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Abstract Background Breast cancer (BC) is the most common cancer in women and incidence rates are increasing; metabolomics may be a promising approach for identifying the drivers of the increasing trends that cannot be explained by changes in known BC risk factors. Methods We conducted a nested case–control study (median followup 6.3 years) within the New York site of the Breast Cancer Family Registry (BCFR) (n = 40 cases and 70 age-matched controls). We conducted a metabolome-wide association study using untargeted metabolomics coupling hydrophilic interaction liquid chromatography (HILIC) and C18 chromatography with high-resolution mass spectrometry (LC-HRMS) to identify BC-related metabolic features. Results We found eight metabolic features associated with BC risk. For the four metabolites negatively associated with risk, the adjusted odds ratios (ORs) ranged from 0.31 (95% confidence interval (CI): 0.14, 0.66) (L-Histidine) to 0.65 (95% CI: 0.43, 0.98) (N-Acetylgalactosamine), and for the four metabolites positively associated with risk, ORs ranged from 1.61 (95% CI: 1.04, 2.51, (m/z: 101.5813, RT: 90.4, 1,3-dibutyl-1-nitrosourea, a potential carcinogen)) to 2.20 (95% CI: 1.15, 4.23) (11-cis-Eicosenic acid). These results were no longer statistically significant after adjusting for multiple comparisons. Adding the BC-related metabolic features to a model, including age, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk score improved the accuracy of BC prediction from an area under the curve (AUC) of 66% to 83%. Conclusions If replicated in larger prospective cohorts, these findings offer promising new ways to identify exposures related to BC and improve BC risk prediction.

Abstract Background Sierra Leone faces a significant challenge in addressing HIV/AIDS, particularly among adolescent girls and young women. This age group is considered highly vulnerable due to biological factors and social inequalities. Understanding the prevalence of HIV testing in this demographic is crucial for designing effective prevention and treatment strategies. This study investigated the spatial distribution of HIV testing and its associated factors among adolescent girls and young women in Sierra Leone. Methods Data from the 2019 Sierra Leone Demographic and Health Survey was used for the study. The sample comprised 6,062 adolescent girls and young women between the ages of 15 and 24. Spatial autocorrelation and Moran’s I statistic were employed to analyze the spatial distribution of HIV testing. An analysis utilising mixed-effect multilevel binary logistic regression was performed to determine the factors associated with HIV testing. The findings were presented as adjusted odds ratios (aOR) and a 95% confidence interval (CI). Results The national prevalence of HIV testing among adolescents and young women in Sierra Leone was 42.1% [40.3,43.9]. Kailahun, Kambia, Tonkolil, some parts of the Western rural area, and Bonthe districts were found to be statistically significant hotspot for HIV testing. Whereas, Karene, Falaba, Bo, kenema, and some parts of Pujuhun were statistically cold spot districts. Adolescent girls and young women aged 20–24 [aOR = 1.63, 95% CI = 1.29, 2.07] had higher odds of HIV testing than those aged 15–19. Those with secondary/higher education [aOR = 1.87, 95% CI = 1.40, 2.51] had higher odds of HIV testing than those with no education. The odds of HIV testing was higher among adolescent girls and young women who use the Internet [aOR = 1.75, 95% CI = 1.32, 2.33] than those who did not use internet. Adolescent girls and young women with one [aOR = 16.56, 95% CI = 12.31, 22.29] and two or more parity [aOR = 16.37, 95% CI = 10.86, 24.68] had higher odds of HIV testing than those with no parity. The likelihood of HIV testing was higher among adolescent girls and young women who had sex below 18 [aOR = 4.54, 95% CI = 3.25, 6.34] and those who had sex at 18+ [aOR = 5.70, 95% CI = 3.84, 8.45] compared to those who had never had sex. Adolescent girls and young women who visited health facilities in the past 12 months [aOR = 1.82, 95% CI = 1.46, 2.26] had higher odds of HIV testing than those who did not. Conclusion Despite some positive trends, HIV testing rates among adolescent girls and young women in Sierra Leone remain moderate. Spatial autocorrelation analysis consistently revealed hotspots and cold spots for HIV testing, with Kailahun, Kambia, Tonkolil, some parts of the Western rural area, and Bonthe districts remaining persistent hotspots. Age, education, internet use, sexual history, parity, and healthcare access are significant factors influencing testing behaviour. To improve testing rates, the government and policymakers should prioritize educational campaigns, expand internet access, integrate HIV testing into routine healthcare, and address stigma associated with HIV.

Abstract Aberrant DNA methylation patterns have been used for cancer detection. However, DNA hemi-methylation, present at about 10% CpG dinucleotides, has been less well studied. Here we show that a majority of differentially hemi-methylated regions (DHMRs) in liver tumor DNA or plasma cells free (cf) DNA do not overlap with differentially methylated regions (DMRs) of the same samples, indicating that DHMRs could serve as independent biomarkers. Furthermore, we analyzed the cfDNA methylomes of 215 samples from individuals with liver or brain cancer and individuals without cancer (controls), and trained machine learning models using DMRs, DHMRs or both. The models incorporated with both DMRs and DHMRs show a superior performance compared to models trained with DMRs or DHMRs, with AUROC being 0.978, 0.990, and 0.983 in distinguishing control, liver and brain cancer, respectively, in a validation cohort. This study supports the potential of utilizing both DMRs and DHMRs for multi-cancer detection.

Abstract Background Cardiovascular diseases (CVDs) comprise major causes of death worldwide, leading to extensive burden on populations and societies. Alterations in normal lipid profiles, i.e., dyslipidemia, comprise important risk factors for CVDs. However, there is lack of comprehensive evidence on the genetic contribution to dyslipidemia in highly admixed populations. The identification of single nucleotide polymorphisms (SNPs) linked to blood lipid traits in the Brazilian population was based on genome-wide associations using data from the São Paulo Health Survey with Focus on Nutrition (ISA-Nutrition). Methods A total of 667 unrelated individuals had genetic information on 330,656 SNPs available, and were genotyped with Axiom™ 2.0 Precision Medicine Research Array. Genetic associations were tested at the 10− 5 significance level for the following phenotypes: low-density lipoprotein cholesterol (LDL-c), very low-density lipoprotein cholesterol (VLDL-c), high-density lipoprotein cholesterol (HDL-c), HDL-c/LDL-c ratio, triglycerides (TGL), total cholesterol, and non-HDL-c. Results There were 19 significantly different SNPs associated with lipid traits, the majority of which corresponding to intron variants, especially in the genes FAM81A, ZFHX3, PTPRD, and POMC. Three variants (rs1562012, rs16972039, and rs73401081) and two variants (rs8025871 and rs2161683) were associated with two and three phenotypes, respectively. Among the subtypes, non-HDL-c had the highest proportion of associated variants. Conclusions The results of the present genome-wide association study offer new insights into the genetic structure underlying lipid traits in underrepresented populations with high ancestry admixture. The associations were robust across multiple lipid phenotypes, and some of the phenotypes were associated with two or three variants. In addition, some variants were present in genes that encode ncRNAs, raising important questions regarding their role in lipid metabolism.

