Non-linear impacts of harmful algae blooms on the coastal tourism economy.

Harmful algae blooms (HABs) occur in water bodies throughout the globe and can have multi-faceted impacts on tourism. However, little is known of the magnitude of economic losses to the tourism sector as a result of HABs. There is limited understanding of the empirical relationships between HAB intensity and duration, and the effects of this phenomenon on the tourism sector. This study is based in the state of Florida, USA, a notable sun, sand, and sea destination in the western hemisphere, where blooms of a marine harmful algae are a recurrent threat to coastal tourism. The empirical framework is based on a month and county-level panel database that combines sales by tourism-related businesses with observations from the official HAB surveillance system of the state of Florida. We use time and space fixed-effects regressions to estimate the loss in tourism revenue associated with one additional day of red tide. Results indicate that impacts of HABs on tourism do not follow a linear pattern with increasing HAB concentrations, but rather appear to follow an inverted-U pattern. In other words, higher concentrations of the HAB organism do not necessarily imply higher economic losses, suggesting that the impacts of HABs on tourism are not driven solely by the biophysical element of cell density. Rather, these impacts appear to be mediated and amplified by human dimensions. The loss to tourism-related businesses due to the 2018 Florida red tide bloom was estimated to be $2.7 billion USD, which implies that HABs and their impact on tourism can be considered as a potential 'billion-dollar' disaster.

Assessing the Utility of Toe Arm Index and Toe Pressure in Predicting Wound Healing in Patients Undergoing Vascular Intervention.

BACKGROUND: Objective measures of perfusion such as an ankle-brachial index (ABI) and toe pressure remain important in prognosticating wound healing. However, the use of ABI is limited in patients with incompressible vessels and toe pressure may not be comparable across patients. While a toe arm index (TAI) may be of value in this setting, its role as clinical indicator of perfusion for healing in patients with lower-extremity wounds has not been well established. METHODS: A retrospective review was performed of all vascular patients with lower-extremity wounds that underwent peripheral vascular intervention between 2014-2019. Data regarding patient demographics, comorbidities, TAI, ABI, toe pressures, and the wound, ischemia, and foot infection (WIfI) score were collected. Associations between patient variables and wound healing at various time points were evaluated. RESULTS: A total of 173 patients (67.7 ± 10.9 years; 71.1% male) were identified with lower-extremity wounds. Most patients underwent endovascular intervention (77.5%). Patients were followed for a median of 416 (IQR 129-900) days. Mean postoperative TAI was 0.35 ± 0.19 and mean WIfI score was 2.60 ± 1.17. Nine percent (15) of patients healed within 1 month, 44.8% (69) healed within 6 months, and 65.5% (97) healed within 1 year of revascularization without need for major amputation. Those that healed within 1 year without any major amputation did not differ from those that did not heal based on age, gender, race, comorbidities, periprocedural medications, or procedures performed. However, patients that healed without major amputation had a higher postoperative TAI (0.38 vs. 0.30, P = 0.02), higher toe pressure (53 vs. 40 mm Hg, P = 0.004), and lower WIfI score (2.26 vs. 3.12, P < 0.001). Patients that healed with 1 year without requiring any amputation had similar associations with postoperative TAI, toe pressure, and WIfI. Additionally, they were more likely to be White (P = 0.019) and have an open surgical procedure (P < 0.001) and less likely to have chronic kidney disease (P = 0.001) or diabetes (P = 0.008). A Youden index was calculated and identified a TAI value of 0.30 that optimized sensitivity and specificity for wound healing. The area under the curve for TAI as a predictor of wound healing was 0.62. CONCLUSIONS: Higher postoperative TAI is associated with higher odds of wound healing without need for major amputation. Toe arm index is therefore a useful tool to identify patients with adequate arterial perfusion to heal lower-extremity wounds. However, the area under the curve is poor for TAI when used as a sole predictor of wound healing potential suggesting that TAI should be one of multiple factors to considered when prognosticating wound healing potential.

