Prevalence and Predictors of Diabetic Retinopathy, Its Progression and Regression in Indian Children and Youth With Type-1 Diabetes.

Objective: There are very few reports on the prevalence of diabetic retinopathy (DR) in children and youth with type-1 diabetes (T1D). Studies have also found very low rates of referral for DR screening in children and youth with T1D. We conducted this study to determine the prevalence of DR, to study the reliability of ISPAD screening recommendations and to identify predictors of DR, its progression and regression in Indian children and youth with T1D. Methods: This study included 882 children and youth with T1D. Demographic data, anthropometry, blood pressure, sexual maturity rating, ophthalmological examination (slit lamp for cataract) and biochemical measurements were performed using standard protocols. Fundus images were captured using the Forus Health 3netra classic digital non-mydriatic fundus camera by the same experienced operator. De-identified images were assessed by a senior grader and ophthalmologist (Belfast Ophthalmic Reading Center). Severity of DR was graded as per the UK National Health Service (NHS) DR classification scale. Result: We report 6.4% and 0.2% prevalence of DR and cataract in Indian children and youth with T1D, respectively. All the subjects with DR had early non-proliferative DR. We report that amongst subjects with DR, only 2 subjects were aged less than 11 years and had duration of illness less than 2 years. Presence of hypertension and older age were significant predictors of DR (P < .05). Subjects with DR had significantly higher triglyceride concentrations (P < .05), of these, 6.9% had progression and 2.9% had regression at 1 year follow up; the change in glycaemic control was a significant positive predictor of progression of DR (P < .05). None of the participants included in the study progressed to develop sight-threatening DR. Conclusion: DR is not uncommon in Indian children and youth with T1D, thus screening for DR needs to be initiated early, particularly in older individuals with higher disease duration. Controlling blood pressure and triglyceride concentrations may prevent occurrence of DR. Improving glycaemic control may prevent progression of DR in Indian children and youth with T1D.

Diabetic retinopathy in Indian children with Type 1 Diabetes We found that 6.4% and 0.2% Indian children and youth with type-1 diabetes had diabetic retinopathy and cataract respectively. We report that amongst subjects with DR, only 2 subjects were aged less than 11 years and had duration of illness less than 2 years. Thus, International Society for Paediatric and Adolescent Diabetes (ISPAD) screening criteria must be implemented by all centres to avoid missing cases. Presence of high blood pressure, high triglyceride levels and older age were significant predictors of DR. Of the subjects with DR, 6.9% had progression and 2.9% had regression at 1 year follow up; the change in glycaemic control was a significant positive predictor of progression of DR. None of the participants included in the study progressed to develop sight-threatening DR. DR is not uncommon in Indian children and youth with T1D, hence, screening for DR needs to be initiated early, particularly in older individuals with higher disease duration. Controlling blood pressure and triglyceride concentrations may prevent occurrence of DR. Improving glycaemic control may prevent progression of DR in Indian children and youth with T1D.

CD4+ T cells exhibit distinct transcriptional phenotypes in the lymph nodes and blood following mRNA vaccination in humans.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mRNA vaccination induce robust CD4+ T cell responses. Using single-cell transcriptomics, here, we evaluated CD4+ T cells specific for the SARS-CoV-2 spike protein in the blood and draining lymph nodes (dLNs) of individuals 3 months and 6 months after vaccination with the BNT162b2 mRNA vaccine. We analyzed 1,277 spike-specific CD4+ T cells, including 238 defined using Trex, a deep learning-based reverse epitope mapping method to predict antigen specificity. Human dLN spike-specific CD4+ follicular helper T (TFH) cells exhibited heterogeneous phenotypes, including germinal center CD4+ TFH cells and CD4+IL-10+ TFH cells. Analysis of an independent cohort of SARS-CoV-2-infected individuals 3 months and 6 months after infection found spike-specific CD4+ T cell profiles in blood that were distinct from those detected in blood 3 months and 6 months after BNT162b2 vaccination. Our findings provide an atlas of human spike-specific CD4+ T cell transcriptional phenotypes in the dLNs and blood following SARS-CoV-2 vaccination or infection.

