Unveiling the Molecular Effects of Replacement and Legacy PFASs: Transcriptomic Analysis of Zebrafish Embryos Reveals Surprising Similarities and Potencies.

The prevalence of per- and poly fluoroalkyl substances (PFASs) in the environment has prompted restrictions on legacy PFASs due to their recognized toxic effects. Consequently, alternative "replacement" PFASs have been introduced and are prevalent in environmental matrices. Few studies have investigated the molecular effects of both legacy and replacement PFASs under short-term exposures. This study aimed to address this by utilizing transcriptomic sequencing to compare the molecular impacts of exposure to concentrations 0.001-5 mg/L of the legacy PFOS and two of its replacements, PFECHS and FBSA. Using zebrafish embryos, the research assessed apical effects (mortality, morphology, and growth), identified differentially expressed genes (DEGs) and enriched pathways, and determined transcriptomic points of departure (tPoDs) for each compound. Results indicated that PFOS exhibited the highest relative potency, followed by PFECHS and then FBSA. While similarities were observed among the ranked DEGs across all compounds, over-representation analysis revealed slight differences. Notably, PFOS demonstrated the lowest tPoD identified to date. These findings raise concerns regarding the safety of emerging replacement PFASs and challenge assumptions about PFAS toxicity solely resulting from their accumulative potential. As replacement PFASs proliferate in the environment, this study underscores the need for heightened scrutiny of their effects and questions current regulatory thresholds.

Acute Exposure of Zebrafish (Danio rerio) to the Next-Generation Perfluoroalkyl Substance, Perfluoroethylcyclohexanesulfonate, Shows Similar Effects as Legacy Substances.

Perfluoroethylcyclohexanesulfonate (PFECHS) is an emerging perfluoroalkyl substance (PFAS) that has been considered a potential replacement for perfluorooctanesulfonic acid (PFOS). However, there is little information characterizing the toxic potency of PFECHS to zebrafish embryos and its potential for effects in aquatic environments. This study assessed toxic potency of PFECHS in vivo during both acute (96-hour postfertilization) and chronic (21-day posthatch) exposures and tested concentrations of PFECHS from 500 ng/L to 2 mg/L. PFECHS was less likely to cause mortalities than PFOS for both the acute and chronic experiments based on previously published values for PFOS exposure, but exposure resulted in a similar incidence of deformities. Exposure to PFECHS also resulted in significantly increased abundance of transcripts of peroxisome proliferator activated receptor alpha (pparα), cytochrome p450 1a1 (cyp1a1), and apolipoprotein IV (apoaIV) at concentrations nearing those of environmental relevance. Overall, these results provide further insight into the safety of an emerging PFAS alternative in the aquatic environment and raise awareness that previously considered "safer" alternatives may show similar effects as legacy PFASs.

Neighborhood socioeconomic deprivation, healthcare access, and 30-day mortality and readmission after sepsis or critical illness: findings from a nationwide study.

BACKGROUND: To determine if neighborhood socioeconomic deprivation independently predicts 30-day mortality and readmission for patients with sepsis or critical illness after adjusting for individual poverty, demographics, comorbidity burden, access to healthcare, and characteristics of treating healthcare facilities. METHODS: We performed a nationwide study of United States Medicare beneficiaries from 2017 to 2019. We identified hospitalized patients with severe sepsis and patients requiring prolonged mechanical ventilation, tracheostomy, or extracorporeal membrane oxygenation (ECMO) through Diagnosis Related Groups (DRGs). We estimated the association between neighborhood socioeconomic deprivation, measured by the Area Deprivation Index (ADI), and 30-day mortality and unplanned readmission using logistic regression models with restricted cubic splines. We sequentially adjusted for demographics, individual poverty, and medical comorbidities, access to healthcare services; and characteristics of treating healthcare facilities. RESULTS: A total of 1,526,405 admissions were included in the mortality analysis and 1,354,548 were included in the readmission analysis. After full adjustment, 30-day mortality for patients was higher for those from most-deprived neighborhoods (ADI 100) compared to least deprived neighborhoods (ADI 1) for patients with severe sepsis (OR 1.35 95% [CI 1.29-1.42]) or with prolonged mechanical ventilation with or without sepsis (OR 1.42 [95% CI 1.31, 1.54]). This association was linear and dose dependent. However, neighborhood socioeconomic deprivation was not associated with 30-day unplanned readmission for patients with severe sepsis and was inversely associated with readmission for patients requiring prolonged mechanical ventilation with or without sepsis. CONCLUSIONS: A strong association between neighborhood socioeconomic deprivation and 30-day mortality for critically ill patients is not explained by differences in individual poverty, demographics, measured baseline medical risk, access to healthcare resources, or characteristics of treating hospitals.