Defining Vascular Deserts to Describe Access to Care and Identify Sites for Targeted Limb Preservation Outreach.

BACKGROUND: Access to care plays a critical role in limb salvage in chronic limb-threatening ischemia (CLTI). A "medical desert" describes a community lacking access to medical necessities, resulting in increased morbidity and mortality. We sought to describe vascular deserts, which we defined as regions with decreased access to specialty care. METHODS: All California providers performing vascular surgery procedures were identified through online provider and health care facility searches. Facility participation in the Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI) lower extremity bypass (LEB) and peripheral vascular intervention (PVI) modules was also determined. Addresses were geocoded with a 30-mile surrounding buffer using ArcGIS (Geographic information systems), creating maps based on care type, including all providers performing vascular procedures, board-certified vascular surgeons, and facilities participating in VQI modules. Public census data overlayed on the maps demonstrated population composition in desert versus nondesert regions. Subsequently, data from the Healthy Places Index (HPI) was overlayed, providing data regarding 25 social factors, comprising an overall HPI score and percent, with lower scores corresponding to poorer health and outcomes. RESULTS: Maps depicting care regions demonstrated decreased provider coverage with increasing specialty care, with the VQI provider map showing the most prominent "desert" regions. When comparing nondesert versus desert regions by care type, demographics including race, the percentage of the population 200% below the poverty line, and the rate of uninsured residents were described. Social determinants of health were then described for desert and nondesert regions by care type, including the HPI percentage and specific domain factors. The percentage of uninsured residents was significant only in the desert and nondesert areas served by board-certified vascular surgeons (19.6 vs. 16.8%, P < 0.001). The mean HPI percentile was significantly lower in board-certified provider and VQI facility deserts than nondeserts (50.48% vs. 40.65%, P < 0.001 and 52.68% vs. 43.12%, P < 0.001, respectively). The economic and education factor percentiles were significantly lower in all desert populations, while the housing, social, and pollution factors were significantly higher in nondesert regions. Health care access, transportation, and neighborhood factor percentiles were significantly lower in board-certified and VQI facility deserts than in the nondesert areas. CONCLUSIONS: Access to vascular care plays a significant role in limb salvage. Through mapping vascular deserts, patient demographics, and social factors in desert regions are better understood, and areas that would benefit most from targeted outreach and limb preservation programs for CLTI are identified.

Provider ankle brachial index and wound classification teaching as part of a comprehensive limb preservation outreach program.

OBJECTIVE: Utilization of evidence-based specialty guidelines is low in primary care settings. Early use of ankle-brachial index (ABI) testing and a validated wound classification system allows prompt referral of patients for specialty care. We implemented a program to teach providers ABI testing and the use of the Wound, Ischemia, and foot Infection (WIfI) classification tool. Here, we report program outcomes and provider perceptions. METHODS: Physicians and non-physicians from wound care centers, nursing and physician education programs, primary care offices, and federally qualified health centers were invited to participate in the educational program teaching ABI testing and the use of the WIfI tool. Pretest and posttest responses and intention to use content in the future were assessed with descriptive statistics. RESULTS: A total of 101 subjects completed the ABI module, and 84 indicated their occupation (59 physicians, 25 non-physicians). Seventy-nine subjects completed the WIfI module, and 89% indicated their occupation (50 physicians, 20 non-physicians). Physicians had lower pre-test knowledge scores for the ABI module than non-physicians (mean scores of 7.9 and 8.2, respectively). Both groups had improved knowledge scores on the post-test (physicians, 13.4; non-physicians, 13.8; P < .001). Non-physicians in practice longer than 10 years at wound care centers had the lowest baseline knowledge scores, whereas physicians in practice for over 10 years had the highest. In the ABI module, the largest knowledge gap included accurately calculating the ABI, followed by the correct use of the Doppler, and management of incompressible vessels. For the WIfI module, providers struggled to accurately score patients based on wound classification. The greatest barriers to the implementation of ABI testing were the availability of trained personnel, followed by limited time for testing. Barriers to the use of the WIfI tool for physicians included lack of time and national guideline support. For non-physicians, the most notable barrier was a lack of training. CONCLUSIONS: Provider understanding of ABI and WIfI tools are limited in wound care centers, primary care offices, and federally qualified health centers. Further barriers include a lack of training in the use of tools, limited potential for point-of-care testing reimbursement, and insufficient dissemination of WIfI guidelines. Such barriers discourage widespread adoption and result in delayed diagnosis of arterial insufficiency.

