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The inhibition of Cd accumulation by Ca in the amphipod Hyalella azteca in short-term (7-d) exposures appears to follow anti-competitive, rather than competitive, inhibition. Increasing Ca reduces Cd accumulation more at high than at low Cd concentrations. Cadmium accumulation and toxicity in chronic exposures can be predicted using the 7-d model to which the effects of acclimation, Cd inhibition of acclimation, and growth dilution are added. The resultant model is complex and species-specific, making it unwieldy for direct application in water quality guideline or criteria development. However, it does demonstrate that a mechanistic explanation of the relationship between short- and long-term accumulation and toxicity is possible, as well as suggest why the acute-to-chronic ratio changes with water chemistry. It is not, therefore, appropriate to estimate chronic Cd toxicity to H. azteca from acute toxicity assuming a constant acute-to-chronic ratio. The standard Biotic Ligand Model (BLM) can also be fit to the chronic bioaccumulation and toxicity data. This may be a more practical approach to guideline or criteria development, provided it is understood that this is an empirical fit of the model and that the underlying mechanisms are far more complex than those invoked in the standard BLM. [ABSTRACT FROM AUTHOR]

Adequate adherence to the 2018 diet and exercise recommendations of the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) can possibly result in less oxidative stress, lower risk to chemo- and radiotoxicity, lower risk of relapse, and increased quality of life in breast cancer survivors. This observational study aims to investigate the influence of adherence to updated recommendations of the WCRF/AICR on oxidative stress biomarkers in women with breast cancer undergoing adjuvant treatment (AT). We hypothesized that adherence to WCRF/AICR recommendations is inversely related to oxidative damage biomarkers and directly associated with antioxidant status. Women (n = 78) were evaluated before (T0) and after AT. After collecting anthropometric, physical activity, and food consumption data, a standardized score of adherence to WCRF/AICR recommendations was applied. The sample was divided into low-medium adherence and high adherence groups. Blood samples were collected at both timepoints for oxidative stress biomarkers analysis. Multiple linear regression analyzes were applied to verify associations between WCRF/AICR score and biomarkers. We found that low-medium adherence to WCRF/AICR recommendations at T0 affected lower levels of reduced glutathione (P= .003) and higher levels of lipid hydroperoxides (P= .002) and plasma carbonylated proteins (P= .001) after AT. The WCRF/AICR score at T0 was inversely associated with changes in plasma carbonylated protein concentrations after AT (adjusted β = -0.359; P= .01). Our findings suggest that high WCRF/AICR score before and during AT may provide greater stability of antioxidant capacity and protection against exacerbated oxidative stress., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Seasonal influenza affects 5% to 15% of Americans annually, resulting in preventable deaths and substantial economic impact. Influenza infection is particularly dangerous for people with cardiovascular disease, who therefore represent a priority group for vaccination campaigns., Objective: We aimed to assess the effects of digital intervention messaging on self-reported rates of seasonal influenza vaccination., Methods: This was a randomized, controlled, single-blind, and decentralized trial conducted at individual locations throughout the United States over the 2020-2021 influenza season. Adults with self-reported cardiovascular disease who were members of the Achievement mobile platform were randomized to receive or not receive a series of 6 patient-centered digital intervention messages promoting influenza vaccination. The primary end point was the between-group difference in self-reported vaccination rates at 6 months after randomization. Secondary outcomes included the levels of engagement with the messages and the relationship between vaccination rates and engagement with the messages. Subgroup analyses examined variation in intervention effects by race. Controlling for randomization group, we examined the impact of other predictors of vaccination status, including cardiovascular condition type, vaccine drivers or barriers, and vaccine knowledge., Results: Of the 49,138 randomized participants, responses on the primary end point were available for 11,237 (22.87%; 5575 in the intervention group and 5662 in the control group) participants. The vaccination rate was significantly higher in the intervention group (3418/5575, 61.31%) than the control group (3355/5662, 59.25%; relative risk 1.03, 95% CI 1.004-1.066; P=.03). Participants who were older, more educated, and White or Asian were more likely to report being vaccinated. The intervention was effective among White participants (P=.004) but not among people of color (P=.42). The vaccination rate was 13 percentage points higher among participants who completed all 6 intervention messages versus none, and at least 2 completed messages appeared to be needed for effectiveness. Participants who reported a diagnosis of COVID-19 were more likely to be vaccinated for influenza regardless of treatment assignment., Conclusions: This personalized, evidence-based digital intervention was effective in increasing vaccination rates in this population of high-risk people with cardiovascular disease., Trial Registration: ClinicalTrials.gov NCT04584645; https://clinicaltrials.gov/ct2/show/NCT04584645., (©Nell J Marshall, Jennifer L Lee, Jessica Schroeder, Wei-Nchih Lee, Jermyn See, Mohammad Madjid, Mrudula R Munagala, John D Piette, Litjen Tan, Orly Vardeny, Michael Greenberg, Jan Liska, Monica Mercer, Sandrine Samson. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 07.10.2022.)