Introduction The deaf and hard of hearing (DHH) community experiences lower cancer screening rates than the general population. Cancer worry and fatalism can influence cancer screening, along with race, and the interaction of intrinsic factors with DHH health behavior needs to be investigated. Objectives The study examines the association of the intersection of race and hearing status with cancer worry and fatalism. Methods This study analyzed cross-sectional survey data from NCI HINTS-ASL (for DHH adults) and NCI HINTS (for hearing adults). Multivariable logistic regression models were used to assess (i) the association of race-hearing status intersection with cancer worry and fatalism, as well as (ii) the relationship between hearing status and outcomes within each race. Results The study found that the overall interaction between race and hearing status was significantly associated with both high cancer worry and fatalism, with African American (AA)/Black and Asian/Other having higher odds of worry [1.17 (0.83, 1.64); 1.19 (0.85, 1.66), respectively] and other groups having lower worry than White hearing ( P < 0.0001), and all deaf having less concern about cancer fatalism ( P < 0.0001). Within each racial group, White DHH respondents had lower odds of cancer worry [aOR (95% CI): 0.72 (0.58, 0.91); P < 0.01] and fatalism [0.55 (0.46, 0.67); P < 0.0001] compared to White hearing respondents, while DHH AA/Black [1.89 (1.06, 3.37); P = 0.03], Asian/Other [2.39 (1.06, 3.37); P = 0.03], and Hispanic [1.95 (1.18, 3.22); P < 0.01] respondents had significantly higher odds of cancer worry and lower odds of cancer fatalism [Black: 0.50 (0.23, 1.09); P = 0.07; Asian/Other: [0.68 (0.42, 1.09); P = 0.10]; Hispanic: [0.69 (0.40, 1.17)]; P = 0.16] compared to their hearing counterparts. Conclusion DHH individuals have different odds of experiencing cancer worry and fatalism compared to their hearing counterparts. Inclusion of individuals with sensory disabilities in a larger cancer study sample enriches the diversity of perspectives, ensuring that the findings reflect a broader range of experiences and needs. More research into contributory factors in the signing DHH population is needed.

Background: Entrepreneurship education has become an important issue worldwide, originating mainly in the United States (US) and the United Kingdom (UK). Different methods have been used to teach entrepreneurship, often without considering local circumstances, which is particularly important in sub-Saharan Africa with its diverse cultures. Therefore, comparing the impact of cultural differences in teaching entrepreneurship education in Western Europe and sub-Saharan African countries is crucial to overcoming such challenges. Aim: This article aims to compare the impact of cultural differences in teaching entrepreneurship education in Western Europe and sub-Saharan African countries with the aim of designing appropriate entrepreneurship education programmes and approaches to the specific cultural contexts. Setting: The study compares the impact of cultural differences in Western Europe (US and UK) and sub-Saharan African countries. Methods: A literature review descriptive study of the impact of cultural differences in teaching entrepreneurship education in Western Europe and sub-Saharan Africa was adopted. Secondary analysis using Hofstede’s cultural dimensions’ model was used for analysis. Results: The main cultural differences are in the dimensions of individualism versus collectivism and power distance. Incorporating team-based learning and focusing on business ideas with a positive collective impact in sub-Saharan Africa can lead to more effective entrepreneurship education. Conclusion: It is crucial to adapt entrepreneurship education approaches to the specific cultural contexts of regions. Using a framework with four guide questions for whom, why, what and how can support the development of programmes. Contribution: Future education programmes can be designed based on a proposed golden circle.

Abstract As a strategy to improve the therapeutic success of chimeric antigen receptor T cells (CART) directed against solid tumors, we here test the combinatorial use of CART and IMSA101, a newly developed stimulator of interferon genes (STING) agonist. In two syngeneic tumor models, improved overall survival is observed when mice are treated with intratumorally administered IMSA101 in addition to intravenous CART infusion. Transcriptomic analyses of CART isolated from tumors show elevated T cell activation, as well as upregulated cytokine pathway signatures, in particular IL-18, in the combination treatment group. Also, higher levels of IL-18 in serum and tumor are detected with IMSA101 treatment. Consistent with this, the use of IL-18 receptor negative CART impair anti-tumor responses in mice receiving combination treatment. In summary, we find that IMSA101 enhances CART function which is facilitated through STING agonist-induced IL-18 secretion.

Abstract Background Cultivation of Cannabis and its use for medical purposes has existed for millennia on the African continent. The plant has also been widely consumed in the African continent since time immemorial. In particular, Lesotho has been largely growing Cannabis since approximately the 1550s and was illegally grown and unlawfully used for both medicinal and recreational purposes. It was only in 2017 when Lesotho started licensing Cannabis companies and regulating cultivation of Cannabis for medicinal purposes. However, the Lesotho Cannabis industry seems to have excluded the Small, Medium and Micro Enterprises (SMMEs) in the legalisation of Cannabis, the sector has the potential for small Cannabis enterprises in Lesotho. Objective This study attempts to examine challenges facing the evolving Cannabis sector in Lesotho as envisaged by Cannabis company managers with the aim of being proactive while addressing such challenges. Methods The qualitative descriptive method was employed using both primary and secondary data. For the selection of the three Cannabis managers exponential non-discriminative snowball sampling was adopted and interviews with the managers were recorded and transcribed verbatim. Thematic analysis was used to analyse the descriptive explanations of the Cannabis managers to determine the themes that were further consolidated into categories. Results The implementation and compliance with the laws in the Lesotho medicinal Cannabis sector has proved very challenging, with long timeframes for finalising regulatory frameworks and not being applied objectively. The industry does not provide opportunities for Small, Medium and Micro Enterprises (SMMEs) to venture into the Cannabis business. Conclusion In Lesotho, the Cannabis sector appears to be faced with many challenges emanating from the implementation and enforcement of Cannabis laws. The Lesotho Government should review its Cannabis laws and regulations with a view to benefiting SMMEs and legalising Cannabis production so as to serve both the domestic and international markets.

Nanopipettes, as a class of solid-state nanopores, have evolved into universal tools in biomedicine for the detection of biomarkers and different biological analytes. Nanopipette-based methods combine high sensitivity, selectivity, single-molecule resolution, and multifunctionality. The features have significantly expanded interest in their applications for the biomolecular detection, imaging, and molecular diagnostics of real samples. Moreover, the ease of manufacturing nanopipettes, coupled with their compatibility with fluorescence and electrochemical methods, makes them ideal for portable point-of-care diagnostic devices. This review summarized the latest progress in nanopipette-based nanopore technology for the detection of biomarkers, DNA, RNA, proteins, and peptides, in particular β-amyloid or α-synuclein, emphasizing the impact of technology on molecular diagnostics. By addressing key challenges in single-molecule detection and expanding applications in diverse biological areas, nanopipettes are poised to play a transformative role in the future of personalized medicine.