Fan cells in lateral entorhinal cortex directly influence medial entorhinal cortex through synaptic connections in layer 1.

Standard models for spatial and episodic memory suggest that the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC) send parallel independent inputs to the hippocampus, each carrying different types of information. Here, we evaluate the possibility that information is integrated between divisions of the entorhinal cortex prior to reaching the hippocampus. We demonstrate that, in mice, fan cells in layer 2 (L2) of LEC that receive neocortical inputs, and that project to the hippocampal dentate gyrus, also send axon collaterals to layer 1 (L1) of the MEC. Activation of inputs from fan cells evokes monosynaptic glutamatergic excitation of stellate and pyramidal cells in L2 of the MEC, typically followed by inhibition that contains fast and slow components mediated by GABAA and GABAB receptors, respectively. Inputs from fan cells also directly activate interneurons in L1 and L2 of MEC, with synaptic connections from L1 interneurons accounting for slow feedforward inhibition of L2 principal cell populations. The relative strength of excitation and inhibition following fan cell activation differs substantially between neurons and is largely independent of anatomical location. Our results demonstrate that the LEC, in addition to directly influencing the hippocampus, can activate or inhibit major hippocampal inputs arising from the MEC. Thus, local circuits in the superficial MEC may combine spatial information with sensory and higher order signals from the LEC, providing a substrate for integration of 'what' and 'where' components of episodic memories.

The potential role of integrin alpha 6 in human mesenchymal stem cells.

Human mesenchymal stem cells (MSCs) are isolated from various adult and perinatal tissues. Although mesenchymal stem cells from multiple sources exhibit similar morphology and cell surface markers, they differ in their properties. In this study, we determined that the expression of integrin alpha 6 (ITGA6) and ITGA6 antisense RNA (ITGA6-AS1) correlates with the proliferation, cell size, and differentiation potential. The expression of ITGA6 was inversely correlated with ITGA6-AS1 in MSCs. The expression of ITGA6 was higher, but ITGA6-AS1 was lower in MSCs from cord placenta junction, cord tissue, and Wharton's jelly. In contrast, ITGA6 expression was lower, while ITGA6-AS1 was higher in MSCs from the placenta. The bioinformatic analysis showed that ITGA6 genomic DNA transcribes ITGA6-AS1 from the reverse strand, overlapping ITGA6 exon-2. Additionally, we identify several putative promoters (P1-P10) of ITGA6. ITGA6-P10 is CG rich and contains CGI. EMBOSS Cpgplot software revealed a CGI length of 180 bp that extends from nucleotide 125 to 304 of the P10 sequence. We suggest that the post-transcriptional regulation of the ITGA6 in mesenchymal stem cells is controlled by the ITGA6-AS1, which could be a critical factor responsible for the heterogeneity in function and cell fate of human MSCs. These results may provide further impetus for investigations to unravel the mechanisms of ITGA6 regulation that could help maintain or improve the properties of mesenchymal stem cells.

Stroke Severity in Ischemic Stroke Patients with a History of Diastolic Blood Pressure Treated in a Telestroke Network.

