Characteristics of patients with non-cancer pain and long-term prescription opioid use who have used medical versus recreational marijuana.

OBJECTIVE: Marijuana use is increasingly common among patients with chronic non-cancer pain (CNCP) and long-term opioid therapy (LTOT). We determined if lifetime recreational and medical marijuana use were associated with more frequent and higher dose prescription opioid use. DESIGN: Cross-sectional SUBJECTS: Eligible patients (n=1,037), who had a new period of prescription opioid use lasting 30-90 days, were recruited from two midwestern health care systems to a study of long-term prescription opioid use and mental health outcomes. The present cross-sectional analyses uses baseline data from this on-going cohort study. METHODS: Primary exposures were participant reported lifetime recreational and medical marijuana use versus no lifetime marijuana use. Prescription opioid characteristics included daily versus non-daily opioid use and ≥50 morphine milligram equivalent (MME) dose per day vs. <50 MME. Multivariate, logistic regression models estimated the association between lifetime recreational and medical marijuana use vs. no use and odds of daily and higher dose prescription opioid use, before and after adjusting for confounding. RESULTS: The sample was an average of 54.9 (SD±11.3) years of age, 57.3% identified as female gender, 75.2% identified as White, and 22.5% identified as Black race. Among all participants, 44.4% were never marijuana users, 21.3% were recreational only, 7.7% medical only and 26.6% were both recreational and medical marijuana users. After controlling for all confounders, lifetime recreational marijuana use, as compared to no use, was significantly associated with increased odds of daily prescription opioid use (OR=1.61; 95%CI:1.02-2.54). There was no association between lifetime recreational or medical marijuana use and daily opioid dose. CONCLUSION: Lifetime medical marijuana use is not linked to current opioid dose, but lifetime recreational use is associated with more than a 60% odds of being a daily prescription opioid user. Screening for lifetime recreational marijuana use may identify patients with chronic pain who are vulnerable to daily opioid use which increases risk for adverse opioid outcomes. Prospective data is needed to determine how marijuana use influences the course of LTOT and vice versa.

Keratinocyte integrin α3ß1 induces expression of the macrophage stimulating factor, CSF-1, through a YAP/TEAD-dependent mechanism.

The development of wound therapy targeting integrins is hampered by inadequate understanding of integrin function in cutaneous wound healing and the wound microenvironment. Following cutaneous injury, keratinocytes migrate to restore the skin barrier, and macrophages aid in debris clearance. Thus, both keratinocytes and macrophages are critical to the coordination of tissue repair. Keratinocyte integrins have been shown to participate in this coordinated effort by regulating secreted factors, some of which crosstalk to distinct cells in the wound microenvironment. Epidermal integrin α3ß1 is a receptor for laminin-332 in the cutaneous basement membrane. Here we show that wounds deficient in epidermal α3ß1 express less epidermal-derived macrophage colony-stimulating factor 1 (CSF-1), the primary macrophage-stimulating growth factor. α3ß1-deficient wounds also have fewer wound-proximal macrophages, suggesting that keratinocyte α3ß1 may stimulate wound macrophages through the regulation of CSF-1. Indeed, using a set of immortalized keratinocytes, we demonstrate that keratinocyte-derived CSF-1 supports macrophage growth, and that α3ß1 regulates Csf1 expression through Src-dependent stimulation of Yes-associated protein (YAP)-Transcriptional enhanced associate domain (TEAD)-mediated transcription. Consistently, α3ß1-deficient wounds in vivo display a substantially reduced number of keratinocytes with YAP-positive nuclei. Overall, our current findings identify a novel role for epidermal integrin α3ß1 in regulating the cutaneous wound microenvironment by mediating paracrine crosstalk from keratinocytes to wound macrophages, implicating α3ß1 as a potential target of wound therapy.

Seeing is believing: The effect of subtle communication in social media on viewers' beliefs about depression and anxiety symptom trajectories.

