in visibility and voice for Indigenous people are being leveraged to attract attention to dire social, environmental, and political issues. However, we need a more unified, organized, and coordinated policy platform, strategy, and public response. NDN Collective, an all Indigenous-led and staffed organization devoted to building Indigenous self-determination and power across Turtle Island, provides cohesion through a strong meta narrative of its Land Back campaign and an ecosystem of resources for Native Nations and peoples built around its three pillars: Defend, Develop, and Decolonize. This article shares a brief history of colonization and the lasting impacts of the American Indian Movement of the 1960s and what is needed from Indigenous leadership today. In recognizing that the collective liberation of Indigenous people is bound together with those of other Black and brown relatives, this article also explores our shared history with Black Americans and the success of the Black Lives Matter movement.

A central question in neuroscience is how sensory inputs are transformed into percepts. At this point, it is clear that this process is strongly influenced by prior knowledge of the sensory environment. Bayesian ideal observer models provide a useful link between data and theory that can help researchers evaluate how prior knowledge is represented and integrated with incoming sensory information. However, the statistical prior employed by a Bayesian observer cannot be measured directly, and must instead be inferred from behavioral measurements. Here, we review the general problem of inferring priors from psychophysical data, and the simple solution that follows from assuming a prior that is a Gaussian probability distribution. As our understanding of sensory processing advances, however, there is an increasing need for methods to flexibly recover the shape of Bayesian priors that are not well approximated by elementary functions. To address this issue, we describe a novel approach that applies to arbitrary prior shapes, which we parameterize using mixtures of Gaussian distributions. After incorporating a simple approximation, this method produces an analytical solution for psychophysical quantities that can be numerically optimized to recover the shapes of Bayesian priors. This approach offers advantages in flexibility, while still providing an analytical framework for many scenarios. We provide a MATLAB toolbox implementing key computations described herein.

STRUCTURED Summary Background Registered nurses perform numerous functions critical to the success of antimicrobial stewardship but only 63% of pre-registration nursing programmes include any teaching about stewardship. Updated nursing standards highlight nurses require antimicrobial stewardship knowledge and skills. Aim To explore the delivery of key antimicrobial stewardship competencies within updated pre-registration nursing programmes. Method A cross-sectional survey design. Data were collected between March and June 2021. Findings Lecturers from 35 UK universities responsible for teaching antimicrobial stewardship participated. The provision of antimicrobial stewardship teaching and learning was inconsistent across programmes with competencies in infection prevention and control, patient centred care, and interprofessional collaborative practice taking precedent over those pertaining to the use, management, and monitoring of antimicrobials. On-line learning and teaching surrounding hand hygiene, personal protective equipment, and immunisation theory was reported to have increased during the pandemic. Only a small number of respondents reported that students shared taught learning with other healthcare professional groups. Conclusion There is a need to ensure consistency in antimicrobial stewardship across programmes, and greater knowledge pertaining to the use, management and monitoring of antimicrobials should be included. Programmes need to adopt teaching strategies and methods that allow nurses to develop interprofessional skill in order to practice collaboratively.

Proprioception of all animals is important in being able to have coordinated locomotion. Stretch activated ion channels (SACs) transduce the mechanical force into electrical signals in the proprioceptive sensory endings. The types of SACs vary among sensory neurons in animals as defined by pharmacological, physiological and molecular identification. The chordotonal organs within insects and crustaceans offer a unique ability to investigate proprioceptive function. The effects of the extracellular environment on neuronal activity, as well as the function of associated SACs are easily accessible and viable in minimal saline for ease in experimentation. The effect of extracellular [Ca2+] on membrane properties which affect voltage-sensitivity of ion channels, threshold of action potentials and SACs can be readily addressed in the chordotonal organ in crab limbs. It is of interest to understand how low extracellular [Ca2+] enhances neural activity considering the SACs in the sensory endings could possibly be Ca2+ channels and that all neural activity is blocked with Mn2+. It is suggested that axonal excitability might be affected independent from the SAC activity due to potential presence of calcium activated potassium channels (K(Ca)) and the ability of Ca2+ to block voltage gated Na+ channels in the axons. Separating the role of Ca2+ on the function of the SACs and the excitability of the axons in the nerves associated with chordotonal organs is addressed. These experiments may aid in understanding the mechanisms of neuronal hyperexcitability during hypocalcemia within mammals.