Background: The relationship between diastolic blood pressure (DBP), risk factors, and stroke severity in acute ischemic stroke (AIS) patients treated in a telestroke network is not fully understood. The present study aims to determine the effect of risk factors on stroke severity in AIS patients with a history of elevated DBP. Material and Methods: We retrospectively analyzed data on stroke severity for AIS patients treated between January 2014 and June 2016 treated in the PRISMA Health telestroke network. Data on the severity of stroke on admission were evaluated using NIHSS scores ≤7 for reduced, and >7 for increased, stroke severity. DBP was stratified as ≤80 mmHg for reduced DBP and >80 mmHg for elevated DBP. The study's primary outcomes were risk factors associated with improving neurologic functions or reduced stroke severity and deteriorating neurologic functions or increased stroke severity. The associations between risk factors and stroke severity for AIS with elevated DBP were determined using multi-level logistic and regression models. Results: In the adjusted analysis, AIS patients with a DBP ≤ 80 mmHg, obesity (OR = 0.388, 95% Cl, 0.182−0.828, p = 0.014) was associated with reduced stroke severity, while an increased heart rate (OR = 1.025, 95% Cl, 1.001−1.050, p = 0.042) was associated with higher stroke severity. For AIS patients with a DBP > 80 mmHg, hypertension (OR = 3.453, 95% Cl, 1.137−10.491, p = 0.029), history of smoking (OR = 2.55, 95% Cl, 1.06−6.132, p = 0.037), and heart rate (OR = 1.036, 95% Cl, 1.009−1.064, p = 0.009) were associated with higher stroke severity. Caucasians (OR = 0.294, 95% Cl, 0.090−0.964, p = 0.002) and obesity (OR = 0.455, 95% Cl, 0.207−1.002, p = 0.05) were more likely to be associated with reduced stroke severity. Conclusions: Our findings reveal specific risk factors that can be managed to improve the care of AIS patients with elevated DBP treated in the telestroke network.

DNA Damage and Oxidative Stress of Tobacco Smoke Condensate in Human Bladder Epithelial Cells.

Smoking is a major risk factor for bladder cancer (BC), with up to 50% of BC cases being attributed to smoking. There are 70 known carcinogens in tobacco smoke; however, the principal chemicals responsible for BC remain uncertain. The aromatic amines 4-aminobiphenyl (4-ABP) and 2-naphthylamine (2-NA) are implicated in BC pathogenesis of smokers on the basis of the elevated BC risk in factory workers exposed to these chemicals. However, 4-ABP and 2-NA only occur at several nanograms per cigarette and may be insufficient to induce BC. In contrast, other genotoxicants, including acrolein, occur at 1000-fold or higher levels in tobacco smoke. There is limited data on the toxicological effects of tobacco smoke in human bladder cells. We have assessed the cytotoxicity, oxidative stress, and DNA damage of tobacco smoke condensate (TSC) in human RT4 bladder cells. TSC was fractionated by liquid-liquid extraction into an acid-neutral fraction (NF), containing polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs, phenols, and aldehydes, and a basic fraction (BF) containing aromatic amines, heterocyclic aromatic amines, and N-nitroso compounds. The TSC and NF induced a time- and concentration-dependent cytotoxicity associated with oxidative stress, lipid peroxide formation, glutathione (GSH) depletion, and apurinic/apyrimidinic (AP) site formation, while the BF showed weak effects. LC/MS-based metabolomic approaches showed that TSC and NF altered GSH biosynthesis pathways and induced more than 40 GSH conjugates. GSH conjugates of several hydroquinones were among the most abundant conjugates. RT4 cell treatment with synthetic hydroquinones and cresol mixtures at levels present in tobacco smoke accounted for most of the TSC-induced cytotoxicity and the AP sites formed. GSH conjugates of acrolein, methyl vinyl ketone, and crotonaldehyde levels also increased owing to TSC-induced oxidative stress. Thus, TSC is a potent toxicant and DNA-damaging agent, inducing deleterious effects in human bladder cells at concentrations of <1% of a cigarette in cell culture media.

Human primitive mesenchymal stem cell-derived retinal progenitor cells improved neuroprotection, neurogenesis, and vision in rd12 mouse model of retinitis pigmentosa.