The Mi-1.2 gene confers resistance to a wide range of Meloidogyne species, being the most important resistance factor employed in tomato breeding so far. However, many aspects related to the interaction of Mi-1.2-carrying tomato cultivars and virulent/avirulent Meloidogyne populations have not yet been clarified. Herein, comparative histopathological analyses were carried after inoculation of the homozygous (Mi-1.2/Mi-1.2) tomato rootstock ‘Guardião’ and the susceptible cultivar ‘Santa Clara’ (mi-1.2/mi-1.2) with virulent and avirulent populations of M. javanica. In the susceptible control, it was possible to visualize second stage juveniles (J2) of avirulent population and feeding sites from 2 to 30 days after infection (DAI) with females reaching maturity at 24-34 DAI. In the resistant rootstock, the Mi-1.2 gene-mediated resistance was related mainly to early defense responses (pre-infection and hypersensitive reaction), which led to an immunity-like phenotype that completely prevented the reproduction of the avirulent Meloidogyne population. On the other hand, J2s of the virulent M. javanica population were able to penetrate roots much more than the avirulent population, migrated and developed normally, showing intense and similar pattern of penetration from 4 to 34 DAI in the root tissues of both resistant and susceptible tomato genotypes. The total numbers of J2, J3, J4, and females counted in ‘Santa Clara’ for the virulent population of M. javanica were higher than in ‘Guardião’.

Even though ammonia is a natural component of aquatic environments, elevated concentrations indicate pollution and environmental degradation. Consequently, efficient analytical methods for monitoring ammonia levels are crucial for preserving water quality. Voltammetry offers a sustainable approach for NH3 quantification, combining good analytical performance with low sample and reagent consumption, minimizing waste generation. However, despite these advantages, the voltammetric determination of ammonia remains relatively unexplored. Therefore, this study investigated the electrochemical behavior of NH3 in alkaline solutions using a non-modified Pt electrode and evaluated the performance of differential pulse voltammetry (DPV) and square wave voltammetry (SWV) for NH3 determination. DPV provided superior performance, with limits of detection and quantification of 0.79 µmol L-1 (0.011 ppmN) and 2.6 µmol L-1 (0.036 ppmN), respectively, which comply with the maximum allowable ammonia concentration in natural waters according to Brazilian and European regulations. The voltammetric method successfully quantified ammonia in tap and river water samples, providing results concordant with the established Berthelot spectrophotometric method, at a 95% confidence level. Additionally, it is simple and fully accessible to non-electrochemist since no sophisticated procedures for electrode modification are needed. Finally, the high analytical performance of the proposed method makes it valuable for pollution monitoring in aquatic environments.

BackgroundThe evaluation of existing resources and services is key to identify gaps and prioritize interventions to expand care capacity for children with central nervous system (CNS) tumors. We sought to evaluate the resources for pediatric neuro-oncology (PNO) in Mexico.MethodsA cross-sectional online survey with 35 questions was designed to assess PNO resources and services, covering aspects including number of patients, infrastructure, human resources, and diagnostic and treatment time intervals. The survey was distributed to the members of the Mexican Association of Pediatric Oncology and Hematology (AMOHP) who belong to the nation’s many different health systems.ResultsResponses were obtained from 33 institutions, distributed throughout the country and part of the many health systems that exist in Mexico. Twenty-one (64%) institutions had less than 10 new cases of pediatric CNS tumors per year. Although 30 (91%) institutions saw pediatric patients up to the age of 18 years, 2 (6%) had a cutoff of 15 years. Twenty-four (73%) institutions had between 1 and 3 pediatric oncologists providing care for children with CNS tumors. Six (18%) institutions did not have a neurosurgeon, while 19 (57%) institutions had a pediatric neurosurgeon. All centers had a pathology department, but 13 (39%) institutions only had access to basic histopathology. Eleven (33%) institutions reported histopathological diagnoses within one week, but 3 (9%) took more than 4 weeks. Radiotherapy for pediatric CNS tumors was referred to outside centers at 18 (55%) institutions. All centers had access to conventional cytotoxic chemotherapy, but only 6 (18%) had access to targeted therapy. Eighteen (55%) respondents estimated a survival rate of less than 60%. Fifteen (45%) centers attributed the main cause of mortality to non-tumor related factors, including infection and post-surgical complications.ConclusionsThis is the first national assessment of the resources available in Mexico for the treatment of CNS tumors. It shows disparities in resource capacity and a lack of the specific and efficient diagnoses that allow timely initiation of treatment. These data will enable the prioritization of collaborative interventions in the future.

Abstract In this work, we describe a novel ruthenium-xanthoxylin complex, [Ru(phen)2(xant)](PF6) (RXC), that can eliminate colorectal cancer (CRC) stem cells by targeting the chaperone Hsp90. RXC exhibits potent cytotoxicity in cancer cell lines and primary cancer cells, causing apoptosis in HCT116 CRC cells, as observed by cell morphology, YO-PRO-1/PI staining, internucleosomal DNA fragmentation, mitochondrial depolarization, and PARP cleavage (Asp214). Additionally, RXC can downregulate the HSP90AA1 and HSP90B1 genes and the expression of HSP90 protein, as well as the expression levels of its downstream/client elements Akt1, Akt (pS473), mTOR (pS2448), 4EBP1 (pT36/pT45), GSK-3β (pS9), and NF-κB p65 (pS529), implying that these molecular chaperones can be molecular targets for RXC. Moreover, this compound inhibited clonogenic survival, the percentage of the CRC stem cell subpopulation, and colonosphere formation, indicating that RXC can eliminate CRC stem cells. RXC reduced cell migration and invasion, decreased vimentin and increased E-cadherin expression, and induced an autophagic process that appeared to be cytoprotective, as autophagy inhibitors enhanced RXC-induced cell death. In vivo studies showed that RXC inhibits tumor progression and experimental metastasis in mice with CRC HCT116 cell xenografts. Taken together, these results highlight the potential of the ruthenium complex RXC in CRC therapy with the ability to eliminate CRC stem cells by targeting the chaperone Hsp90.

Aim. To study the long-term results of surgical treatment of postmenopausal patients with genital prolapse III and IV according to the POP-Q classification in combination with endometrial hyperplastic processes and to assess their quality of life. Materials and methods. Fifty one elderly and senile patients with grade III–IV prolapse according to the POP-Q classification in combination with endometrial hyperplastic processes. 2 groups were formed: 1st – 21 patients after one-stage vaginal extirpation of the uterus with appendages and unilateral sacrospinous fixation of the vaginal stump with a synthetic endoprosthesis-tape in combination with reconstruction of II and III levels of pelvic floor support according to DeLancey; 2nd – 30 patients after one-stage vaginal extirpation of the uterus with appendages and median colporrhaphy using the Lefort and Neugebauer technique. Results. The study was evaluated 1–7 years after surgical treatment. The average age of patients at the time of surgery in group 1 was 63.12±4.32 years, in group 2 – 74.2±3.28 years. The number of women with somatic pathology in the 1st group was 1.7 times less in percentage terms than in the 2nd. The disappearance of symptoms of an overactive bladder after surgery was noted by 4 (50.0%) of 8 patients of the 1st group and 4 (26.7%) of 15 women of the 2nd. Uroflowmetry after surgical treatment showed an increase in the maximum flow rate (Qmax) and a decrease in the volume of residual urine (Vom) in both groups (p0.001). Recurrence of genital prolapse was detected in the apical region in 1 (4.8%) woman, prolapse of the anterior vaginal wall in 1 (4.8%). There were no recurrences of genital prolapse in the 2nd group. A significant improvement in the quality of life after surgery, according to the results of processing the PFDI-20 questionnaire, was noted by 19 (90.5%) women in the 1st group and 29 (96.7%) – in the 2nd. Conclusion. The long-term results of the proposed operational benefits have shown satisfactory results and can be successfully used in the elderly and senile age. The choice of the volume of surgery taking into account age, sexual activity, concomitant gynecological and somatic pathology reduces the number of complications and improves the results of surgical treatment in this category of patients.