Introduction The NHS Long Term Plan aims to ‘prevent up to 150,000 heart attacks, strokes and dementia cases over the next 10 years’.1 People with Familial Hypercholesterolaemia (FH) are considered to be at high-risk of heart attack, stroke and dementia but an estimated 90% remain undiagnosed.1 The Chesterfield and Dronfield Primary Care Network were commissioned to set-up a 12-month pharmacist-led clinic across 9 practices to identify, treat and refer FH patients. Patients with suspected FH benefit from referral to specialist services.2 Aim This study aimed to evaluate the number of FH patients identified and any unintended benefits of the Lipid Clinic. Methods Ethical approval was not required for this service evaluation. Informed consent was sought prior to data collection and the dataset was anonymised. Searches of practice patient records identified patients with a previously raised lipid level (total Cholesterol >7.5mmol/L and/or non-HDL-C > 5.9mmol/L)2 for review in the Lipid Clinic. Patients reviewed in the Lipid Clinic were initiated/optimised on lipid lowering medication as appropriate.2 Data were collected for patients invited for review in the Lipid Clinic between May-July 2022. Patients’ attendance as well as decline/non-response to the Clinic was recorded. The data collected included family history, QRISK score (where applicable), lipid lowering treatment the patient was taking (if any) and blood tests results (serum lipids, HBA1c and thyroid function tests). If bloods were deranged it was documented whether or not it was a new finding. The data was analysed by categorising patients into potential FH, primary/secondary prevention of cardiovascular disease and whether they needed referral to secondary care. Results Out of the 260 patients invited for review, 219 attended the clinic. Of these, 30 (13.7%) were provided with lifestyle advice as they did not meet the criteria for treatment. Twenty-three patients (10.5%) met the Simon-Broom criteria for possible FH. A further 3 patients identified were known to have FH but had not undergone genetic cascade testing. These 26 patients (11.8%) were referred to secondary care for genetic testing and specialist input. Newly raised HbA1c indicative of either diabetes or non-diabetic hyperglycaemia was incidentally found in 39 patients (17.8%). Lipid-lowering medication was initiated/titrated in 189 patients (86.3%). Discussion/Conclusion The significant proportion of patients requiring follow up in secondary care (11.8%) suggesting targeted searches are effective in identifying patients with possible FH. Identifying FH patients, testing and treating their family members appropriately reduces their risk of cardiovascular events.2 The Lipid Clinic has identifying that nearly a fifth of patients were previously undiagnosed with either diabetes or non-diabetic hyperglycaemia (17.8%) suggests that this is also an opportunity to identify and treat these patients earlier than they would otherwise have been identified. The results highlight the need for primary care staff education on the new AAC NHS Guidelines2 relating to managing lipid results. One limitation of the study is although the Lipid Clinic has received good informal feedback, formal feedback is yet to be collected from patients and stake holders. In addition, the clinic is still ongoing, and more data is being collected. References 1. NHS Long Term Plan. Chapter 3: Further progress on care quality and outcomes. Better care for major health conditions. Cardiovascular Disease. 2019. Available from: https://www.longtermplan.nhs.uk/online-version/chapter-3-further-progress-on-care-quality-and-outcomes/better-care-for-major-health-conditions/cardiovascular-disease/ 2. Khatib R, Neely D, on behalf of the AAC Clinical Subgroup. Summary of National Guidance for Lipid Management for Primary and Secondary Prevention of CVD, AAC NHS Guidelines, Nov 2021. Review date: Nov 2022. NICE endorsed Dec 2021. 3. National Institution for Health and Care Excellence (NICE). Cardiovascular disease: risk assessment and reduction, including lipid modification, Clinical guideline [CG181] Published: 18 July 2014 Last updated: 27 September 2016.

This work was supported by a Wellcome Trust Four-Year PhD Studentship in Basic Science to J.B. (219992/Z/19/Z) and a Wellcome Trust Senior Research Fellowship to N.P. (090868/Z/09/Z). C.M. was supported by a Sir Henry Wellcome Fellowship (103986/Z/14/Z) and University of Manchester Presidential Fellowship. M.R.’s work was supported by a Wellcome Trust Investigator Award (204832/B/16/Z). Gene expression dynamics, such as stochastic oscillations and aperiodic fluctuations, have been associated with cell fate changes in multiple contexts, including development and cancer. Single cell live imaging of protein expression with endogenous reporters is widely used to observe such gene expression dynamics. However, the experimental investigation of regulatory mechanisms underlying the observed dynamics is challenging, since these mechanisms include complex interactions of multiple processes, including transcription, translation and protein degradation. Here, we present a Bayesian method to infer kinetic parameters of oscillatory gene expression regulation using an auto-negative feedback motif with delay. Specifically, we use a delay-adapted nonlinear Kalman filter within a Metropolis-adjusted Langevin algorithm to identify posterior probability distributions. Our method can be applied to time-series data on gene expression from single cells and is able to infer multiple parameters simultaneously. We apply it to published data on murine neural progenitor cells and show that it outperforms alternative methods. We further analyse how parameter uncertainty depends on the duration and time resolution of an imaging experiment, to make experimental design recommendations. This work demonstrates the utility of parameter inference on time course data from single cells and enables new studies on cell fate changes and population heterogeneity. Publisher PDF