OBJECTIVE: One barrier to treatment seeking, uptake, and engagement is the belief that nothing can be done to reduce symptoms. Given the widespread use of social media to disseminate information about important issues, including psychological health, we sought to understand how the influence of social media communication regarding mental health impacts viewers' beliefs about psychopathology recovery. METHOD: Undergraduate participants from a large Midwestern university (N = 322) were randomized to view a series of Tweets characterizing psychopathology from a fixed mindset perspective, a growth mindset perspective, or, in the control condition, Tweets unrelated to psychopathology. Afterward, they completed a series of questionnaires designed to assess beliefs about recovery from depression and anxiety. RESULTS: Participants in the growth mindset condition endorsed less pessimistic beliefs about their ability (i.e., self-efficacy) to alleviate symptoms of depression and anxiety, and they believed these symptoms to be less stable and innate relative to those in the fixed mindset condition. CONCLUSION: Social media communication that characterizes psychopathology from a growth mindset perspective may be a viable intervention for improving beliefs around mental health self-efficacy and the malleable nature of mental illness, particularly depression and anxiety. Clinicians may be able to use social media platforms to promote functional beliefs around mental illness.

MiR-199a-5p Decreases Esophageal Cancer Cell Proliferation Partially through Repression of Jun-B.

MicroRNA (miR)-199a-5p has been shown to function as a tumor suppressor in some malignancies but its role in esophageal cancer is poorly understood. To further explore its role in esophageal cancer, we sought to investigate the interaction between miR-199a-5p and Jun-B, an important component of the AP1 transcription factor, which contains a potential binding site for miR-199a-5p in its mRNA. We found that levels of miR-199a-5p are reduced in both human esophageal cancer specimens and in multiple esophageal cancer cell lines compared to esophageal epithelial cells. Jun-B expression is correspondingly elevated in these tumor specimens and in several cell lines compared to esophageal epithelial cells. Jun-B mRNA expression and stability, as well as protein expression, are markedly decreased following miR-199a-5p overexpression. A direct interaction between miR-199a-5p and Jun-B mRNA was confirmed by a biotinylated RNA-pull down assay and luciferase reporter constructs. Either forced expression of miR-199a-5p or Jun-B silencing led to a significant decrease in cellular proliferation as well as in AP-1 promoter activity. Our results provide evidence that miR-199a-5p functions as a tumor suppressor in esophageal cancer cells by regulating cellular proliferation, partially through repression of Jun B.

The dependence of cerebral interstitial fluid on diffusion-sensitizing directions: A multi-b-value diffusion MRI study in a memory clinic sample.

Three-component intravoxel incoherent motion (3C-IVIM) imaging with spectral analysis provides a proxy for interstitial fluid (ISF) (e.g., in perivascular spaces (PVS), granting a potential marker for altered cerebral clearance. When 3C-IVIM images are acquired with three orthogonal diffusion-sensitizing directions, these are often averaged into the Trace image. This may result in loss of valuable direction-specific information, particularly in PVS-rich regions (basal ganglia (BG) and centrum semiovale (CSO)). This study assessed the dependence of individual diffusion-sensitizing directions to the ISF fraction in PVS-rich regions. Additionally, we explored the value of diffusion direction-specific information on ISF characteristics in distinguishing thirty-one patients with cognitive impairment (CI) (Alzheimer's disease (n = 15) or Mild Cognitive Impairment (n = 16)) from thirty cognitively healthy elderly controls (CON). Multi-b-value diffusion-weighted images were acquired in three orthogonal directions (L-R (left-right), A-P (anterior-posterior) and S-I (superior-inferior)) at 3 T. Voxel-based spectral analysis using non-negative least squares was conducted to independently analyze the L-R, A-P, S-I, and Trace images. 3C-IVIM measures were first compared between diffusion-sensitizing directions and the Trace within the BG using repeated measures ANOVA. Subsequently, the 3C-IVIM measures were compared per direction between the CI and CSO group in the BG and CSO with multivariable linear regression. Our results show that the ISF fraction significantly differs between all diffusion-sensitizing directions and Trace in the BG, with the highest ISF fraction detected using S-I. Solely using S-I, a higher ISF fraction was identified in CI compared to CON in the BG (p = .020) and CSO (p = .046). Thereby, this study found that the measured ISF fraction depends on the acquired diffusion-sensitizing direction, where S-I is most sensitive to detect ISF and differences between CI and CON. The Trace approach is not always sensitive enough to ISF characteristics. Solely acquiring S-I may offer an alternative to reduce scanning time.