Abstract Brain radiation has been medically used to alter the metabolism of cancerous cells and induce their elimination. Rarely, though, brain radiation has been used to interfere with the pathomechanisms of non-cancerous brain disorders, especially neurodegenerative disorders. Data from low-dose radiation (LDR) on swine brains demonstrated reduced levels of phosphorylated-tau (CP13) and amyloid precursor protein (APP) in radiated (RAD) versus sham (SH) animals. Phosphorylated-tau and APP are involved in Alzheimer’s disease (AD) pathogenesis. We determined if the expression levels of hyperphosphorylated-tau, 3R-tau, 4R-tau, synaptic, intraneuronal damage, and DNA damage/oncogenic activation markers were altered in RAD versus SH swine brains. Quantitative analyses demonstrated reduced levels of AT8 and 3R-tau in hippocampus (H) and striatum (Str), increased levels of synaptophysin and PSD-95 in frontal cortex (FCtx), and reduced levels of NF-L in cerebellum (CRB) of RAD versus SH swine. DNA damage and oncogene activation markers levels did not differ between RAD and SH animals, except for histone-H3 (increased in FCtx and CRB, decreased in Str), and p53 (reduced in FCtx, Str, H and CRB). These findings confirm the region-based effects of sLDR on proteins normally expressed in larger mammalian brains and support the potential applicability of LDR to beneficially interfere against neurodegenerative mechanisms.

Although rarely fatal, Chikungunya virus (CHIKV) infection can lead to chronic debilitating sequelae. We describe the outbreak of suspected CHIKV in 93 subjects who presented voluntarily over 2 months to a remote rural Haitian general medical clinic staffed by international healthcare providers. Diagnosis was made on clinical signs and symptoms, as no serum analysis was available in this remote rural site. The subjects were 18.0 ± 16.2 (median±standard deviation) years of age and were of similar gender distribution. The presenting vital signs included a temperature of 102.3°± 0.6F with fever lasting for 3.0 ± 0.7 days. Symptoms mainly consisted of symmetrical polyarthralgia in 82.8%, headache in 28.0%, abdominal pain in 17.2%, cough in 8.6%, maculopapular rash in 30.0%, and extremity bullae in 12.9%. In 84.9% of subjects, symptoms persisted for 7.1 ± 8.3 days with 16.1% having ongoing disability due to persistent pain (?14 day’s duration). There were no deaths. In Haiti, especially in remote, rural regions, the risk for CHIKV spread is high given the shortage of detection methods and treatment in this tropical climate. Preventative efforts are similarly lacking. Implications for a global public health impact are likely with outbreak extension and spread to neighboring countries.

Abstract Objective Examine the influence of household income on health‐related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML). Design Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States. Exposure Household income was self‐reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity. Outcome Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey. Result Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income

Abstract Introduction/aims Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS. Methods This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R). Discussion The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life. Trial registration This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.

IntroductionPatients with optic pathway gliomas (OPG) have good survival rates although their long-term quality of life can be affected by the tumor or treatment-related morbidity. This retrospective study sought to describe the clinical presentation and outcomes of children with OPG at a tertiary center in Mexico.MethodsConsecutive patients

BackgroundHousing is a major social determinant of health that affects health status and outcomes across the lifespan.ObjectivesAn interagency portfolio analysis assessed the level of funding invested in "health and housing research" from fiscal years (FY) 2016-2020 across the National Institutes of Health (NIH), the United States Department of Housing and Urban Development (HUD), and the Centers for Disease Control and Prevention (CDC) to characterize the existing health and housing portfolio and identify potential areas for additional research and collaboration.Methods/resultsWe identified NIH, HUD, and CDC research projects that were relevant to both health and housing and characterized them by housing theme, health topic, population, and study design. We organized the assessment of the individual housing themes by four overarching housing-to-health pathways. From FY 2016-2020, NIH, HUD, and CDC funded 565 health and housing projects combined. The Neighborhood pathway was most common, followed by studies of the Safety and Quality pathway. Studies of the Affordability and Stability pathways were least common. Health topics such as substance use, mental health, and cardiovascular disease were most often studied. Most studies were observational (66%); only a little over one fourth (27%) were intervention studies.DiscussionThis review of the research grant portfolios of three major federal funders of health and housing research in the United States describes the diversity and substantial investment in research at the intersection between housing and health. Analysis of the combined portfolio points to gaps in studies on causal pathways linking housing to health outcomes. The findings highlight the need for research to better understand the causal pathways from housing to health and prevention intervention research, including rigorous evaluation of housing interventions and policies to improve health and well-being.

There is a growing interest in low dose radiation (LDR) to counteract neurodegeneration. However, LDR effects on normal brain have not been completely explored yet. Recent analyses showed that LDR exposure to normal brain tissue causes expression level changes of different proteins including neurodegeneration-associated proteins. We assessed the proteomic changes occurring in radiated vs. sham normal swine brains. Due to its involvement in various neurodegenerative processes, including those associated with cognitive changes after high dose radiation exposure, we focused on the hippocampus first. We observed significant proteomic changes in the hippocampus of radiated vs. sham swine after LDR (1.79Gy). Mass spectrometry results showed 190 up-regulated and 120 down-regulated proteins after LDR. Western blotting analyses confirmed increased levels of TPM1, TPM4, PCP4 and NPY (all proteins decreased in various neurodegenerative processes, with NPY and PCP4 known to be neuroprotective) in radiated vs. sham swine. These data support the use of LDR as a potential beneficial tool to interfere with neurodegenerative processes and perhaps other brain-related disorders, including behavioral disorders.

Insecticidal Bacillus thuringiensis Berliner (Bt) toxins produced by transgenic cotton (Gossypium hirsutum L.) plants have become an essential component of cotton pest management. Bt toxins are the primary management tool in transgenic cotton for lepidopteran pests, the most important of which is the bollworm (Helicoverpa zea Boddie) (Lepidoptera: Noctuidae) in the United States (U.S.). However, bollworm larvae that survive after consuming Bt toxins may experience sublethal effects, which could alter interactions with other organisms, such as natural enemies. Experiments were conducted to evaluate how sublethal effects of a commercial Bt product (Dipel) incorporated into artificial diet and from Bt cotton flowers impact predation from the convergent lady beetle (Hippodamia convergens Guérin-Méneville) (Coleoptera: Coccinellidae), common in cotton fields of the mid-southern U.S. Sublethal effects were detected through reduced weight and slower development in bollworm larvae which fed on Dipel incorporated into artificial diet, Bollgard II, and Bollgard 3 cotton flowers. Sublethal effects from proteins incorporated into artificial diet were found to significantly alter predation from third instar lady beetle larvae. Predation of bollworm larvae also increased significantly after feeding for three days on a diet incorporated with Bt proteins. These results suggest that the changes in larval weight and development induced by Bt can be used to help predict consumption of bollworm larvae by the convergent lady beetle. These findings are essential to understanding the potential level of biological control in Bt cotton where lepidopteran larvae experience sublethal effects.

