Benchmark Dose Modeling with Covariates for Nanomaterials

In the last decade, the use of engineered nanomaterials (ENMs) such as titanium dioxide (TiO2), carbon nanotubes (CNTs), carbon nanofibers (CNFs), as well as a variety of other materials have become increasingly popular in commerce because of their many beneficial properties (e.g. ability to manufacture products that are lighter, stronger, and/or more compact). However, according to the National Institute of Occupational Safety and Health, with the development of new nanotechnology it is prudent to ensure the health and safety of workers who are producing or using these materials at the forefront. For many ENMs, occupational exposure limits (OELs) are not available and the OELs developed for microscale materials may not be adequate for ENMs. In the absence of human data, rodent assays are often used to find a dose estimate which can then be used as a point of departure (POD) to extrapolate to humans. Some bioassays report summary statistics, which can be used to determine benchmark dose (BMD) estimates – the dose that corresponds to a specified level of increased response called a benchmark response or BMR [4]. Pooling data across studies with a small number of dose groups (as in many of the studies in this dataset) provides a more robust dataset by increasing the sample size, although also adding variability across different experimental designs (i.e. species, strain, gender). Thus, the aim of this project was to examine the influence of material type on the dose-response relationship using statistical regression modeling in R (statistical software) since the EPA’s Benchmark Dose Software (BMDS) does not allow for covariates, and building upon these regression models by adding covariates to account for experimental design features which add variability that may obscure these relationships

Who has more? The influence of linguistic form on quantity judgments

Quantity judgment tasks have been increasingly used within and across languages as a diagnostic for noun semantics. Overwhelmingly, results show that notionally atomic nouns (Who has more cats?) are counted, while notionally non-atomic nouns (Who has more milk?) are measured by volume. There are two primary outliers to the strict atomicity-tracking pattern. First, some nouns, like furniture, show primarily cardinality-based results in some studies, indicating atomicity, but nevertheless show systematic non-cardinality judgments in other studies, with comparison based instead on value/utility. Second, it has been reported that speakers of the Amazonian language Yudja favor cardinality-based quantity comparison for all nouns regardless of notional atomicity. In the current study, we show that both of these patterns arise in naïve English speakers in the absence of clear linguistic cues to atomicity, and suggest that the absence or mis-diagnosis of linguistic cues may be behind the reported outliers to atomicity-tracking

A volunteer-run, face-to-face, early intervention service for reducing suicidality: a service evaluation of the listening place

Background: Befriending is one of many strategies with the potential to reduce suicidal ideation and decrease the risk of suicide. Aims: To measure change in suicidal ideation and behavior among visitors (service users) supported at The Listening Place (TLP), a charity which offers volunteer-run, face-to-face befriending to people who are suicidal. Method: This study was peer reviewed and preregistered on the Open Science Framework prior to data extraction. Anonymized data were extracted for visitors at the point of referral and after 3 months of receiving support. Paired-sample tests were used to test whether self-reported suicidal ideation and behaviors changed after 3 months of support from TLP. Multivariable regressions were used to test whether change in suicidal feelings was associated with demographic characteristics or baseline self-reported suicidality. Results: TLP received 13,938 referrals from July 2016 to February 2022. Self-reported suicidal ideation, suicidal behavior, and feelings of distress decreased after 3 months, while feelings of support increased. Only self-reported suicidal behavior prior to referral was associated with a lesser reduction in self-reported suicidality after 3 months. Limitations: In the absence of a control group, it cannot be concluded that TLP causes the reduction in self-reported suicidality. Conclusions: An empathetic, nonjudgmental, listening service for people who are feeling suicidal was well received by users, who experienced a reduction in suicidality

Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous immune population with diverse immunosuppressive functions in solid tumors. Here, we explored the role of the tumor microenvironment in regulating MDSC differentiation and immunosuppressive properties via signal-regulatory protein alpha (SIRPα)/CD47 signaling. In a murine melanoma model, we observed progressive increases in monocytic MDSCs and monocyte-derived dendritic cells that exhibited potent T cell-suppressive capabilities. These adaptations could be recapitulated in vitro by exposing hematopoietic stem cells to tumor-derived factors. Engagement of CD47 with SIRPα on myeloid cells reduced their phagocytic capability, enhanced expression of immune checkpoints, increased reactive oxygen species production, and suppressed T cell proliferation. Perturbation of SIRPα signaling restored phagocytosis and antigen presentation by MDSCs, which was accompanied by renewed T cell activity and delayed tumor growth in multiple solid cancers. These data highlight that therapeutically targeting myeloid functions in combination with immune checkpoint inhibitors could enhance anti-tumor immunity

Software for Spatial Statistics

We give an overview of the papers published in this special issue on spatial statistics, of the Journal of Statistical Software. 21 papers address issues covering visualization (micromaps, links to Google Maps or Google Earth), point pattern analysis, geostatistics, analysis of areal aggregated or lattice data, spatio-temporal statistics, Bayesian spatial statistics, and Laplace approximations. We also point to earlier publications in this journal on the same topic

Anti-tumour necrosis factor therapy for Dupuytren's Disease: a randomised dose response proof of concept phase 2a clinical trial

Background Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. Methods Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). Findings We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ± 84 pg/μg total protein) compared with placebo (817 ± 78 pg/μg). There were two serious adverse events, both considered unrelated to the study drug. Interpretation In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease

Identification of medically actionable secondary findings in the 1000 genomes

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations

The development of the British Red Cross' psychosocial framework: 'calmer'

This paper presents the history, development and approach of the new psychosocial framework which in 2008 was adopted by the British Red Cross, and a piece of research designed to review its fitness for purpose as an educational tool. The framework CALMER is a single, overarching approach for considering and delivering psychosocial services across all of the British Red Cross. It is being included in all relevant training programmes, such as within first aid and psychosocial support and within services in emergency response, event first aid, health and social care, international tracing and message and refugee services and across human resources. The framework includes six prompts which should be followed sequentially, with guidance on facilitative behaviours within each. The research considered the levels of confidence and worry of participants on one day training programmes delivered to three different groups of personnel in three different countries. While finding support for the CALMER framework, further recommendations are made for future research

Loss of SNORA73 reprograms cellular metabolism and protects against steatohepatitis

Lipid induced stress contributes to metabolic diseases. Here the authors identify small nucleolar RNA 73 (SNORA73) in a screen for genes that protect against lipotoxicity and show that deficiency of SNORA73 reprograms oxidative metabolism and protects against steatohepatitis in mice