A single Haemoproteus plataleae haplotype is widespread in white ibis (Eudocimus albus) from urban and rural sites in southern Florida.

The American white ibis (Eudocimus albus), a common bird species in Florida, has become increasingly urban, with many populations relying heavily on urban and suburban habitats, which may alter parasite transmission. Parasites of ibis, especially haemosporidians, are understudied. Avian haemosporidia can have a wide range of impacts on birds, including decreased reproductive success or increased mortality. Because southern Florida is subtropical and has a high diversity of potential vectors for haemosporidia, we hypothesized that there will be a high prevalence and genetic diversity of haemosporidia in white ibis. A total of 636 ibis from South Florida were sampled from 2010 to 2022, and blood samples were tested for haemosporidia by examination of Giemsa-stained thin blood smears and/or nested PCRs targeting the cytochrome b gene. A total of 400 (62.9%, 95% CI 59-66.7%) ibis were positive for parasites that were morphologically identified as Haemoproteus plataleae. Sequences of 302 positives revealed a single haplotype of Haemoproteus (EUDRUB01), which was previously reported from white ibis in South Florida and captive scarlet ibis (E. ruber) in Brazil. No Plasmodium or Leucocytozoon infections were detected. Parasitemias of the 400 positive birds were very low (average 0.084%, range 0.001%-2.16% [although only 2 birds had parasitemias >1%]). Prevalence and parasitemias were similar for males and females (68% vs. 61.6% and 0.081% vs. 0.071%, respectively). Prevalence in juveniles was lower compared with adults (52% vs. 67.4%) but parasitemias were higher in juveniles (0.117% vs. 0.065%). This data shows that H. plataleae is common in ibis in South Florida. Although parasitemias were generally low, additional research is needed to determine if this parasite has subclinical effects on ibis, if additional haplotypes or parasite species infect ibis in other regions of their range, or if H. plataleae is pathogenic for other sympatric avian species.

Exclusion of Horizontal and Vertical Transmission as Major Sources of Trypanosoma Cruzi Infections in a Breeding Colony of Rhesus Macaques (Macaca Mulatta).

The vector-borne protozoal parasite Trypanosoma cruzi causes Chagas disease in humans and animals. This parasite is endemic to the southern United States where outdoor-housed NHP at biomedical facilities are at risk of infection. In addi- tion to the direct morbidity caused by T. cruzi, infected animals are of limited biomedical research use because infections can produce confounding pathophysiologic changes even in animals with no clinical disease. In part due to concerns for direct T. cruzi transmission between animals, infected NHP at some institutions have been culled, removed, or otherwise isolated from uninfected animal populations. However, data that document horizontal or vertical transmission in captive NHP in the United States are not available. To evaluate the potential for inter-animal transmission and to identify environmental factors that affect the distribution of new infections in NHPs, we conducted a retrospective epidemiologic study of a rhesus macaque ( Macaca mulatta ) breeding colony in south Texas. We used archived biologic samples and husbandry records to identify the time and location of macaque seroconversion. These data were used to perform a spatial analysis of how geographic location and animal associations affected the spread of disease and to infer the importance of horizontal or vertical routes of transmission. The majority of T. cruzi infections were spatially clustered, suggesting that environmental factors promoted vector exposure in various areas of the facility. Although we cannot not rule out horizontal transmission, our data suggest that horizontal transmission was not a critical route for spread for the disease. Vertical transmission was not a contributing factor in this colony. In conclusion, our findings suggest that local triatome vectors were the major source of T. cruzi infections in captive macaques in our colony. Therefore, limiting contact with vectors, rather than segregation of infected macaques, is a key strategy for disease prevention at institutions that house macaques outdoors in the southern United States.

