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In March 2020, when public health stay home orders began in order to halt the spread of COVID-19, child care as an industry was drastically and abruptly impacted. This public health emergency highlighted the weaknesses in the child care system in the United States. This study investigated the changes in operations cost, child enrollment and attendance, and state and federal support that occurred during the first year of the COVID-19 pandemic among both center-based and home-based child care programs. A total of 196 licensed centers and 283 home-based programs across Iowa participated in an online survey as a part of the 2020 Iowa Narrow Costs Analysis. This mixed method study utilizes qualitative analysis of response as well as descriptive statistics and pre- post comparison testing. Analysis of qualitative and quantitative data revealed that the COVID-19 pandemic had a marked impact on child care enrollment, the operational cost of child care, the availability of child care, and a variety of other areas including staff workload and mental health. In many instances, participants shared that state and federal COVID-19 relief funds were critical. Although state and federal COVID-19 relief funds were critical for child care providers in Iowa during the pandemic, results suggest similar financial support will be necessary beyond the pandemic to sustain the workforce. Policy suggestions are made for how to continue to support the child care workforce in the future.

We examined changes in school discipline policies and the odds of suspension for students by race in one state. Consistent with previous research findings, Black students continue to be suspended at higher rates than White students. School district code of conduct policies indicated that many school districts have started to incorporate alternatives to suspension in their codes of conduct; nonetheless, in- and out-of-school suspension continued to be the most prominent consequences found in school district handbooks to respond to student behavioral infractions. We examined these policy changes alongside out-of-school suspension data to discuss the implications this has for school administrators and policy reform at the local, state, and national level.

Background Digital Mental Health Interventions (DMHIs) that meet the definition of a medical device are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. The MHRA uses procedures that were originally developed for pharmaceuticals to assess the safety of DMHIs. There is recognition that this may not be ideal, as is evident by an ongoing consultation for reform led by the MHRA and the National Institute for Health and Care Excellence. Aims The aim of this study was to generate an experts’ consensus on how the medical regulatory method used for assessing safety could best be adapted for DMHIs. Method An online Delphi study containing three rounds was conducted with an international panel of 20 experts with experience/knowledge in the field of UK digital mental health. Results Sixty-four items were generated, of which 41 achieved consensus (64%). Consensus emerged around ten recommendations, falling into five main themes: Enhancing the quality of adverse events data in DMHIs; Re-defining serious adverse events for DMHIs; Reassessing short-term symptom deterioration in psychological interventions as a therapeutic risk; Maximising the benefit of the Yellow Card Scheme; and Developing a harmonised approach for assessing the safety of psychological interventions in general. Conclusion The implementation of the recommendations provided by this consensus could improve the assessment of safety of DMHIs, making them more effective in detecting and mitigating risk.

Abstract Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Oxygen minimum zones (OMZs), due to their large volumes of perennially deoxygenated waters, are critical regions for understanding how the interplay between anaerobic and aerobic nitrogen (N) cycling microbial pathways affects the marine N budget. Here, we present a suite of measurements of the most significant OMZ N cycling rates, which all involve nitrite (NO2-) as a product, reactant, or intermediate, in the eastern tropical North Pacific (ETNP) OMZ. These measurements and comparisons to data from previously published OMZ cruises present additional evidence that NO3- reduction is the predominant OMZ N flux, followed by NO2- oxidation back to NO3-. The combined rates of both of these N recycling processes were observed to be much greater (up to nearly 200 times) than the combined rates of the N loss processes of anammox and denitrification, especially in waters near the anoxic–oxic interface. We also show that NO2- oxidation can occur when O2 is maintained near 1 nM by a continuous-purge system, NO2- oxidation and O2 measurements that further strengthen the case for truly anaerobic NO2- oxidation. We also evaluate the possibility that NO2- dismutation provides the oxidative power for anaerobic NO2- oxidation. The partitioning of N loss between anammox and denitrification differed widely from stoichiometric predictions of at most 29 % anammox; in fact, N loss rates at many depths were entirely due to anammox. Our new NO3- reduction, NO2- oxidation, dismutation, and N loss data shed light on many open questions in OMZ N cycling research, especially the possibility of truly anaerobic NO2- oxidation.

