Social determinants of health correlations and resource usefulness at a Milwaukee free clinic for uninsured individuals: A cross-sectional study.

Introduction: Addressing social determinants of health (SDOH) is fundamental to improving health outcomes. At a student-run free clinic, we developed a screening process to understand the SDOH needs and resource utilization of Milwaukee's uninsured population. Methods: In this cross-sectional study, we screened adult patients without health insurance (N = 238) for nine traditional SDOH needs as well as their access to dental and mental health care between October 2021 and October 2022. Patients were surveyed at intervals greater than or equal to 30 days. We assessed correlations between SDOH needs and trends in patient-reported resource usefulness. Results: Access to dental care (64.7%) and health insurance (51.3%) were the most frequently endorsed needs. We found significant correlations (P ≤ 0.05) between various SDOH needs. Notably, mental health access needs significantly correlated with dental (r = 0.41; 95% CI = 0.19, 0.63), medications (r = 0.51; 95% CI = 0.30, 0.72), utilities (r = 0.39; 95% CI = 0.17, 0.61), and food insecurity (r = 0.42; 95% CI = 0.19, 0.64). Food-housing (r = 0.55; 95% CI = 0.32, 0.78), housing-medications (r = 0.58; 95% CI = 0.35, 0.81), and medications-food (r = 0.53; 95% CI = 0.32, 0.74) were significantly correlated with each other. Longitudinal assessment of patient-reported usefulness informed changes in the resources offered. Conclusions: Understanding prominent SDOH needs can inform resource offerings and interventions, addressing root causes that burden under-resourced patients. In this study, patient-reported data about resource usefulness prompted the curation of new resources and volunteer roles. This proof-of-concept study shows how longitudinally tracking SDOH needs at low-resource clinics can inform psychosocial resources.

Acrylonitrile derivatives: In vitro activity and mechanism of cell death induction against Trypanosoma cruzi and Leishmania amazonensis.

Leishmaniasis and Chagas disease are parasitic infections that affect millions of people worldwide, producing thousands of deaths per year. The current treatments against these pathologies are not totally effective and produce some side effects in the patients. Acrylonitrile derivatives are a group of compounds that have shown activity against these two diseases. In this work, four novels synthetic acrylonitriles were evaluated against the intracellular form and extracellular forms of L. amazonensis and T. cruzi. The compounds 2 and 3 demonstrate to have good selectivity indexes against both parasites, specifically the compound 3 against the amastigote form (SI = 6 against L. amazonensis and SI = 7.4 against T. cruzi). In addition, the parasites treated with these two compounds demonstrate to produce a programmed cell death, since they were positive for the events studied related to this type of death, including chromatin condensation, accumulation of reactive oxygen species and alteration of the mitochondrial membrane potential. In conclusion, this work confirms that acrylonitriles is a source of possible new compounds against kinetoplastids, however, more studies are needed to corroborate this activity.

Synthesis, biological and computational evaluation of novel cyanomethyl vinyl ether derivatives.

This work explores the biological evaluation of novel cyanomethyl vinyl ether derivatives as antiproliferative agents. Tubulin, crucial to microtubule structure and function, is a target for cancer therapies. In vitro cytotoxicity assessments revealed significant activity in SKOV3 ovarian carcinoma cells and A549 lung carcinoma cells. Structure-Activity Relationship (SAR) analysis indicated that the E isomer and specific substitutions influenced the biological activity. Computational assays predicted favorable ADME properties, highlighting potential as anticancerous agents. Molecular docking studies demonstrated that compound 12E, with the E geometry of the double bond and fused polyaromatic rings such as phenanthrene, has robust interaction with tubulin, suggesting enhanced stability due to diverse amino acid interactions. Comparative spatial distributions with colchicine further indicated potential mechanistic similarities.

Conformational control enables boroxine-to-boronate cage metamorphosis.