Assessing opportunities and inequities in undergraduate ecological forecasting education.

Conducting ecological research in a way that addresses complex, real-world problems requires a diverse, interdisciplinary and quantitatively trained ecology and environmental science workforce. This begins with equitably training students in ecology, interdisciplinary science, and quantitative skills at the undergraduate level. Understanding the current undergraduate curriculum landscape in ecology and environmental sciences allows for targeted interventions to improve equitable educational opportunities. Ecological forecasting is a sub-discipline of ecology with roots in interdisciplinary and quantitative science. We use ecological forecasting to show how ecology and environmental science undergraduate curriculum could be evaluated and ultimately restructured to address the needs of the 21st century workforce. To characterize the current state of ecological forecasting education, we compiled existing resources for teaching and learning ecological forecasting at three curriculum levels: online resources; US university courses on ecological forecasting; and US university courses on topics related to ecological forecasting. We found persistent patterns (1) in what topics are taught to US undergraduate students at each of the curriculum levels; and (2) in the accessibility of resources, in terms of course availability at higher education institutions in the United States. We developed and implemented programs to increase the accessibility and comprehensiveness of ecological forecasting undergraduate education, including initiatives to engage specifically with Native American undergraduates and online resources for learning quantitative concepts at the undergraduate level. Such steps enhance the capacity of ecological forecasting to be more inclusive to undergraduate students from diverse backgrounds and expose more students to quantitative training.

The double-barrel wet colostomy: An alternative for urinary diversion after pelvic exenteration.

AIM: Pelvic exenteration is a radical procedure used to treat locally advanced and/or recurrent pelvic malignancies. Different reconstruction options exist, the most popular being the end colostomy with ileal conduit. The double barrel wet colostomy (DBWC) offers concomitant fecal and urinary diversion through a single stoma, but is infrequently utilized. We aim to review the evidence base of the postoperative complications, long-term oncologic risks and quality of life following creation of a double barrel wet colostomy. METHODS: A narrative review of the literature was performed evaluating the DBWC. Patient demographics, perioperative complications, operative variables, long terms oncologic outcomes and quality of life data were extracted. Descriptive statistics were used to define the data. RESULTS: Fourteen articles with a total of 300 patients undergoing DBWC following pelvic exenteration were selected. 41% of malignancies were gastrointestinal in origin while 41.7% were gynecologic and 5.3% genitourinary. 42% of patients experienced at least one complication within in 40 days of surgery, the most common being wound infection (8.7%) and urinary leak (8.3%). There was no evidence of malignancy within the DBWC during long-term surveillance. Quality of life following DBWC is comparable to other reconstructive methods. CONCLUSION: The DBWC is a well described reconstructive method for urinary and fecal diversion utilizing a single stoma following pelvic exenteration. The short- and long-term outcomes following DBWC are comparable to other reconstructive methods and the quality of life with a DBWC is acceptable. DBWC should remain a readily available option for reconstruction following pelvic exenteration.

Subarachnoid CSF hyperintensities at 7 tesla FLAIR MRI: A novel marker in cerebral amyloid angiopathy.