Abstract Soil microbiota of the rhizosphere are an important extension of the plant phenotype because they impact the health and fitness of host plants. The composition of these communities is expected to differ among host plants due to influence by host genotype. Given that many plant populations exhibit fine‐scale genetic structure (SGS), associated microbial communities may also exhibit SGS. In this study, we tested this hypothesis using Chamaecrista fasciculata, a legume species that has previously been determined to have significant SGS. We collected genetic data from prokaryotic and fungal rhizosphere communities in association with 70 plants in an area of ~400 square meters to investigate the presence of SGS in microbial communities. Bacteria of Acidobacteria, Protobacteria, and Bacteroidetes and fungi of Basidiomycota, Ascomycota, and Mortierellomycota were dominant members of the rhizosphere. Although microbial alpha diversity did not differ significantly among plants hosts, we detected significant compositional differences among the microbial communities as well as isolation by distance. The strongest factor associated with microbial distance was genetic distance of the other microbial community, followed by geographic distance, but there was not a significant association with plant genetic distance for either microbial community. This study further demonstrates the strong potential for spatial structuring of soil microbial communities at the smallest spatial scales and provides further insight into the complexity of factors that influence microbial composition in soils and in association with host plants.

Abstract Gastrointestinal tract (gut) inflammation increases stress and threat-coping behaviors, which are associated with altered activity in fear-related neural circuits, such as the basolateral amygdala and hippocampus. It remains to be determined whether inflammation from the gut affects neural activity by altering dendritic spines. We hypothesized that acute inflammation alters dendritic spines in a brain region-specific manner. Here we show that acute gut inflammation (colitis) evoked by dextran sodium sulfate (DSS) did not affect the overall spine density in the CA1 region of hippocampus, but increased the relative proportion of immature spines to mature spines on basal dendrites of pyramidal neurons. In contrast, in animals with colitis, no changes in spine density or composition on dendrites of pyramidal cells was observed in the basolateral amygdala. Rather, we observed decreased spine density on dendrites of stellate neurons, but not the relative proportions of mature vs immature spines. We used cFos expression evoked by the forced swim task as a measure of neural activity during stress and found no effect of DSS on the density of cFos immunoreactive neurons in basolateral amygdala. In contrast, fewer CA1 neurons expressed cFos in mice with colitis, relative to controls. Furthermore, CA1 cFos expression negatively correlated with active stress-coping in the swim task and was negatively correlated with gut inflammation. These data reveal that the effects of acute gut inflammation on synaptic remodeling depend on brain region, neuronal phenotype, and dendrite location. In the hippocampus, a shift to immature spines and hypoactivity are more strongly related to colitis-evoked behavioral changes than is remodeling in basolateral amygdala.

Abstract Background Racial inequities in maternal mortality in the U.S. continue to be stark. Methods The 2015–2018, 4-year total population, county-level, pregnancy-related mortality ratio (PRM; deaths per 100,000 live births; National Center for Health Statistics (NCHS), restricted use mortality file) was linked with the Public Health Exposome (PHE). Using data reduction techniques, 1591 variables were extracted from over 62,000 variables for use in this analysis, providing information on the relationships between PRM and the social, health and health care, natural, and built environments. Graph theoretical algorithms and Bayesian analysis were applied to PHE/PRM linked data to identify latent networks. Results PHE variables most strongly correlated with total population PRM were years of potential life lost and overall life expectancy. Population-level indicators of PRM were overall poverty, smoking, lack of exercise, heat, and lack of adequate access to food. Conclusions In this high-dimensional analysis, overall life expectancy, poverty indicators, and health behaviors were found to be the strongest predictors of pregnancy-related mortality. This provides strong evidence that maternal death is part of a broader constellation of both similar and unique health behaviors, social determinants and environmental exposures as other causes of death.

Primary and booster vaccines for COVID-19 are the most effective method of preventing infection and are generally considered safe. However, many cutaneous adverse events have been reported following vaccination. To date there have been seven reported cases of Sweet syndrome occurring following the first dose of the SARS-CoV-2 vaccine. We describe a rare case of atypical giant-cellulitis like Sweet syndrome reemerging after receiving the SARS-CoV-2 booster vaccine.

