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Background: The University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) is a tool to assess the capacity of participants to consent in psychiatric research. However, little is known about the psychometric properties in low and middle-income countries. This study aimed to examine the psychometric properties of the UBACC. Methods: We examined the reliability, latent factor structure, and item response of the first attempt of the UBACC items in a sample of 32,208 adults (16,467 individuals with psychosis and 15,741 controls) in Ethiopia, Kenya, South Africa, and Uganda; exploring these properties in the full sample and stratified by country, diagnostic status, sex, and ethnolinguistic language groups. Results: Exploratory factor analysis (EFA) suggested a two-factor model for the overall sample. However, a three-factor model was more appropriate when examining the latent structure across country, language, and sex. Confirmatory factor analyses (CFA) revealed an adequately fitting three-factor model for the full sample and across country, sex, and language. A two-factor model, however, was more appropriate for English and Amharic languages. Across all groups, the internal consistency of the UBACC was low, indicating below-threshold reliability (Cronbach's α (95 % CI = 0.58 (0.57–0.59). Using a multidimensional item-response theory framework for the full sample revealed that UBACC item 8, measuring understanding of the benefits of study participation, was the most discriminating item. Many of the other items had below-threshold discriminating characteristics. Conclusion: EFA and CFA converged towards a two and three-dimensional structure for the UBACC, in line with the developers of the original scale. The differences in properties between populations and language groups, low internal consistency, and below-threshold item functioning suggest that investigations into the cultural and linguistic nuances are still warranted. Understanding the utility of consent tools, such as the UBACC, in underrepresented populations will be a part of the larger process which ensures that research participants are adequately protected.

Background: Inadequate pain control after lung transplantation increases perioperative complications. Standard opioid-based regimens are associated with adverse effects and epidural catheters that reduce opioid use are limited by contraindications and technical challenges. We report the use of intercostal nerve cryoablation to enhance perioperative pain control as part of an opioid-sparing protocol for lung transplant recipients (LTR). Methods: We conducted a retrospective cohort study of LTRs from January 1, 2016 to December 31, 2021, before (precryo) and after (postcryo) initiation of an opioid-sparing protocol utilizing intraoperative intercostal nerve cryoablation. The precryo cohort included consecutive patients treated with opioids and selective use of epidural catheters. The postcryo cohort received intercostal nerve cryoablation at levels 3 to 7, scheduled acetaminophen, gabapentin, and tramadol. Additional opioids or epidural catheters were used for breakthrough pain. Results: In total, 49 precryo and 40 postcryo patients were analyzed. Baseline demographics were similar aside from a shift to performing more bilateral lung transplants in the postcryo cohort (57% vs 95%, p

Background: Monovalent booster/additional doses of COVID-19 vaccines were first authorized in August 2021 in the United States. We evaluated the real-world effectiveness of receipt of a monovalent booster/additional dose of COVID-19 vaccine compared with receiving a primary vaccine series without a booster/additional dose. Methods: Cohorts of individuals receiving a COVID-19 booster/additional dose after receipt of a complete primary vaccine series were identified in 2 administrative insurance claims databases (Optum, CVS Health) supplemented with state immunization information system data between August 2021 and March 2022. Individuals with a complete primary series but without a booster/additional dose were one-to-one matched to boosted individuals on calendar date, geography, and clinical factors. COVID-19 diagnoses were identified in any medical setting, or specifically in hospitals/emergency departments (EDs). Propensity score-weighted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated with Cox proportional hazards models; vaccine effectiveness (VE) was estimated as 1 minus the HR by vaccine brand overall and within subgroups of variant-specific eras, immunocompromised status, and homologous/heterologous booster status. Results: Across both data sources, we identified 752,165 matched pairs for BNT162b2, 410,501 for mRNA-1273, and 11,398 for JNJ-7836735. For any medically diagnosed COVID-19, meta-analyzed VE estimates for BNT162b2, mRNA-1273, and JNJ-7836735, respectively, were: BNT162b2, 54% (95% CI, 53%-56%); mRNA-1273, 58% (95% CI, 56%-59%); JNJ-7836735, 34% (95% CI, 23%-44%). For hospital/ED-diagnosed COVID-19, VE estimates ranged from 70% to 76%. VE was generally lower during the Omicron era than the Delta era and for immunocompromised individuals. There was little difference observed by homologous or heterologous booster status. Conclusion: The original, monovalent booster/additional doses were reasonably effective in real-world use among the populations for which they were indicated during the study period. Additional studies may be informative in the future as new variants emerge and new vaccines become available.Registration: The study protocol was publicly posted on the BEST Initiative website (https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf).

