Neuronal Mechanisms that Drive Organismal Aging Through the Lens of Perception.

Sensory neurons provide organisms with data about the world in which they live, for the purpose of successfully exploiting their environment. The consequences of sensory perception are not simply limited to decision-making behaviors; evidence suggests that sensory perception directly influences physiology and aging, a phenomenon that has been observed in animals across taxa. Therefore, understanding the neural mechanisms by which sensory input influences aging may uncover novel therapeutic targets for aging-related physiologies. In this review, we examine different perceptive experiences that have been most clearly linked to aging or age-related disease: food perception, social perception, time perception, and threat perception. For each, the sensory cues, receptors, and/or pathways that influence aging as well as the individual or groups of neurons involved, if known, are discussed. We conclude with general thoughts about the potential impact of this line of research on human health and aging.

Integrating sensory ecology and predator-prey theory to understand animal responses to fire.

Fire regimes are changing dramatically worldwide due to climate change, habitat conversion, and the suppression of Indigenous landscape management. Although there has been extensive work on plant responses to fire, including their adaptations to withstand fire and long-term effects of fire on plant communities, less is known about animal responses to fire. Ecologists lack a conceptual framework for understanding behavioural responses to fire, which can hinder wildlife conservation and management. Here, we integrate cue-response sensory ecology and predator-prey theory to predict and explain variation in if, when and how animals react to approaching fire. Inspired by the literature on prey responses to predation risk, this framework considers both fire-naïve and fire-adapted animals and follows three key steps: vigilance, cue detection and response. We draw from theory on vigilance tradeoffs, signal detection, speed-accuracy tradeoffs, fear generalization, neophobia and adaptive dispersal. We discuss how evolutionary history with fire, but also other selective pressures, such as predation risk, should influence animal behavioural responses to fire. We conclude by providing guidance for empiricists and outlining potential conservation applications.

Proton density water fraction as a reproducible MR-based measurement of breast density.

PURPOSE: To introduce proton density water fraction (PDWF) as a confounder-corrected (CC) MR-based biomarker of mammographic breast density, a known risk factor for breast cancer. METHODS: Chemical shift encoded (CSE) MR images were acquired using a low flip angle to provide proton density contrast from multiple echo times. Fat and water images, corrected for known biases, were produced by a six-echo CC CSE-MRI algorithm. Fibroglandular tissue (FGT) volume was calculated from whole-breast segmented PDWF maps at 1.5T and 3T. The method was evaluated in (1) a physical fat-water phantom and (2) normal volunteers. Results from two- and three-echo CSE-MRI methods were included for comparison. RESULTS: Six-echo CC-CSE-MRI produced unbiased estimates of the total water volume in the phantom (mean bias 3.3%) and was reproducible across protocol changes (repeatability coefficient [RC] = 14.8 cm3 and 13.97 cm3 at 1.5T and 3.0T, respectively) and field strengths (RC = 51.7 cm3 ) in volunteers, while the two- and three-echo CSE-MRI approaches produced biased results in phantoms (mean bias 30.7% and 10.4%) that was less reproducible across field strengths in volunteers (RC = 82.3 cm3 and 126.3 cm3 ). Significant differences in measured FGT volume were found between the six-echo CC-CSE-MRI and the two- and three-echo CSE-MRI approaches (p = 0.002 and p = 0.001, respectively). CONCLUSION: The use of six-echo CC-CSE-MRI to create unbiased PDWF maps that reproducibly quantify FGT in the breast is demonstrated. Further studies are needed to correlate this quantitative MR biomarker for breast density with mammography and overall risk for breast cancer.

Dermatology urgent care model reduces costs and healthcare utilization for psychodermatology patients - a retrospective chart review.

BACKGROUND: Patients with psychiatric dermatoses may be high users of healthcare, especially emergency services. A dermatology urgent care model may reduce healthcare utilization in this population. OBJECTIVE: To determine whether a dermatology urgent care model can reduce healthcare utilization among patients with psychiatric dermatoses. METHODS: We conducted a retrospective chart review of patients seen in dermatology urgent care at Oregon Health and Science University between 2018 and 2020 with diagnoses of Morgellons disease and neurotic excoriations. Rates of diagnosis-related healthcare visits and emergency department visits were annualized before and during engagement with the dermatology department. Rates were compared using paired t-tests. RESULTS: We found an 88.0% reduction in annual rates of healthcare visits (P<0.001) and 77.0% reduction in emergency room visits (P<0.003). Results were unchanged when controlled for gender identity, diagnosis, and substance use. LIMITATIONS: We could not account for healthcare use not included in electronic health record. CONCLUSION: Urgent care models in dermatology may reduce overuse of healthcare and emergency services among patients with psychiatric dermatoses.