Abstract Objective To create and validate a methodology to assign a severity level to an episode of COVID-19 for retrospective analysis in claims data. Data Source Secondary data obtained by license agreement from Optum provided claims records nationally for 19,761,754 persons, of which, 692,094 persons had COVID-19 in 2020. Study Design The World Health Organization (WHO) COVID-19 Progression Scale was used as a model to identify endpoints as measures of episode severity within claims data. Endpoints used included symptoms, respiratory status, progression to levels of treatment and mortality. Data Collection/Extraction methods The strategy for identification of cases relied upon the February 2020 guidance from the Centers for Disease Control and Prevention (CDC). Principal Findings A total of 709,846 persons (3.6%) met the criteria for one of the nine severity levels based on diagnosis codes with 692,094 having confirmatory diagnoses. The rates for each level varied considerably by age groups, with the older age groups reaching higher severity levels at a higher rate. Mean and median costs increased as severity level increased. Statistical validation of the severity scales revealed that the rates for each level varied considerably by age group, with the older ages reaching higher severity levels (p

Abstract Background Substantial changes in abortion care regulations, available medications and national clinical practice guidelines have occurred since a 2012 national Canadian Abortion Provider Survey (CAPS). We developed and piloted the CAPS 2019 survey instrument to explore changes of the abortion provider workforce, their clinical care as well as experiences with stigma and harassment. Methods We undertook development and piloting in three phases: (1) development of the preliminary survey sections and questions based on the 2012 survey instrument, (2) content validation and feasibility of including certain content aspects via a modified Delphi Method with panels of clinical and research experts, and (3) pilot testing of the draft survey for face validity and clarity of language; assessing usability of the web-based Research Electronic Data Capture platform including the feasibility of complex skip pattern functionality. We performed content analysis of phase 2 results and used a general inductive approach to identify necessary survey modifications. Results In phase 1, we generated a survey draft that reflected the changes in Canadian abortion care regulations and guidelines and included questions for clinicians and administrators providing first and second trimester surgical and medical abortion. In phase 2, we held 6 expert panel meetings of 5–8 participants each representing clinicians, administrators and researchers to provide feedback on the initial survey draft. Due to the complexity of certain identified aspects, such as interdisciplinary collaboration and interprovincial care delivery differences, we revised the survey sections through an iterative process of meetings and revisions until we reached consensus on constructs and questions to include versus exclude for not being feasible. In phase 3, we made minor revisions based on pilot testing of the bilingual, web-based survey among additional experts chosen to be widely representative of the study population. Demonstrating its feasibility, we included complex branching and skip pattern logic so each respondent only viewed applicable questions based on their prior responses. Conclusions We developed and piloted the CAPS 2019 survey instrument suitable to explore characteristics of a complex multidisciplinary workforce, their care and experience with stigma on a national level, and that can be adapted to other countries.

Japan is often surrounded by the myth of featuring a unique “love for nature”, and its traditional culture and lifestyle as having been “in harmony with nature” before it was corrupted by modernization and Westernization. In this paper, I employ three examples to delineate images of nature in different times of Japanese history and point out the discrepancy between discourse on nature and physical engagement with nature. I argue that the environmental destruction that peaked in the Meiji period (1868–1912) is not primarily derived from a new, dualistic Euro-American understanding of nature. Rather, I demonstrate that environmental harm was already inherent in premodern Japan and was reconcilable with the respective concepts of nature. Therefore, industrialization and the adoption of Western technology solely released the potential for large-scale environmental impact.

Abstract Homophily, the tendency for individuals to preferentially interact with others similar to themselves is typically documented via self-report and, for children, adult report. Few studies have investigated homophily directly using objective measures of social movement. We quantified homophily in children with developmental disabilities (DD) and typical development (TD) using objective measures of position/orientation in preschool inclusion classrooms, designed to promote interaction between these groups of children. Objective measurements were collected using ultra-wideband radio-frequency tracking to determine social approach and social contact, measures of social movement and interaction. Observations of 77 preschoolers (47 with DD, and 30 TD) were conducted in eight inclusion classrooms on a total of 26 days. We compared DD and TD groups with respect to how children approached and shared time in social contact with peers using mixed-effects models. Children in concordant dyads (DD-DD and TD-TD) both moved toward each other at higher velocities and spent greater time in social contact than discordant dyads (DD-TD), evidencing homophily. DD-DD dyads spent less time in social contact than TD-TD dyads but were comparable to TD-TD dyads in their social approach velocities. Children’s preference for similar peers appears to be a pervasive feature of their naturalistic interactions.

Air pollution can cause several negative impacts on health and the environment. In large urban centers, this pollution is directly related to anthropogenic activities, mainly activities in the transportation sector. This study analyzed data on black carbon, fine particulate material (PM2.5) and its main trace elements from automotive vehicles (S, P, K, V, Cr, Fe, Cu, Ni, Zn, Cd, Br and Pb), collected during a long sampling period, carried out in the Metropolitan Area of São Paulo (MASP), Brazil. The filters used were analyzed by various analytical techniques, enabling the identification of the different elements present in the samples, their respective concentrations and the main sources of these pollutants and their contributions to the sampled total. Thus, it was possible to separate the total contributions of each source and use only the contributions of anthropogenic origin to define the emission factors (EF) and the crustal enrichment factors (EFc) for the different studied pollutants. We used these factors to compare different environments/studies. We chose two studies carried out previously, also in the MASP, in the Jânio Quadros (TJQ) and Rodoanel (TRA) tunnels, and found that these tunnels are respectively 2.3 and 3.8 times more polluted than the region from our study.

Vitamin A, supplied by the diet, is critical for brain health, but little is known about its delivery across the blood–brain barrier (BBB). Brain microvascular endothelial-like cells (BMECs) differentiated from human-derived induced pluripotent stem cells (iPSCs) form a tight barrier that recapitulates many of the properties of the human BBB. We paired iPSC-derived BMECs with recombinant vitamin A serum transport proteins, retinol-binding protein (RBP), and transthyretin (TTR), to create an in vitro model for the study of vitamin A (retinol) delivery across the human BBB. iPSC-derived BMECs display a strong barrier phenotype, express key vitamin A metabolism markers, and can be used for quantitative modeling of retinol accumulation and permeation. Manipulation of retinol, RBP, and TTR concentrations, and the use of mutant RBP and TTR, yielded novel insights into the patterns of retinol accumulation in, and permeation across, the BBB. The results described herein provide a platform for deeper exploration of the regulatory mechanisms of retinol trafficking to the human brain.