Acute coronary syndrome is a rare complication of vasculitis. We present a case of fulminant medium-vessel vasculitis, most likely PAN, complicated by STEMI and stroke, that was successfully treated with percutaneous revascularization, high-quality stroke care, and immunosuppression. This case highlights the importance of prompt diagnosis and treatment of vasculitis and the recognition of coronary and cerebral ischemia as potentially serious complications.

Purpose North Carolina macular dystrophy (NCMD) is an autosomal dominant, congenital disorder affecting the central retina. Here, we report clinical and genetic findings in three families segregating NCMD and use epigenomic datasets from human tissues to gain insights into the effect of NCMD-implicated variants. Methods Clinical assessment and genetic testing were performed. Publicly available transcriptomic and epigenomic datasets were analyzed and the activity-by-contact method for scoring enhancer elements and linking them to target genes was used. Results A previously described, heterozygous, noncoding variant upstream of the PRDM13 gene was detected in all six affected study participants (chr6:100,040,987G>C [GRCh37/hg19]). Interfamilial and intrafamilial variability were observed; the visual acuity ranged from 0.0 to 1.6 LogMAR and fundoscopic findings ranged from visually insignificant, confluent, drusen-like macular deposits to coloboma-like macular lesions. Variable degrees of peripheral retinal spots (which were easily detected on widefield retinal imaging) were observed in all study subjects. Notably, a 6-year-old patient developed choroidal neovascularization and required treatment with intravitreal bevacizumab injections. Computational analysis of the five single nucleotide variants that have been implicated in NCMD revealed that these noncoding changes lie within two putative enhancer elements; these elements are predicted to interact with PRDM13 in the developing human retina. PRDM13 was found to be expressed in the fetal retina, with greatest expression in the amacrine precursor cell population. Conclusions We provide further evidence supporting the role of PRDM13 dysregulation in the pathogenesis of NCMD and highlight the usefulness of widefield retinal imaging in individuals suspected to have this condition.

Gene expression dynamics, such as stochastic oscillations and aperiodic fluctuations, have been associated with cell fate changes in multiple contexts, including development and cancer. Single cell live imaging of protein expression with endogenous reporters is widely used to observe such gene expression dynamics. However, the experimental investigation of regulatory mechanisms underlying the observed dynamics is challenging, since these mechanisms include complex interactions of multiple processes, including transcription, translation, and protein degradation. Here, we present a Bayesian method to infer kinetic parameters of oscillatory gene expression regulation using an auto-negative feedback motif with delay. Specifically, we use a delay-adapted nonlinear Kalman filter within a Metropolis-adjusted Langevin algorithm to identify posterior probability distributions. Our method can be applied to time series data on gene expression from single cells and is able to infer multiple parameters simultaneously. We apply it to published data on murine neural progenitor cells and show that it outperforms alternative methods. We further analyse how parameter uncertainty depends on the duration and time resolution of an imaging experiment, to make experimental design recommendations. This work demonstrates the utility of parameter inference on time course data from single cells and enables new studies on cell fate changes and population heterogeneity.