Previous studies indicate that pollution exposure can increase risks of adverse birth outcomes, but Black communities are underrepresented in this research, and the potential moderating role of neighborhood context has not been explored. These issues are especially relevant in Louisiana, which has a high proportion of Black residents, an entrenched history of structural racism, the most pounds of toxic industrial emissions annually, and among the nation’s highest rates of low birthweight (LBW), preterm birth (PTB), and infant mortality. We investigated whether air pollution and social polarization by race and income (measured via the index of concentration at the extremes [ICE]) were associated with LBW and PTB among Louisiana census tracts ( n = 1101) using spatial lag models. Data sources included 2011–2020 birth records, U.S. Census Bureau 2017 demographic data, and 2017 respiratory hazard (RH) from the U.S. Environmental Protection Agency. Both RH and ICE were associated with LBW ( z = 4.4, P < 0.0001; z = −27.0, P < 0.0001) and PTB ( z = 2.3, P = 0.019; z = −16.7, P < 0.0001), with no interaction. Severely polluted tracts had 36% higher and 25% higher risks of LBW and PTB, respectively, versus unpolluted tracts. On average, 2166 low birthweight and 3583 preterm births annually were attributable to pollution exposure. Tracts with concentrated social deprivation (i.e. low ICE scores) had 53% higher and 34% higher risks of LBW and PTB, respectively, versus intermediate or mixed tracts. On average, 1171 low birthweight and 1739 preterm births annually were attributable to concentrated deprivation. Our ecological study found that a majority of adverse birth outcomes in Louisiana (i.e. 67% of LBW and PTB combined) are linked to air pollution exposure or disadvantage resulting from social polarization. These findings can inform research, policy, and advocacy to improve health equity in marginalized communities.

The rupture of an abdominal aortic aneurysm (AAA) causes about 200,000 deaths worldwide each year. However, there are currently no effective drug therapies to prevent AAA formation or, when present, to decrease progression and rupture, highlighting an urgent need for more research in this field. Increased vascular inflammation and enhanced apoptosis of vascular smooth muscle cells (VSMCs) are implicated in AAA formation. Here, we investigated whether hydralazine, which has anti-inflammatory and anti-apoptotic properties, inhibited AAA formation and pathological hallmarks. In cultured VSMCs, hydralazine (100 μM) inhibited the increase in inflammatory gene expression and apoptosis induced by acrolein and hydrogen peroxide, two oxidants that may play a role in AAA pathogenesis. The anti-apoptotic effect of hydralazine was associated with a decrease in caspase 8 gene expression. In a mouse model of AAA induced by subcutaneous angiotensin II infusion (1 µg/kg body weight/min) for 28 days in apolipoprotein E-deficient mice, hydralazine treatment (24 mg/kg/day) significantly decreased AAA incidence from 80% to 20% and suprarenal aortic diameter by 32% from 2.26 mm to 1.53 mm. Hydralazine treatment also significantly increased the survival rate from 60% to 100%. In conclusion, hydralazine inhibited AAA formation and rupture in a mouse model, which was associated with its anti-inflammatory and anti-apoptotic properties.