Developmental exposure to ethanol is a leading cause of cognitive, emotional and behavioral problems, with fetal alcohol spectrum disorder (FASD) affecting more than 1:100 children. Recently, comorbid sleep deficits have been highlighted in these disorders, with sleep repair a potential therapeutic target. Animal models of FASD have shown non-REM (NREM) sleep fragmentation and slow-wave oscillation impairments that predict cognitive performance. Here we use a mouse model of perinatal ethanol exposure to explore whether reduced sleep pressure may contribute to impaired NREM sleep, and compare the function of a brain network reported to be impacted by insomnia–the Salience network–in developmental ethanol-exposed mice with sleep-deprived, saline controls. Mice were exposed to ethanol or saline on postnatal day 7 (P7) and allowed to mature to adulthood for testing. At P90, telemetered cortical recordings were made for assessment of NREM sleep in home cage before and after 4 h of sleep deprivation to assess basal NREM sleep and homeostatic NREM sleep response. To assess Salience network functional connectivity, mice were exposed to the 4 h sleep deprivation period or left alone, then immediately sacrificed for immunohistochemical analysis of c-Fos expression. The results show that developmental ethanol severely impairs both normal rebound NREM sleep and sleep deprivation induced increases in slow-wave activity, consistent with reduced sleep pressure. Furthermore, the Salience network connectome in rested, ethanol-exposed mice was most similar to that of sleep-deprived, saline control mice, suggesting a sleep deprivation-like state of Salience network function after developmental ethanol even without sleep deprivation.

Substance use disorders (SUDs) are characterized by maladaptive signaling in the prefrontal cortex and associated regions, however precisely how these drug-induced abnormalities may be linked to drug seeking/taking behaviors is not well understood. Here, in vivo local field potential (LFP) electrophysiology was used in rats to examine the relationship between overall spontaneous (resting state) activity within the prelimbic cortex (PrL) and nucleus accumbens (NAc) core, and their functional connectivity, to cocaine taking and seeking behaviors. Adult, male Sprague-Dawley rats were trained to self-administer either intravenous cocaine (0.33 mg/inf) or water reinforcement during 6-hour daily sessions over 2 weeks; extinction sessions were completed immediately after self-administration training and following 30 days experimenter-imposed abstinence. Rest LFP recordings were completed during 3 recording periods (15 min each in a chamber different from the self-administration context) conducted (1) prior to self-administration training (rest LFP 1) (2) immediately after 2 weeks of self-administration training (rest LFP 2) and (3) following 1 month abstinence (rest LFP 3). Our findings show that resting state LFP power in the PrL recorded prior to training (Rest LFP 1) was positively correlated with total cocaine intake and escalation of cocaine seeking at the beta frequency range. Immediately after self-administration training (Rest LFP 2) power in the NAc core at gamma frequency was negatively correlated with incubation of cocaine craving. For rats trained to self-administer water, no significant correlations were observed. Together, these findings show that resting state LFP at specific timepoints in the addiction cycle can serve as unique predictors (biomarkers) of cocaine use disorders.

Abstract Background Up to half of adults with advanced cancer report anxiety or depression symptoms, which can cause avoidance of future planning. We present a study protocol for an innovative, remotely-delivered, acceptance-based, multi-modal palliative care intervention that addresses advance care planning (ACP) and unmet psychological needs commonly experienced by adults with metastatic cancer. Methods A two-armed, prospective randomized controlled trial (RCT) randomizes 240 adults with Stage IV (and select Stage III) solid tumor cancer who report moderate to high anxiety or depression symptoms to either the multi-modal intervention or usual care. The intervention comprises five weekly two-hour group sessions (plus a booster session one month later) delivered via video conferencing, with online self-paced modules and check-ins completed between the group sessions. Intervention content is based on Acceptance and Commitment Therapy (ACT), an acceptance, mindfulness, and values-based model. Participants are recruited from a network of community cancer care clinics, with group sessions led by the network’s oncology clinical social workers. Participants are assessed at baseline, mid-intervention, post-intervention, and 2-month follow-up. The primary outcome is ACP completion; secondary outcomes include anxiety and depression symptoms, fear of dying, and sense of life meaning. Relationships between anxiety/depression symptoms and ACP will be evaluated cross-sectionally and longitudinally and theory-based putative mediators will be examined. Discussion Among adults with advanced cancer in community oncology settings, this RCT will provide evidence regarding the efficacy of the group ACT intervention on ACP and psychosocial outcomes as well as examine the relationship between ACP and anxiety/ depression symptoms. This trial aims to advance palliative care science and inform clinical practice. Trial Registration Clinicaltrials.gov NCT04773639 on February 26, 2021.

The purpose of this research was to determine the effect of behavioral aspects of attitudes, perceptions, and emotions on the application of the inventory accounting system at the Department of Public Works and Spatial Planning of North Sulawesi Province. The method used in this research is a quantitative method with multiple linear regression approach. The population of this research is the employees of the Department of Public Works and Regional Spatial Planning of the Province of North Sulawesi. While the research sample used by the researcher was 14 respondents. The results showed that the behavioral aspect of the attitude had no effect with a value of 0.078 on the implementation of the inventory accounting system. The behavioral aspect of perception has no effect with a value of 0.555 on the application of the inventory accounting system. Aspects of emotional behavior have no effect with a value of 0.714 on the implementation of the inventory accounting system. This is because the Department of Public Works and Spatial Planning of the Province of North Sulawesi has a good culture where this culture is the basis for employees to work based on standard operating procedures that have been set so that there is no opportunity to raise debates in aspects of behavior, attitudes, perceptions and emotions. The R Square value is 0.312 or 31.2%. This figure shows that the contribution of the behavioral aspects of attitudes, perceptions and emotions to explain the variables of the application of the inventory accounting system.

No abstract available.

Objectives Radicular low back pain (rLBP) is often treated off-label with gabapentin or by chiropractors using chiropractic spinal manipulative therapy (CSMT). To date, no studies have examined the association between these interventions. We hypothesised that adults under 50 years of age receiving CSMT for newly diagnosed rLBP would have reduced odds of receiving a gabapentin prescription over 1 year-follow-up.Design Retrospective cohort study.Setting US network including linked medical records, medical claims and pharmacy claims of >122 million patients attending large healthcare organisations (TriNetX), queried 15 June 2023, yielding data from 2017 to 2023.Participants Adults aged 18–49 were included at their first occurrence of rLBP diagnosis. Exclusions were severe pathology, other spinal conditions, on-label gabapentin indications and gabapentin contraindications. Propensity score matching controlled for variables associated with gabapentin use and receipt of prescription medication over the preceding year.Interventions Patients were divided into CSMT or usual medical care cohorts based on the care received on the index date of rLBP diagnosis.Primary and secondary outcome measures OR for gabapentin prescription.Results After propensity matching, there were 1635 patients per cohort (mean age 36.3±8.6 years, 60% women). Gabapentin prescription over 1-year follow-up was significantly lower in the CSMT cohort compared with the usual medical care cohort, with an OR (95% CI) of 0.53 (0.40 to 0.71; p