Anemia is a common complication of chronic kidney disease (CKD) and is associated with increased mortality and reduced health-related quality of life. Anemia is characterized by a decrease in hemoglobin, the iron-rich protein that the body uses for oxygen transport. Iron is required to produce hemoglobin, and disruptions in the iron homeostasis can lead to iron-deficiency anemia. Management of anemia in individuals with CKD is typically performed by a team of physicians, nurse practitioners, physician assistants, or registered nurses. Throughout the care continuum, the management can be enhanced by multidisciplinary care, and individuals with CKD can benefit from the involvement of other specialties, with dietitians/nutritionists playing an important role. However, a key area of unmet clinical need is how to assess and address iron-deficiency anemia. This review aims to provide an overview of iron-deficiency anemia in CKD and how this may be diagnosed and managed by the entire kidney care team, such as describing the mechanisms underlying iron homeostasis, the complications of iron-deficiency anemia, and the current challenges associated with its diagnosis and treatment in CKD. Opportunities for each multidisciplinary team member to add value to the care of individuals with CKD and iron-deficiency anemia are also described.

Background: Pharmacy-provided influenza vaccination services have become more prevalent among the older adult population. However, little is known about the characteristics of older adults associated with receiving the influenza vaccination at retail pharmacies and how these associated characteristics have changed. Objective: To examine characteristics of older adults associated with use of retail pharmacy-provided influenza vaccination services and how the characteristics changed between 2009 and 2015. Methods: The study used a retrospective, cross-sectional design with data from the 2009 and 2015 Medicare Current Beneficiary Survey. Older adults aged 65 and older who completed a community questionnaire and received the influenza vaccination during the previous winter were identified. Andersen's Behavioral Model of Health Services Use was the conceptual framework for inclusion of the population characteristics. A multivariable log-binomial regression was performed to estimate the association between the population characteristics and use of pharmacy-provided vaccination service, and the relative change in associations between 2009 and 2015. Survey weights were applied in all analyses. Results: The results showed older adults who were non-Hispanic black (compared to non-Hispanic white), who did not have secondary private insurance (compared to those who had), who did not have physician office visit (compared to those who had) and who lived in non-metro area (compared to those who lived in metro area) had become more likely to use pharmacy-provided influenza vaccination services in 2015 than in 2009. Conclusions: Pharmacy-provided influenza vaccination services appear to reduce access barriers for racially and socioeconomically disadvantaged older adults. Findings could help inform not only the retail pharmacies that provide vaccination services to better outreach to potential target populations but also policy makers about the disadvantaged populations that would benefit from the vaccination services provided by retail pharmacies.

Introduction: Early stage lung cancer (LC) outcomes depend on the receipt of timely therapy. We aimed to determine the proportions of Veterans with stage I NSCLC in the age group eligible for LC screening (LCS) receiving timely curative treatment (≤12 wk after diagnosis), the factors associated with timely treatment and modality, and the factors associated with overall mortality. Methods: Retrospective cohort study in Veterans aged 55 to 80 years when diagnosed with stage I NSCLC during 2011 to 2015. We used multivariate logistic regression models to determine factors associated with receiving timely therapy and receiving surgery versus stereotactic body radiation therapy (SBRT). We used multivariate Cox proportional hazards regression analysis to determine factors associated with overall mortality. Results: We identified 4796 Veterans with stage I NSCLC; the cohort was predominantly older, White males, current or former smokers, and living in urban areas. Overall, 84% underwent surgery and 16% underwent SBRT. The median time to treatment was 63 days (61 d for surgery; 71 d for SBRT), with 30% treated more than 12 weeks. Unmarried Veterans with higher social deprivation index were less likely to receive timely therapy. Black race, female sex, and never smoking were associated with lower overall mortality. Older Veterans receiving treatment >12 wk, with higher comorbidity index, and squamous cell carcinoma had higher overall mortality. Conclusions: A total of 30% of the Veterans with stage I NSCLC in the age group eligible for LCS received curative treatment more than 12 weeks after diagnosis, which was associated with higher overall mortality. Delays in LC treatment could decrease the mortality benefits of LCS among the Veterans.