Understanding how natural selection acts on intraspecific variation to bring about phenotypic divergence is critical to understanding processes of evolutionary diversification. The orchid family is well known for pollinator-mediated selection of floral phenotypes operating among species and along environmental or geographic gradients. Its effectiveness at small spatial scales is less understood, making the geographic scale at which intraspecific floral variation is examined important to evaluating causes of phenotypic divergence. In this study, we quantified phenotypic variation in the orchid Platanthera dilatata across 26 populations in coastal Southeast Alaska and compared this to edaphic and genetic variation at microsatellite loci. We sought to determine (1) if flower morphological variation is structured at smaller geographic scales, (2) the extent of genetic divergence in relation to phenotypic divergence, (3) the scale at which inter-population gene flow occurs, and (4) the relative importance of geographic distance and abiotic factors on population genetic structure. Two morphological groups were found to separate based on lip and spur length and are restricted to different habitats. Small-flowered forms occur in muskeg bogs, whereas large-flowered forms occur in fens and meadows, and rarely in sub-alpine habitat. Genetic analyses were concordant with the morphological clusters, except for four small-flowered populations that were genetically indistinguishable from large-flowered populations and considered to be introgressed. In fact, most populations exhibited some admixture, indicating incomplete reproductive isolation between the flower forms. Pollinators may partition phenotypes but also facilitate gene flow because short-tongued Noctuidae moths pollinate both phenotypes, but longer-tongued hawkmoths were only observed pollinating the large-flowered phenotype, which may strengthen phenotypic divergence. Nevertheless, pollinator movement between habitats could have lasting effects on neutral genetic variation. At this small spatial scale, population genetic structure is only associated with environmental distance, likely due to extensive seed and pollinator movement. While this study corroborates previous findings of cryptic genetic lineages and phenotypic divergence in P. dilatata, the small scale of examination provided greater understanding of the factors that may underlie divergence.

Abstract Background: The number of older adults living with companion animals (pets) is increasing worldwide. While evidence revealing positive relationships between companion animals and healthy aging is well established, there is a dearth of research regarding companion animal death and subsequent human grieving. Some emerging research suggests that grief over companion animal death is often discounted or even unrecognized (disenfranchised) by others. The extent and consequences of disenfranchised grief (DG) are poorly understood. This study deepens our understanding of older adults’ experiences of DG in relation to companion animal death. Methods: Participants from Alberta, Canada, were recruited through social media platforms to participate in an online questionnaire that collected demographic information and standardized measures of companion animal attachment, bereavement, and DG. Results: The majority of the 98 participants were between 60 and 70 years of age, female, and living alone. Following their companion animal’s death, 38.1% identified a decrease in physical activity, and 47% reported that their emotional health had declined. One-third identified that they needed to be careful about who they disclosed their grief, as they were not certain that they would be supported. This group had a significantly greater likelihood of perceived decrease in physical health, and they were more likely to score higher on the Pet Bereavement Questionnaire. Conclusions: This study adds weight to the emergent body of evidence highlighting companion animal bereavement as a legitimate and impactful health and well-being issue. The study found that DG is experienced by a sizable group of older adults following their companion animal’s death and that many participants perceived that socially legitimized recognition of loss and accompanying bereavement resources were lacking. These shortfalls contribute to health risks that negatively affect older adults’ ability to successfully age in the community.

Summary: Background: Influenza virus infection is associated with incident ischemic heart disease (IHD) events. Here, we estimate the global, regional, and national IHD mortality burden attributable to influenza. Methods: We used vital registration data from deaths in adults ≥50 years (13.2 million IHD deaths as underlying cause) to assess the relationship between influenza activity and IHD mortality in a non-linear meta-regression framework from 2010 to 2019. This derived relationship was then used to estimate the global influenza attributable IHD mortality. We estimated the population attributable fraction (PAF) of influenza for IHD deaths based on the relative risk associated with a given level of weekly influenza test positivity rate and multiplied PAFs by IHD mortality from the Global Burden of Disease study. Findings: Influenza activity was associated with increased risk of IHD mortality across all countries analyzed. The mean PAF of influenza for IHD mortality was 3.9% (95% uncertainty interval [UI] 2.5–5.3%), ranging from

