Trends in the Use and Discussion of Race in Pediatrics Articles Over 75 Years.

BACKGROUND AND OBJECTIVES: Race-based medicine, which falsely assumes that race is biological, is common in the published medical literature. We analyzed trends in the use of race in Pediatrics articles over a 75-year period. METHODS: We analyzed a random sample of 50 original research articles published each decade in Pediatrics from 1948 to 2022. RESULTS: Of 375 articles, 39% (n = 147) included race. Among articles, 85% (n = 116) used race only to describe study subjects, 7% (n = 9) described race as a social construct, and 11% (n = 15) described race as a biological construct. Only 7% (n = 10) of studies provided a reason for including race. Statements reflective of racial bias or discrimination were identified in 22% (n = 30) of the articles that mentioned race. Although statements concerning for explicit racial bias were uncommon, with none identified in the most recent decade, statements suggestive of implicit racial bias still occurred (22%, 5 of 23). Race was presented as a dichotomy, such as "white/nonwhite," in 9% of studies (n = 12). Regarding currently nonrecommended terminology, the term "minorities" was used in 13% of studies (n = 18); 25% of studies used the term "others" (n = 34), and among these, 91% (n = 31 of 34) did not provide any definition, an occurrence that increased over time at a rate of 0.9%/year. CONCLUSIONS: Although there has been improvement over the past 75 years in the reporting of race in published studies in Pediatrics, significant opportunities for further improvement remain.

Household water use and greywater management in Khulna city, Bangladesh.

While substantial progress has been made in improving water and sanitation services in low- and middle-income countries, aligned basic services such as greywater, stormwater, and solid waste management have progressed little in recent decades. Data was collected in Khulna city, Bangladesh via a household survey (n = 192) of low-income areas exploring domestic water use and greywater volumes, characteristics, and disposal practices. Most households (71%) use a piped water supply for domestic purposes, supplemented by seasonal rainwater harvesting (26%) and greywater use (13%). Of the total water used by households (mean: 594 L/household/day and equivalent to 116 L/person/day), approximately 58% becomes greywater through bathing, dishwashing, religious practices, handwashing, laundry, and mopping. Greywater produced ranges from 61-1274 L/household/day, with a mean of 345 L/household/day and equivalent to 78.4 L/person/day. Greywater characteristics vary depending on the activity, individual behaviours and any products used during cooking, bathing, or cleaning. After generation, households dispose greywater to open drains (67%), nearby waterbodies (17%) directly to the ground (9%), or decentralised wastewater treatment system (7%). Without services for greywater management, greywater disposal may have considerable public and environmental health implications, necessitating careful attention and oversight from service-providers and stakeholders beyond the household-level.

Valuing the health benefits of nature-based recreational physical activity in England.

Physical activity (PA) reduces the risk of several non-communicable diseases (NCDs). Natural environments support recreational PA. Using data including a representative cross-sectional survey of the English population, we estimated the annual value of nature-based PA conducted in England in 2019 in terms of avoided healthcare and societal costs of disease. Population-representative data from the Monitor of Engagement with the Natural Environment (MENE) survey (n = 47,580; representing 44,386,756) were used to estimate the weekly volume of nature-based recreational PA by adults in England in 2019. We used epidemiological dose-response data to calculate incident cases of six NCDs (ischaemic heart disease (IHD), ischaemic stroke (IS), type 2 diabetes (T2D), colon cancer (CC), breast cancer (BC) and major depressive disorder (MDD)) prevented through nature-based PA, and estimated associated savings using published costs of healthcare, informal care and productivity losses. We investigated additional savings resulting from hypothetical increases in: (a) visitor PA and (b) visitor numbers. In 2019, 22million adults > 16 years of age in England visited natural environments at least weekly. At reported volumes of nature-based PA, we estimated that 550 cases of IHD, 168 cases of IS, 1,410 cases of T2D, 41 cases of CC, 37 cases of BC and 10,552 cases of MDD were prevented, creating annual savings of £108.7million (95 % uncertainty interval: £70.3million; £150.3million). Nature-based recreational PA in England results in reduced burden of disease and considerable annual savings through prevention of priority NCDs. Strategies that increase nature-based PA could lead to further reductions in the societal burden of NCDs.

A review of the mesotheliogenic potency of cleavage fragments found in talc.

It has long been recognized that amphibole minerals, such as cleavage fragments of tremolite and anthophyllite, may exist in some talc deposits. We reviewed the current state of the science regarding the factors influencing mesotheliogenic potency of cleavage fragments, with emphasis on those that may co-occur in talc deposits, including dimensional and structural characteristics, animal toxicology, and the most well-studied cohort exposed to talc-associated cleavage fragments. Based on our review, multiple lines of scientific evidence demonstrate that inhaled cleavage fragments associated with talc do not pose a mesothelioma hazard.

Mono-ortho-beryllated Carbodiphosphoranes: Synthesis, Structure, Bonding and Reactivity.