The coronavirus disease 2019 (COVID-19) pandemic has strained health care systems and personal protective equipment (PPE) supplies globally. We hypothesized that a collaborative robot system could perform health care worker effector tasks inside a simulated intensive care unit (ICU) patient room, which could theoretically reduce both PPE use and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposures. We planned a prospective proof-of-concept feasibility and design pilot study to test 5 discrete medical tasks in a simulated ICU room of a COVID-19 patient using a collaborative robot: push a button on intravenous pole machine when alert occurs for downstream occlusion, adjust ventilator knob, push button on ICU monitor to silence false alerts, increase oxygen flow on wall-mounted flow meter to allow the patient to walk to the bathroom and back (dial-up and dial-down oxygen flow), and push wall-mounted nurse call button. Feasibility was defined as task completion robotically. A training period of 45 minutes to 1 hour was needed to program the system de novo for each task. In less than 30 days, the team completed 5 simple effector task experiments robotically. Selected collaborative robotic effector tasks appear feasible in a simulated ICU room of the COVID-19 patient. Theoretically, this robotic approach could reduce PPE use and staff SARS-CoV-2 exposure. It requires future validation and health care worker learning similar to other ICU device training.

Arteriovenous fistulas are known to be one of the most enduring and safe hemodialysis access modalities. However, access preservation can be challenging in the setting of degeneration, including the development of complex pseudoaneurysms. Prolonged compression or thrombin injection can risk thrombosis of the fistula, and covered stent use can predispose the access to infection and other stent complications. We present a case in which endovascular balloon occlusion was used to facilitate the use of ultrasound-guided thrombin injection to resolve a dialysis access pseudoaneurysm by transiently reducing flow and preventing thromboembolism. This method is a safe, effective, and minimally invasive technique that should be considered for salvage of autogenous access compromised by pseudoaneurysm development.

Chimeric antigen receptor (CAR)-T cells show great promise in treating cancers and viral infections. However, most protocols developed to expand T cells require relatively long periods of time in culture, potentially leading to progression toward populations of terminally differentiated effector memory cells. Here, we describe in detail a 9-day protocol for CAR gene transduction and expansion of primary rhesus macaque peripheral blood mononuclear cells (PBMCs). Cells produced and expanded with this method show high levels of viability, high levels of co-expression of two transduced genes, retention of the central memory phenotype, and sufficient quantity for immunotherapeutic infusion of 1–2 × 108 cells/kg in a 10 kg rhesus macaque. This 9-day protocol may be broadly used for CAR-T cell and other T cell immunotherapy approaches to decrease culture time and increase maintenance of central memory populations. Keywords: CAR-T cells, transduction, expansion, retrovirus, PBMC, central memory, rhesus macaque

Introduction: There has been limited development and uptake of machine-learning methods to automate data extraction for literature-based assessments. Although advanced extraction approaches have been applied to some clinical research reviews, existing methods are not well suited for addressing toxicology or environmental health questions due to unique data needs to support reviews in these fields. Objectives: To develop and evaluate a flexible, web-based tool for semi-automated data extraction that: 1) makes data extraction predictions with user verification, 2) integrates token-level annotations, and 3) connects extracted entities to support hierarchical data extraction. Methods: Dextr was developed with Agile software methodology using a two-team approach. The development team outlined proposed features and coded the software. The advisory team guided developers and evaluated Dextr’s performance on precision, recall, and extraction time by comparing a manual extraction workflow to a semi-automated extraction workflow using a dataset of 51 environmental health animal studies. Results: The semi-automated workflow did not appear to affect precision rate (96.0% vs. 95.4% manual, p = 0.38), resulted in a small reduction in recall rate (91.8% vs. 97.0% manual, p

