Transient and Sustained Ganglion Cell Light Responses Are Differentially Modulated by Intrinsically Produced Reactive Oxygen Species Acting upon Specific Voltage-Gated Na+ Channel Isoforms.

Increasing spike rates drive greater neuronal energy demand. In turn, mitochondrial ATP production leads to the generation of reactive oxygen species (ROS) that can modulate ion channel gating. Does ROS production autoregulate the excitability of a neuron? We investigated the links between retinal ganglion cell (RGC) excitability and spike activity-driven ROS production in male and female mice. Changes to the light-evoked and current-evoked spike patterns of functionally identified αRGC subtypes, along with their NaV channel-gating properties, were recorded during experimentally induced decreases and increases of intracellular ROS. During periods of highest spike rates (e.g., following light onset in ON sustained RGCs and light offset in OFF sustained RGCs), these αRGC subtypes responded to reductions of ROS (induced by catalase or glutathione monoethyl ester) with higher spike rates. Increases in ROS (induced by mercaptosuccinate, antimycin-A, or H2O2) lowered spike rates. In ON and OFF transient RGCs, there were no changes in spike rate during ROS decreases but increased ROS increased spiking. This suggests that endogenous ROS are intrinsic neuromodulators in RGCs having high metabolic demands but not in RGCs with lower energy needs. We identified ROS-induced shifts in the voltage-dependent gating of specific isoforms of NaV channels that account for the modulation of ON and OFF sustained RGC spike frequency by ROS-mediated feedback. ROS-induced changes to NaV channel gating, affecting activation and inactivation kinetics, are consistent with the differing spike pattern alterations observed in RGC subtypes. Cell-autonomous generation of ROS during spiking contributes to tuning the spike patterns of RGCs.SIGNIFICANCE STATEMENT Energy production within retinal ganglion cells (RGCs) is accompanied by metabolic by-products harmful to cellular function. How these by-products modulate the excitability of RGCs bears heavily on visual function and the etiology of optic neuropathies. A novel hypothesis of how RGC metabolism can produce automodulation of electrical signaling was tested by identifying the characteristics and biophysical origins of changes to the excitability of RGCs caused by oxidizing by-products in the retina. This impacts our understanding of the pathophysiology of RGC dysfunction, supporting an emerging model in which increases in oxidizing chemical species during energy production, but not necessarily bioenergetic failure, lead to preferential degeneration of specific subtypes of RGCs, yielding loss of different aspects of visual capacity.

Enhancing Congenital Cardiac Postprocedural Care: A QR Code-Enabled Medical Bracelet Pilot Study.

The study aimed to evaluate the feasibility of using QR code-enabled medical bracelets for congenital heart disease (CHD) patients after hospital discharge to ensure quick communication of vital information to other medical personnel in emergency situations. A prospective study was conducted where QR code-enabled medical bracelets were given to families of postoperative pediatric cardiac patients. The QR code linked to a secure medical information sheet detailing the patient's cardiac history. Post-study surveys were completed by providers and families to assess their experiences with the bracelet. Of the 20 participants enrolled, 65% used the QR bracelet when seeking medical care. 55% found the bracelet useful, and 70% rated their experience as either "positive" or "very positive". Additionally, 80% recommended the bracelet for other patients undergoing cardiac procedures. The use of QR code bracelets for postoperative CHD patients has shown high levels of satisfaction from families and providers, potentially reducing medical errors and treatment delays.

Current Epidemiology and Clinical Features of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand.

BACKGROUND: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete. METHODS: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included. RESULTS: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89). CONCLUSIONS: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV.

A Photoredox Reaction for the Selective Modification of 5-Carboxycytosine in DNA.

Covalent epigenetic modifications contribute to the regulation of important cellular processes during development and differentiation, and changes in their genomic distribution and frequency are linked to the emergence of genetic disease states. Chemical and enzymatic methods that selectively target the orthogonal chemical functionality of epigenetic markers are central to the study of their distribution and function, and considerable research effort has been focused on the development of nondestructive sequencing approaches which preserve valuable DNA samples. Photoredox catalysis enables transformations with tunable chemoselectivity under mild, biocompatible reaction conditions. We report the reductive decarboxylation of 5-carboxycytosine via a novel iridium-based treatment, which represents the first application of visible-light photochemistry to epigenetic sequencing via direct base conversion. We propose that the reaction involves an oxidative quenching cycle beginning with single-electron reduction of the nucleobase by the photocatalyst, followed by hydrogen atom transfer from a thiol. The saturation of the C5-C6 backbone permits decarboxylation of the nonaromatic intermediate, and hydrolysis of the N4-amine constitutes a conversion from a cytosine derivative to a T-like base. This conversion demonstrates selectivity for 5-carboxycytosine over other canonical or modified nucleoside monomers, and is thereby applied to the sequencing of 5-carboxycytosine within modified oligonucleotides. The photochemistry explored in this study can also be used in conjunction with enzymatic oxidation by TET to profile 5-methylcytosine at single-base resolution. Compared to other base-conversion treatments, the rapid photochemical reaction takes place within minutes, which could provide advantages for high-throughput detection and diagnostic applications.