Cluster Randomized Trial of Diabetes Group Visits in Community Health Centers across the Midwest.

BACKGROUND: Diabetes group visits (GVs) have not been rigorously evaluated in community health centers. METHODS: This cluster randomized controlled study recruited adults with diabetes mellitus with glycosylated hemoglobin, A1C greater than or equal to eight percent: 75 intervention and 120 usual care. Group visit patients completed a six-month program. Primary outcome was A1C change from baseline to 12 months. RESULTS: Participants improved their A1C by 0.38%-0.40% with no difference across arms (p=.63). Group visit patients improved their diabetes social support, knowledge, and distress and were more likely to receive guideline-based care compared with control. Group visit patients with anxiety or depression were more likely to have a visit with behavioral health compared with usual care (p=.02). CONCLUSIONS: Community health center patients with diabetes had improvements in glucose control across arms. Group visits improved the receipt of mental health care and guideline-based care.

Nonoperative Versus Operative Treatment of Z-Type Comminuted Clavicle Fractures in Adolescents: A Prospective Substratified Cohort Analysis.

OBJECTIVES: To compare the clinical, radiographic, and patient-reported outcomes of nonoperative and operative treatment of adolescents with comminuted "Z-type" midshaft clavicle fractures. DESIGN: Prospective observational cohort. SETTING: Eight tertiary care pediatric centers. PATIENT SELECTION CRITERIA: Patients aged 10-18 years who were treated either operatively or nonoperatively for a diaphyseal clavicle fracture between 2013 and 2017 were screened/enrolled at the time of injury. The current subcohort analysis was derived from a larger adolescent clavicle study population of 907 patients. OUTCOME MEASUREMENTS AND COMPARISONS: Complications and validated patient-reported outcome measures (PROs):(ASES, QuickDASH, Marx Shoulder Activity Score, EQ-5D, EQ-VAS, and patient satisfaction score) were compared between operative and nonoperative cohorts. RESULTS: Eighty-one patients (69 male [85.2%], 12 female; average age 15 years [11.1-18.7]; 78 with sports participation [96.2%]) were followed through bony healing and return to sports, while 59 patients (73%) completed 2-year follow-up with PROs, 26 of whom were treated nonoperatively and 33 treated operatively. All demographic and fracture characteristics were similar (P > 0.05) between the 2-year follow-up cohorts except for fracture shortening, which was greater in the operative cohort (23 vs. 29 mm, P = 0.01). After controlling for this potential confounder through both regression and propensity matched subgroup analysis, nonoperative versus operative cohorts showed no difference in rates of nonunion (0%), delayed union (0% vs. 2.3%, P = 1.0), symptomatic malunion (2.7% vs. 0%, P = 0.4), refracture (2.7% vs. 2.2%, P = 1.0), unexpected subsequent surgery (5.4% vs. 11.4%, P = 0.45), or clinically significant complications (5.4% vs. 16%, P = 0.17). There were no differences in any PROs between cohorts, both before and after controlling for the difference in fracture shortening (all P-values >0.05). CONCLUSIONS: In this prospective comparison of complications and 2-year PROs in adolescents with comminuted Z-type clavicle fractures, nonoperative and operative treatment yielded similar outcomes. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Threshold for increased liver weight is protective of other effects in Peromyscus exposed to PFNA.