Summary: Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear. Using a Simon’s two-stage design, we present results of a single-arm phase-II trial where 12 patients with stage II-IVA OCSCC received 3 to 4 biweekly doses of 3 mg/kg nivolumab followed by definitive surgical resection with curative intent. Presurgical nivolumab therapy in this cohort shows an overall response rate of 33% (n = 4 patients; 95% CI: 12%–53%). With a median follow up of 2.23 years, 10 out of 12 treated patients remain alive. Neoadjuvant nivolumab is safe, well-tolerated, and is not associated with delays in definitive surgical treatment in this study. This work demonstrates feasibility and safety for incorporation of nivolumab in the neoadjuvant setting for OCSCC (ClinicalTrials.gov: NCT03021993).

Summary: We recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets.

Investigations evaluating the effectiveness of music-based interventions as a complementary approach to symptom management and health promotion for cognitively-impaired children with life-limiting conditions and their families are needed to minimize the physical and psychological burdens on individuals and their caregivers. Songwriting is one music-based strategy for a remote family-centered complementary approach to improve outcomes for cognitively-impaired children with life-limiting conditions, their parents, and families. The overall purpose of this study is to test the feasibility and preliminary efficacy of a songwriting intervention for cognitively-impaired children (ages 5–17 years) who are receiving palliative or complex care and their parents. Specific aims are to: (1) determine the feasibility of songwriting for cognitively-impaired children with life-limiting conditions and their parents, and (2) examine preliminary efficacy of songwriting for child psychological distress and physical symptoms, parent psychological distress, and family environment. The protocol for this 1-group pre-and post-intervention clinical trial (N = 25) is described.

Summary: The Everest region is characterized by its alpine glacial environment. In an effort to understand environmental change and tectonic activity, our team cored Taboche Lake, situated at 4,712 m along the western margin of the Ngozumpa Glacier. This research catalogs past earthquakes using geological records of the lake core that are important for the assessment of future earthquake hazards in the region and provides information for tectonic risk of glacial lake floods. Core grain size characteristics and internal sedimentary structures from computed tomographic scan were coupled with radiocarbon dating of organic matter preserved in the core to reconstruct the environmental history of the area. The 58-cm-long core consists of laminated silty sands and sandy silts with particle diameters

Weight bias internalization (WBI) is an understudied form of internalized stigma, particularly among treatment-seeking adults with overweight/obesity. The current study surveyed 13,996 adults currently engaged in weight management in the first multinational study of WBI. From May to July 2020, participants in six Western countries completed the Modified Weight Bias Internalization Scale (WBIS-M) and measures of weight change, health behaviors, psychosocial well-being, and health-related quality of life (HRQOL). Participants were majority white, female, middle-aged, and categorized as having overweight or obesity based on body mass index. Results showed higher mean WBIS-M scores among participants in the UK, Australia, and France than in Germany, the US, and Canada. Across all countries, and controlling for participant characteristics and experiences of weight stigma, WBIS-M scores were associated with greater weight gain in the past year. Participants with higher WBIS-M scores also reported poorer mental and physical HRQOL, less eating and physical activity self-efficacy, greater engagement in eating as a coping strategy, more avoidance of going to the gym, poorer body image, and greater perceived stress. Few interaction effects were found between experiences and internalization of weight stigma. Overall, the current findings support WBI as a robust correlate of adverse weight-related health indices across six Western countries. Prospective and experimental studies are needed to determine directionality and causality in the relationship between WBI and poor health outcomes.