Background: Improved postoperative care for renal transplant recipients has advanced both duration and overall quality of life. However, degenerative spinal pathology is increasingly prevalent after transplant. Outcomes following spinal fusion among the renal transplant population in the United States are rarely addressed., Methods: The Healthcare Cost and Utilization Project National Inpatient Sample database was employed. Cases in years 2008-2014 for patients ≥18 years old receiving spinal fusion, exploration/decompression, and/or spinal revision/re-fusion surgeries were included. Cases were divided into kidney transplant recipients (KTR) and non-kidney transplant recipients. Complications, demographics, and socioeconomic outcomes were compared between cohorts., Results: Of 579,726 patients who met inclusion criteria, 685 (0.1%) were KTRs. The KTR population was older and included more men compared with the non-kidney transplant recipient population (60.1 years vs. 56.6 years, P < 0.001; 58% male vs. 45.5% male, P < 0.001). KTRs experienced higher total complication rates (29.8% vs. 18.9%, P < 0.001). Prevalence of acute posthemorrhagic anemia and need for transfusion was markedly higher for KTRs (15.8% vs. 9.1%, P < 0.001; 13.6% vs. 6.2%, P < 0.001). Multivariate analysis revealed longer length of stay (median 1.23 days, interquartile range 0.94-1.53, P < 0.001), lower routine discharge (odds ratio = 0.57, 95% confidence interval 0.48-0.69, P < 0.001), and higher discharge to alternative care facilities (odds ratio = 1.91, 95% confidence interval 1.57-2.33, P < 0.001) for KTRs. The inpatient course for KTRs undergoing spinal operations was significantly costlier ($87,445 vs. $71,589, P < 0.001)., Conclusions: History of renal transplant was associated with increased inpatient medical and socioeconomic complications following spinal fusion. Physicians and patients must understand and respect the potentially increased perioperative challenges facing KTRs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

On December 20, 2017, the FDA granted regular approval to pertuzumab in combination with trastuzumab and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC) at high risk of recurrence. Approval was based on data from the APHINITY trial, which randomized patients to receive pertuzumab or placebo in combination with trastuzumab and chemotherapy. After 45.4-month median follow-up, the proportion of invasive disease-free survival (IDFS) events in the intent-to-treat population was 7.1% ( n = 171) in the pertuzumab arm and 8.7% ( n = 210) for placebo [hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.67-1.00; P = 0.047]. The proportion of IDFS events in patients with hormone receptor-negative disease was 8.2% ( n = 71) and 10.6% ( n = 91) in the pertuzumab and placebo arms, respectively (HR, 0.76; 95% CI, 0.56-1.04). The proportion of IDFS events for patients with node-positive disease was 9.2% ( n = 139) and 12.1% ( n = 181) in the pertuzumab and placebo arms, respectively (HR, 0.77; 95% CI, 0.62-0.96). Adverse reactions in ≥30% of patients receiving pertuzumab were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting. From a regulatory standpoint, the benefits of the addition of pertuzumab to adjuvant treatment outweighed the risks for patients with EBC at high risk of recurrence., (©2018 American Association for Cancer Research.)