The discovery of molecular organic cages (MOCs) is inhibited by the limited organic-chemical space of the building blocks designed to fulfill strict geometric requirements for efficient assembly. Using intramolecular attractive or repulsive non-covalent interactions to control the conformation of flexible systems can effectively augment the variety of building blocks, ultimately facilitating the exploration of new MOCs. In this study, we introduce a set of boronic acid tripods that were designed using rational design principles. Conformational control was induced by extending the tripod's arms by a 2,3-dimethylbenzene unit, leading to the efficient formation of a tetrapodal nanometer-sized boroxine cage. The new building block's versatility was demonstrated by performing cage metamorphosis upon adding an aromatic tetraol. This led to a quantitative boroxine-to-boronate transformation and a topological shift from tetrahedral to trigonal bipyramidal.

Structure and immunogenicity of the murine astrovirus capsid spike.

Human astroviruses (HAstVs) are small, non-enveloped icosahedral RNA viruses that are a significant cause of diarrhoea in young children. Despite their worldwide prevalence, HAstV pathogenesis studies and vaccine development remain challenging due to the lack of an animal model for HAstV infection. The recent development of a murine astrovirus (MuAstV) infection model in mice provides the opportunity to test proof-of-concept vaccines based on MuAstV antigens. To help establish a system in which an astrovirus capsid spike-based vaccine could be tested in vivo, we designed and produced a recombinant MuAstV capsid spike protein based on predicted secondary structure homology to HAstV spike proteins. The recombinant MuAstV spike can be expressed with high efficiency in Escherichia coli and retains antigenicity to polyclonal antibodies elicited by MuAstV infection. We determined the crystal structure of the MuAstV spike to 1.75 Å and assessed its structural conservation with HAstV capsid spike. Despite low sequence identity between the MuAstV and HAstV spikes and differences in their overall shapes, they share related structural folds. Additionally, we found that vaccination with MuAstV spike induced anti-MuAstV-spike antibodies, highlighting that the recombinant spike is immunogenic. These studies lay a foundation for future in vivo MuAstV challenge studies to test whether MuAstV spike can be the basis of an effective vaccine.

Assessing the impact of preferred web app-based music-listening on pain processing at the central nervous level in older black adults with low back pain: An fNIRS study.

BACKGROUND: Low back pain (LBP) disproportionately affects older black adults, often leading to inadequate treatment due to clinician biases. Objective pain measures are imperative, and Functional Near-Infrared Spectroscopy (fNIRS) shows promise for pain detection. AIM: To determine the impact of listening to home-based preferred web app-based music on underlying pain processing mechanisms at the central nervous level in older black adults aged ≥65 with LBP. METHODS: Twenty older black adults with LBP listened to preferred music twice daily for four days using the MUSIC CARE® app. Neuroimaging data were collected using fNIRS. Data were transformed to changes in oxy-hemoglobin and deoxy-hemoglobin concentrations and analyzed. RESULTS: Significant cortical activation pattern differences were observed between pre-and post-intervention scans, particularly in somatosensory regions. Post-intervention scans showed significantly reduced hemodynamic activities. CONCLUSION: Preferred music listening has the potential to alleviate pain, and fNIRS emerges as a promising tool for exploring cortical-level pain-related neural circuits.

In vitro activity and mechanism of cell death induction of cyanomethyl vinyl ethers derivatives against Trypanosoma cruzi.

Chagas disease causes a problematic pathology that can lead to megacolon and heart disease, and can even cause the death of the patient. Current therapies for this disease are the same as they were 50 years ago, are not fully effective and have strong side effects. The lack of a safe and effective therapy makes it necessary to search for new, less toxic and totally effective compounds against this parasite. In this work, the antichagasic activity of 46 novel cyanomethyl vinyl ether derivatives was studied. In addition, to elucidate the type of cell death that these compounds produce in parasites, several events related to programmed cell death were studied. The results highlight four more selective compounds, E63, E64, E74 and E83, which also appear to trigger programmed cell death, and are therefore postulated as good candidates to use in future therapeutics for Chagas disease.

Galvanic vestibular stimulation activates the parietal and temporal cortex in humans: A functional near-infrared spectroscopy (fNIRS) study.