Groups and individuals: conformity and diversity in the performance of gendered identities.

The nature and role of social groups is a central tension in sociology. On the one hand, the idea of a group enables sociologists to locate and describe individuals in terms of characteristics that are shared with others. On the other, emphasizing the fluidity of categories such as gender or ethnicity undermines their legitimacy as ways of classifying people and, by extension, the legitimacy of categorization as a goal of sociological research. In this paper, we use a new research method known as the Imitation Game to defend the social group as a sociological concept. We show that, despite the diversity of practices that may be consistent with self-identified membership of a group, there are also shared normative expectations - typically narrower in nature than the diversity displayed by individual group members - that shape the ways in which category membership can be discussed with, and performed to, others. Two claims follow from this. First, the Imitation Game provides a way of simultaneously revealing both the diversity and 'groupishness' of social groups. Second, that the social group, in the quasi-Durkheimian sense of something that transcends the individual, remains an important concept for sociology.

Mixtures of legacy and replacement perfluorosulphonic acids (PFSAs) demonstrate ratio-, concentration- and endpoint-dependent synergistic interactions in vitro.

The extensive use of poly- and per-fluoroalkyl substances (PFASs) has les to their widespread presence in the environment, raising concerns about potential toxicity. While certain PFASs of concern have been phased-out or banned, new PFASs continue to be produced. Two such substances are perfluoroethylcyclohexane sulphonate (PFECHS) and perfluorobutane sulphamide (FBSA), replacements of perfluoroctanesulphonic acid (PFOS) that have recently been detected in multiple environmental media around the globe. Despite PFASs generally occurring in the environment as mixtures, few data are available outlining the effects of PFAS mixtures. Therefore, this research investigated the interaction potential of binary and ternary mixtures of emerging and legacy PFASs. The immortalized rainbow trout gill cell line (RTgill-W1) was chosen as the experimental model to investigate two apical endpoints: cytotoxicity and phospholipidosis. RTgill-W1 cells were exposed for 24 h to each compound to obtain endpoint-specific effect concentrations (LCx; ECx). These values were then applied to formulate mixture predictions following the Loewes Additivity and Steel and Peckham methods. Based on cytotoxicity, relative potencies of individual compounds were: PFOS > PFECHS > FSBA. PFOS and PFECHS had nearly identical effects on phospholipidosis, while FSBA did not have any effects. Most mixtures had a synergistic effect on cytotoxicity, but the effect was both dose- and ratio-dependent. PFOS and PFECHS were additive at lower concentrations (LC10) and synergistic at higher concentrations (LC50; 3:1, 1:1, and 1:3). PFECHS and FSBA mixtures were synergistic at all doses and ratios (3:1, 1:1, 1:3), while FBSA and PFOS were mainly synergistic at higher concentrations and at ratios favouring PFOS (1:1, 1:3). Tertiary combinations were mainly synergistic. For phospholipidosis, mixtures were strictly additive. These results are strongly suggestive of synergism between emerging PFAS replacements and highlight that independent apical mechanisms of different PFASs could combine to induce unexpected toxicity. Considering that emerging replacements are continuing to increase in concentration in the environment, such mixture scenarios are also likely to continue to increase in probability.

The Effect of Social Drivers of Health on 90-Day Readmission Rates and Costs After Primary Total Hip and Total Knee Arthroplasty.