Perfluorononanoic acid (PFNA) is a commercially relevant, long-chain (8 fully fluorinated carbon) perfluorinated carboxylic acid. PFNA has limited terrestrial ecotoxicity data and is detected in humans, animals, and the environment. This study is the fourth in a series with the objective of investigating the toxicity of a suite of per- and polyfluoroalkyl substances (PFAS) detected on military installations in a mammal indigenous to North America. Peromyscus leucopus (white-footed mice, ∼25/sex/dose) were exposed via oral gavage to either 0, 0.03, 0.14, 1, or 3 mg PFNA/kg-d for 112 consecutive days (4 wk premating exposure followed by an additional 12 wk of exposure after onset of mating). Parental generation animals were assessed for potential reproductive and developmental effects, organ weight changes, thyroid modulation, and immunotoxicity. Pup weight and survival were assessed at postnatal days 0, 1, 4, 7, and 10. Change in liver weight was determined to yield the most sensitive dose response according to benchmark dose analysis, and serves as the most protective point of departure (BMDL = 0.37 mg/kg-d PFNA). Other effects of PFNA exposure included reduced formation of plaque-forming cells, which are indicative of functional immune deficits (BMDL = 2.31 mg/kg-d); decreased serum thyroxine (BMDL = 0.93 mg/kg-d) without changes in some other hormones; and increased stillbirths (BMDL = 0.61 mg/kg-d PFNA). Pup weight and survival were not affected by PFNA exposure. Combined with data from previous studies, data from Peromyscus provide a One Health perspective on health effects of PFAS.

Protocol for a systematic review of the application of the kidney failure risk equation and Oxford classification in estimating prognosis in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is a common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Outcomes are highly variable and predicting risk of disease progression at an individual level is challenging. Accurate risk stratification is important to identify individuals most likely to benefit from treatment. The Kidney Failure Risk Equation (KFRE) has been extensively validated in CKD populations and predicts the risk of ESRD at 2 and 5 years using non-invasive tests; however, its predictive performance in IgAN is unknown. The Oxford classification (OC) describes pathological features demonstrated on renal biopsy that are associated with adverse clinical outcomes that may also inform prognosis. The objective of this systematic review is to compare the KFRE with the OC in determining prognosis in IgAN. METHODS: A systematic review will be conducted and reported in line with PRISMA guidelines (PRISMA-P checklist attached as Additional file 1). Inclusion criteria will be cohort studies that apply the KFRE or OC to determine the risk of CKD progression or ESRD in individuals with IgAN. Multiple databases will be searched in duplicate to identify relevant studies, which will be screened first by title, then by abstract and then by full-text analysis. Results will be collated for comparison. Risk of bias and confidence assessments will be conducted independently by two reviewers, with a third reviewer available if required. DISCUSSION: Identifying individuals at the highest risk of progression to ESRD is challenging in IgAN, due to the heterogeneity of clinical outcomes. Risk prediction tools have been developed to guide clinicians; however, it is imperative that these aids are accurate and reproducible. The OC is based on observations made by specialist renal pathologists and may be open to observer bias, therefore the utility of prediction models incorporating this classification may be diminished, particularly as in the future novel biomarkers may be incorporated into clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022364569.

Reanalysis of genomic data in rare disease: current practice and attitudes among Australian clinical and laboratory genetics services.

Reanalyzing stored genomic data over time is highly effective in increasing diagnostic yield in rare disease. Automation holds the promise of delivering the benefits of reanalysis at scale. Our study aimed to understand current reanalysis practices among Australian clinical and laboratory genetics services and explore attitudes towards large-scale automated re-analysis. We collected audit data regarding testing and reanalysis volumes, policies and procedures from all Australian diagnostic laboratories providing rare disease genomic testing. A genetic health professionals' survey explored current practices, barriers to reanalysis, preferences and attitudes towards automation. Between 2018 and 2021, Australian diagnostic laboratories performed over 25,000 new genomic tests and 950 reanalyses, predominantly in response to clinician requests. Laboratory and clinical genetic health professionals (N = 134) identified workforce capacity as the principal barrier to reanalysis. No specific laboratory or clinical guidelines for genomic data reanalysis or policies were identified nationally. Perceptions of acceptability and feasibility of automating reanalysis were positive, with professionals emphasizing clinical and workflow benefits. In conclusion, there is a large and rapidly growing unmet need for reanalysis of existing genomic data. Beyond developing scalable automated reanalysis pipelines, leadership and policy are needed to successfully transform service delivery models and maximize clinical benefit.