Direct Costs of Healthcare among Patients with Deliberate Self-harm: A Pilot Study from a Tertiary Care Hospital in South India.

Background: Deliberate self-harm (DSH) in developing nations has a significant impact on health and economic conditions of patients and families. Materials and methods: This retrospective study aims to study the cost of hospitalization and the factors affecting the cost of medical care. Adult patients with a diagnosis of DSH were included. Results: A total of 107 patients were included with the most common type of poison consumed being pesticides (35.5%) followed by a tablet overdose (31.8%). There was a male preponderance with a mean (SD) age of 30.04 (9.03) years. The median cost of admission was ₹13,690 (USD 195.57); DSH with pesticide increased the cost of care by 67% as compared to non-pesticides. Other factors which increased the cost were need for intensive care, ventilation, use of vasopressors, and development of ventilator-associated pneumonia (VAP). Conclusions: Pesticide-based poisoning is the most frequent cause of DSH. Among different types of DSH, pesticide poisoning is associated with a higher direct cost of hospitalization. How to cite this article: Barnabas R, Yadav B, Jayakaran J, Gunasekaran K, Johnson J, Pichamuthu K, et al. Direct Costs of Healthcare among Patients with Deliberate Self-harm: A Pilot Study from a Tertiary Care Hospital in South India. Indian J Crit Care Med 2022;26(7):836-838.

Life history predicts flight muscle phenotype and function in birds.

Functional traits are the essential phenotypes that underlie an organism's life history and ecology. Although biologists have long recognized that intraspecific variation is consequential to an animals' ecology, studies of functional variation are often restricted to species-level comparisons, ignoring critical variation within species. In birds, interspecific comparisons have been foundational in connecting flight muscle phenotypes to species-level ecology, but intraspecific variation has remained largely unexplored. We asked how age- and sex-dependent demands on flight muscle function are reconciled in birds. The flight muscle is an essential multifunctional organ, mediating a large range of functions associated with powered flight and thermoregulation. These functions must be balanced over an individual's lifetime. We leveraged within- and between-species comparisons in a clade of small passerines (Tarsiger bush-robins) from the eastern edge of the Qinghai-Tibet Plateau. We integrated measurements of flight muscle physiology, morphology, behaviour, phenology and environmental data, analysing trait data within a context of three widespread, adaptive life-history strategies-sexual dichromatism, age and sex-structured migration, and delayed plumage maturation. This approach provides a framework of the selective forces that shape functional variation within and between species. We found more variation in flight muscle traits within species than has been previously described between species of birds under 20 g. This variation was associated with the discovery of mixed muscle fibre types (i.e. both fast glycolytic and fast oxidative fibres), which differ markedly in their physiological and functional attributes. This result is surprising given that the flight muscles of small birds are generally thought to contain only fast oxidative fibres, suggesting a novel ecological context for glycolytic muscle fibres in small birds. Within each species, flight muscle phenotypes varied by age and sex, reflecting the functional demands at different life-history stages and the pressures that individuals face as a result of their multi-class identity (i.e. species, age and sex). Our findings reveal new links between avian physiology, ecology, behaviour and life history, while demonstrating the importance of demographic-dependent selection in shaping functional phenotypic variation.

Inpatient teledermatology: Diagnostic and therapeutic concordance among a hospitalist, dermatologist, and teledermatologist using store-and-forward teledermatology.

BACKGROUND: Inpatient dermatology has been shown to improve patient outcomes at a reduced cost. Few hospitals have dermatologists available. Teledermatology may allow dermatologists to assess hospitalized patients remotely. OBJECTIVE: To examine the diagnostic concordance between a hospitalist, dermatologist, and teledermatologist using store-and-forward teledermatology. METHODS: For 100 consecutive patients requiring inpatient dermatology consultation, a survey was conducted by all 3 raters to convey diagnostic impressions and therapeutic recommendations. Complete and partial agreements were assessed using the Cohen kappa statistic. RESULTS: Inpatient dermatology consultation often resulted in a change in diagnosis (50.9%) and a change in systemic therapy (41.5%). Likewise, virtual teledermatology consultation would have resulted in a change in diagnosis (54.7%) and a change in systemic therapy (47.2%) at similar rates. Comparing the dermatologist and teledermatologists, diagnostic complete and partial agreement were 52.8% and 84.9%, respectively. Systemic therapy agreement was 77.4%. Teledermatologists recommended biopsy more often (68.5% vs 43.5%). LIMITATIONS: Small sample size, tertiary academic medical center, single rater for inpatient teledermatology with specific inpatient niche. CONCLUSION: Teledermatologists performed comparably to an in-person dermatologist for the diagnosis and management of hospitalized patients with skin conditions. Teledermatology may be a suitable alternative for delivery of inpatient care if no dermatologist is available.