INTRODUCTION: The effect of social drivers of health (SDOH) on readmissions and costs after total hip arthroplasty (THA) and total knee arthroplasty (TKA) is poorly understood. Policies such as the Hospital Readmissions Reduction Program have targeted overall readmission reduction, using value-based strategies to improve healthcare quality. However, the implications of SDOH on these outcomes are not yet understood. We hypothesized that the area deprivation index (ADI) as a surrogate for SDOH would markedly influence readmission rates and healthcare costs in the 90-day postprocedural period for THA and TKA. METHODS: We used the 100% US fee-for-service Medicare claims data from 2019 to 2021. Patients were identified using diagnosis-related groups. Our primary outcomes included 90-day unplanned readmission after hospital discharge and cost of care, treated as "high cost" if > 1 standard deviation above the mean. The relationships between ADI and primary outcomes were estimated with logistic regression models. RESULTS: A total of 628,399 patients were included in this study. The mean age of patients was 75.6, 64% were female, and 7.8% were dually eligible for Medicaid. After full covariate adjustment, readmission was higher for patients in more deprived areas (high Area Deprivation Index (ADI)) (low socioeconomic status (SES) group OR: 1.30 [95% confidence intervals 1.23, 1.38]). ADI was associated with high cost before adjustment (low SES group odds ratio 1.08 [95% confidence intervals 1.04, 1.11], P < 0.001), although, after adjustment, this association was lost. DISCUSSION: This analysis highlights the effect of SDOH on readmission rates after THA and TKA. A nuanced understanding of neighborhood-level disparities may facilitate targeted strategies to reduce avoidable readmissions in orthopaedic surgery. Regarding cost, although there is some association between ADI and cost, this study may illustrate that ADI for THA and TKA is not sufficiently granular to identify the contribution of social drivers to elevated costs.

Race differences in patient trust and distrust from audio-recorded cardiology encounters.

OBJECTIVE: Many have reported racial disparities in self-reported trust in clinicians but have not directly assessed expressions of trust and distrust in physician-patient encounters. We created a codebook to examine racial differences in patient trust and distrust through audio-recorded cardiologist-patient interactions. METHODS: We analyzed data from a randomized controlled trial of audio-recorded outpatient cardiology encounters (50 White and 51 Black patients). We created a codebook for trust and distrust that was applied to recordings between White cardiologists and White and Black patients. We assessed differences in trust, distrust, and guardedness while adjusting for patient age, sex, and first appointment with the cardiologist. RESULTS: Compared to White patients, Black patients had significantly lower expressions of trust ([IRR] [95 % CI]: 0.59 [0.41, 0.84]) and a significantly lower mean guarded/open score ([ß] [95 % CI] -0.38 [-0.71, -0.04]). There was no statistically significant association between race and odds of at least one distrustful expression (OR [95 % CI] 1.36 [0.37, 4.94]). CONCLUSION AND PRACTICE IMPLICATIONS: We found that coders can reliably identify patient expressions of trust and distrust rather than relying on problematic self-reported measures. Results suggest that White clinicians can improve their communication with Black patients to increase expressions of trust.

Neighborhood Socioeconomic Disadvantage and 30-Day Outcomes for Common Cardiovascular Conditions.

BACKGROUND: Understanding the relationship between neighborhood environment and cardiovascular outcomes is important to achieve health equity and implement effective quality strategies. We conducted a population-based cohort study to determine the association of neighborhood socioeconomic deprivation and 30-day mortality and readmission rate for patients admitted with common cardiovascular conditions. METHODS AND RESULTS: We examined claims data from fee-for-service Medicare beneficiaries aged ≥65 years between 2017 and 2019 admitted for heart failure, valvular heart disease, ischemic heart disease, or cardiac arrhythmias. The primary exposure was the Area Deprivation Index; outcomes were 30-day all-cause death and unplanned readmission. More than 2 million admissions were included. After sequential adjustment for patient characteristics (demographics, dual eligibility, comorbidities), area health care resources (primary care clinicians, specialists, and hospital beds per capita), and admitting hospital characteristics (ownership, size, teaching status), there was a dose-dependent association between neighborhood socioeconomic deprivation and 30-day mortality rate for all conditions. In the fully adjusted model for death, estimated effect sizes of residence in the most disadvantaged versus least disadvantaged neighborhoods ranged from adjusted odds ratio 1.29 (95% CI, 1.22-1.36) for the heart failure group to adjusted odds ratio 1.63 (95% CI, 1.36-1.95) for the valvular heart disease group. Neighborhood deprivation was associated with increased adjusted 30-day readmission rates, with estimated effect sizes from adjusted odds ratio 1.09 (95% CI, 1.05-1.14) for heart failure to adjusted odds ratio 1.19 (95% CI, 1.13-1.26) for arrhythmia. CONCLUSIONS: Neighborhood socioeconomic disadvantage was associated with 30-day mortality rate and readmission for patients admitted with common cardiovascular conditions independent of individual demographics, socioeconomic status, medical risk, care access, or admitting hospital characteristics.