BACKGROUND: We observed subarachnoid cerebrospinal fluid (CSF) hyperintensities at non-contrast 7-tesla (T) fluid-attenuated inversion recovery (FLAIR) MRI, frequently topographically associated with cortical superficial siderosis (cSS), in participants with cerebral amyloid angiopathy (CAA). To systemically evaluate these CSF hyperintensities we investigated their frequency and anatomical and temporal relationship with cSS on 7T and 3T MRI in hereditary Dutch-type CAA (D-CAA), sporadic CAA (sCAA), and non-CAA controls. METHODS: CAA participants were included from two prospective natural history studies and non-CAA controls from a 7T study in healthy females and females with ischemic stroke. CSF hyperintensities were scored by two independent observers. RESULTS: We included 38 sCAA participants (mean age 72y), 50 D-CAA participants (mean age 50y) and 44 non-CAA controls (mean age 53y, 15 with stroke). In total 27/38 (71 %, 95 %CI 56-84) sCAA and 23/50 (46 %, 95 %CI 33-60) D-CAA participants had subarachnoid CSF hyperintensities at baseline 7T. Most (96 %) of those had cSS, in 54 % there was complete topographical overlap with cSS. The remaining 46 % had ≥1 sulcus with CSF hyperintensities without co-localizing cSS. None of the healthy controls and 2/15 (13 %, 95 %CI 2-41, 100 % cSS overlap) of the stroke controls had CSF hyperintensities. In 85 % of the CAA participants CSF hyperintensities could retrospectively be identified at 3T. Of the 35 CAA participants with follow-up 7T after two years, 17/35 (49 %) showed increase and 6/35 (17 %) decrease of regional CSF hyperintensities. In 2/11 (18 %) of participants with follow-up who had baseline CSF hyperintensities without overlapping cSS, new cSS developed at those locations. CONCLUSIONS: Subarachnoid CSF hyperintensities at 7T FLAIR MRI occur frequently in CAA and are associated with cSS, although without complete overlap. We hypothesize that the phenomenon could be a sign of subtle plasma protein or blood product leakage into the CSF, resulting in CSF T1-shortening.

Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats.

The nonsteroidal anti-inflammatory drug (NSAID) sulindac demonstrates attractive anticancer activity, but the toxicity resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins precludes its long-term, high dose use in the clinic for cancer prevention or treatment. While inflammation is a known tumorigenic driver, evidence suggests that sulindac's antineoplastic activity is partially or fully independent of its COX inhibitory activity. One COX-independent target proposed for sulindac is cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) isozymes. Sulindac metabolites, i.e., sulfide and sulfone, inhibit cGMP PDE enzymatic activity at concentrations comparable with those associated with cancer cell growth inhibitory activity. Additionally, the cGMP PDE isozymes PDE5 and PDE10 are overexpressed during the early stages of carcinogenesis and appear essential for cancer cell proliferation and survival based on gene silencing experiments. Here, we describe a novel amide derivative of sulindac, sulindac sulfide amide (SSA), which was rationally designed to eliminate COX-inhibitory activity while enhancing cGMP PDE inhibitory activity. SSA was 68-fold and 10-fold less potent than sulindac sulfide (SS) in inhibiting COX-1 and COX-2, respectively, but 10-fold more potent in inhibiting growth and inducing apoptosis in breast cancer cells. The pro-apoptotic activity of SSA was associated with inhibition of cGMP PDE activity, elevation of intracellular cGMP levels, and activation of cGMP-dependent protein kinase (PKG) signaling, as well as the inhibition of ß-catenin/Tcf transcriptional activity. SSA displayed promising in vivo anticancer activity, resulting in a 57% reduction in the incidence and a 62% reduction in the multiplicity of tumors in the N-methyl-N-nitrosourea (MNU)-induced model of breast carcinogenesis. These findings provide strong evidence for cGMP/PKG signaling as a target for breast cancer prevention or treatment and the COX-independent anticancer properties of sulindac. Furthermore, this study validates the approach of optimizing off-target effects by reducing the COX-inhibitory activity of sulindac for future targeted drug discovery efforts to enhance both safety and efficacy.

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Psychosocial and medical factors associated with intrathecal baclofen pump explants: A case series.