BACKGROUND: Currently, there is no treatment for retinal degenerative diseases (RDD) such as retinitis pigmentosa (RP). Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. Thus far, primarily adult mesenchymal stem cells (MSCs) have been investigated in preclinical and clinical studies, and the results have not been convincing. We applied a new approach in which primitive (p) MSC-derived retinal progenitor cells (RPCs) were examined to treat retinal degeneration in an rd12 mouse model of RP. METHODS: Well-characterized pMSCs and RPCs labeled with PKH26 were intravitreally injected into rd12 mice. The vision and retinal function of transplanted animals were analyzed using electroretinography. Animals were killed 4 and 8 weeks after cell transplantation for histological, immunological, molecular, and transcriptomic analyses of the retina. RESULTS: Transplanted RPCs significantly improved vision and retinal thickness as well as function in rd12 mice. pMSCs and RPCs homed to distinct retinal layers. pMSCs homed to the retinal pigment epithelium, and RPCs migrated to the neural layers of the retina, where they improved the thickness of the respective layers and expressed cell-specific markers. RPCs induced anti-inflammatory and neuroprotective responses as well as upregulated the expression of genes involved in neurogenesis. The transcriptomic analysis showed that RPCs promoted neurogenesis and functional recovery of the retina through inhibition of BMP and activation of JAK/STAT and MAPK signaling pathways. CONCLUSIONS: Our study demonstrated that RPCs countered inflammation, provided retinal protection, and promoted neurogenesis resulting in improved retinal structure and physiological function in rd12 mice.

Catastrophic chemotherapy toxicity leading to diagnosis of Fanconi anaemia due to FANCD1/BRCA2 during adulthood: description of an emerging phenotype.

Fanconi anaemia due to biallelic loss of BRCA2 (Fanconi anaemia subtype D1) is traditionally diagnosed during childhood with cancer rates historically reported as 97% by 5.2 years. This report describes an adult woman with a history of primary ovarian failure, who was diagnosed with gastrointestinal adenocarcinoma and BRCA2-associated Fanconi anaemia at 23 years of age, only after she suffered severe chemotherapy toxicity. The diagnostic challenges include atypical presentation, initial false-negative chromosome fragility testing and variant classification. It highlights gastrointestinal adenocarcinoma as a consideration for adults with biallelic BRCA2 pathogenic variants with implications for surveillance. After over 4 years, the patient has no evidence of gastrointestinal cancer recurrence although the tumour was initially considered only borderline resectable. The use of platinum-based chemotherapy, to which heterozygous BRCA2 carriers are known to respond, may have had a beneficial anticancer effect, but caution is advised given its extreme immediate toxicity at standard dosing. Fanconi anaemia should be considered as a cause for women with primary ovarian failure of unknown cause and referral to cancer genetic services recommended when there is a family history of cancer in the hereditary breast/ovarian cancer spectrum.

Pediatric Clinicians' Use of Telemedicine: Qualitative Interview Study.

BACKGROUND: Bedside manner describes how clinicians relate to patients in person. Telemedicine allows clinicians to connect virtually with patients using digital tools. Effective virtual communication or webside manner may require modifications to traditional bedside manner. OBJECTIVE: This study aims to understand the experiences of telemedicine providers with patient-to-provider virtual visits and communication with families at a single large-volume children's hospital to inform program development and training for future clinicians. METHODS: A total of 2 focus groups of pediatric clinicians (N=11) performing virtual visits before the COVID-19 pandemic, with a range of experiences and specialties, were engaged to discuss experiential, implementation, and practice-related issues. Focus groups were facilitated using a semistructured guide covering general experience, preparedness, rapport strategies, and suggestions. Sessions were digitally recorded, and the corresponding transcripts were reviewed for data analysis. The transcripts were coded based on the identified main themes and subthemes. On the basis of a higher-level analysis of these codes, the study authors generated a final set of key themes to describe the collected data. RESULTS: Theme consistency was identified across diverse participants, although individual clinician experiences were influenced by their specialties and practices. A total of 3 key themes emerged regarding the development of best practices, barriers to scalability, and establishing patient rapport. Issues and concerns related to privacy were salient across all themes. Clinicians felt that telemedicine required new skills for patient interaction, and not all were comfortable with their training. CONCLUSIONS: Telemedicine provides benefits as well as challenges to health care delivery. In interprofessional focus groups, pediatric clinicians emphasized the importance of considering safety and privacy to promote rapport and webside manner when conducting virtual visits. The inclusion of webside manner instructions within training curricula is crucial as telemedicine becomes an established modality for providing health care.