Abstract Background The intestinal microbiota plays an important role in regulating gastrointestinal (GI) physiology in part through interactions with the enteric nervous system (ENS). Alterations in the gut microbiome frequently occur together with disturbances in enteric neural control in pathophysiological conditions. However, the mechanisms by which the microbiota regulates GI function and the structure of the ENS are incompletely understood. Using a mouse model of antibiotic (Abx)-induced bacterial depletion, we sought to determine the molecular mechanisms of microbial regulation of intestinal function and the integrity of the ENS. Spontaneous reconstitution of the Abx-depleted microbiota was used to assess the plasticity of structure and function of the GI tract and ENS. Microbiota-dependent molecular mechanisms of ENS neuronal survival and neurogenesis were also assessed. Results Adult male and female Abx-treated mice exhibited alterations in GI structure and function, including a longer small intestine, slower transit time, increased carbachol-stimulated ion secretion, and increased intestinal permeability. These alterations were accompanied by the loss of enteric neurons in the ileum and proximal colon in both submucosal and myenteric plexuses. A reduction in the number of enteric glia was only observed in the ileal myenteric plexus. Recovery of the microbiota restored intestinal function and stimulated enteric neurogenesis leading to increases in the number of enteric glia and neurons. Lipopolysaccharide (LPS) supplementation enhanced neuronal survival alongside bacterial depletion, but had no effect on neuronal recovery once the Abx-induced neuronal loss was established. In contrast, short-chain fatty acids (SCFA) were able to restore neuronal numbers after Abx-induced neuronal loss, demonstrating that SCFA stimulate enteric neurogenesis in vivo. Conclusions Our results demonstrate a role for the gut microbiota in regulating the structure and function of the GI tract in a sex-independent manner. Moreover, the microbiota is essential for the maintenance of ENS integrity, by regulating enteric neuronal survival and promoting neurogenesis. Molecular determinants of the microbiota, LPS and SCFA, regulate enteric neuronal survival, while SCFA also stimulates neurogenesis. Our data reveal new insights into the role of the gut microbiota that could lead to therapeutic developments for the treatment of enteric neuropathies. Video abstract

Abstract Background Companion animal death is a common source of grief, although the extent and context of that grief is poorly understood, especially in older adulthood. The aim of this multiple-methods study was to develop a greater understanding of the impact of companion animal death on older women living alone in the community, as older women are a distinct at-risk group, and the supports that should be available to help these individuals with their grief. Methods Participants were recruited from across Alberta, a Canadian province, through seniors’ organizations, pet rescue groups, and social media groups of interest to older women. After completing a pre-interview online questionnaire to gain demographic information and standardized pet attachment and grief measures data, participants were interviewed through the Zoom ® computer program or over the telephone. An interpretive description methodology framed the interviews, with Braun and Clarke’s 6-phase analytic method used for thematic analysis of interview data. Results In 2020, twelve participants completed the pre-interview questionnaires and nine went on to provide interview data for analysis. All were older adult (age 55+) women, living alone in the community, who had experienced the death of a companion animal in 2019. On the standardized measures, participants scored highly on attachment and loss, but low on guilt and anger. The interview data revealed three themes: catastrophic grief and multiple major losses over the death of their companion animal, immediate steps taken for recovery, and longer-term grief and loss recovery. Conclusions The findings highlight the importance of acknowledging and addressing companion animal grief to ensure the ongoing well-being and thus the sustained successful aging-in-place of older adult women in the community.

Abstract Lewis Knudson first successfully germinated orchid seeds asymbiotically on artificial medium in 1922. While many orchid species have since been grown asymbiotically, the tremendous variation in how species respond to artificial medium and growth conditions ex situ has also become apparent in the past century. In this study, we reviewed published journal articles on asymbiotic orchid seed germination to provide a summary of techniques used and to evaluate if these differ between terrestrial and epiphytic species, to identify areas where additional research is needed, and to evaluate whether asymbiotic germination could be used more often in ex situ conservation. We found articles reporting successful asymbiotic germination of 270 species and 20 cultivars across Orchidaceae. Researchers often used different techniques with epiphytic versus terrestrial species, but species‐specific responses to growth media and conditions were common, indicating that individualized protocols will be necessary for most species. The widespread success in generating seedlings on artificial media suggests that asymbiotic techniques should be another tool for the conservation of rare orchid species. Further advances are needed in understanding how to introduce mycorrhizae to axenically grown orchids and to maximize the viability of seedlings reintroduced into natural habitats to fully utilize these methods for conservation.