PurposeNorth Carolina macular dystrophy (NCMD) is an autosomal dominant, congenital disorder affecting the central retina. Here, we report clinical and genetic findings in three families segregating NCMD and use epigenomic datasets from human tissues to gain insights into the effect of NCMD-implicated variants.MethodsClinical assessment and genetic testing were performed. Publicly-available transcriptomic and epigenomic datasets were analyzed and the ‘Activity-by-Contact’ (ABC) method for scoring enhancer elements and linking them to target genes was used.ResultsA previously-described, heterozygous, non-coding variant upstream of the PRDM13 gene was detected in all six affected study participants (chr6:100,040,987G>C [GRCh37/hg19]). Inter- and intra-familial variability were observed; the visual acuity ranged from 0.0 to 1.6 LogMAR and fundoscopic findings ranged from visually insignificant, confluent, drusen-like macular deposits to coloboma-like macular lesions. Variable degrees of peripheral retinal spots (which were easily detected on widefield retinal imaging) were observed in all study subjects. Notably, a 6-year-old patient developed choroidal neovascularization and required treatment with intravitreal bevacizumab injections. Computational analysis of the five single nucleotide variants that have been implicated in NCMD revealed that these non-coding changes lie within two putative enhancer elements; these elements are predicted to interact with PRDM13 in the developing human retina. PRDM13 was found to be expressed in the fetal retina, with highest expression in the amacrine precursor cell population.ConclusionsWe provide further evidence supporting the role of PRDM13 dysregulation in the pathogenesis of NCMD and highlight the utility of widefield retinal imaging in individuals suspected to have this condition.

Curriculum that informs students about social work practice with Native Peoples must be culturally relevant and responsive. However, the voices of Native Peoples are often excluded from identification of needs and relevant practice models for services. A unique partnership between the Native People from several tribes and a rural southwestern social work program led to an innovative project of curriculum development for social work practice with Native Peoples. The curriculum content evolved directly from the experiences of Native tribal members in the region. A retreat format initiated the process with subsequent quarterly meetings that provided a venue for course development with specific attention to the development of Native faculty as authors and teachers. The impact of this process is discussed through the voices of Council members, students, and Native instructors. This paper offers guidance to social work programs who are interested in expanding their understanding of Native curriculum development.

Positive Youth Development (PYD) is a theoretically founded, developmental framework that is strengths-based, incorporates ecological assets, and has been effective in supporting at-risk youth. A growing number of adolescents and young adults (AYA) with chronic conditions will survive into adulthood, and thus greater focus on understanding their long-term development is paramount. This chapter presents the development of the PYD model from a historical and theoretical lens. It introduces Lerner and Lerner’s 5Cs framework as an empirically supported perspective shown to positively impact long-term outcomes in at-risk youth. Next, the utility of the application of PYD to AYA with childhood onset chronic conditions (COCC) is examined. Finally, empirical evidence on PYD-based interventions and programs for AYA with COCC are described, and recommendations for practice are outlined. PYD remains a promising approach to support the development of positive assets and life skills in AYA with COCC.

Introduction: A study of 42,000 cardiology consults within the Veterans Health Administration (VHA) in 2016 found that patients who received electronic consultation (e-consults) had similar healthcare costs at 6 months compared to those who received face-to-face (F2F) consults. However, results may have been confounded if patients with less costly conditions received e-consults. Our aim was to compare costs between those receiving F2F vs. e-consults for a similar indication. Hypothesis: Electronic rather than F2F consultation for atrial fibrillation (AF) management will be associated with lower total healthcare costs. Methods: We conducted a retrospective cohort study of a national sample of VHA patients who received cardiology consultation in 2016. We used a natural language processing script to identify consults for AF management. Primary outcomes were total healthcare costs at 3 and 6 months. Secondary outcomes included inpatient and outpatient costs. We compared costs between groups using a generalized linear model with a gamma distribution and log link. We adjusted for community wage and Charlson comorbidity indices, distance to nearest facility, age, and gender. Standard errors were clustered at the facility level. Results: We sampled 176 F2F and 136 e-consults from 43 facilities. Mean total 6-month costs were $12,928 (95% confidence interval [CI]: 1,377; 40,644) and $8,286 (95% CI: 959; 31,320) among e-consult and F2F groups, respectively. The e-consult group had 12.3% higher 3-month (p Conclusions: Use of e-consults for AF management is associated with reduced inpatient costs at 3 months, but higher total costs, which were largely driven by outpatient costs. Improving our understanding of healthcare utilization after initial consultation, or in differences in reasons for consultation within AF management may help explain these differences.