Perfluoroethylcyclohexane sulphonate, an emerging perfluoroalkyl substance, disrupts mitochondrial membranes and the expression of key molecular targets in vitro.

Perfluoroethylcyclohexane sulphonate (PFECHS) is an emerging, replacement perfluoroalkyl substance (PFAS) with little information available on the toxic effects or potencies with which to characterize its potential impacts on aquatic environments. This study aimed to characterize effects of PFECHS using in vitro systems, including rainbow trout liver cells (RTL-W1 cell line) and lymphocytes separated from whole blood. It was determined that exposure to PFECHS caused minor acute toxic effects for most endpoints and that little PFECHS was concentrated into cells with a mean in vitro bioconcentration factor of 81 ± 25 L/kg. However, PFECHS was observed to affect the mitochondrial membrane and key molecular receptors, such as the peroxisome proliferator receptor, cytochrome p450-dependent monooxygenases, and receptors involved in oxidative stress. Also, glutathione-S-transferase was significantly down-regulated at a near environmentally relevant exposure concentration of 400 ng/L. These results are the first to report bioconcentration of PFECHS, as well as its effects on the peroxisome proliferator and glutathione-S-transferase receptors, suggesting that even with little bioconcentration, PFECHS has potential to cause adverse effects.

Patient and Caregiver Expression of Reluctance and Ambivalence During Palliative Care Encounters.

Context: Patients with serious illness and their caregivers often face challenging decisions. When faced with these decisions, patients and caregivers may display signs of ambivalence and reluctance toward end-of-life decision making. Methods: We recruited 22 palliative care clinicians to participate in a communication coaching study. Clinicians audio recorded four of their palliative care encounters with adult patients and family caregivers. A team of 5 coders used inductive coding methods to create a codebook and then coded instances of patients and caregivers expressing ambivalence and reluctance. They also coded when the decision-making process was initiated and whether a decision was made. The group coded 76 encounters, and 10% (n = 8) of those encounters were double coded to assess inter-rater reliability. Results: We found that ambivalence occurred in 82% (n = 62) of the encounters, while reluctance occurred in 75% (n = 57) of the encounters. The overall prevalence of either was 89% (n = 67). The presence of ambivalence was negatively associated with a decision being made once initiated (r = -0.29, p = 0.06). Conclusion: We found that coders can reliably identify patient and caregiver reluctance and ambivalence. Further, reluctance and ambivalence occur frequently in palliative care encounters. When patients and caregivers have ambivalence, decision making might be hampered.

Neighborhood Socioeconomic Disadvantage, Healthcare Access, and Outcomes of Hospitalizations for Common Pulmonary Conditions: A National Study of Medicare Beneficiaries.