PURPOSE: The goal of this retrospective chart review study was to explore factors that contributed to consideration of or actual pump explantation in pediatric patients with intrathecal baclofen (ITB) pumps. METHODS: Medical records of 30 patients with ITB pumps were reviewed. Quantitative data, including demographic, clinical, psychosocial, and service utilization variables were culled from the records. Qualitative data were collected from clinic visit notes, pump-related follow-up phone calls, and any pump-related emergency room visits. RESULTS: Of those reviewed, six underwent ITB pump explantation, and two considered explantation. Factors contributing to pump explantation or consideration of explantation included the following: postoperative infection, pump malfunction, non-adherence, anxiety/behavioral factors impacting the patient's tolerance of the pump, distance to the medical provider, frequency of required pump refill appointments, lack or perceived lack of intrathecal baclofen effect, and difficulty transitioning to adult care providers. CONCLUSION: Due to the complex care regimen associated with ITB pumps and various psychosocial and logistical factors that impact treatment success, a standardized multidisciplinary pre-implantation education, screening, and assessment process should be developed. Such a process would ensure that patients/families receive appropriate education, including proactively identifying treatment barriers and potential complications, possibly minimizing dissatisfaction with treatment and the need for explantation.

Hope therapy.

Research over the past three decades has established that hope is related to positive outcomes. Hope therapy was originally developed to optimize successful goals pursuits by increasing hopeful thought. Here, we briefly review the current state of hope therapy research and offer directions for future investigations. We note that hope therapy has been adapted to be delivered in different formats, by providers from various professional backgrounds, and to participants presenting with a variety of chronic health conditions. We suggest there is a need to reach a consensus about what characterizes hope therapy. Further, we note the need for well-designed trials to test potential mechanisms of change. We believe that these future directions will result in a more efficacious hope therapy that can be widely disseminated.

MiR-214-3p targets Ras-related protein 14 (RAB14) to inhibit cellular migration and invasion in esophageal Cancer cells.

BACKGROUND: MicroRNA (miR)-214-3p is emerging as an important tumor suppressor in esophageal cancer. In this study, we examined the interaction between miR-214-3p and RAB14, a membrane trafficking protein shown to exert oncogenic functions in other malignancies, in esophageal cancer cells. METHODS: Studies were performed in a human esophageal epithelial cell line and a panel of esophageal cancer cell lines, as well in human specimens. MiR-214-3p expression was measured by digital PCR. Biotinylated RNA pull-down and luciferase reporter assays assessed binding. The xCELLigence RTCA system measured cell migration and invasion in real time. A lentiviral expression vector was used to create an esophageal cancer cell line stably expressing miR-214-3p. RESULTS: MiR-214-3p expression was decreased in esophageal cancer cell lines and human specimens compared to non-malignant controls. RAB14 mRNA stability and protein expression were decreased following miR-214-3p overexpression. Binding between miR-214-3p and RAB14 mRNA was observed. Either forced expression of miR-214-3p or RAB14 silencing led to a marked decrease in cellular migration and invasion. Esophageal cancer cells stably expressing miR-214-3p demonstrated decreased growth in a subcutaneous murine model. CONCLUSIONS: These results further support the tumor-suppressive role of miR-214-3p in esophageal cancer cells by demonstrating its ability to regulate RAB14 expression.