Galvanic vestibular stimulation (GVS) helps stabilize subjects when balance and posture are compromised. This work aimed to define the cortical regions that GVS activates in normal subjects. We used functional near-infrared spectroscopy (fNIRS) to test the hypothesis that GVS activates similar cortical areas as a passive movement. We used transcranial current stimulation (cathode in the right mastoid process and anode in the FPz frontopolar point) of bipolar direct current (2 mA), false GVS (sham), vibration (neutral stimulus), and back and forth motion (positive control of vestibular movement) in 18 clinically healthy volunteers. Seventy-two brain scans were performed, applying a crossover-type experimental design. We measured the heart rate, blood pressure, body temperature, head capacitance, and resistance before and after the experiment. The haemodynamic changes of the cerebral cortex were recorded with an arrangement of 26 channels in four regions to perform an ROI-level analysis. The back-and-forth motion produced the most significant oxygenated haemoglobin (HbO2 ) increase. The response was similar for the GVS stimulus on the anterior and posterior parietal and right temporal regions. Sham and vibrational conditions did not produce significant changes ROI-wise. The results indicate that GVS produces a cortical activation coherent with displacement percept.

Cyanomethyl Vinyl Ethers Against Naegleria fowleri.

Naegleria fowleri is a pathogenic amoeba that causes a fulminant and rapidly progressive disease affecting the central nervous system called primary amoebic meningoencephalitis (PAM). Moreover, the disease is fatal in more than 97% of the reported cases, mostly affecting children and young people after practicing aquatic activities in nontreated fresh and warm water bodies contaminated with these amoebae. Currently, the treatment of primary amoebic meningoencephalitis is based on a combination of different antibiotics and antifungals, which are not entirely effective and lead to numerous side effects. In the recent years, research against PAM is focused on the search of novel, less toxic, and fully effective antiamoebic agents. Previous studies have reported the activity of cyano-substituted molecules in different protozoa. Therefore, the activity of 46 novel synthetic cyanomethyl vinyl ethers (QOET-51 to QOET-96) against two type strains of N. fowleri (ATCC 30808 and ATCC 30215) was determined. The data showed that QOET-51, QOET-59, QOET-64, QOET-67, QOET-72, QOET-77, and QOET-79 were the most active molecules. In fact, the selectivity index (CC50/IC50) was sixfold higher when compared to the activities of the drugs of reference. In addition, the mechanism of action of these compounds was studied, with the aim to demonstrate the induction of a programmed cell death process in N. fowleri.

Functional near infrared spectroscopy detects cortical activation changes concurrent with memory loss in postmenopausal women with Type II Diabetes.

Older adults with Type II Diabetes Mellitus (DM) experience mild cognitive impairment, specifically in the domain of recall/working memory. No consistent causative structural cortical deficits have been identified in persons with DM (PwDM). Memory deficits may be exacerbated in older adult females, who are at the highest risk of cardiovascular decline due to DM. The focus of the current study was to evaluate functional cortical hemodynamic activity during memory tasks in postmenopausal PwDM. Functional Near Infrared Spectroscopy (fNIRS) was used to monitor oxyhemoglobin (HbO) and deoxyhemoglobin (HbR) during memory-based tasks in a cross-sectional sample of postmenopausal women with DM. Twenty-one community-dwelling DM females (age = 65 ± 6 years) and twenty-one age- and sex-matched healthy controls (age = 66 ± 6 years) were evaluated. Working memory performance (via N-back) was evaluated while study participants donned cortical fNIRS. Health state, metabolic data, and menopausal status data were also collected. Deficits in working memory accuracy were found in the DM group as compared to controls. Differences in HbO responses emerged in the DM group. The DM group exhibited altered PFC activity magnitudes and increased functional cortical activity across ROIs compared to controls. HbO and HbR responses were not associated with worsened health state measures. These data indicate a shift in cortical activity patterns with memory deficits in postmenopausal PwDM. This DM-specific shift of HbO is a novel finding that is unlikely to be detected by fMRI. This underscores the value of using non-MRI-based neuroimaging techniques to evaluate cortical hemodynamic function to detect early mild cognitive impairment.