The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). The primary endpoint, confirmed objective response rate, was 23.5% (95% confidence interval [CI]: 16.2%-32.2%) in patients receiving atezolizumab and 28.6% (95% CI: 24.1%-33.5%) in patients receiving pembrolizumab. The median duration of response was not reached in either study and responses were seen regardless of PD-L1 status. The safety profiles of both drugs were generally consistent with approved agents targeting PD-1/PD-L1. Two ongoing trials (IMvigor130 and KEYNOTE-361) are verifying benefit of these drugs. Based on concerning preliminary reports from these trials, FDA revised the indications for both agents in cisplatin-ineligible patients. Both drugs are now indicated for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors/infiltrating immune cells express a high level of PD-L1. The indications for atezolizumab and pembrolizumab in patients who have received prior platinum-based therapy have not been changed. This article summarizes the FDA thought process and data supporting the accelerated approval of both agents and the subsequent revision of the indications. IMPLICATIONS FOR PRACTICE: The accelerated approvals of atezolizumab and pembrolizumab for cisplatin-ineligible patients with advanced urothelial carcinoma represent the first approved therapies for this patient population. These approvals were based on single-arm trials demonstrating reasonable objective response rates and favorable durations of response with an acceptable toxicity profile compared with available non-cisplatin-containing chemotherapy regimens. However, based on concerning preliminary reports from two ongoing phase III trials, the FDA revised the indication for both agents in cisplatin-ineligible patients. Both are now indicated either for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors have high expression of PD-L1., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Persons with schizophrenia have a reduced life expectancy largely due to death from natural causes. Factors that have been previously associated with excess mortality include cigarette smoking and antipsychotic medication. The role of other environmental factors such as exposure to infectious agents has been the subject of only limited investigation. We prospectively assessed a cohort of persons with schizophrenia with a clinical evaluation and a blood sample from which antibodies to human herpes viruses and Toxoplasma gondii were measured. Mortality was determined with data from the National Death Index following a period of up to 11 years. We examined the role of demographic, serological, and clinical factors on mortality. A total of 25 (5%) of 517 persons died of natural causes. The standardized mortality ratio was 2.80 (95% CI 0.89, 6.38). After adjusting for age and gender, mortality from natural causes was predicted in separate models by cigarette smoking (relative risk [RR] = 4.66, P = .0029); lower cognitive score (RR = 0.96, P = .013); level of antibodies to Epstein-Barr virus (RR = 1.22, P = .0041) and to Herpes Simplex virus type 1 (RR = 1.19, P = .030); immunologic disease (RR = 3.14, P = .044); and genitourinary disease (RR = 2.70; P = .035). Because cigarette smoking confers an almost 5-fold risk of mortality, smoking cessation is an urgent priority. Having an elevated level of antibodies to Epstein-Barr virus and to Herpes Simplex virus type 1 are also significant predictors of death from natural causes., (© The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Providing an effective defense for individuals charged with capital crimes requires a diligent, thorough investigation by a mitigation specialist. However, research suggests that mitigation often plays a small role in the decision for life. Jurors often make sentencing decisions prematurely, basing those decisions on their personal reactions to the defendant (for example, fear, anger), their confusion about the rules of law, and their lack of understanding regarding their role and responsibilities. This article proposes an evidence-based conceptual model of the complicating problems surrounding mitigation practice and a focused discussion about how traditional social work mitigation strategies might be evolved to a set of best practices that more effectively ensure jurors' careful consideration of mitigation evidence.