Ultradian oscillations of HES Transcription Factors (TFs) at the single‐cell level enable cell state transitions. However, the tissue‐level organisation of HES5 dynamics in neurogenesis is unknown. Here, we analyse the expression of HES5 ex vivo in the developing mouse ventral spinal cord and identify microclusters of 4–6 cells with positively correlated HES5 level and ultradian dynamics. These microclusters are spatially periodic along the dorsoventral axis and temporally dynamic, alternating between high and low expression with a supra‐ultradian persistence time. We show that Notch signalling is required for temporal dynamics but not the spatial periodicity of HES5. Few Neurogenin 2 cells are observed per cluster, irrespective of high or low state, suggesting that the microcluster organisation of HES5 enables the stable selection of differentiating cells. Computational modelling predicts that different cell coupling strengths underlie the HES5 spatial patterns and rate of differentiation, which is consistent with comparison between the motoneuron and interneuron progenitor domains. Our work shows a previously unrecognised spatiotemporal organisation of neurogenesis, emergent at the tissue level from the synthesis of single‐cell dynamics., Live imaging of HES5 expression in the ventral mouse spinal cord combined with computational modelling is used to identify and analyse spatially periodic HES5 micro‐patterns that emerge from the synthesis of single cell dynamics.

Nanobubbles filled with air or a variety of pure gases are observed to persist in bulk water for weeks and months. Nanoemulsions consisting of oil droplets in water are also remarkably stable against coagulation, with lifetimes up to weeks even if not coated with surfactants. The inverse system of nanodroplets of water in oil is also accessible for study and application. Voids on the nanoscale are formed in simulations of water under strong tension and are stable during the time of the simulation. The stability of these nano-entities is ultimately determined by the molecular-level structure of their interfaces. However, a thermodynamic theory might also be capable of providing some insight. We therefore consider spherical gas nanobubbles, immiscible liquid nanodroplets, and nanocavities formed in water under negative pressure on the same footing, and give a unified thermodynamic analysis of these systems. In all cases, mechanical equilibrium (local free energy maximum or minimum) is expressed by the Laplace equation, and thermodynamic stability (local free energy minimum) follows from the radius dependence of surface tension. All of them would be unstable if their surface tensions were constant. Data from the literature allow construction of numerical examples for cavities and gas nanobubbles. Spectroscopic data are cited in support of an interfacial water structure in gas nanobubbles and water droplets in oil that differ from their flat surface counterparts. The observed longevity of nanobubbles in particular has been thought to violate fundamental principles of diffusion and solubility. A close look at the Laplace equation and its derivation shows why this widespread belief is incorrect.

We present a theory for a universal gel based on a McMillan-Mayer treatment of a solute-solvent fluid as a generalization of the universal van der Waals equation of state for a pure liquid/vapor system. The elastic resilience of the networked gel is modeled by a universal Langevin function. This combination of van der Waals interactions and nonlinear Langevin elasticity produces an abrupt onset of large-amplitude density fluctuations deep in the interior of the gel at a critical temperature. Then, at a second, lower, critical temperature, the entire swollen gel collapses to a high-density phase. The universal gel has an "upper" critical temperature behavior, meaning that the gel transition to high density occurs on decreasing the temperature. At the cost of loss of universality, the theory is generalized to predict lower critical temperature dependence, whereby an aqueous hydrophobic gel exhibits phase coexistence when the temperature is raised. The theory is consistent with the Gibbs phase rule, suitably generalized to coexisting phases that are not at the same pressure in equilibrium conditions.

This study presents a new framework for extracting single ion diffusion coefficients in ion exchange membranes from experimental ion sorption, salt permeability, and ionic conductivity data. The framework was used to calculate cation and anion diffusion coefficients in a series of commercial ion exchange membranes contacted by aqueous NaCl solutions. Counterion diffusion coefficients were greater than co-ion diffusion coefficients for all membranes after accounting for inherent differences due to ion size. A model for ion diffusion coefficients in ion exchange membranes, incorporating ideas from counterion condensation theory, was proposed to interpret the experimental results. The model predicted co-ion diffusion coefficients reasonably well with no adjustable parameters, while a single adjustable parameter was required to accurately describe counterion diffusion coefficients. The results suggest that for cross-linked ion exchange membranes in which counterion condensation occurs condensed counterions mi...

The physical principles underlying expansion of a single-chain polyelectrolyte coil caused by Coulomb repulsions among its ionized groups, and the expansion of a cross-linked polyelectrolyte gel, are probably the same. In this paper, we analyze a "one-dimensional" version of a gel, namely, a linear chain of charged beads connected by Hooke's law springs. In the Debye-Hückel range of relatively weak Coulomb strength, where counterion condensation does not occur, the springs are realistically stretched on a nanolength scale by the repulsive interactions among the beads, if we use a spring constant normalized by the inverse square of the solvent Bjerrum length. The persistence length and radius of gyration counter-intuitively decrease when Coulomb strength is increased, if analyzed in the framework of an OSF-type theory; however, a buckling theory generates the increase that is consistent with bead-spring simulations.