Rationale: Understanding how systemic forces and environmental exposures impact patient outcomes is critical to advancing health equity and improving population health for patients with pulmonary disease. This relationship has not yet been assessed at the population level nationally. Objectives: To determine whether neighborhood socioeconomic deprivation is independently associated with 30-day mortality and readmission for hospitalized patients with pulmonary conditions, after controlling for demographics, access to healthcare resources, and characteristics of admitting healthcare facilities. Methods: This was a retrospective, population-level cohort study of 100% of United States nationwide Medicare inpatient and outpatient claims from 2016-2019. Patients were admitted for one of four pulmonary conditions (pulmonary infections, chronic lower respiratory disease, pulmonary embolism, and pleural and interstitial lung diseases), defined by diagnosis-related group. The primary exposure was neighborhood socioeconomic deprivation, measured by the area deprivation index. The main outcomes were 30-day mortality and 30-day unplanned readmission, defined by Centers for Medicare and Medicaid Services methodologies. Generalized estimating equations were used to estimate logistic regression models for the primary outcomes, addressing clustering by hospital. A sequential adjustment strategy was first adjusted for age, legal sex, Medicare-Medicaid dual eligibility, and comorbidity burden, then adjusted for metrics of access to healthcare resources, and finally adjusted for characteristics of the admitting healthcare facility. Results: After full adjustment, patients from low socioeconomic status neighborhoods had greater 30-day mortality after admission for pulmonary embolism (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.13-1.40), respiratory infections (OR, 1.20; 95% CI, 1.16-1.25), chronic lower respiratory disease (OR, 1.31; 95% CI, 1.22-1.41), and interstitial lung disease (OR, 1.15; 95% CI, 1.04-1.27) when compared to patients from the highest SES neighborhoods. Low neighborhood socioeconomic status was also associated with 30-day readmission for all groups except the interstitial lung disease group. Conclusions: Neighborhood socioeconomic deprivation may be a key factor driving poor health outcomes for patients with pulmonary diseases.

Effect of elevated embryonic incubation temperature on the temperature preference of juvenile lake (Coregonus clupeaformis) and round whitefish (Prosopium cylindraceum).

Anthropogenic impacts can lead to increased temperatures in freshwater environments through thermal effluent and climate change. Thermal preference of aquatic organisms can be modulated by abiotic and biotic factors including environmental temperature. Whether increased temperature during embryogenesis can lead to long-term alterations in thermal preference has not been explicitly tested in native freshwater species. Lake (Coregonus clupeaformis) and round (Prosopium cylindraceum) whitefish were incubated at natural and elevated temperatures until hatching, following which, all groups were moved to common garden conditions (15°C) during the post-hatching stage. Temperature preference was determined at 8 months (Lake whitefish only) and 12 months of age (both species) using a shuttle box system. Round whitefish preferred a cooler temperature when incubated at 2 and 6°C compared with 0.5°C. Lake whitefish had similar temperature preferences regardless of age, weight and incubation temperature. These results reveal that temperature preference in freshwater fish can be programmed during early development, and that round whitefish may be more sensitive to incubation temperature. This study highlights the effects that small increases in temperature caused by anthropogenic impacts may have on cold-adapted freshwater fish.

Next generation per- and poly-fluoroalkyl substances: Status and trends, aquatic toxicity, and risk assessment.

Widespread application of poly- and per-fluoroalkyl substances (PFAS) has resulted in some substances being ubiquitous in environmental matrices. That and their resistance to degradation have allowed them to accumulate in wildlife and humans with potential for toxic effects. While specific substances of concern have been phased-out or banned, other PFAS that are emerging as alternative substances are still produced and are being released into the environment. This review focuses on describing three emerging, replacement PFAS: perfluoroethylcyclohexane sulphonate (PFECHS), 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFAES), and hexafluoropropylene oxide dimer acid (HFPO-DA). By summarizing their physicochemical properties, environmental fate and transport, and toxic potencies in comparison to other PFAS compounds, this review offers insight into the viabilities of these chemicals as replacement substances. Using the chemical scoring and ranking assessment model, the relative hazards, uncertainties, and data gaps for each chemical were quantified and related to perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) based on their chemical and uncertainty scores. The substances were ranked PFOS > 6:2 Cl-PFAES > PFOA > HFPO-DA > PFECHS according to their potential toxicity and PFECHS > HFPO-DA > 6:2 Cl-PFAES > PFOS > PFOA according to their need for future research. Since future uses of PFAS remain uncertain in the face of governmental regulations and production bans, replacement PFAS will continue to emerge on the world market and in the environment, raising concerns about their general lack of information on mechanisms and toxic potencies.