The reaction of organoberyllium compounds with hexaphenylcarbodiphosphorane yields mono-ortho-beryllated complexes, which feature a double dative Be=C bond. The bonding situation in these compounds together with a simple carbodiphosphorane and an N-heterocyclic carbene adduct was analysed with energy decomposition analysis in combination with natural orbital for chemical valence as well as with quantum theory of atoms-in-molecules. Furthermore, the driving forces accountable for mono-ortho-beryllation were elucidated along with the reactivity of the Be=C bond.

Conceptualizing Sexual Wellbeing: A Qualitative Investigation to Inform Development of a Measure (Natsal-SW).

Despite increasing scientific and policy interest in sexual wellbeing, it remains poorly conceptualized. Many studies purporting to measure it instead measure related but distinct concepts, such as sexual satisfaction. This lack of conceptual clarity impedes understanding, measuring, and improving sexual wellbeing. We present qualitative research from multi-stage, mixed-methods work to develop a new measure of sexual wellbeing (Natsal-SW) for the fourth British National Survey of Sexual Attitudes & Lifestyles. Literature review and discussion generated a conceptual framework with seven proposed domains: respect, self-esteem, comfort, self-determination, safety and security, forgiveness, and resilience. Semi-structured interviews with 40 adults aged 18-64 then explored whether and how these domains aligned with participants' own understandings, experiences, and language of sexual wellbeing. Data were analyzed thematically. Participants conceptualized sexual wellbeing as distinct from sexual satisfaction and sexual health and as multidimensional, dynamic, and socially and structurally influenced. All seven proposed domains resonated with accounts of sexual wellbeing as a general construct. The personal salience of different domains and their dimensions varied between individuals (especially by gender and sexual orientation) and fluctuated individually over time. This study clarifies dimensions of domains that participants considered important, providing an empirical basis to inform development of a new measure of sexual wellbeing.

Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts.

Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.

Synthesis and Derivatives of Beryllium Triflate.

Various pathways for the synthesis of beryllium triflate were investigated. The reaction of triflic acid or trimethylsilyl triflate with beryllium metal in liquid ammonia led to the formation of mono-, di-, and tetra-nuclear beryllium ammine complexes. Utilization of SMe2 as a solvent gave homoleptic Be(OTf)2. Various beryllium triflate complexes with N- and O-donor ligands as well as the complex anions [Be(OTf)4]2- and [Be2(OTf)6]2- were synthesized to evaluate the reactivity and solution properties of beryllium triflate. This showed that OTf- is not a weakly coordinating anion for Be2+ cations and that it exhibits good bridging properties.

Considerations for the development of guidance on dose level selection for developmental and reproductive toxicity studies.

In 2022, the European Chemicals Agency issued advice on the selection of high dose levels for developmental and reproductive toxicity (DART) studies indicating that the highest dose tested should aim to induce clear evidence of reproductive toxicity without excessive toxicity and severe suffering in parental animals. In addition, a recent publication advocated that a 10% decrease in body weight gain should be replaced with a 10% decrease in bodyweight as a criterion for dose adequacy. Experts from the European Centre for Ecotoxicology and Toxicology of Chemicals evaluated these recent developments and their potential impact on study outcomes and interpretation and identified that the advice was not aligned with OECD test guidelines or with humane endpoints guidance. Furthermore, data analysis from DART studies indicated that a 10% decrease in maternal body weight during gestation equates to a 25% decrease in body weight gain, which differs from the consensus of experts at a 2010 ILSI/HESI workshop. Dose selection should be based on a biological approach that considers a range of other factors. Excessive dose levels that cause frank toxicity and overwhelm homeostasis should be avoided as they can give rise to effects that are not relevant to human health assessments.

Terahertz Vibrational Dynamics and DFT Calculations for the Quantum Spin Chain Linarite, PbCuSO4(OH)2.

The low-dimensional quantum-magnet, linarite, PbCuS4(OH)2, has been investigated using terahertz (THz) spectroscopy coupled with detailed density functional theory (DFT) calculations in order to explore the effects of the temperature on its lattice vibrations. Linarite is characterized by largely isolated CuO chains propagating along the crystallographic b-axis, which at very low temperatures are responsible for exotic, quasi-1D magnetism in this material. To better understand the synergy between the structural bonds and lattice oscillations that contribute to these chains, polarized THz spectroscopic measurements were performed. Consolidating these results with detailed DFT calculations has revealed that the anisotropic vibrational motion for the THz modes is correlated with extreme motion associated with the crystallographic b-axis. An unexpected feature observed in the infrared spectrum is attributed to subtle lattice distortions which break the centro-symmetry in linarite at high temperatures. This phenomenon has not previously been observed in linarite and likely results from anharmonicity in lattice oscillations.

The effects of short-term, progressive exercise training on disease activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance: a single-arm pilot study.

BACKGROUND: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity. METHODS: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation. RESULTS: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged. CONCLUSIONS: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM). REGISTRATION: https://www.isrctn.com/ISRCTN65527208 (14/05/2018).