In 2019, novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began infecting humans, resulting in the COVID-19 pandemic. While the push for development of vaccines has yielded some positive results, the emergence of additional variants has led to concerns surrounding sustained vaccine effectiveness as the variants become the dominant strains. This work was undertaken to develop peptide-based antivirals capable of targeting both the wildtype (WT) heptad repeat 1 (HR1) domain of SARS-CoV-2 and the new HR1 variants which have developed. In silico protein mutagenesis, structural characterization, and protein–protein molecular docking were utilized to determine molecular interactions which facilitated binding of peptide-based antivirals targeting the HR1 domains. Molecular dynamics simulations were utilized to predict the final binding affinities of the top five peptide inhibitors designed. This work demonstrated the importance of hydrophobic interactions in the hydrophobic gorge and in the rim of the HR1 domain. Additionally, the placement of charged residues was shown to be essential in maximizing electrostatic interactions. The top five designed peptide inhibitors were all demonstrated to maintain good binding affinity to the WT and the variant HR1 SARS-CoV-2 domains. Therefore, the peptide inhibitors designed in this work could serve as potent antivirals which are effective in targeting both the original SARS-CoV-2 and the HR1 variants that have developed.

Praise in the context of behavior-specific encouragement, positive reinforcement, and recognition may provide a linkage in positive youth development to teen leaders’ feelings of contribution and motivation at 4-H Camp. Existing literature on praise in academic settings, combined with literature related to positive youth development, organized camping programs, and 4-H, lends credibility to the theory that there is an influence on teen attitudes and participation regarding contributing to their community at 4-H Camp. Practical implications are presented, along with suggestions for future research.

Abstract Background Dynamic consent has been proposed as a process through which participants and patients can gain more control over how their data and samples, donated for biomedical research, are used, resulting in greater trust in researchers. It is also a way to respond to evolving data protection frameworks and new legislation. Others argue that the broad consent currently used in biobank research is ethically robust. Little empirical research with cohort study participants has been published. This research investigated the participants’ opinions of adding a dynamic consent interface to their existing study. Methods Adult participants in the Extended Cohort for E-health, Environment and DNA (EXCEED) longitudinal cohort study who are members of the EXCEED Public and Participant Engagement Group were recruited. Four focus groups were conducted and analysed for thematic content. Discussion topics were derived from a review of the current literature on dynamic consent. Results Participants were in favour of many aspects of a dynamic consent interface, such as being able to update their information, add additional data to their records and choose withdrawal options. They were supportive provided it was simple to use and not intrusive. Participants expressed a markedly high level of trust in the study and its investigators and were unanimously happy with their current participation. No strong support was found for adding a dynamic consent interface to EXCEED. Conclusions Trust in the study researchers was the strongest theme found. Openness and good data security were needed to retain their trust. While happy to discuss dynamic consent, participants were satisfied with the current study arrangements. There were indications that changing the study might unnecessarily disturb their trust. This raised the question of whether there are contexts where dynamic consent is more appropriate than others. This study was limited by the small number of participants who were committed to the study and biased towards it. More research is needed to fully understand the potential impact of adding a dynamic consent interface to an existing cohort study.

Background: Sleep and diet contribute to cardiometabolic disease, but evidence is sparse for the association between these behaviors. This study analyzed the cross-sectional relationship between diet quality and multiple sleep outcomes in the Bogalusa Heart Study (BHS). Methods: Diet and sleep characteristics, including insomnia and sleep apnea symptoms, were measured with validated questionnaires. Poisson regression using generalized estimating equations with a log link estimated prevalence rate ratios (PRR) of sleep outcomes by dietary pattern scores (quintile (Q) and per SD). Models were adjusted for body mass index (BMI), multi-level socioeconomic factors, physical activity, depressive symptoms, and other potential confounders. Results: In 824 participants, higher diet quality, measured by the Alternate Healthy Eating Index-2010, was associated with lower sleep apnea risk score after adjustment (PRR [95% confidence interval (CI)] Q5 vs. Q1: 0.59 [0.44, 0.79], per SD increase: 0.88 [0.81, 0.95], p-trend < 0.0001). There were no statistically significant associations with the Healthy Eating Index 2015 or the Alternate Mediterranean dietary patterns, or for insomnia symptoms or a healthy sleep score. Conclusions: Higher diet quality, after adjustment for BMI, was associated with a lower sleep apnea risk score in a cohort with substantial minority representation from a semi-rural, lower-income community.