Myotonic dystrophy type 1 (DM1) is a multisystemic disease caused by an expanded CTG repeat in the 3′ UTR of the dystrophia myotonica protein kinase (DMPK) gene. Short, DNA-based antisense oligonucleotides termed gapmers are a promising strategy to degrade toxic CUG expanded repeat (CUGexp) RNA. Nucleoside analogs are incorporated to increase gapmer affinity and stability; however, some analogs also exhibit toxicity. In this study, we demonstrate that the 2′,4′-BNANC[NMe] (BNANC) modification is a promising nucleoside analog with high potency similar to 2′,4′-LNA (LNA). BNANC gapmers targeting a nonrepetitive region of the DMPK 3′ UTR show allele-specific knockdown of CUGexp RNA and revert characteristic DM1 molecular defects including mis-splicing and accumulation of RNA foci. Notably, the BNANC gapmers tested in this study did not induce caspase activation, in contrast to a sequence matched LNA gapmer. This study indicates that BNANC gapmers warrant further study as a promising RNA targeting therapeutic.

Accurate evaluation of salt diffusion coefficients from transport rate data in ion exchange membranes requires accounting for frame of reference and non-ideal thermodynamic effects. Due to a lack of models and experimental data quantifying membrane ion activity coefficients, it has been impossible to evaluate the impact of non-ideal thermodynamic effects on observed salt diffusion coefficients. Here, a framework is presented that includes both frame of reference (i.e., convection) and non-ideal thermodynamic effects in calculating salt diffusion coefficients in ion exchange membranes. Effective concentration averaged NaCl diffusion coefficients were determined as a function of upstream NaCl concentration in commercial ion exchange membranes from NaCl permeability and sorption measurements via the solution-diffusion model. Frame of reference effects were evaluated using a version of Fick's law that accounts for convection. The factors necessary to account for non-ideal thermodynamic effects were developed using Manning's counter-ion condensation theory. At low upstream NaCl concentrations, frame of reference and non-ideal thermodynamic effects on diffusion coefficients were negligible. However, at higher upstream NaCl concentrations (e.g., >0.1 M), both effects contribute measurably to NaCl diffusion coefficients. Correcting for frame of reference effects increased apparent NaCl diffusion coefficients. However, correcting for thermodynamic non-idealities of the ions sorbed into the membranes reduced apparent NaCl diffusion coefficients. Fortuitously, for the materials considered in this study, frame of reference and non-ideal thermodynamic effects nearly cancel each other.

During embryogenesis cells make fate decisions within complex tissue environments. The levels and dynamics of transcription factor expression regulate these decisions. Here, we use single cell live imaging of an endogenous HES5 reporter and absolute protein quantification to gain a dynamic view of neurogenesis in the embryonic mammalian spinal cord. We report that dividing neural progenitors show both aperiodic and periodic HES5 protein fluctuations. Mathematical modelling suggests that in progenitor cells the HES5 oscillator operates close to its bifurcation boundary where stochastic conversions between dynamics are possible. HES5 expression becomes more frequently periodic as cells transition to differentiation which, coupled with an overall decline in HES5 expression, creates a transient period of oscillations with higher fold expression change. This increases the decoding capacity of HES5 oscillations and correlates with interneuron versus motor neuron cell fate. Thus, HES5 undergoes complex changes in gene expression dynamics as cells differentiate., The single-cell gene expression changes during spinal cord formation and neurogenesis in mice are unclear. Here, the authors use a HES5 reporter to live image, then mathematically model, oscillations in single cells in presumed progenitors and neurons of the developing spinal cord.