Management and Outcomes of Diffuse Large B-cell Lymphoma Post-transplant Lymphoproliferative Disorder in the Era of PET and Rituximab: A Multicenter Study From the Australasian Lymphoma Alliance.

There are limited data on post-transplant lymphoproliferative disorder (PTLD) in the era of positron emission tomography (PET) and rituximab (R). Furthermore, there is limited data on the risk of graft rejection with modern practices in reduction in immunosuppression (RIS). We studied 91 patients with monomorphic diffuse large B-cell lymphoma PTLD at 11 Australian centers: median age 52 years, diagnosed between 2004 and 2017, median follow-up 4.7 years (range, 0.5-14.5 y). RIS occurred in 88% of patients. For patients initially treated with R-monotherapy, 45% achieved complete remission, rising to 71% with the addition of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) for those not in complete remission. For patients initially treated with R-CHOP, the complete remission rate was 76%. There was no difference in overall survival (OS) between R-monotherapy and R-chemotherapy patients. There was no difference in OS for patients with systemic lymphoma (n = 68) versus central nervous system (CNS) involvement (n = 23) (3-y OS 72% versus 73%; P = 0.78). Treatment-related mortality was 7%. End of treatment PET was prognostic for patients with systemic lymphoma with longer OS in the PET negative group (3-y OS 91% versus 57%; P = 0.01). Graft rejection occurred in 9% (n = 4 biopsy-proven; n = 4 suspected) during the entire follow-up period with no cases of graft loss. RIS and R-based treatments are safe and effective with a low likelihood of graft rejection and high cure rate for patients achieving complete remission with CNS or systemic PTLD.

How Has the Pandemic Affected Women in Medicine? A Survey-Based Study on Perceptions of Personal and Career Impacts of COVID-19.

Background: Gender inequity is apparent for women in medicine. With the onset of the COVID-19 pandemic, there are concerns about how women physicians are personally and professionally impacted. Materials and Methods: Participants of the Women in Medicine Summit were anonymously surveyed about their perspectives about COVID-19 affecting women in medicine. Questions were centered around perceived gender bias, productivity expectations, and stressors. Results: At the Women in Medicine Summit, 454 attendees were invited to complete the survey with a response rate of 27% (n = 124). Of those participants, 46% of participants perceived gender bias in the workplace, with 39% citing further inequities with intersectional identities (p < 0.05). Productivity expectations were reported to be higher than before the pandemic in 41% of survey participants. The majority of respondents (70%) reported experiencing high levels of stress during the pandemic, compared with only 16% reporting high levels of stress before the pandemic (p < 0.05). Discussion: It is clear that women physicians are experiencing the pandemic differently. Gender bias is a common occurrence, especially by individuals with intersectional identities. These stressors are not new to women in medicine, but with the overriding impact of the pandemic, higher expectations for productivity, and increased personal responsibilities, employers should focus on preventing further exacerbations of gender inequity in medicine.

Deep entorhinal cortex: from circuit organization to spatial cognition and memory.