Self-administered transcranial direct current stimulation treatment of knee osteoarthritis alters pain-related fNIRS connectivity networks.

Significance: Knee osteoarthritis (OA) is a disease that causes chronic pain in the elderly population. Currently, OA is mainly treated pharmacologically with analgesics, although research has shown that neuromodulation via transcranial direct current stimulation (tDCS) may be beneficial in reducing pain in clinical settings. However, no studies have reported the effects of home-based self-administered tDCS on functional brain networks in older adults with knee OA. Aim: We used functional near-infrared spectroscopy (fNIRS) to investigate the functional connectivity effects of tDCS on underlying pain processing mechanisms at the central nervous level in older adults with knee OA. Approach: Pain-related brain connectivity networks were extracted using fNIRS at baseline and for three consecutive weeks of treatment from 120 subjects randomly assigned to two groups undergoing active tDCS and sham tDCS. Results: Our results showed that the tDCS intervention significantly modulated pain-related connectivity correlation only in the group receiving active treatment. We also found that only the active treatment group showed a significantly reduced number and strength of functional connections evoked during nociception in the prefrontal cortex, primary motor (M1), and primary somatosensory (S1) cortices. To our knowledge, this is the first study in which the effect of tDCS on pain-related connectivity networks is investigated using fNIRS. Conclusions: fNIRS-based functional connectivity can be effectively used to investigate neural circuits of pain at the cortical level in association with nonpharmacological, self-administered tDCS treatment.

Combination of SABR With Anti-PD-1 in Oligoprogressive Non-Small Cell Lung Cancer and Melanoma: Results of a Prospective Multicenter Observational Study.

PURPOSE: The percentage of patients with metastatic non-small cell lung cancer (NSCLC) and melanoma who benefit from anti-programmed cell death protein 1 (anti-PD-1) is low owing to resistance mechanisms. SABR has a role in oligoprogressive disease and can improve responses to anti-PD-1. This multicenter prospective observational study aimed to determine whether concomitant anti-PD-1 and SABR to oligoprogressive sites enhance tumor response in metastatic NSCLC and melanoma. METHODS AND MATERIALS: Patients with metastatic NSCLC or melanoma in progression to anti-PD-1 but continuing the same line owing to clinical benefit were referred for palliative SABR. All patients received concomitant pembrolizumab or nivolumab and SABR to 1 to 5 lesions, maintaining anti-PD-1 until further progression, unacceptable toxicity, or medical/patient decision. Objective response rate-complete responses and partial responses-was evaluated during all follow-up according to Response Evaluation Criteria in Solid Tumors 1.1. The abscopal response was evaluated 8 weeks after SABR as a ≥30% reduction in 1 to 2 predefined nonirradiated lesions. RESULTS: Of the 61 patients enrolled, 50 could be analyzed. With a median follow-up of 32.8 months, objective response rate was 42% (30% complete responses and 12% partial responses). Median progression-free survival was 14.2 months (95% confidence interval, 6.9-29 months). Median overall survival since SABR was 37.4 months (95% confidence interval, 22.9 months-not reached). Abscopal response was 65%, evaluated in 40 patients who fulfilled the criteria. CONCLUSIONS: Combined anti-PD-1 and SABR in oligoprogressive metastatic NSCLC or melanoma can achieve high rates of response and extend the clinical benefit of immunotherapy by delaying further progression and a new systemic therapy. This approach should be assessed in larger randomized trials.

In vitro activity and cell death mechanism induced by acrylonitrile derivatives against Leishmania amazonensis.