BackgroundPatients with chronic lymphocytic leukemia (CLL) have reduced seroconversion rates and lower binding antibody (Ab) and neutralizing antibody (NAb) titers than healthy individuals following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. Here, we dissected vaccine-mediated humoral and cellular responses to understand the mechanisms underlying CLL-induced immune dysfunction.Methods and findingsWe performed a prospective observational study in SARS-CoV-2 infection-naïve CLL patients (n = 95) and healthy controls (n = 30) who were vaccinated between December 2020 and June 2021. Sixty-one CLL patients and 27 healthy controls received 2 doses of the Pfizer-BioNTech BNT162b2 vaccine, while 34 CLL patients and 3 healthy controls received 2 doses of the Moderna mRNA-1273 vaccine. The median time to analysis was 38 days (IQR, 27 to 83) for CLL patients and 36 days (IQR, 28 to 57) for healthy controls. Testing plasma samples for SARS-CoV-2 anti-spike and receptor-binding domain Abs by enzyme-linked immunosorbent assay (ELISA), we found that all healthy controls seroconverted to both antigens, while CLL patients had lower response rates (68% and 54%) as well as lower median titers (23-fold and 30-fold; both p < 0.001). Similarly, NAb responses against the then prevalent D614G and Delta SARS-CoV-2 variants were detected in 97% and 93% of controls, respectively, but in only 42% and 38% of CLL patients, who also exhibited >23-fold and >17-fold lower median NAb titers (both p < 0.001). Interestingly, 26% of CLL patients failed to develop NAbs but had high-titer binding Abs that preferentially reacted with the S2 subunit of the SARS-CoV-2 spike. Since these patients were also seropositive for endemic human coronaviruses (HCoVs), these responses likely reflect cross-reactive HCoV Abs rather than vaccine-induced de novo responses. CLL disease status, advanced Rai stage (III-IV), elevated serum beta-2 microglobulin levels (β2m >2.4 mg/L), prior therapy, anti-CD20 immunotherapy (ConclusionsCLL pathogenesis is characterized by a progressive loss of adaptive immune functions, including in most treatment-naïve patients, with preexisting memory being preserved longer than the capacity to mount responses to new antigens. In addition, higher NAb titers and response rates identify mRNA-1273 as a superior vaccine for CLL patients.

Abstract Background Lumbar magnetic resonance imaging (LMRI) is often performed early in the course of care, which can be discordant with guidelines for non-serious low back pain. Our primary hypothesis was that adults receiving chiropractic spinal manipulative therapy (CSMT) for incident radicular low back pain (rLBP) would have reduced odds of early LMRI over 6-weeks’ follow-up compared to those receiving other care (a range of medical care, excluding CSMT). As a secondary hypothesis, CSMT recipients were also expected to have reduced odds of LMRI over 6-months’ and 1-years’ follow-up. Methods A national 84-million-patient health records database including large academic healthcare organizations (TriNetX) was queried for adults age 20–70 with rLBP newly-diagnosed between January 31, 2012 and January 31, 2022. Receipt or non-receipt of CSMT determined cohort allocation. Patients with prior lumbar imaging and serious pathology within 90 days of diagnosis were excluded. Propensity score matching controlled for variables associated with LMRI utilization (e.g., demographics). Odds ratios (ORs) of LMRI over 6-weeks’, 6-months’, and 1-years’ follow-up after rLBP diagnosis were calculated. Results After matching, there were 12,353 patients per cohort (mean age 50 years, 56% female), with a small but statistically significant reduction in odds of early LMRI in the CSMT compared to other care cohort over 6-weeks’ follow-up (9%, 10%, OR [95% CI] 0.88 [0.81–0.96] P = 0.0046). There was a small but statistically significant increase in odds of LMRI among patients in the CSMT relative to the other care cohort over 6-months’ (12%, 11%, OR [95% CI] 1.10 [1.02–1.19], P

Abstract Background Anal squamous cell carcinoma (SCC) generally carries a favorable prognosis, as most tumors are highly sensitive to standard of care chemoradiation. However, outcomes are poor for the 20–30% of patients who are refractory to this approach, and many will require additional invasive procedures with no guarantee of disease resolution. Methods To identify the patients who are unlikely to respond to the current standard of care chemoradiation protocol, we explored a variety of objective clinical findings as a potential predictor of treatment failure and/or mortality in a single center retrospective study of 42 patients with anal SCC. Results Patients with an increase in total peripheral white blood cells (WBC) and/or neutrophils (ANC) had comparatively poor clinical outcomes, with increased rates of death and treatment failure, respectively. Using pre-treatment biopsies from 27 patients, tumors with an inflamed, neutrophil dominant stroma also had poor therapeutic responses, as well as reduced overall and disease-specific survival. Following chemoradiation, we observed uniform reductions in nearly all peripheral blood leukocyte subtypes, and no association between peripheral white blood cells and/or neutrophils and clinical outcomes. Additionally, post-treatment biopsies were available from 13 patients. In post-treatment specimens, patients with an inflamed tumor stroma now demonstrated improved overall and disease-specific survival, particularly those with robust T-cell infiltration. Conclusions Combined, these results suggest that routinely performed leukocyte subtyping may have utility in risk stratifying patients for treatment failure in anal SCC. Specifically, pre-treatment patients with a high WBC, ANC, and/or a neutrophil-dense tumor stroma may be less likely to achieve complete response using the standard of care chemoradiation regimen, and may benefit from the addition of a subsequent line of therapy.

Abstract DNA repair phenotype can be measured in blood and may be a potential biomarker of cancer risk. We conducted a systematic review and meta-analysis of epidemiological studies of DNA repair phenotype and cancer through March 2021. We used random-effects models to calculate pooled odds ratios (ORs) of cancer risk for those with the lowest DNA repair capacity compared with those with the highest capacity. We included 55 case–control studies that evaluated 12 different cancers using 10 different DNA repair assays. The pooled OR of cancer risk (all cancer types combined) was 2.92 (95% Confidence Interval (CI) 2.49, 3.43) for the lowest DNA repair. Lower DNA repair was associated with all studied cancer types, and pooled ORs (95% CI) ranged from 2.02 (1.43, 2.85) for skin cancer to 7.60 (3.26, 17.72) for liver cancer. All assays, except the homologous recombination repair assay, showed statistically significant associations with cancer. The effect size ranged from 1.90 (1.00, 3.60) for the etoposide-induced double-strand break assay to 5.06 (3.67, 6.99) for the γ-H2AX assay. The consistency and strength of the associations support the use of these phenotypic biomarkers; however large-scale prospective studies will be important for understanding their use related to age and screening initiation.

Perennial grasslands, including prairie and pasture, have declined with tremendous environmental and social costs. This decline reflects unequal policy support for grasslands and managed grazing compared to row crops. To create a resource for community partners and decision-makers, we reviewed and analyzed the policy tools and implementation capacity that supports and constrains grasslands and managed grazing in the U.S. Upper Midwest. Risk reduction subsidies for corn and soybeans far outpace the support for pasture. Some states lost their statewide grazing specialist when the federal Grazing Lands Conservation Initiative lapsed. The United States Department of Agriculture, Natural Resources Conservation Service support for lands with prescribed grazing practices declined after 2005 but remained relatively steady 2010–2020. These results reveal the policy disadvantage for grasslands and managed grazing in comparison with row crop agriculture for milk and meat production. Grassland and grazing policies have an important nexus with water quality, biodiversity, carbon and outdoor recreation policy. Socially just transitions to well-managed, grazed grasslands require equity-oriented interventions that support community needs. We synthesized recommendations for national and state policy that farmers and other grazing professionals assert would support perennial grasslands and grazing, including changes in insurance, conservation programs, supply chains, land access, and fair labor. These policies would provide critical support for grass-based agriculture and prairies that we hope will help build soil, retain nutrients, reduce flooding and enhance biodiversity while providing healthy food, jobs, and communities.