Persistent human papillomavirus (HPV) infection seems central to cervical carcinogenesis. Smoking is associated with cervical cancer in HPV DNA-positive women, but its association with HPV persistence is unclear, particularly with respect to human immunodeficiency virus (HIV) serostatus. The authors evaluated smoking and HPV clearance by HIV serostatus among 801 women from the HIV Epidemiology Research Study (United States, 1993-2000). Type-specific HPV duration was defined as the interval between initial MY09/11 polymerase chain reaction positivity and the first of two consecutive HPV-negative study visits. Hazard ratios adjusted for study site and risk behaviors (sexual activity or injection drug use) were estimated using Cox regression. This analysis included 522 HIV-seropositive and 279 HIV-seronegative women (median follow-up, 4.4 years). Ever smoking was associated with reduced clearance of high-risk HPV in HIV-seronegative women (hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.30, 0.88) but not in HIV-seropositive women (HR = 0.96, 95% CI: 0.65, 1.42); similar results were found for current smoking. Current smoking was not associated with clearance of any type-specific HPV in HIV-seropositive (HR = 0.99, 95% CI: 0.82, 1.20) or HIV-seronegative (HR = 0.93, 95% CI: 0.68, 1.26) women. HPV clearance did not appear to vary by amount or duration of smoking. Smoking did not modify overall clearance but was associated with lower high-risk HPV clearance in HIV-seronegative women.

The U.S. government recently implemented rules for awarding compensation to individuals with cancer who were exposed to ionizing radiation while working in the nuclear weapons complex. Under these rules, chronic lymphocytic leukemia (CLL) is considered to be a nonradiogenic form of cancer. In other words, workers who develop CLL automatically have their compensation claim rejected because the compensation rules hold that the risk of radiation-induced CLL is zero. In this article we review molecular, clinical, and epidemiologic evidence regarding the radiogenicity of CLL. We note that current understanding of radiation-induced tumorigenesis and the etiology of lymphatic neoplasia provides a strong mechanistic basis for expecting that ionizing radiation exposure increases CLL risk. The clinical characteristics of CLL, including prolonged latency and morbidity periods and a low case fatality rate, make it relatively difficult to evaluate associations between ionizing radiation and CLL risk via epidemiologic methods. The epidemiologic evidence of association between external exposure to ionizing radiation and CLL is weak. However, epidemiologic findings are consistent with a hypothesis of elevated CLL mortality risk after a latency and morbidity period that spans several decades. Our findings in this review suggest that there is not a persuasive basis for the conclusion that CLL is a nonradiogenic form of cancer.

New collaboratory opportunities in ultrastructural research and diagnostics are now available on the Internet through the combination of digital image acquisition, remote operation of modern digitally controlled and automated electron microscopes, and the development of software specifically tailored for collaboratory needs. Remote experts can examine samples directly, and unique instruments can be utilized from anywhere. In the case of diagnostic dilemmas, the second-opinion expert is no longer constrained by problems inherent in the interpretation of preselected images. The remote examiner can independently choose the area of interest on the sample as well as select the appropriate magnification for an accurate diagnosis. With these capabilities and together with teleconferencing tools and securely accessible databases on-line, telepathology can provide increased effectiveness and support for diagnostics, research, and teaching in many areas. The authors report their experience with remote electron microscope diagnoses of pathological samples using two different dynamic imaging systems and discuss the main technical issues encountered. It appears that only minor technical issues need to be resolved before ultrastructural telepathology can be promoted for routine use in areas with high-speed Internet access.

A recent study of hereditary prostate cancer has provided evidence for a prostate cancer-susceptibility locus, HPC20, which maps to 20q13. To assess further the potential contribution of this locus to prostate cancer susceptibility, we studied 172 unrelated families affected by prostate cancer, using 17 polymorphic markers across a 98.5-cM segment of chromosome 20 that contains the candidate region. Parametric analysis, allowing for heterogeneity, resulted in an overall HLOD score of 0.09 (P=.39) at D20S171, under the assumption of linkage in 6% of families. Mode-of-inheritance-free analysis of the entire data set resulted in a maximal Zlr score of 0.76 (LOD 0.13; P=.22) at the same location. The strongest evidence for linkage was seen in the subset of 16 black families (LOD 0.86; Zlr=1.99; P=.023) between markers D20S893 and D20S120, near the putative location of HPC20. Although some positive results were observed, our linkage study does not provide statistically significant support for the existence of a prostate cancer-susceptibility locus HPC20 at 20q13.