Community-derived recommendations for healthcare systems and medical students to support people who are houseless in Portland, Oregon: a mixed-methods study.

BACKGROUND: People who are houseless (also referred to as homeless) perceive high stigma in healthcare settings, and face disproportionate disparities in morbidity and mortality versus people who are housed. Medical students and the training institutions they are a part of play important roles in advocating for the needs of this community. The objective of this study was to understand perceptions of how medical students and institutions can meet needs of the self-identified needs of the houseless community. METHODS: Between February and May 2018, medical students conducted mixed-methods surveys with semi-structured qualitative interview guides at two community-based organizations that serve people who are houseless in Portland, Oregon. Medical students approach guests at both locations to ascertain interest in participating in the study. Qualitative data were analyzed using thematic analysis rooted in an inductive process. RESULTS: We enrolled 38 participants in this study. Most participants were male (73.7%), white (78.9%), and had been houseless for over a year at the time of interview (65.8%). Qualitative themes describe care experiences among people with mental health and substance use disorders, and roles for medical students and health-care institutions. Specifically, people who are houseless want medical students to 1) listen to and believe them, 2) work to destigmatize houselessness, 3) engage in diverse clinical experiences, and 4) advocate for change at the institutional level. Participants asked healthcare institutions to use their power to change laws that criminalize substance use and houselessness, and build healthcare systems that take better care of people with addiction and mental health conditions. CONCLUSIONS: Medical students, and the institutions they are a part of, should seek to reduce stigma against people who are houseless in medical systems. Additionally, institutions should change their approaches to healthcare delivery and advocacy to better support the health of people who are houseless.

Comparative Effectiveness of Topically Administered Tranexamic Acid Versus Topical Oxymetazoline Spray for Achieving Hemostasis in Epistaxis.

BACKGROUND: The use of tranexamic acid (TXA) has recently gained popularity as a treatment modality for epistaxis in the emergency department. Previous studies have compared topical TXA to nasal packing. However, topical TXA has not yet been compared with topical oxymetazoline in the treatment of epistaxis. OBJECTIVES: This study compares the efficacy of the intravenous formulation of TXA applied topically vs. the vasoconstrictor oxymetazoline applied topically in achieving hemostasis in patients presenting to the emergency department with anterior epistaxis. METHODS: In this prospective study, patients presenting to the emergency department with the chief complaint of epistaxis, and meeting inclusion criteria, were allocated into 2 treatment groups; topical oxymetazoline vs. topical application of the intravenous preparation of TXA. Patients were assessed for time to hemostasis in the emergency department as well as the occurrence of rebleeding within the next 48 h after discharge. RESULTS: Hemostasis was achieved in 14 (78%) of the 18 patients in the TXA group compared with 7 (35%) of the 20 patients in the oxymetazoline group. While there were occurrences of rebleeding in the emergency department before discharge and at 48 h in both groups, 11 patients in the TXA group had no recurrence of bleeding compared with 5 in the oxymetazoline group. CONCLUSION: This study demonstrated that the topical application of the intravenous preparation of TXA is more effective than topical oxymetazoline for achievement of hemostasis in anterior epistaxis. This has clinical significance toward preventing an avoidable need for escalation of treatment that could include applying nasal packing or cautery as well as preventing avoidable return emergency department visits. These outcomes would increase cost, potentially increase patient discomfort, and prolong emergency department throughput time.

Adsorption kinetics of the herbicide safeners, benoxacor and furilazole, to activated carbon and agricultural soils.