BackgroundTumors often progress to a more aggressive phenotype to resist drugs. Multiple dysregulated pathways are behind this tumor behavior which is known as cancer chemoresistance. Thus, there is an emerging need to discover pivotal signaling pathways involved in the resistance to chemotherapeutic agents and cancer immunotherapy. Reports indicate the critical role of the toll-like receptor (TLR)/nuclear factor-κB (NF-κB)/Nod-like receptor pyrin domain-containing (NLRP) pathway in cancer initiation, progression, and development. Therefore, targeting TLR/NF-κB/NLRP signaling is a promising strategy to augment cancer chemotherapy and immunotherapy and to combat chemoresistance. Considering the potential of phytochemicals in the regulation of multiple dysregulated pathways during cancer initiation, promotion, and progression, such compounds could be suitable candidates against cancer chemoresistance.ObjectivesThis is the first comprehensive and systematic review regarding the role of phytochemicals in the mitigation of chemoresistance by regulating the TLR/NF-κB/NLRP signaling pathway in chemotherapy and immunotherapy.MethodsA comprehensive and systematic review was designed based on Web of Science, PubMed, Scopus, and Cochrane electronic databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to include papers on TLR/NF-κB/NLRP and chemotherapy/immunotherapy/chemoresistance by phytochemicals.ResultsPhytochemicals are promising multi-targeting candidates against the TLR/NF-κB/NLRP signaling pathway and interconnected mediators. Employing phenolic compounds, alkaloids, terpenoids, and sulfur compounds could be a promising strategy for managing cancer chemoresistance through the modulation of the TLR/NF-κB/NLRP signaling pathway. Novel delivery systems of phytochemicals in cancer chemotherapy/immunotherapy are also highlighted.ConclusionTargeting TLR/NF-κB/NLRP signaling with bioactive phytocompounds reverses chemoresistance and improves the outcome for chemotherapy and immunotherapy in both preclinical and clinical stages.

Abstract Background Social media and academic literature suggest that more people are using cannabis to treat their own or their dog’s chronic pain. This study identifies the reasons people use cannabis products to treat their own pain or their dog’s pain and explores whether these products have fulfilled their expectations. Methods An anonymous, online survey was used to collect quantitative and qualitative self-report data on respondents’ perceptions, motivations and expectations about their or their dog’s chronic pain and cannabis use. The analyses are based on U.S. adults who reported using cannabis products to treat their own (N = 313) or their dog’s (N = 204) chronic pain. Quantitative responses from the two groups were compared using Chi-Square tests and qualitative data were analyzed using a thematic analysis. Results Human patients and dog owners reported similar motivations for using cannabis products to treat chronic pain, with the more popular reasons being that cannabis products are natural, are preferred over conventional medication, are believed to be the best treatment or good treatment option for pain. Similar proportions of human patients and dog owners reported that the use of cannabis products fulfilled their expectations (86% vs. 82% respectively, χ2 (1, 200) = .59, p = .32). The qualitative data revealed that their expectations were met by reducing pain, increasing relaxation, and improving sleep, coping, functionality and overall well being. Additionally, the qualitative data suggests that cannabis products offer a return to normalcy and a restored sense of self to human and dog patients. Conclusions The results suggest that people choose cannabis products because they are natural and a possible solution to managing chronic pain when conventional medicines have not been effective. Most people report that their expectations regarding pain management are fulfilled by these products. More accurate assessments are vital, however, for understanding both the objective biomedical and subjective socioemotional benefits of cannabis products for effective pain management for human and dog patients. In addition, objective factual information regarding cannabis products for effective pain management in humans and dogs is needed. It is recommended that both physicians and veterinarians work towards feeling more comfortable proactively broaching the subject of cannabis use with additional training and education.