Barriers and facilitators to smartwatch-based prehabilitation participation among frail surgery patients: a qualitative study.

BACKGROUND: For older, frail adults, exercise before surgery through prehabilitation (prehab) may hasten return recovery and reduce postoperative complications. We developed a smartwatch-based prehab program (BeFitMe) for older adults that encourages and tracks at-home exercise. The objective of this study was to assess patient perceptions about facilitators and barriers to prehab generally and to using a smartwatch prehab program among older adult thoracic surgery patients to optimize future program implementation. METHODS: We recruited patients, aged ≥50 years who had or were having surgery and were screened for frailty (Fried's Frailty Phenotype) at a thoracic surgery clinic at a single academic institution. Semi-structured interviews were conducted by telephone after obtaining informed consent. Participants were given a description of the BeFitMe program. The interview questions were informed by The Five "Rights" of Clinical Decision-Making framework (Information, Person, Time, Channel, and Format) and sought to identify the factors perceived to influence smartwatch prehab program participation. Interview transcripts were transcribed and independently coded to identify themes in for each of the Five "Rights" domains. RESULTS: A total of 29 interviews were conducted. Participants were 52% men (n = 15), 48% Black (n = 14), and 59% pre-frail (n = 11) or frail (n = 6) with a mean age of 68 ± 9 years. Eleven total themes emerged. Facilitator themes included the importance of providers (right person) clearly explaining the significance of prehab (right information) during the preoperative visit (right time); providing written instructions and exercise prescriptions; and providing a preprogrammed and set-up (right format) Apple Watch (right channel). Barrier themes included pre-existing conditions and disinterest in exercise and/or technology. Participants provided suggestions to overcome the technology barrier, which included individualized training and support on usage and responsibilities. CONCLUSIONS: This study reports the perceived facilitators and barriers to a smartwatch-based prehab program for pre-frail and frail thoracic surgery patients. The future BeFitMe implementation protocol must ensure surgical providers emphasize the beneficial impact of participating in prehab before surgery and provide a written prehab prescription; must include a thorough guide on smartwatch use along with the preprogrammed device to be successful. The findings are relevant to other smartwatch-based interventions for older adults.

Mixed methods approach to understanding COVID-19 vaccine hesitancy among immigrants in the Chicago.

BACKGROUND: COVID-19 vaccine hesitancy has been particularly high among immigrant populations, whose experience is shaped by a history of racism and discriminations, and distrust of the healthcare system. In this study we draw from the Theory of Planned Behavior to examine COVID-19 vaccine hesitancy among immigrants in Chicago. METHODS: A mixed-methods approach comprising of both focus groups and a health survey was conducted from February to August 2022. Five focus groups were held (N = 35) among Black, Asian and Arab/Palestine participants to understand attitudes and beliefs around the COVID-19 vaccine. Focus groups were analyzed using a modified template approach to text analysis. Based on these findings and themes, we developed a survey that was conducted among 413 immigrants from the mentioned communities. We used hierarchical ordinal regression analyses to examine the relationship between COVID-19 vaccine hesitancy and vaccination status. RESULTS: Qualitative analysis suggest that the major factors influencing COVID-19 vaccine hesitancy included fear of adverse reactions, misinformation around COVID-19 and the vaccine, negative social norms around vaccination, and external pressure to get vaccinated. From our quantitative analysis we found that 24% of participants were unvaccinated, 5% were partially vaccinated, 32.3% were vaccinated but not boosted, and 39% were vaccinated and boosted for COVID-19. Hierarchical regression models suggest that immigrants who hold negative attitudes and social norms around the COVID-19 vaccine are less likely to vaccinate. CONCLUSIONS: Understanding vaccine hesitancy among immigrants allows for the creation of culturally and linguistically tailored education that can be utilized to increase vaccine confidence and uptake.