Chloroacetamide herbicides, namely acetochlor and metolachlor, are common herbicides used on corn and soybean fields. Dichloroacetamide safeners, namely benoxacor and furilazole, are commonly used in formulations containing chloroacetamide herbicides. Extensive reports on adsorption of chloroacetamide herbicides are available, yet little information exists regarding adsorption potential of co-applied safeners. Herein, the adsorption and desorption characteristics of selected herbicide safeners to granular activated carbon (GAC) and in agricultural soils are reported. Further, soil column studies were performed to understand the leaching behaviour of the herbicide Dual II Magnum. Equilibrium sorption experiments of safeners to three agricultural soils and one GAC showed that adsorption was best fitted by the Freundlich isotherm. The Freundlich adsorption constant, Kf, for benoxacor and furilazole sorption onto three agricultural soils ranged from 0.1 to 0.27 and 0.1 to 0.13 (mg/g) × (mg/L)ˆ(1/n), respectively. The Kf for benoxacor and furilazole to GAC was 6.4 and 3.4 (mg/g) × (mg/L)ˆ(1/n), respectively, suggesting more favorable sorption of benoxacor to GAC than furilazole to GAC. The sorption to soils was reversible as almost 40%-90% of both safeners was desorbed from three soils. These results were validated in four replicated soil column studies, where S-metolachlor was shown to leach similarly to the safener benoxacor, originating from the herbicide formulation. The leaching of S-metolachlor and benoxacor was influenced by soil texture. Cumulatively, these results show that safeners will move through the environment to surface waters similarly to the active ingredients in herbicides, but may be removed during drinking water treatment via GAC.

Gene expression signature of atypical breast hyperplasia and regulation by SFRP1.

BACKGROUND: Atypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by ~ 4-fold. AH lesions are estrogen receptor alpha positive (ERα+) and represent risk indicators and/or precursor lesions to low grade ERα+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation. METHODS: In this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues. RESULTS: A 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERα, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels. CONCLUSIONS: The alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.

Stainless-Steel Column for Robust, High-Temperature Microchip Gas Chromatography.

This paper reports the first results of a robust, high-performance, stainless-steel microchip gas-chromatography (GC) column that is capable of analyzing complex real-world mixtures as well as operating at very high temperatures. Using a serpentine design, a 10 m column with an approximately semicircular cross-section with a 52 µm hydraulic diameter ( Dh) was produced in a 17 × 6.3 × 0.1 cm rectangular steel chip. The channels were produced using a multilayer-chemical-etch and diffusion-bonding process, and metal nuts were brazed onto the inlet and outlet ports allowing for column interfacing with ferrules and fused silica capillary tubing. After deactivating the metal surface, channels were statically coated with a ≈0.1 µm layer of 5% phenyl-1% vinyl-methylpolysiloxane (SE-54) stationary phase and cross-linked with dicumyl peroxide. By using n-tridecane ( n-C13) as a test analyte with a retention factor ( k) of 5, a total of 44 500 plates (≈4500 plates per meter) was obtained isothermally at 120 °C. The column was thermally stable to at least 350 °C, and rapid temperature programming (35 °C/min) was demonstrated for the boiling-point range from n-C5 to n-C44 (ASTM D2887 simulated-distillation standard). The column was also tested for separation of two complex mixtures: gasoline headspace and kerosene. These initial experiments demonstrate that the planar stainless-steel column with proper interfacing can be a viable alternative platform for portable, robust microchip GC that is capable of high-temperature operation for low-volatility-compound analysis.

Three additional patients with EED-associated overgrowth: potential mutation hotspots identified?

Variants have been identified in the embryonic ectoderm development (EED) gene in seven patients with syndromic overgrowth similar to that observed in Weaver syndrome. Here, we present three additional patients with missense variants in the EED gene. All the missense variants reported to date (including the three presented here) have localized to one of seven WD40 domains of the EED protein, which are necessary for interaction with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). In addition, among the seven patients reported in the literature and the three new patients presented here, all of the reported pathogenic variants except one occurred at one of four amino acid residues in the EED protein. The recurrence of pathogenic variation at these loci suggests that these residues are functionally important (mutation hotspots). In silico modeling and calculations of the free energy changes resulting from these variants suggested that they not only destabilize the EED protein structure but also adversely affect interactions between EED, EZH2, and/or H3K27me3. These cases help demonstrate the mechanism(s) by which apparently deleterious variants in the EED gene might cause overgrowth and lend further support that amino acid residues in the WD40 domain region may be mutation hotspots.

Relationship of Activity Patterns to Acute Mountain Sickness in South Pole Workers.