Modeling incentive salience in Pavlovian learning more parsimoniously using a multiple attribute model.

We present a multi-attribute incentive salience (MAIS) model as a computational account of incentive salience in model-based Pavlovian learning. A model of incentive salience as a joint function of reward value and physiological state has been previously proposed by Zhang et al. (2009). In that model, the function takes additive or multiplicative forms depending on whether a preference shifts from positive to negative or vice versa. We demonstrate that arbitrarily varying this function is unnecessary to explain observed data. A multiplicative function is sufficient if one takes into account empirical data suggesting the incentive salience function for an incentive is comprised of multiple physiological signals. We compare our model to the previously proposed model on two datasets. We find the MAIS model predicts the outcomes equally well, fits empirical data describing multiple sensory representations of a single stimulus, better approximates the dual-structure appetitive-aversive nature of the reward system, is compatible with existing knowledge about incentive salience in Pavlovian learning, and better describes revaluation in Pavlovian learning. This model addresses a call (Dayan & Berridge, 2014) for algorithmic and computational models of model-based Pavlovian learning that consistently and fully explain empirical observations. Because a multi-attribute model is relevant even for simple Pavlovian associations, it should be useful in a wide variety of decision-making contexts, including agent modeling and addiction research.

Antibiotic treatment of common infections: more evidence to support shorter durations.

PURPOSE OF REVIEW: Although there is increasing recognition of the link between antibiotic overuse and antimicrobial resistance, clinician prescribing is often unnecessarily long and motivated by fear of clinical relapse. High-quality evidence supporting shorter treatment durations is needed to give clinicians confidence to change prescribing habits. Here we summarize recent randomized controlled trials investigating antibiotic short courses for common infections in adult patients. RECENT FINDINGS: Randomized trials in the last five years have demonstrated noninferiority of short-course therapy for a range of conditions including community acquired pneumonia, intraabdominal sepsis, gram-negative bacteraemia and vertebral osteomyelitis. SUMMARY: Treatment durations for many common infections have been based on expert opinion rather than randomized trials. There is now evidence to support shorter courses of antibiotic therapy for many conditions.

Outcomes for Ectopia Cordis.

OBJECTIVES: To utilize a large multicenter neonatal cohort to describe survival and clinical outcomes of very low birth weight (VLBW) or preterm infants with ectopia cordis. STUDY DESIGN: Data were prospectively collected on 2 211 262 infants (born 2000-2017) from 845 US centers. Both VLBW (401-1500 g or 22-29 weeks of gestation) and non-VLBW (>1500 g and >29 weeks) infants had diagnoses or anatomic descriptors consistent with ectopia cordis and/or pentalogy of Cantrell. The primary outcome was neonatal survival, defined as hospital discharge or initial length of stay of ≥12 months. RESULTS: In total, 180 infants had ectopia cordis, 135 (76%) with findings of pentalogy of Cantrell. VLBW infants comprised 52% of the population. VLBW mortality was 96% with 79% dying within 12 hours, compared with 59% and 36%, respectively, for non-VLBW. One-third of VLBW infants received life support compared with 65% of non-VLBW. Surgery was reported for 34% of VLBW and 68% of non-VLBW infants. Congenital heart disease was reported in 8% of VLBW and 36% of non-VLBW, with conotruncal abnormalities most common. Survival exceeded 50% for infants >2500 g and >37 weeks of gestation. CONCLUSIONS: Survival of VLBW infants with ectopia cordis was poor and substantially worse compared with non-VLBW, with notable discrepancies in resuscitative efforts and surgical interventions. Although gestational age and weight strongly influence current survival, more detailed information regarding the severity of cardiac and noncardiac abnormalities is required to fully determine prognosis and inform counseling.

Using Neural Networks as Models of Personality Process: A Tutorial.