Leishmaniasis produces approximately-one million of new cases annually, making it one of the most important tropical diseases. As current treatments are not fully effective and are toxic, it is necessary to develop new therapies that are more effective and less toxic, and cause a controlled cell death, with which we can avoid the immunological problems caused by necrosis. In this work 32 acrylonitriles were studied in vitro against Leishmania amazonensis. Three compounds Q20 (12.41), Q29 (11.2) and Q31 (11.56) had better selectivity than the reference compound, miltefosine (11.14) against promastigotes of these parasites, for this reason they were selected to determine their mechanism of action to know the cell death type of they produce. The results of the mechanisms of action show that these three acrylonitriles tested produce chromatin condensation, decreased mitochondrial membrane potential, altered plasma permeability and production of reactive oxygen species. All these characteristic events seem to indicate programmed cell death. Therefore, this study demonstrates the activity of acrylonitriles derivatives as possible leishmanicidal agents.

Impact of the Semiconductor Defect Density on Solution-Processed Flexible Schottky Barrier Diodes.

Schottky barrier diodes, developed by low-cost techniques and low temperature processes (LTP-SBD), have gained attention for different kinds of novel applications, including flexible electronic fabrication. This work analyzes the behavior of the I-V characteristic of solution processed, ZnO Schottky barrier diodes, fabricated at a low temperature. It is shown that the use of standard extraction methods to determine diode parameters in these devices produce significant dispersion of the ideality factor with values from 2.2 to 4.1, as well as a dependence on the diode area without physical meaning. The analysis of simulated I-V characteristic of LTP-SBD, and its comparison with experimental measurements, confirmed that it is necessary to consider the presence of a density of states (DOS) in the semiconductor gap, to understand specific changes observed in their performance, with respect to standard SBDs. These changes include increased values of Rs, as well as its dependence on bias, an important reduction of the diode current and small rectification values (RR). Additionally, it is shown that the standard extraction methodologies cannot be used to obtain diode parameters of LTP-SBD, as it is necessary to develop adequate parameter extraction methodologies for them.

Links between socioeconomic disadvantage, neural function, and working memory in early childhood.

Children reared in socioeconomically disadvantaged environments are at risk for academic, cognitive, and behavioral problems. Mounting evidence suggests that childhood adversities, encountered at disproportionate rates in contexts of socioeconomic risk, shape the developing brain in ways that explain disparities. Circuitries that subserve neurocognitive functions related to memory, attention, and cognitive control are especially affected. However, most work showing altered neural function has focused on middle childhood and adolescence. Understanding alterations in brain development during foundational points in early childhood is a key next step. To address this gap, we examined functional near-infrared-spectroscopy-based neural activation during a working memory (WM) task in young children aged 4-7 years (N = 30) who varied in socioeconomic risk exposure. Children who experienced greater disadvantage (lower income to needs ratio and lower Hollingshead index) exhibited lower activation in the lateral prefrontal cortex than children who experienced less to no disadvantage. Variability in prefrontal cortex activation, but not behavioral performance on the WM task, was associated with worse executive functioning in children as reported by parents. These findings add to existing evidence that exposure to early adversity, such as socioeconomic risk, may lead to foundational changes in the developing brain, which increases risk for disparities in functioning across multiple cognitive and social domains.

Acrylonitrile Derivatives against Trypanosoma cruzi: In Vitro Activity and Programmed Cell Death Study.

The neglected infection known as Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, results in more than 7000 deaths per year, with an increasing number of cases in non-endemic areas such as Europe or the United States. Moreover, with the current available therapy, only two compounds which are active against the acute phase of the disease are readily available. In addition, these therapeutic agents display multiple undesired side effects such as high toxicity, they are expensive, the treatment is lengthy and the resistant strain has emerged. Therefore, there is a need to find new compounds against Chagas disease which should be active against the parasite but also cause low toxicity to the patients. In the present work, the activity of novel acrylonitriles against Trypanosoma cruzi was evaluated as well as the analysis of the physiological events induced in the treated parasites related to the cell death process. Hence, the characteristic features of an apoptosis-like process such as chromatin condensation and mitochondrial membrane potential, among others, were studied. From the 32 compounds tested against the epimastigote stage of T. cruzi, 11 were selected based on their selectivity index to determine if these compounds were able to induce programmed cell death (PCD) in the treated parasites. Furthermore, acrylonitriles Q5, Q7, Q19, Q27 and Q29 were shown to trigger physiological events related in the PCD. Therefore, this study highlights the therapeutic potential of acrylonitriles as novel trypanocidal agents.