Associations between occupational magnetic field exposure and non-Hodgkin's lymphoma (NHL), Hodgkin's disease, and multiple myeloma mortality were evaluated in 138,905 electrical utility workers. A job-exposure matrix based on measured magnetic fields was used to derive individual exposure estimates. There was a small positive association between all NHL and low-grade NHL and duration of employment in any magnetic field-exposed job, but only up to 20 years. Cumulative magnetic field exposure was associated with a rising, then falling, risk of NHL. Rate ratios for intermediate/high-grade lymphoma were increased for the highest levels of lifetime cumulative exposure (RR = 3.7 and RR = 2.3), and were most pronounced for those exposures occurring 10-20 years previously. Hodgkin's disease and multiple myeloma mortality did not appear to be associated with exposure. Associations were stronger for NHL subgroups, suggesting that further analysis by subgroup may be warranted, but the absence of dose-response gradients diminishes the likelihood that associations represent causal relationships.

We determined the pattern of mutations in exons 2-11 and adjacent intronic regions in breast cancers from Midwestern US white women. Twenty-one mutations were detected in 53 tumors (39.6%). Comparisons of the pattern of mutations within exons 5-9 showed that the frequency of missense mutations (44%) was lower in breast cancers of US Midwestern women than in most tumor types including breast cancers in other populations. Compared to breast cancers reported in a Scottish population, US women had a high frequency of G:C-->T:A transversions (P = 0.046). These findings suggest that environmental or endogenous factors contribute to p53 mutagenesis in mammary tissue to different extents among different populations. With a median follow-up of 19 months, the presence of a mutation was associated with shorter time to disease recurrence (P = 0.05) and shorter survival (P = 0.003). Putative dominant negative missense-type mutations (missense and in-frame microdeletions; P = 0.001) and null mutations (hemizygous nonsense and frameshift mutations; P = 0.007) were equally ominous. Thus, tumors with missense p53 mutations resulting in over-expression of a dysfunctional but otherwise intact protein have a clinical outcome similar to tumors with null mutations resulting in a truncated or garbled protein.

Background: Mutation in the p53 gene is the most common genetic lesion in human cancers. The pattern of mutation in the p53 gene differs among cancers and may be a useful epidemiological tool for identification of factors contributing to carcinogenesis., Purpose: Our purpose was to determine if the pattern of p53 mutation in breast carcinomas in our population of women residing in the midwestern region of the United States is similar to the pattern of p53 mutation in breast cancers in patients from other regions of the United States and Europe and in other epithelial tumors., Methods: With a technique we recently developed for the analysis of p53 mutations in genomic DNA from tumor cell clusters in touch preparations of solid tumors, we sequenced exons 5-9 and adjacent splice junctions of the gene in 44 breast cancers. Cells from each tumor were also stained with three monoclonal antibodies which recognize different epitopes of the p53 protein., Results: We detected p53 mutations in 14 (32.6%) of 44 breast carcinomas. Only half of the mutations were missense changes. The other half included five microdeletions (three producing frame-shifts), one single-base substitution generating a stop codon, and one single-base substitution generating a splice junction abnormality. Nuclear expression of p53 antigen was present in eight of 44 cancers, including six with hemizygous missense mutations in the p53 gene., Conclusions: The pattern of p53 mutations in our breast cancer population differs from that reported in breast cancer populations by other investigators in which most p53 mutations were missense. Among 14 mutations in our population, at least five drastically altered the structure of p53, suggesting that a recessive mechanism of inactivation of the p53 gene may be more common than in other populations., Implications: Differences in the pattern of p53 mutation in breast cancers in Midwestern women and in breast cancers in other populations may reflect selection bias or small sample sizes currently available. However, our data are compatible with the possibility that an endogenous or exogenous factor influences p53 carcinogenesis in some women with breast cancer in the Midwest to a greater extent than in other regions of the United States and Europe.