This paper presents a tutorial for creating neural network models of personality processes. Such models enable researchers to create explicit models of both personality structure and personality dynamics, and to address issues of recent concern in personality, such as, "If personality is stable, then how is it possible that within subject variability in personality states can be as large as or larger than between subject variability in personality?" or "Is it possible to understand personality dynamics and personality structure within a common framework?" We discuss why one should want to use neural networks, review what a neural network model is, review a previous model we have constructed, discuss how to conceptualize issues in such a way that they can be computationally modeled, show how that conceptualization can be translated into a model, and discuss the utility of such models for understanding personality structure and personality dynamics. To build our model we use a neural network modeling package called emergent that is freely available, and a specific architecture called Leabra to build a runnable model that addresses one of the questions posed above: How can within subject variability in personality related states be as large as between subject variability in personality?

PAs are a solution to the growing need for clinicians to treat an aging population.

OBJECTIVE: To elucidate the types of patients cared for by physician assistants (PAs), specifically older adults and those with complex medical conditions. METHODS: A nationwide survey was sent to PAs asking about their practice demographics, including the complexity of their patients and the types of treatment they provide; 676 responded. RESULTS: Less than 2% of PAs specialize in geriatrics but 92.1% of PAs see patients over age 65 years. Most PAs see patients with conditions associated with aging, including hypertension (85.8%) and osteoarthritis (82.1%) as well as those with three or more comorbidities (54.8%) or who are medically complex (52.8%). CONCLUSIONS: Although few PAs work exclusively in geriatrics, most PAs are providing medical care for older adults and patients with complex healthcare needs. PAs should be considered to fill healthcare needs that will continue to exist when caring for this patient population.

Specialty certification and clinical flexibility.

The ability for PAs to easily move from one specialty to another without additional formal training is a unique feature of the profession that is valued by PAs and their employers. Specialty certification has been viewed as a threat to this flexibility, yet 73% of PAs are in specialty practice. How can the desire to preserve flexibility be balanced against the desire of specialized PAs to distinguish themselves in their chosen specialty? This article reviews the issue of specialty certification in the context of contemporary PA practice and concludes that although specialty certification remains a threat to the flexibility of the PA model, it may be appropriate in some situations. In particular, specialty certification may be appropriate as a means for promotion within healthcare systems so long as it is not used as a requirement for entry into specialty practice, credentialing, or third-party reimbursement. A portfolio model may give stakeholders an alternative way to assess the experience and competencies of PAs in specialty practice areas.

The role of the dorsal anterior insula in sexual risk: Evidence from an erotic Go/NoGo task and real-world risk-taking.

The insula plays an important role in response inhibition. Most relevant here, it has been proposed that the dorsal anterior insular cortex (dAIC) plays a central role in a salience network that is responsible for switching between the default mode network and the executive control network. However, the insula's role in sexually motivated response inhibition has not yet been studied. In this study, eighty-five 18- to 30-year-old sexually active men who have sex with men (MSM) performed an erotic Go/NoGo task while in an MRI scanner. Participants' real-world sexual risk-taking (frequency of condomless anal intercourse over the past 90 days) was then correlated with their neural activity during the task. We found greater activity in bilateral anterior insular cortex (both dorsal and ventral) on contrasts with stronger motivational information (attractive naked male pictures versus pictures of clothed, middle-aged females) and on contrasts requiring greater response inhibition (NoGo versus Go). We also found that activity in the right dAIC was negatively correlated with participants' real-world sexual risk-taking. Our results confirmed the involvement of the insular cortex in motivated response inhibition. Especially, the decreased right dAIC activity may reduce the likelihood that the executive control network will come online when individuals are faced with situations requiring inhibitory control and thus lead them to make more risky choices.

Prefrontal Cortical Activity During the Stroop Task: New Insights into the Why and the Who of Real-World Risky Sexual Behavior.

Background: Research suggests that deficits in both executive functioning and trait impulsivity may play a role in risky sexual behavior. At the neural level, differences in regulation of the prefrontal cortex have been linked to impulsivity, measured neurocognitively and through self-report. The relationship between neurocognitive measures of executive control and trait impulsivity in predicting risky sexual behavior has not been investigated. Purpose: To investigate the relationship between neural functioning during the Stroop task and risky sexual behavior, as well as the effect of individual differences in urgent (positive and negative) impulsivity on this relationship. Methods: A total of 105 sexually active men who have sex with men completed the Stroop task during functional magnetic resonance imaging scanning. They also completed impulsivity inventories and self-reported their risky sexual behavior (events of condomless anal sex in the last 90 days). Results: Risky participants had greater activation than safe participants during the color congruent condition of the Stroop task in anterior cingulate cortex/dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, left frontal pole, and right insula. Across these regions, this neural activation mediated the link between (positive and/or negative) urgent impulsivity and risky sexual behavior. Conclusions: Findings suggest that the brains of men who engage in risky sexual behavior may employ a different distribution of cognitive resources during tasks of executive functioning than men who practice safe sex, and that this may relate to differences in the prefrontal cortical/fronto-insular system responsible for impulse control.