Assessing knowledge of end-stage kidney disease and treatment options in hospitalized African American patients undergoing hemodialysis.

OBJECTIVE: African Americans are more likely to develop end-stage kidney disease (ESKD) than whites and face multiple inequities regarding ESKD treatment, renal replacement therapy (RRT), and overall care. This study focused on determining gaps in participants' knowledge of their chronic kidney disease and barriers to RRT selection in an effort to identify how we can improve health care interventions and health outcomes among this population. METHODS: African American participants undergoing hemodialysis were recruited from an ongoing research study of hospitalized patients at an urban Midwest academic medical center. Thirty-three patients were interviewed, and the transcribed interviews were entered into a software program. The qualitative data were coded using template analysis to analyze text and determine key themes. Medical records were used to obtain demographic and additional medical information. RESULTS: Three major themes emerged from the analysis: patients have limited information on ESKD causes and treatments, patients did not feel they played an active role in selecting their initial dialysis unit, and interpersonal interactions with the dialysis staff play a large role in overall unit satisfaction. DISCUSSION: Although more research is needed, this study provides information and suggestions to improve future interventions and care quality, specifically for this population.

A Pilot Efficacy Trial to Educate Muslim Americans about the Islamic Bioethical Perspectives in End-of-Life Healthcare.

In the US, end-of-life health care (EOLHC) is often intensive and invasive, and at times may involve care that is inconsistent with patient values. US Muslims may not receive appropriate religious support, experience uncertainty around end-of-life decision-making, and under-utilize palliative and hospice care. As technological advancements and treatment options rise in EOLHC, Muslim American patients and their families need to understand more about the treatment options that are consistent with their beliefs. The objective of this study was to determine the efficacy of a pilot mosque-based educational workshop focused on increasing Muslim Americans' religious bioethics knowledge about end-of-life healthcare. Intervention sites were four mosques with racially and ethnically diverse members, two in the Chicago metropolitan area and two in the Washington, D.C. area. Eligible participants were self-reported Muslims, aged 18 years or older, who were proficient in English. The intervention included a pre and post-test survey and a workshop focused on the Islamic bioethical perspectives on EOLHC. Knowledge was measured with six true-false questions. Baseline and post-intervention scores were analyzed by McNemar's test and bivariate correlation. Overall, the analysis showed a significant improvement in post-intervention participant knowledge. There was increased knowledge of Islamic bioethical views on the moral status of seeking healthcare, brain death controversies, and religious perspectives on withholding or withdrawing life support near the end of life. Our pilot intervention successfully increased participant knowledge and underscores the need to improve the Muslim community's knowledge about the bioethical dimensions of EOLHC.

Antigen-specific CD4+ T cells exhibit distinct transcriptional phenotypes in the lymph node and blood following vaccination in humans.

SARS-CoV-2 infection and mRNA vaccination induce robust CD4+ T cell responses that are critical for the development of protective immunity. Here, we evaluated spike-specific CD4+ T cells in the blood and draining lymph node (dLN) of human subjects following BNT162b2 mRNA vaccination using single-cell transcriptomics. We analyze multiple spike-specific CD4+ T cell clonotypes, including novel clonotypes we define here using Trex, a new deep learning-based reverse epitope mapping method integrating single-cell T cell receptor (TCR) sequencing and transcriptomics to predict antigen-specificity. Human dLN spike-specific T follicular helper cells (TFH) exhibited distinct phenotypes, including germinal center (GC)-TFH and IL-10+ TFH, that varied over time during the GC response. Paired TCR clonotype analysis revealed tissue-specific segregation of circulating and dLN clonotypes, despite numerous spike-specific clonotypes in each compartment. Analysis of a separate SARS-CoV-2 infection cohort revealed circulating spike-specific CD4+ T cell profiles distinct from those found following BNT162b2 vaccination. Our findings provide an atlas of human antigen-specific CD4+ T cell transcriptional phenotypes in the dLN and blood following vaccination or infection.