Blood-brain barrier leakage and perivascular inflammation in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is a small vessel disease associated with cortical microbleeds and lobar intracerebral haemorrhage due to amyloid-ß deposition in the walls of leptomeningeal and cortical arterioles. The mechanisms of cerebral amyloid angiopathy-related haemorrhage remain largely unknown. Recent work has demonstrated that ruptured blood vessels have limited (or no) amyloid-ß at the site of bleeding and evidence of local vascular remodelling. We hypothesized that blood-brain barrier leakage and perivascular inflammation may be involved in this remodelling process. This study examined cortical arterioles at various stages of cerebral amyloid angiopathy-related vascular pathology (without evidence of microhaemorrhage) in autopsy tissue from seven cases with definite cerebral amyloid angiopathy. We included temporo-occipital sections with microbleeds guided by ex vivo MRI from two cases with severe cerebral amyloid angiopathy and systematically sampled occipital sections from five consecutive cases with varying cerebral amyloid angiopathy severity. Haematoxylin and eosin stains and immunohistochemistry against amyloid-ß, fibrin(ogen), smooth muscle actin, reactive astrocytes (glial fibrillary acidic protein) and activated microglia (cluster of differentiation 68) were performed. Arterioles were graded using a previously proposed scale of individual vessel cerebral amyloid angiopathy severity, and a blinded assessment for blood-brain barrier leakage, smooth muscle actin and perivascular inflammation was performed. Blood-brain barrier leakage and smooth muscle actin loss were observed in significantly more vessels with mild amyloid-ß deposition (Grade 1 vessels; P = 0.044 and P = 0.012, respectively) as compared to vessels with no amyloid-ß (Grade 0), and blood-brain barrier leakage was observed in 100% of vessels with evidence of vessel remodelling (Grades 3 and 4). Perivascular inflammation in the form of reactive astrocytes and activated microglia was observed predominantly surrounding arterioles at later stages of vessel pathology (Grades 2-4) and consistently around vessels with the same morphological features as ruptured vessel segments (Grade 4). These findings suggest a role for blood-brain barrier leakage and perivascular inflammation leading to arteriolar remodelling and haemorrhage in cerebral amyloid angiopathy, with early blood-brain barrier leakage as a potential trigger for subsequent perivascular inflammation.

Membrane acting Povarov-Doebner derived compounds potently disperse preformed multidrug resistant Gram-positive bacterial biofilms.

The National Institute of Health (NIH) estimates that the majority of human microbial infections are either linked to or directly caused by bacterial biofilms and these infections are immune to most currently approved FDA drugs. Hence, there is a need for the development of potent antibiotics against biofilms. We have previously shown that pentafluorosulfanyl (SF5)-containing quinoline compounds, which were synthesized via the Povarov reaction, kill persister bacteria (Onyedibe et al. RSC Med Chem, 2021, 12, 1879-1893). Inspired by this earlier discovery, we expanded upon the compounds in the library to identify additional members that could have similar or better potencies, with a goal of increasing the diversity of compounds that could be further developed into therapeutics. Compounds from the Povarov derived SF5-containing compounds inhibited both clinical and laboratory strains of Gram-positive bacteria at minimum inhibitory concentration (MIC) of 0.5 µg/mL to 2 µg/mL. Interestingly, the lead compound, HSD 1919 exhibited rapid bactericidal mode of action against multidrug resistant (MDR) staphylococcal and enterococcal strains such as MRSA and VRE via bacterial membrane disruption. HSD 1919 eradicated persister MRSA in 2 h-8 h. Most remarkably, we found that HSD 1919 (newly identified compound) and HSD 1835 (previously disclosed, Onyedibe et al. RSC Med Chem, 2021, 12, 1879-1893), dispersed preformed MRSA and VRE biofilms at relatively low concentrations (8 µg/mL). Bithionol (at 1 µg/mL) or nitroxoline (at 4 µg/mL) did not appreciably disperse pre-existing biofilms but when combined with HSD 1919 or HSD 1835 (at 0.5-4 µg/mL), preformed MRSA biofilms could be dispersed, highlighting exciting synergy at reasonably low concentrations of the drugs. Biofilm dispersal was verified by scanning electron microscopy (SEM) whilst membrane disruption properties of HSD 1919 were confirmed by both transmission electron microscopy (TEM) and SEM. Further mechanistic studies showed inhibition of DNA, RNA, cell wall and protein synthesis in a macromolecular biosynthesis assay indicating that these compounds inhibit bacteria via multiple mechanisms, which is now being appreciated as an effective way to tackle resistant bacteria. Toxicity studies showed that HSD 1919 was nontoxic in-vitro to mammalian red blood cells at 10X MIC. Herein, we report HSD 1919 and analogs thereof as critical chemical scaffolds, which can be harnessed to develop highly potent antibiofilm therapeutics.