The deep layers of the entorhinal cortex are important for spatial cognition, as well as memory storage, consolidation and retrieval. A long-standing hypothesis is that deep-layer neurons relay spatial and memory-related signals between the hippocampus and telencephalon. We review the implications of recent circuit-level analyses that suggest more complex roles. The organization of deep entorhinal layers is consistent with multi-stage processing by specialized cell populations; in this framework, hippocampal, neocortical, and subcortical inputs are integrated to generate representations for use by targets in the telencephalon and for feedback to the superficial entorhinal cortex and hippocampus. Addressing individual sublayers of the deep entorhinal cortex in future experiments and models will be important for establishing systems-level mechanisms for spatial cognition and episodic memory.

Neural stem cells derived from primitive mesenchymal stem cells reversed disease symptoms and promoted neurogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). MS affects millions of people and causes a great economic and societal burden. There is no cure for MS. We used a novel approach to investigate the therapeutic potential of neural stem cells (NSCs) derived from human primitive mesenchymal stem cells (MSCs) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: MSCs were differentiated into NSCs, labeled with PKH26, and injected into the tail vein of EAE mice. Neurobehavioral changes in the mice assessed the effect of transplanted cells on the disease process. The animals were sacrificed two weeks following cell transplantation to collect blood, lymphatic, and CNS tissues for analysis. Transplanted cells were tracked in various tissues by flow cytometry. Immune infiltrates were determined and characterized by H&E and immunohistochemical staining, respectively. Levels of immune regulatory cells, Treg and Th17, were analyzed by flow cytometry. Myelination was determined by Luxol fast blue staining and immunostaining. In vivo fate of transplanted cells and expression of inflammation, astrogliosis, myelination, neural, neuroprotection, and neurogenesis markers were investigated by using immunohistochemical and qRT-PCR analysis. RESULTS: MSC-derived NSCs expressed specific neural markers, NESTIN, TUJ1, VIMENTIN, and PAX6. NSCs improved EAE symptoms more than MSCs when transplanted in EAE mice. Post-transplantation analyses also showed homing of MSCs and NSCs into the CNS with concomitant induction of an anti-inflammatory response, resulting in reducing immune infiltrates. NSCs also modulated Treg and Th17 cell levels in EAE mice comparable to healthy controls. Luxol fast blue staining showed significant improvement in myelination in treated mice. Further analysis showed that NSCs upregulated genes involved in myelination and neuroprotection but downregulated inflammatory and astrogliosis genes more significantly than MSCs. Importantly, NSCs differentiated into neural derivatives and promoted neurogenesis, possibly by modulating BDNF and FGF signaling pathways. CONCLUSIONS: NSC transplantation reversed the disease process by inducing an anti-inflammatory response and promoting myelination, neuroprotection, and neurogenesis in EAE disease animals. These promising results provide a basis for clinical studies to treat MS using NSCs derived from primitive MSCs.

Seasonal variation in North American level crossing crash rates is due to weather, not day length.

OBJECTIVE: Collisions between road vehicles and trains at level (grade) crossings can be devastating. Injury and economic considerations make prevention efforts of significant interest to society at all levels, and raise important safety concerns. Improving our understanding of the nature and pattern of crashes at level crossings can help inform a variety of types of safety mitigation strategies, including public education, crossing equipment and vehicle design efforts. METHOD: To this end, a database search of Canadian level crossing crashes for the 11-year period between 2007 and 2017 was conducted to confirm a previously identified seasonal variation in the frequency of level crossing crashes. To determine whether the observed winter increase in crashes was due primarily to winter reductions in light levels/day length or to other seasonal weather factors, a subsequent comparison of Canadian data to American Federal Railroad Administration (FRA) crash data was carried out. A separate inferential log-linear model analysis, using season, time of day and crossing protection type, was also used to explore the increase. RESULTS: As expected, the average rate of crossing collisions in Canada increased during winter months compared to non-winter months. While the seasonal pattern was evident in those U.S. states that experience significant changes in weather patterns (i.e., northern states), it was almost completely absent in those states that do not (i.e., southern states). The log-linear model analysis confirmed these findings. CONCLUSIONS: The seasonal variation in North American level crossing crash rate is a result of winter weather conditions, rather than differences in light levels. Future research is planned that will elucidate the specific environmental and human factors contributing to the increase.