Heading perception in primates depends heavily on visual optic-flow cues. Yet during self-motion, heading percepts remain stable even though smooth-pursuit eye movements often distort optic flow. Electrophysiological studies have identified visual areas in monkey cortex, including the dorsal medial superior temporal area (MSTd), that signal the true heading direction during pursuit. According to theoretical work, self-motion can be represented accurately by compensating for these distortions in two ways: via retinal mechanisms or via extraretinal efference-copy signals, which predict the sensory consequences of movement. Psychophysical evidence strongly supports the efference-copy hypothesis, but physiological evidence remains inconclusive. Neurons that signal the true heading direction during pursuit are found in visual areas of monkey cortex, including the dorsal medial superior temporal area (MSTd). Here we measured heading tuning in MSTd using a novel stimulus paradigm, in which we stabilize the optic-flow stimulus on the retina during pursuit. This approach isolates the effects on neuronal heading preferences of extraretinal signals, which remain active while the retinal stimulus is prevented from changing. Our results demonstrate a significant but small influence of extraretinal signals on the preferred heading directions of MSTd neurons. Under our stimulus conditions, which are rich in retinal cues, we find that retinal mechanisms dominate physiological corrections for pursuit eye movements, suggesting that extraretinal cues, such as predictive efference-copy mechanisms, have a limited role under naturalistic conditions.Significance StatementSensory systems discount stimulation caused by the animal’s own behavior. For example, eye movements cause irrelevant retinal signals that could interfere with motion perception. The visual system compensates for such self-generated motion, but how this happens is unclear. Two theoretical possibilities are a purely visual calculation or one using an internal signal of eye movements to compensate for their effects. Such a signal can be isolated by experimentally stabilizing the image on a moving retina, but this approach has never been adopted to study motion physiology. Using this method, we find that eye-movement signals have little influence on neural activity in visual cortex, while feed-forward visual calculation has a strong effect and is likely important under real-world conditions.

The dynamic process underlying muscle contraction is the parallel sliding of thin actin filaments along an immobile thick myosin fiber powered by oar-like movements of protruding myosin cross bridges (myosin heads). The free energy for functioning of the myosin nanomotor comes from the hydrolysis of ATP bound to the myosin heads. The unit step of translational movement is based on a mechanical-chemical cycle involving ATP binding to myosin, hydrolysis of the bound ATP with ultimate release of the hydrolysis products, stress-generating conformational changes in the myosin cross bridge, and relief of built-up stress in the myosin power stroke. The cycle is regulated by a transition between weak and strong actin-myosin binding affinities. The dissociation of the weakly bound complex by addition of salt indicates the electrostatic basis for the weak affinity, while structural studies demonstrate that electrostatic interactions among negatively charged amino acid residues of actin and positively charged residues of myosin are involved in the strong binding interface. We therefore conjecture that intermediate states of increasing actin-myosin engagement during the weak-to-strong binding transition also involve electrostatic interactions. Methods of polymer solution physics have shown that the thin actin filament can be regarded in some of its aspects as a net negatively charged polyelectrolyte. Here we employ polyelectrolyte theory to suggest how actin-myosin electrostatic interactions might be of significance in the intermediate stages of binding, ensuring an engaged power stroke of the myosin motor that transmits force to the actin filament, and preventing the motor from getting stuck in a metastable pre-power stroke state. We provide electrostatic force estimates that are in the pN range known to operate in the cycle.

Background Up to one-third of children will have a mental health condition. However, only 20% of these children receive mental health care and half of mental health referrals from primary care providers result in children being connected to care. Highlighting the need to improve pediatric resident training in the management of mental health issues, the AAP published a policy statement calling for enhanced mental health curriculums in pediatric residencies. Methods We developed a novel 6-month longitudinal mental health curriculum based on several existing models used to train practicing pediatricians. All pediatric residents were invited to participate; this project was IRB-exempt. The curriculum included a child psychiatrist-led, half-day orientation focused on assessment, diagnosis and management of major depressive disorder (MDD), generalized anxiety disorder (GAD), attention deficit hyperactivity disorder (ADHD) and acute behavioral events through a case-based, interactive format, as well as monthly group-based discussions of resident patients. Residents were paired with a psychiatrist consultant for as needed, real-time consultation throughout the projects duration. Residents were surveyed pre- and post-orientation for perceived comfort in the diagnosis and treatment of pediatric mental health conditions. Results Nineteen percent of (14/74) residents participated. Post-orientation, residents reported clinically meaningful increased comfort in all survey domains. Statistically significant (p Conclusions Developing and implementing a longitudinal mental health curriculum in conjunction with child psychiatrists is both feasible and results in overall improvement in residents comfort level with common mental health diagnoses.