River phosphorus cycling during high flow may constrain Lake Erie cyanobacteria blooms.

Cyanobacterial harmful blooms have been increasing worldwide, due in part to excessive phosphorus (P) losses from agriculture-dominated watersheds. Unfortunately, cyanobacteria bloom management is often complicated by uncertainty associated with river P cycling. River P cycling mediates P exports during low flow but has been assumed to be unimportant during high flows. Thus, we examined interactions between dissolved reactive phosphorus (DRP) and suspended sediment P during high flows in the Maumee River network, focusing on March-June Maumee River DRP exports, which fuel recurring cyanobacteria blooms in Lake Erie. We estimate that during 2003-2019 March to June high flow events, P sorption reduced DRP exports by an average of 13-27%, depending upon the colloidal-P:DRP ratio, decreasing the bioavailability of P exports, and potentially constraining cyanobacteria blooms by 13-40%. Phosphorus sorption was likely lower during 2003-2019 than 1975-2002 due to reductions in suspended sediment loads, associated with soil-erosion-minimizing agricultural practices. This unintended outcome of erosion management has likely decreased P sorption, increased DRP exports to Lake Erie, and subsequent cyanobacteria blooms. In other watersheds, DRP-sediment P interactions during high flow could have a positive or negative effect on DRP exports; therefore, P management should consider riverine P cycles, particularly during high flow events, to avoid undermining expensive P mitigation efforts.

Rich-Club Connectivity of the Structural Covariance Network Relates to Memory Processes in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: Though mediotemporal lobe volume changes are well-known features of Alzheimer's disease (AD), grey matter volume changes may be distributed throughout the brain. These distributed changes are not independent due to the underlying network structure and can be described in terms of a structural covariance network (SCN). OBJECTIVE: To investigate how the cortical brain organization is altered in AD we studied the mutual connectivity of hubs in the SCN, i.e., the rich-club. METHODS: To construct the SCNs, cortical thickness was obtained from structural MRI for 97 participants (normal cognition, n = 37; mild cognitive impairment, n = 41; Alzheimer-type dementia, n = 19). Subsequently, rich-club coefficients were calculated from the SCN, and related to memory performance and hippocampal volume using linear regression. RESULTS: Lower rich-club connectivity was related to lower memory performance as well as lower hippocampal volume. CONCLUSION: Therefore, this study provides novel evidence of reduced connectivity in hub areas in relation to AD-related cognitive impairments and atrophy.

Appraising the need for audiological assessment before autism spectrum disorder referral.

Objectives: Mandatory audiological testing before autism spectrum disorder (ASD) assessment is common practice. Hearing impairment (HI) in the general paediatric population is estimated at 3%; however, hearing impairment prevalence among children with ASD is poorly established. Our objective was to determine which children referred for ASD assessment require preliminary audiological assessment. Methods: Retrospective chart review of children (n=4,173; 0 to 19 years) referred to British Columbia's Autism Assessment Network (2010 to 2014). We analyzed HI rate, risk factors, and timing of HI diagnosis relative to ASD referral. Results: ASD was diagnosed in 53.4%. HI rates among ASD referrals was 3.3% and not significantly higher in children with ASD (ASD+; 3.5%) versus No-ASD (3.0%). No significant differences in HI severity or type were found, but more ASD+ females (5.5%) than ASD+ males (3.1%) had HI (P<0.05). Six HI risk factors were significant (problems with intellect, language, vision/eye, ear, genetic abnormalities, and prematurity) and HI was associated with more risk factors (P<0.01). Only 12 children (8.9%) were diagnosed with HI after ASD referral; all males 6 years or younger and only one had no risk factors. ASD+ children with HI were older at ASD referral than No-ASD (P<0.05). Conclusions: Children with ASD have similar hearing impairment rates to those without ASD. HI may delay referral for ASD assessment. As most children were diagnosed with HI before ASD referral or had at least one risk factor, we suggest that routine testing for HI among ASD referrals should only be required for children with risk factors.