Costs and Health Care Utilization Analysis of Medical Group Visits for Adults With Type 2 Diabetes in Community Health Centers.

OBJECTIVE: We evaluated the economic impact of group visits (GVs) in adults with uncontrolled diabetes in community health centers (CHCs) in the United States. RESEARCH DESIGN AND METHODS: In this prospective controlled trial, we implemented 6 monthly GV sessions in 5 CHCs and compared intervention patients (n=49) to control patients (n=72) receiving usual care within the same CHCs. We conducted patient chart reviews to obtain health care utilization data for the prior 6 months at baseline, 6 months (during the GV implementation), and 12 months (after the implementation). We also collected monthly logs of CHC expenses and staff time spent on activities related to GVs. Per-patient total costs included CHCs' expenses and costs associated with staff time and patients' health care use. For group comparison, we used the Wilcoxon rank-sum test and the bootstrapping method that was to bootstrap generalized estimating equation models. RESULTS: The GV group had fewer 6-month hospitalizations (mean: GV: 0.06 vs. control: 0.24, rate: 6.1% vs. 19.4%) ( P ≤ 0.04) and similar emergency department visits at 12 months than the control group. Implementing GV incurred $1770 per-patient. The intervention cost $1597 more than the control at 6 months ($3021 vs. $1424) but saved $1855 at 12 months ($857 vs. $2712) ( P =0.002). CONCLUSIONS: The diabetes GV care model reduced hospitalizations and had cost savings at 12 months, while it improved patients' diabetes-related quality of life and glucose control. Future studies should assess its lifetime cost-effectiveness through a randomized controlled trial.

The Role of Family in Diabetes Management for Mexican American Adults.

Introduction: The purpose of this study was to characterize how family influences diabetes self-management in Mexican American adults. Methods: Data were analyzed from previously collected data that included 34 semi-structured interviews with Hispanic adults with diabetes and six focus groups with 37 adults with diabetes and family members. Themes related to family and diabetes management were identified and analyzed using a modified template approach. Results: Family-related facilitators to T2DM self-management were (1) provides support, (2) provides motivation, and (3) desire to protect family from diabetes. Family-related challenges were (1) lack of support, (2) family responsibilities, and (3) stress related to family. Diabetes education was shared with family members. Family member perspectives on T2DM included (1) not knowing how to help, (2) effect on emotional wellbeing, (3) diabetes affects the whole family, and (4) family provides support. Conclusion: Most participants with T2DM felt supported by family, but many desired more social support and support surrounding dietary changes from family. Many felt family did not understand what living with diabetes meant for them. Most family members wished to learn more about how to help. Future interventions should include family members and teach them supportive strategies to support beneficial diabetes self-management behaviors.

Distinct profiles of multisensory processing between professional goalkeepers and outfield football players.

In association football (soccer), the position of goalkeeper is the most specialised position in the sport and has the primary objective of stopping the opposing team from scoring. While previous studies have highlighted differences in physiological and match performance profiles between goalkeepers and outfield players1, surprisingly little research has focused on whether goalkeepers differ in terms of their perceptual-cognitive abilities. Given that goalkeepers use multiple sensory cues and are often required to make rapid decisions based on incomplete multisensory information to fulfil their role2, we hypothesised that professional goalkeepers would display enhanced multisensory temporal processing relative to their outfield counterparts. To test this hypothesis, we measured the temporal binding windows - the time window within which signals from the different senses are integrated into a single percept - of professional goalkeepers, professional outfield players, and a control group with no professional football experience using the sound-induced flash illusion3. Our results indicated a marked difference in multisensory processing between the three groups. Specifically, we found that the goalkeepers displayed a narrower temporal binding window relative to both outfielders and control participants, indicating more precise audiovisual timing estimation. However, this enhanced multisensory temporal processing was accompanied by a general reduction in crossmodal interactions relative to the other two groups that could be attributed to an a priori tendency to segregate sensory signals. We propose that these differences stem from the idiosyncratic nature of the goalkeeping position that puts a premium on the ability of goalkeepers to make quick decisions, often based on partial or incomplete sensory information.