Cytotoxicity and genotoxicity of the carcinogen aristolochic acid I (AA-I) in human bladder RT4 cells.

Aristolochic acid (AA-I) induces upper urothelial tract cancer (UUTC) and bladder cancer (BC) in humans. AA-I forms the 7-(2'-deoxyadenosin-N6-yl)aristolactam I (dA-AL-I) adduct, which induces multiple A:T-to-T:A transversion mutations in TP53 of AA-I exposed UTUC patients. This mutation is rarely reported in TP53 of other transitional cell carcinomas and thus recognized as an AA-I mutational signature. A:T-to-T:A transversion mutations were recently detected in bladder tumors of patients in Asia with known AA-I-exposure, implying that AA-I contributes to BC. Mechanistic studies on AA-I genotoxicity have not been reported in human bladder. In this study, we examined AA-I DNA adduct formation and mechanisms of toxicity in the human RT4 bladder cell line. The biological potencies of AA-I were compared to 4-aminobiphenyl, a recognized human bladder carcinogen, and several structurally related carcinogenic heterocyclic aromatic amines (HAA), which are present in urine of smokers and omnivores. AA-I (0.05-10 µM) induced a concentration- and time-dependent cytotoxicity. AA-I (100 nM) DNA adduct formation occurred at over a thousand higher levels than the principal DNA adducts formed with 4-ABP or HAAs (1 µM). dA-AL-I adduct formation was detected down to a 1 nM concentration. Studies with selective chemical inhibitors provided evidence that NQO1 is the major enzyme involved in AA-I bio-activation in RT4 cells, whereas CYP1A1, another enzyme implicated in AA-I toxicity, had a lesser role in bio-activation or detoxification of AA-I. AA-I DNA damage also induced genotoxic stress leading to p53-dependent apoptosis. These biochemical data support the human mutation data and a role for AA-I in BC.

Evidence for the additive effects of dispositional negative mood regulation expectancies and placebo-induced expectancies on mood recovery.

OBJECTIVE: Low negative mood regulation expectancies (NMRE) are associated with greater anticipated and experienced negative mood states, as well as with coping strategies that prolong these states. Individuals with low NMRE may be especially responsive to placebos because confidence in an external source of mood improvement can provide the positive mood expectancies and motivation for active coping that they typically lack. This study investigated how NMRE and placebo-induced expectancies contribute to mood recovery. METHOD: Participants (N = 125) completed personality scales, including NMRE, online. During a subsequent in-person session, participants were randomly assigned to one of three conditions: (1) placebo treatment-participants learned of a mood-enhancing treatment and received it; (2) treatment deprivation-participants learned of the same treatment, but did not receive it; (3) control-treatment was never mentioned. Participants also completed measures of mood, active coping, and expectations. RESULTS: NMRE was a stronger predictor of mood recovery than placebo-induced expectancies regardless of group assignment. Additionally, pessimistic expectations arose when participants believed treatment was being deprived, and these participants exhibited the least active coping. CONCLUSION: Our results confirm the reliability of NMRE in predicting affective outcomes and suggest that personality and placebo-induced expectations have additive effects on mood recovery.

Applying principles of fatigue science to accident investigation: Transportation Safety Board of Canada (TSB) fatigue investigation methodology.

Fatigue that is related to the amount and quality of sleep obtained can impair human performance in ways that can lead to accidents. As many transportation industries operate around the clock, fatigue and its effects cannot be eliminated completely; instead, they must be managed. A first step is to document the prevalence and role of fatigue in accidents that occur. The Transportation Safety Board of Canada (TSB) routinely investigates such transportation industry incidents to determine if fatigue was present, if it played a role, and if there were practices in place to effectively manage it and associated risks. Herein, we summarize and describe the TSB's fatigue investigation methodology in the hopes that investigators of other organizations and domains will find the concepts applicable to their operational context.