Abstract Background Insufficient physical activity (PA) is a common health risk and more prevalent in rural populations. Few studies have assessed relationships between the built environment and PA in rural settings, and community policy guidance to promote PA through built environment interventions is primarily based on evidence from urban studies. Methods Participants in the Bogalusa Heart Study, a longitudinal study in rural Louisiana, with International Physical Activity Questionnaire data from 2012 to 2013 and a valid residential address (N = 1245) were included. PA was summarized as the number of weekly metabolic equivalent (MET)-minutes of total, transportation, and leisure time PA. The Rural Active Living Assessment street segment audit tool and Google Street View were used to assess features of the built environment overall and in six categories (path features, pedestrian safety features, aesthetics, physical security, destinations and land use) that influence PA. Scores for street segment built environment (overall and in categories) were calculated, for segments and buffers of 0.25, 0.50, 1.00 and 1.50 miles. Associations between built environment scores and PA were assessed with generalized estimating equations. Results Participants reported little weekly total, leisure time, and transportation PA (mean 470, 230 and 43 MET-minutes per week, respectively). A 1-point increase in the overall built environment score was associated with 10.30 additional weekly leisure time MET-minutes within a 1.50 mile buffer (p-value 0.05), with a similar magnitude observed for a 1.00-mile buffer. A 1-point increase in the aesthetic score was associated with significantly higher leisure time PA for all geographic units (from 22.21 to 38.75 MET-minutes weekly) when adjusted for individual covariates, but was attenuated and only significant for the segment of the residence after accounting for other neighborhood characteristics. Conclusions Significant associations between features of the environment (overall and aesthetic scores) with leisure time PA were observed among adults in this rural population. Built environment interventions in rural settings face additional barriers of lower population density and greater distances for infrastructure projects, and it is important to identify approaches that are both feasible for rural communities and can promote PA.

Both cardiovascular and reproductive complications may have origins in utero or in early life. Women in the Bogalusa Heart Study (n = 1401) had been linked to birth certificates for birthweight and gestational data, which were examined relative to childhood (ages 4–16) cardiometabolic indicators, indicated by mean levels overall and total risk factor burden as estimated by area under the curve (AUC) computed from longitudinal quadratic random-effects growth models. Women reported the birthweight and gestational age of each of their own pregnancies, and delivery medical records were linked to interview data where possible. Path analyses were conducted to examine the relationships among a woman’s own birth outcomes, childhood and preconception adult cardiovascular health, and birth outcomes. Mean blood pressure (systolic blood pressure (SBP) adjusted relative risk (aRR) per 1-SD increase, 1.27, 95% CI 1.04–1.57) and low-density lipoprotein (aRR 1.21, 95% CI 1.02–1.44) in childhood predicted preterm birth (PTB), while mean SBP (aRR 1.33, 95% CI 1.02–1.74) predicted term low birthweight. The AUC data suggested an association between blood pressure and PTB (aRR for SBP top 10%, 1.86, 95% CI 1.08–3.21). Pre-pregnancy total cholesterol was negatively associated with gestational age. In path analyses, positive associations were found for each step between own birthweight, childhood BMI, pre-pregnancy BMI, and child’s birthweight. Childhood levels of some, though not all, cardiovascular risk factors may predict adverse birth outcomes (preterm birth and reduced fetal growth).

Summary: The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.

Despite the vast amounts of research and remarkable discoveries that have been made in recent decades, cancer remains a leading cause of death and a major public health concern worldwide. Gossypol, a natural polyphenolic compound derived from the seeds, roots, and stems of cotton (Gossypium hirsutum L.), was first used as a male contraceptive agent. Due to its diverse biological properties, including antifertility, antiviral, antioxidant, antibacterial, antimalarial, and most notably antitumor activities, gossypol has been the subject of numerous studies. Nevertheless, no systematic review has been performed that analyzes the antineoplastic potential of gossypol and related natural compounds in an organ-specific manner while delineating the molecular mechanisms of action. Hence, we have performed an extensive literature search for anticancer properties of gossypol and their natural derivatives against various types of cancer cells utilizing PubMed, ScienceDirect, Google Scholar, and Scopus. The sources, distribution, chemical structure, and toxicity of gossypol and its constituents are briefly reviewed. Based on emerging evidence, gossypol and related compounds exhibit significant antineoplastic effects against various cancer types through the modulation of different cancer hallmarks and signaling pathways. Additionally, the synergistic activity of gossypol and its derivatives with chemotherapeutic agents has been observed. Our evaluation of the current literature suggests the potential of gossypol and its derivatives as multitargeting drug candidates to combat multiple human malignancies.