The physical principle underlying the familiar condensation transition from vapor to liquid is the competition between the energetic tendency to condense owing to attractive forces among molecules of the fluid and the entropic tendency to disperse toward the maximum volume available as limited only by the walls of the container. Van der Waals incorporated this principle into his equation of state and was thus able to explain the discontinuous nature of condensation as the result of instability of intermediate states. The volume phase transition of gels, also discontinuous in its sharpest manifestation, can be understood similarly, as a competition between net free energy attraction of polymer segments and purely entropic dissolution into a maximum allowed volume. Viewed in this way, the gel phase transition would require nothing more to describe it than van der Waals’ original equation of state (with osmotic pressure Π replacing pressure P). But the polymer segments in a gel are networked by cross-links, and a consequent restoring force prevents complete dissolution. Like a solid material, and unlike a van der Waals fluid, a fully swollen gel possesses an intrinsic volume of its own. Although all thermodynamic descriptions of gel behavior contain an elastic component, frequently in the form of Flory-style rubber theory, the resulting isotherms usually have the same general appearance as van der Waals isotherms for fluids, so it is not clear whether the solid-like aspect of gels, that is, their intrinsic volume and shape, adds any fundamental physics to the volume phase transition of gels beyond what van der Waals already knew. To address this question, we have constructed a universal chemical potential for gels that captures the volume transition while containing no quantities specific to any particular gel. In this sense, it is analogous to the van der Waals theory of fluids in its universal form, but although it incorporates the van der Waals universal equation of state, it also contains a network elasticity component, not based on Flory theory but instead on a nonlinear Langevin model, that restricts the radius of a fully swollen spherical gel to a solid-like finite universal value of unity, transitioning to a value less than unity when the gel collapses. A new family of isotherms arises, not present in a preponderately van der Waals analysis, namely, profiles of gel density as a function of location in the gel. There is an abrupt onset of large amplitude density fluctuations in the gel at a critical temperature. Then, at a second critical temperature, the entire swollen gel collapses to a high-density phase.

The objective of this study was to use estrous behavior alone to determine the appropriate time for beginning an oxytocin treatment protocol for estrus suppression. We hypothesized that administration of oxytocin beginning 8 days after the onset of estrus will prolong the luteal phase in mares. Twenty-three light breed mares (aged 4-20 years) were exposed to a stallion and observed for signs of sexual receptivity. Mares not displaying signs received 250 μg of cloprostenol intramuscularly (IM) and were teased again 3-4 days later. On the day that estrous behavior was observed (Day 0), mares were randomly divided into two groups: oxytocin (n = 11): oxytocin (60 IU, IM) was administered once daily from Day 8-17; control (n = 12): did not receive treatment. Blood was collected from all mares every 4 days throughout Day 17, and every 7 days thereafter until Day 45. Serum progesterone concentrations1.0 ng/mL were indicative of a functioning corpus luteum. Interestrus interval was defined as the period between Day 0 and the day when progesterone next reached1.0 ng/mL. The average interestrus interval was higher for treated mares compared with control mares (32.4 ± 4.2 vs. 21.8 ± 1.5 days, respectively, P = .01). In the oxytocin group, the interestrus interval was longer than 31 days in 6 of 11 (54.5%) mares and up to 45 days in 5 of 11 mares (45.5%). We conclude that luteal maintenance beyond 30 days was attained by once-daily oxytocin administration beginning 8 days following behavioral estrus in a majority of mares.

The equilibrium volume of a polyelectrolyte gel results from a balance between the tendency to swell caused by outbound polymer/counterion diffusion along with Coulomb interactions on the one hand; and, on the other, the elastic resilience of the cross-linked polymer network. Direct Coulomb forces contribute both to non-ideality of the equilibrated Donnan osmotic pressure, but also to stretching of the network. To isolate the effect of polyelectrolyte expansion, we have analyzed a “one-dimensional” version of a gel, a linear chain of charged beads connected by Hooke’s law springs. As in the range of weak Coulomb strengths previously studied, the springs are significantly stretched by the repulsive interactions among the beads even when the Coulomb strength is strong enough to cause condensation of counterions. There is a quasi-abrupt transition from a stretched state to a partially collapsed state in a transition range between weak and strong Coulomb strengths. Fluctuations between stretched and contracted conformations occur within the transition range. As the solvent quality decreases past the transition range, a progressive collapse can result if the condensed counterions strengthen the spring constant.

We examine twist-stretch coupling of unconstrained DNA using polyelectrolyte theory as applied to a line-charge model along with published data on the ionic-strength dependence of the twist angle. We conclude that twist-stretch coupling is negative: environmental changes that stretch free DNA, unconstrained by externally applied pulling or twisting forces, are accompanied by unwinding of the double helix. We also analyze a helical model and conclude that the observed unwinding of the DNA helix when ionic strength is decreased is driven by radial swelling of the helix.