The grazing gait, and implications of toppling table geometry for primate footfall sequences.

Many medium and large herbivores locomote forwards very slowly and intermittently when grazing. While the footfall order during grazing is the same as for walking, the relative fore-hind timing-phasing-is quite different. Extended periods of static stability are clearly required during grazing; however, stability requirements are insufficient to account for the timing. Aspects of relatively rapid rolling and pitching-toppling due to the resistance of the back to bending and twisting-can be included in a simplifying geometric model to explain the observation that, in grazing livestock, a step forward with a forefoot is consistently and immediately followed by a step forward from the hind; but not vice versa. The same principles and geometry, but applied to the footfall pattern of walking primates, show that toppling would occur at a different point in the gait cycle. This provides a potential account for the distinctive diagonal-sequence footfall pattern of primates, as it prevents the instant of toppling from being at forefoot placement. Careful and controlled hand positioning would thus be facilitated, presumably beneficial to walking on top of branches, despite a slight energetic cost compared with the usual lateral sequence pattern of horses.

Alopecia due to high androgen index contraceptives.

Adverse reactions to hormonal contraceptives are a common patient concern. Alopecia, an adverse reaction to androgen activity caused by the progestin component of hormonal contraceptives, can cause considerable psychosocial distress for women. This article discusses how to identify the level of androgen activity in certain progestins, how increased androgen activity can lead to hair loss, and alternatives for patients experiencing androgenic alopecia due to high androgen index contraceptives.

Preparing patients for biologic medications for dermatologic and rheumatic diseases.

Psoriasis, psoriatic arthritis, and rheumatoid arthritis are prevalent conditions that often require a team of primary care and specialist healthcare professionals for the most optimum patient outcomes. Primary care providers can facilitate referrals to dermatology and rheumatology specialists by obtaining the needed screening workup for patients who need treatment with immunosuppressive therapies. This article reviews tuberculosis screening, hepatitis screening, and vaccinations to be administered before patients begin biologic medications.

Accreditation and implications of clinical postgraduate PA training programs.

No consensus definition exists for postgraduate physician assistant (PA) training. This report from the AAPA Task Force on Accreditation of Postgraduate PA Training Programs describes the types of clinical training programs and their effects on hiring and compensation of PAs. Although completing a postgraduate program appears to have no effect on compensation, PAs who complete these programs may be favored in the hiring process and frequently report greater confidence in their skills. More research is needed and program accreditation is key to monitoring the effectiveness of these programs.

Influences of Dilute Organic Adsorbates on the Hydration of Low-Surface-Area Silicates.

Competitive adsorption of dilute quantities of certain organic molecules and water at silicate surfaces strongly influence the rates of silicate dissolution, hydration, and crystallization. Here, we determine the molecular-level structures, compositions, and site-specific interactions of adsorbed organic molecules at low absolute bulk concentrations on heterogeneous silicate particle surfaces at early stages of hydration. Specifically, dilute quantities (∼0.1% by weight of solids) of the disaccharide sucrose or industrially important phosphonic acid species slow dramatically the hydration of low-surface-area (∼1 m(2)/g) silicate particles. Here, the physicochemically distinct adsorption interactions of these organic species are established by using dynamic nuclear polarization (DNP) surface-enhanced solid-state NMR techniques. These measurements provide significantly improved signal sensitivity for near-surface species that is crucial for the detection and analysis of dilute adsorbed organic molecules and silicate species on low-surface-area particles, which until now have been infeasible to characterize. DNP-enhanced 2D (29)Si{(1)H}, (13)C{(1)H}, and (31)P{(1)H} heteronuclear correlation and 1D (29)Si{(13)C} rotational-echo double-resonance NMR measurements establish hydrogen-bond-mediated adsorption of sucrose at distinct nonhydrated and hydrated silicate surface sites and electrostatic interactions with surface Ca(2+) cations. By comparison, phosphonic acid molecules are found to adsorb electrostatically at or near cationic calcium surface sites to form Ca(2+)-phosphonate complexes. Although dilute quantities of both types of organic molecules effectively inhibit hydration, they do so by adsorbing in distinct ways that depend on their specific architectures and physicochemical interactions. The results demonstrate the feasibility of using DNP-enhanced NMR techniques to measure and assess dilute adsorbed molecules and their molecular interactions on low-surface-area materials, notably for compositions that are industrially relevant.