Mechanisms underlying the associations between different types of nature exposure and sleep duration: An 18-country analysis.

Whilst green space has been linked to healthier sleep outcomes, the roles of specific types of nature exposure, potential underlying mechanisms, and between-country variations in nature-sleep associations have received little attention. Drawing on cross-sectional survey data from an 18-country sample of adults (N = 16,077) the current study examined: 1) the relative associations between six different types of nature exposure (streetscape greenery, blue view from home, green space within 1 km, coast within 1 km, green space visits, blue space visits) and insufficient sleep (<6 h vs. 7-10 h per day); 2) whether these relationships were mediated by better mental wellbeing and/or physical activity; and 3) the consistency of these pathways among the different countries. After controlling for covariates, neighbourhood nature measures (green space, coast within 1 km) were not significantly associated with insufficient sleep; but nature visible from home (streetscape greenery, blue views) and recreational visits to green and blue spaces were each associated with less insufficient sleep. Significant nature-sleep associations were mediated, to varying degrees, by better mental wellbeing, but not self-reported physical activity. Country-level heterogeneity in the strength of nature-sleep associations was observed. Increasing nature visible from the home may represent a promising strategy for promoting healthier sleep duration at the population level, whilst nature-based interventions encouraging individuals to spend time in local green/blue spaces may be an appropriate target to assist individuals affected by insufficient sleep.

An effective route to the additive manufacturing of a mechanically gradient supramolecular polymer nanocomposite structure.

3D Printing techniques are additive methods of fabricating parts directly from computer-aided designs. Whilst the clearest benefit is the realisation of geometrical freedom, multi-material printing allows the introduction of compositional variation and highly tailored product functionality. The paper reports a proof-of-concept additive manufacturing study to deposit a supramolecular polymer and a complementary organic filler to form composites with gradient composition to enable spatial distribution of mechanical properties and functionality by tuning the number of supramolecular interactions. We use a dual-feed extrusion 3D printing process, with feed stocks based on the supramolecular polymer and its organic composite, delivered at ratios predetermined. This allows for production of a graded specimen with varying filler concentration that dictates the mechanical properties. The printed specimen was inspected under dynamic load in a tensile test using digital image correlation to produce full-field deformation maps, which showed clear differences in deformation in regions with varying compositions, corresponding to the designed-in variations. This approach affords a novel method for printing material with graded mechanical properties which are not currently commercially available or easily accessible, however, the method can potentially be directly translated to the generation of biomaterial-based composites featuring gradients of mechanical properties.

SerpinB3/4 Expression Is Associated with Poor Prognosis in Patients with Cholangiocarcinoma.

Cholangiocarcinoma (CCA), the second most common primary liver tumor, is associated with a dismal outcome, and useful prognostic markers are not currently available in clinical practice. SerpinB3, a serine protease inhibitor, was recently found to play a relevant role in malignant transformation in different cancers. The aim of the present study was to determine the expression of SerpinB3/4 in tissue and serum samples of patients with CCA in relation to clinical outcomes. SerpinB3/4 was assessed in the tissue microarrays (TMAs) of 123 surgically resected CCAs. ELISA assays were carried out in 188 patients with CCA to detect the free and IgM-linked forms of SerpinB3/4. Overall survival was analyzed in relation to SerpinB3/4 expression, and Cox models were used to identify the variables associated with survival. High levels of SerpinB3/4 (TMA score 2+/3+) were detected in 15 tumors (12.2%), characterized by a more advanced TNM stage (III/IV: 64.3% vs. 31.3%; p = 0.031) and lower overall patient survival, independently of CCA subclass (intrahepatic CCA: median 1.1 (0.8-Not Estimable, NE) vs. 2.4 (1.8-3.4) years; p = 0.0007; extrahepatic CCA: median 0.8 (0.2-NE) vs. 2.2 (1.5-5.4) years; p = 0.011). Vascular invasion (p = 0.027) and SerpinB3/4 scores (p = 0.0016) were independently associated with mortality in multivariate analysis. Patients who had detectable free or IgM-linked SerpinB3/4 in their serum showed poorer survival (1 vs. 2.4 years, p = 0.015, for free SerpinB3/4, and 1 vs. 2.6 years, p = 0.0026, for SerpinB3/4-IgM). In conclusion, high levels of SerpinB3/4 in tissue and serum in CCA are associated with poor outcomes after surgery, regardless of tumor subclass.

Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort.

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051.

Racial and ethnic disparities in untreated patients with hepatitis C virus-related hepatocellular carcinoma but not in those with sustained virologic response.

BACKGROUND: Racial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival. AIM: To evaluate the impact of HCV treatment on such disparities. METHODS: In a retrospective cohort study, we analysed 6069 patients with HCV-related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia. RESULTS: The mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%-15%, 20% vs. 10%-17% and 10% vs. 5%-7%, respectively; all p < 0.0001). Treatment rate with direct-acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10-year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non-U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001). CONCLUSION: DAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.