This study aimed to evaluate the influence of physical activity on incidence of acute mountain sickness (AMS) by continuous activity monitoring in a free-living sample of South Pole workers over the initial 72 h at altitude exposure of 2,840 m (9,318 ft). Body Media activity monitors were worn by 47 healthy participants. AMS was defined by the Lake Louise symptom questionnaire. Venous blood samples were taken at sea level and approximately 48 h after high altitude exposure. AMS incidence was 34% (n=16/47) over the first 48 h and 40% (n=19/47) over 72 h. On day 2 at high altitude, individuals with AMS demonstrated a significantly greater increase in the percent change in physical activity metrics from baseline: total energy expenditure 19±13 vs. 5±7%, total steps 65±51 vs. 10±18%, metabolic equivalent of tasks 21±13 vs. 7±13%, and time spent performing moderate to vigorous physical activity 114±79 vs. 26±27% for individuals with AMS vs. no AMS, respectively, p<0.05. In addition, erythropoietin and vascular endothelial growth factor were 1.69 and 1.75 times higher, respectively, in those with AMS. In conclusion, workers who engaged in increased physical activity and activity intensity during initial exposure to the South Pole were more susceptible to developing AMS.

Ex Vivo Reconstruction and Autotransplantation for Hilar Renal Artery Aneurysms in Patients with Congenital Anomalies.

Renal artery aneurysms (RAAs) are an uncommon finding but are more often associated with other congenital disorders. The complex (hilar) RAAs constitute a subset of RAAs that present a therapeutic dilemma for the vascular surgeon because of their anatomic location. This dilemma worsens when hilar RAAs occur with a solitary kidney where organ preservation is vital. Ex vivo reconstruction with autotransplantation is especially suitable for hilar RAAs, even when they are associated with a solitary kidney. We report 2 of such cases of RAAs with a solitary kidney in patients with pertinent congenital anomalies. In 1 case, the hilar RAA was associated with a significant accessory renal artery, whereas in the other case, the hilar RAA was associated with a significant connective tissue disorder. Ex vivo reconstruction and autotransplantation was successful in both cases; however, treatment modalities had to be adapted to the patient's unique conditions.

Widespread Central Nervous System Gene Transfer and Silencing After Systemic Delivery of Novel AAV-AS Vector.

Effective gene delivery to the central nervous system (CNS) is vital for development of novel gene therapies for neurological diseases. Adeno-associated virus (AAV) vectors have emerged as an effective platform for in vivo gene transfer, but overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. Here, we investigated the possibility of improving CNS transduction of existing AAV capsids by genetically fusing peptides to the N-terminus of VP2 capsid protein. A novel vector AAV-AS, generated by the insertion of a poly-alanine peptide, is capable of extensive gene transfer throughout the CNS after systemic administration in adult mice. AAV-AS is 6- and 15-fold more efficient than AAV9 in spinal cord and cerebrum, respectively. The neuronal transduction profile varies across brain regions but is particularly high in the striatum where AAV-AS transduces 36% of striatal neurons. Widespread neuronal gene transfer was also documented in cat brain and spinal cord. A single intravenous injection of an AAV-AS vector encoding an artificial microRNA targeting huntingtin (Htt) resulted in 33-50% knockdown of Htt across multiple CNS structures in adult mice. This novel AAV-AS vector is a promising platform to develop new gene therapies for neurodegenerative disorders.

In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy.

Adeno-associated viral (AAV) vectors have shown promise as a platform for gene therapy of neurological disorders. Achieving global gene delivery to the central nervous system (CNS) is key for development of effective therapies for many of these diseases. Here we report the isolation of a novel CNS tropic AAV capsid, AAV-B1, after a single round of in vivo selection from an AAV capsid library. Systemic injection of AAV-B1 vector in adult mice and cat resulted in widespread gene transfer throughout the CNS with transduction of multiple neuronal subpopulations. In addition, AAV-B1 transduces muscle, ß-cells, pulmonary alveoli, and retinal vasculature at high efficiency. This vector is more efficient than AAV9 for gene delivery to mouse brain, spinal cord, muscle, pancreas, and lung. Together with reduced sensitivity to neutralization by antibodies in pooled human sera, the broad transduction profile of AAV-B1 represents an important improvement over AAV9 for CNS gene therapy.

"π-Hole-π" Interaction Promoted Photocatalytic Hydrodefluorination via Inner-Sphere Electron Transfer.

We describe a metal-free, photocatalytic hydrodefluorination (HDF) of polyfluoroarenes (FA) using pyrene-based photocatalysts (Py). The weak "π-hole-π" interaction between Py and FA promotes the electron transfer against unfavorable energetics (ΔGET up to 0.63 eV) and initiates the subsequent HDF. The steric hindrance of Py and FA largely dictates the HDF reaction rate, pointing to an inner-sphere electron transfer pathway. This work highlights the importance of the size and shape of the photocatalyst and the substrate in controlling the electron transfer mechanism and rates as well as the overall photocatalytic processes.