Dopamine modulation of rod pathway signaling by suppression of GABAC feedback to rod-driven depolarizing bipolar cells.

Reducing signal gain in the highly sensitive rod pathway prevents saturation as background light levels increase, allowing the dark-adapted retina to encode stimuli over a range of background luminances. Dopamine release is increased during light adaptation and is generally accepted to suppress rod signaling in light-adapted retinas. However, recent research has suggested that dopamine, acting through D1 receptors, could additionally produce a sensitization of the rod pathway in dim light conditions via gamma-aminobutyric acid (GABA) type C receptors. Here, we evaluated the overall activity of the depolarizing bipolar cell (DBC) population in vivo to ensure the integrity of long-distance network interactions by quantifying the b-wave of the electroretinogram in mice. We showed that dopamine, acting through D1 receptors, reduced the amplitude and sensitivity of rod-driven DBCs during light adaptation by suppressing GABA type A receptor-mediated serial inhibition onto rod DBC GABA type C receptors. Block of D1 receptors did not suppress rod-driven DBC sensitivity when GABAA -mediated serial inhibition was blocked by gabazine, suggesting that the reduction in rod-driven DBC sensitivity in the absence of D1 receptors was due to disinhibition of serial inhibitory GABAergic circuitry rather than a direct facilitatory effect on GABA release onto rod-driven DBC GABA type C receptors. Finally, the large population of GABAergic A17 wide-field amacrine cells known to maintain reciprocal inhibition with rod DBCs could be excluded from the proposed disinhibitory circuit after treatment with 5,7-dihydroxytryptamine.

Contribution of retinal ganglion cells to the mouse electroretinogram.

PURPOSE: To quantify the direct contribution of retinal ganglion cells (RGCs) on individual components of the mouse electroretinogram (ERG). METHODS: Dark- and light-adapted ERGs from mice 8 to 12 weeks after optic nerve transection (ONTx, n=14) were analyzed through stimulus response curves for a- and b-waves, oscillatory potentials (OPs), positive and negative scotopic threshold response (p/n STR), and the photopic negative response (PhNR) and compared with unoperated and sham-operated controls, as well as to eyes treated with 6-cyano-7-nitroquinoxaline-2,3-dion (CNQX). RESULTS: We confirmed in mice that CNQX intravitreal injection reduced the scotopic a-wave amplitude at high flash strength, confirming a post-receptoral contribution to the a-wave. We found that ONTx, which is more specific to RGCs, did not affect the a-wave amplitude and implicit time in either photopic or scotopic conditions while the b-wave was reduced. Both the pSTR and nSTR components were reduced in amplitude, with the balance between the two components resulting in a shortening of the nSTR peak implicit time. On the other hand, amplitude of the PhNR was increased while the OPs were minimally affected. CONCLUSION: With an intact a-wave demonstrated following ONTx, we find that the most robust indicators of RGC function in the mouse full-field ERG were the STR components.

Origins of saccharide-dependent hydration at aluminate, silicate, and aluminosilicate surfaces.

Sugar molecules adsorbed at hydrated inorganic oxide surfaces occur ubiquitously in nature and in technologically important materials and processes, including marine biomineralization, cement hydration, corrosion inhibition, bioadhesion, and bone resorption. Among these examples, surprisingly diverse hydration behaviors are observed for oxides in the presence of saccharides with closely related compositions and structures. Glucose, sucrose, and maltodextrin, for example, exhibit significant differences in their adsorption selectivities and alkaline reaction properties on hydrating aluminate, silicate, and aluminosilicate surfaces that are shown to be due to the molecular architectures of the saccharides. Solid-state (1)H, (13)C, (29)Si, and (27)Al nuclear magnetic resonance (NMR) spectroscopy measurements, including at very high magnetic fields (19 T), distinguish and quantify the different molecular species, their chemical transformations, and their site-specific adsorption on different aluminate and silicate moieties. Two-dimensional NMR results establish nonselective adsorption of glucose degradation products containing carboxylic acids on both hydrated silicates and aluminates. In contrast, sucrose adsorbs intact at hydrated silicate sites and selectively at anhydrous, but not hydrated, aluminate moieties. Quantitative surface force measurements establish that sucrose adsorbs strongly as multilayers on hydrated aluminosilicate surfaces. The molecular structures and physicochemical properties of the saccharides and their degradation species correlate well with their adsorption behaviors. The results explain the dramatically different effects that small amounts of different types of sugars have on the rates at which aluminate, silicate, and aluminosilicate species hydrate, with important implications for diverse materials and applications.