Cyanovinylation of Aldehydes: Organocatalytic Multicomponent Synthesis of Conjugated Cyanomethyl Vinyl Ethers.

A novel organocatalytic multicomponent cyanovinylation of aldehydes was designed for the synthesis of conjugated cyanomethyl vinyl ethers. The reaction was implemented for the synthesis of a 3-substituted 3-(cyanomethoxy)acrylates, using aldehydes as substrates, acetone cyanohydrin as the cyanide anion source, and methyl propiolate as the source of the vinyl component. The multicomponent reaction is catalyzed by N-methyl morpholine (2.5 mol%) to deliver the 3-(cyanomethoxy)acrylates in excellent yields and with preponderance of the E-isomer. The multicomponent reaction manifold is highly tolerant to the structure and composition of the aldehyde (aliphatic, aromatic, heteroaromatics), and it is instrumentally simple (one batch, open atmospheres), economic (2.5 mol% catalyst, stoichiometric reagents), environmentally friendly (no toxic waste), and sustainable (easy scalability).

Molecular Modes of Attosecond Charge Migration.

First-principles calculations are employed to elucidate the modes of attosecond charge migration (CM) in halogenated hydrocarbon chains. We use constrained density functional theory (DFT) to emulate the creation of a localized hole on the halogen and follow the subsequent dynamics via time-dependent DFT. We find low-frequency CM modes (∼1 eV) that propagate across the molecule and study their dependence on length, bond order, and halogenation. We observe that the CM speed (∼4 Å/fs) is largely independent of molecule length, but is lower for triple-bonded versus double-bonded molecules. Additionally, as the halogen mass increases, the hole travels in a more particlelike manner as it moves across the molecule. These heuristics will be useful in identifying molecules and optimal CM detection methods for future experiments, especially for halogenated hydrocarbons which are promising targets for ionization-triggered CM.

Modification of the Electron Entropy Production in a Plasma.

A modified expression of the electron entropy production in a plasma is deduced by means of the Kelly equations of state instead of the ideal gas equations of state. From the Debye-Hückel model which considers the interaction between the charges, such equations of state are derived for a plasma and the entropy is deduced. The technique to obtain the modified entropy production is based on usual developments but including the modified equations of state giving the regular result plus some extra terms. We derive an expression of the modified entropy production in terms of the tensorial Hermitian moments hr1…rm(m) by means of the irreducible tensorial Hermite polynomials.

Functional Near-Infrared Spectroscopy to Assess Central Pain Responses in a Nonpharmacologic Treatment Trial of Osteoarthritis.

BACKGROUND AND PURPOSE: Knee osteoarthritis (OA) is a common source of pain in older adults. Although OA-induced pain can be relieved with analgesics and anti-inflammatory drugs, the current opioid epidemic is fostering the exploration of nonpharmacologic strategies for pain mitigation. Amongs these, transcranial direct current stimulation (tDCS) and mindfulness-based meditation (MBM) hold potential for pain-relief efficacy due to their neuromodulatory effects of the central nervous system, which is known to play a fundamental role in pain perception and processing. METHODS: In this double-blind study, we used functional near-infrared spectroscopy (fNIRS) to investigate the effects of tDCS combined with MBM on underlying pain processing mechanisms at the central nervous level in older adults with knee OA. Nineteen subjects were randomly assigned to two groups undergoing a 10-day active tDCS and MBM regimen and a sham tDCS and MBM regimen, respectively. RESULTS: Our results showed that the neuromodulatory intervention significantly relieved pain only in the group receiving active treatment. We also found that only the active treatment group showed a significant increase in oxyhemoglobin activation of the superior motor and somatosensory cortices colocated to the placement of the tDCS anodal electrode. To our knowledge, this is the first study in which the combined effect of tDCS and MBM is investigated using fNIRS. CONCLUSION: In conclusion, fNIRS can be effectively used to investigate neural mechanisms of pain at the cortical level in association with nonpharmacological, self-administered treatments.