State and local health departments established the California Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Respiratory Virus Sentinel Surveillance System to conduct enhanced surveillance for SARS-CoV-2 and other respiratory pathogens at sentinel outpatient testing sites in 10 counties throughout California, USA. We describe results obtained during May 10, 2020‒June 12, 2021, and compare persons with positive and negative SARS-CoV-2 PCR results by using Poisson regression. We detected SARS-CoV-2 in 1,696 (19.6%) of 8,662 specimens. Among 7,851 specimens tested by respiratory panel, rhinovirus/enterovirus was detected in 906 (11.5%) specimens and other respiratory pathogens in 136 (1.7%) specimens. We also detected 23 co-infections with SARS-CoV-2 and another pathogen. SARS-CoV-2 positivity was associated with male participants, an age of 35–49 years, Latino race/ethnicity, obesity, and work in transportation occupations. Sentinel surveillance can provide useful virologic and epidemiologic data to supplement other disease monitoring activities and might become increasingly useful as routine testing decreases.

Abstract There has been a steady rise in the use of dormant propagules to study biotic responses to environmental change over time. This is particularly important for organisms that strongly mediate ecosystem processes, as changes in their traits over time can provide a unique snapshot into the structure and function of ecosystems from decades to millennia in the past. Understanding sources of bias and variation is a challenge in the field of resurrection ecology, including those that arise because often‐used measurements like seed germination success are imperfect indicators of propagule viability. Using a Bayesian statistical framework, we evaluated sources of variability and tested for zero‐inflation and overdispersion in data from 13 germination trials of soil‐stored seeds of Schoenoplectus americanus, an ecosystem engineer in coastal salt marshes in the Chesapeake Bay. We hypothesized that these two model structures align with an ecological understanding of dormancy and revival: zero‐inflation could arise due to failed germinations resulting from inviability or failed attempts to break dormancy, and overdispersion could arise by failing to measure important seed traits. A model that accounted for overdispersion, but not zero‐inflation, was the best fit to our data. Tetrazolium viability tests corroborated this result: most seeds that failed to germinate did so because they were inviable, not because experimental methods failed to break their dormancy. Seed viability declined exponentially with seed age and was mediated by seed provenance and experimental conditions. Our results provide a framework for accounting for and explaining variability when estimating propagule viability from soil‐stored natural archives which is a key aspect of using dormant propagules in eco‐evolutionary studies.

Abstract The vascular system is sensitive to radiation injury, and vascular damage is believed to play a key role in delayed tissue injury such as pulmonary fibrosis. However, the response of endothelial cells to radiation is not completely understood. We examined the response of primary human lung microvascular endothelial cells (HLMVEC) to 10 Gy (1.15 Gy/min) X-irradiation. HLMVEC underwent senescence (80–85%) with no significant necrosis or apoptosis. Targeted RT-qPCR showed increased expression of genes CDKN1A and MDM2 (10–120 min). Western blotting showed upregulation of p2/waf1, MDM2, ATM, and Akt phosphorylation (15 min–72 h). Low levels of apoptosis at 24–72 h were identified using nuclear morphology. To identify novel pathway regulation, RNA-seq was performed on mRNA using time points from 2 to 24 h post-irradiation. Gene ontology and pathway analysis revealed increased cell cycle inhibition, DNA damage response, pro- and anti- apoptosis, and pro-senescence gene expression. Based on published literature on inflammation and endothelial-to-mesenchymal transition (EndMT) pathway genes, we identified increased expression of pro-inflammatory genes and EndMT-associated genes by 24 h. Together our data reveal a time course of integrated gene expression and protein activation leading from early DNA damage response and cell cycle arrest to senescence, pro-inflammatory gene expression, and endothelial-to-mesenchymal transition.

Abstract Objective The aim of this study is to compare a portable ultrasound (US) device and a traditional US for performing transcranial ultrasonography (CCT) in patients with Parkinson's disease (PD). Methods This is a cross‐sectional, observational, and analytical study. The study recruited a total of 129 individuals from two public hospitals in the city of Rio de Janeiro in a prospective and non‐randomized manner between September 2019 and July 2021 as follows: group A with 31 patients with PD, group B with 65 patients with PD, and group C with 64 healthy individuals. Group A was used to collect data to establish the agreement analysis of the TCS measurements between the two devices. Groups B and C provided data for constructing the receiver operating characteristic curve for the handheld US. The subjects underwent the assessment of the transtemporal bone window (TW) quality, the mesencephalon area, the size of the third ventricle, and the substantia nigra (SN) hyperechogenicity area. Results There was a good agreement between the methods regarding the quality of the TW–Kappa concordance coefficient of 100% for the right TW and 83% for the left, the midbrain area—intraclass correlation coefficient (ICC) of 69%, the SN area ICC = 90% for the right SN and 93% for the left and the size of the third ventricle ICC = 96%. The cutoff point for the SN echogenic area in the handheld US was 0.20 cm2. Conclusions The handheld US is a viable imaging method for performing TCS because it shows good agreement with the measurements performed with traditional equipment, and the measurement of SN echogenic area for PD diagnosis presents good sensitivity and specificity.

Abstract Cation mole precents (XCa, XMg, and XNa) on clay minerals in a siliciclastic coastal aquifer calculated from groundwater compositions, can aid in distinguishing fluvial from marine sediments and locate the fluvial/marine transition zone. The clay‐cation compositions of two clay‐rich siliciclastic coastal aquifers calculated from the composition of the groundwater were compared to the location of fluvial, fluvial‐marine transition and marine environments identified by traditional core, well log and paleontological analyses. The traditionally defined fluvial depositional environment is distinguished by clays with low XNa < 8% (for 92% of the samples) and high XCa from 55% to 98% with the remainder XMg. In comparison, the traditionally defined marine depositional environment is distinguished by clays with higher XNa > 8.0% (for 86% of the samples) and lower XCa ranging from 5% to 39% with the remainder XMg. The traditionally defined fluvial/marine transition zone has values overlapping the fluvial and marine end members, with 59% with XNa < 8% (fluvial) and 41% with XNa > 8% (marine), and XCa ranging from 45% to 98% with the remainder XMg. Calculations support that the excess Na (XNa > 8%) on marine clays can be retained for 10s of millions of years despite flushing with meteoric water, because of the high clay content in marine sediments. The calculated cation composition of clays deposited from river water are XNa < 8%. In contrast XNa 8%–54% is possible for seawater equilibrated clays supporting that the values found in the different depositional zones are possible. Calculated cation compositions might supplement traditional stratigraphic interpretations in distinguishing fluvial/marine depositional environments.