Evaluating Effects of Virtual Diabetes Group Visits in Community Health Centers During the COVID-19 Pandemic.

Diabetes is the seventh leading cause of death in the US. Diabetes group visits (GVs), which include group education and individual medical visits have been shown to improve clinical outcomes. However, few studies have evaluated virtual GVs. We conducted a single-arm pilot study to test the impact of virtual diabetes GVs in Midwestern community health centers (CHCs). Adult patients with diabetes participated in monthly virtual GVs for 6 months. Surveys and chart abstraction were used to assess patient-reported and clinical outcomes. Five CHCs implemented virtual GVs with 34 patients attending at least one session. Virtual GVs show promise as evidenced by these findings: (1) Patients had a nonsignificant decrease in A1C. (2) In the subgroup of patients with baseline A1C ≥ 9%, there was a significant decrease in A1C. (3) Patients had significant increases in diabetes knowledge and support as well as a decrease in diabetes distress. Future studies with a larger sample size and a control comparison group are needed to assess the impact of virtual GVs on patient outcomes.

Comparative Toxicity of Seven Aqueous Film-Forming Foam to In Vitro Systems and Mus.

The comparative toxicity of six per- and polyfluoroalkyl substance (PFAS)-free and one PFAS-containing aqueous film-forming foam (AFFF) was evaluated in an outbred mouse species as well as several in vitro assays. The in vivo toxicological profile of PFAS-free AFFFs in short-term, high-concentration exposures is different than that of a PFAS-containing AFFF. The PFAS-containing reference product induced increased liver weights, while the PFAS-free AFFFs were linked to either decreased or unaffected relative liver weights. The in vitro toxicological profile across PFAS-free AFFFs was uniform except in the Microtox® assay, where thresholds were variable and spanned several orders of magnitude. This direct comparison of products through short-term toxicity tests and in vitro screenings represents early data to support evaluation of potential regrettable substitutions when selecting alternative PFAS-free AFFFs. Further work in diverse taxa (e.g., aquatic organisms, terrestrial invertebrates, birds) and mammalian studies capturing sensitive life stages will refine and expand this data set across a range of risk-relevant toxicological endpoints. Environ Toxicol Chem 2023;42:2364-2374. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

Reproductive and immune effects emerge at similar thresholds of PFHxS in deer mice.

Although perfluorohexane sulfonate (PFHxS) is structurally similar to perfluorooctane sulfonate (PFOS) and also widely detected in humans and the environment, comparatively fewer toxicity data exists on this 6-chain perfluoroalkyl sulfonic acid. In this study, repeated oral doses of PFHxS were administered to deer mice (Peromyscus maniculatus) to evaluate subchronic toxicity and potential effects on reproduction and development. Maternal oral exposure to PFHxS caused increased stillbirths, which is relevant for ecological risk assessment, and resulted in a benchmark dose lower limit (BMDL) of 5.72 mg/kg-d PFHxS. Decreased plaque formation, which is relevant for human health risk assessment, occurred in both sexes of adult animals (BMDL = 8.79 mg/kg-d PFHxS). These data are the first to suggest a direct link between PFHxS and decreased functional immunity in an animal model. Additionally, female animals exhibited increased liver:body weight and animals of both sexes exhibited decreased serum thyroxine (T4) levels. Notably, since reproductive effects were used to support 2016 draft health advisories and immune effects were used in 2022 drinking water health advisories released by the United States Environmental Protection Agency for PFOS and perfluorooctanoic acid (PFOA), these novel data can potentially support advisories for PFHxS because relevant points of departure emerge at similar thresholds in a wild mammal and corroborate the general understanding of per- and polyfluoroalkyl substances (PFAS).

Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. METHODS: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. FINDINGS: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. INTERPRETATION: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. FUNDING: National Health and Medical Research Council and National Cancer Institute.

Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare.

Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.