Background: Animal studies suggest that organophosphorus pesticides (OPs) may be environmental obesogens. While prenatal OP exposures have been associated with altered infant glucose metabolism, associations with pediatric adiposity remain unknown. Methods: We summed concentrations of three dimethylphosphate (∑DMP) and three diethylphosphate (∑DEP) metabolites of OPs measured in third trimester spot urine samples collected from pregnant women enrolled in New York City, 1998–2002. We measured percent fat mass using bio-electrical impedance analysis and calculated age- and sex-standardized body mass index (BMI) z-scores from anthropometric measurements collected at approximately 4, 6, and 7–9 years of age (166 children, 333 observations). We assessed covariate-adjusted associations of OPs with repeated adiposity measures using linear mixed models and evaluated effect measure modification (EMM) by sex and paroxonase (PON) 1 –108C/T and Q192R polymorphisms measured in maternal peripheral blood samples. Results: The geometric mean urinary concentration of ∑DMP metabolites (29.9 nmol/L, IQR: 105.2 nmol/L) was higher than ∑DEP metabolites (8.8 nmol/L, IQR: 31.2 nmol/L). Adjusted associations were null, with differences in fat mass per 10-fold increase in prenatal ∑DMP and ∑DEP concentrations of 0.7% (95% CI: −0.6, 2.0) and 0.8% (95% CI: −0.4, 2.0), respectively. Maternal PON1-108C/T polymorphisms modified relationships of prenatal ∑DMP with percent fat mass (EMM p-value = 0.18) and ∑DEP with BMI z-scores (EMM p-value = 0.12). For example, ∑DMP was modestly associated with increased percent fat mass among children of mothers with the at-risk CT or TT genotype (β = 1.2%, 95% CI: −0.6, 3.0) but not among those whose mothers had the CC genotype (β = −0.4%, 95% CI: −2.4, 1.5). Associations were not modified by sex or maternal PON1 Q192R polymorphisms. Conclusions: We observed little evidence of a relationship between prenatal OP exposures and child adiposity, although there was some suggestion of increased risk among offspring of mothers who were slow OP metabolizers. Larger studies are warranted to further evaluate possible associations of prenatal OP exposures with child adiposity and differences by maternal PON1 genotype, which regulates OP metabolism and may increase susceptibility to exposure.

Introduction: Cross-sectional studies suggest that postnatal blood lead (PbB) concentrations are negatively associated with child growth. Few studies prospectively examined this association in populations with lower PbB concentrations. We investigated longitudinal associations of childhood PbB concentrations and subsequent anthropometric measurements in a multi-ethnic cohort of girls. Methods: Data were from The Breast Cancer and the Environment Research Program at three sites in the United States (U.S.): New York City, Cincinnati, and San Francisco Bay Area. Girls were enrolled at ages 6–8 years in 2004–2007. Girls with PbB concentrations collected at ≤10 years old (mean 7.8 years, standard deviation (SD) 0.82) and anthropometry collected at ≥3 follow-up visits were included (n = 683). The median PbB concentration was 0.99 μg/d (10th percentile = 0.59 μg/dL and 90th percentile = 2.00 μg/dL) and the geometric mean was 1.03 μg/dL (95% Confidence Interval (CI): 0.99, 1.06). For analyses, PbB concentrations were dichotomized as

Background: Environmental phenols, compounds used widely in personal care and consumer products, are known endocrine disruptors. Few epidemiologic studies have examined the association of phenol biomarkers with breast cancer incidence and, to our knowledge, none have considered associations with mortality following breast cancer. We examined seven urinary phenol biomarkers in association with breast cancer incidence and subsequent mortality, and examined effect measure modification by body mass index (BMI). Methods: Participants included 711 women with breast cancer and 598 women without breast cancer who were interviewed for the population-based Long Island Breast Cancer Study Project. Among women with breast cancer, phenol biomarkers were quantified in spot urine samples collected on average within three months of a first diagnosis of primary in situ or invasive breast cancer in 1996–1997. Women with breast cancer were monitored for vital status using the National Death Index. After a median follow-up of 17.6 years, we identified 271 deaths, including 98 deaths from breast cancer. We examined creatinine-corrected phenol concentrations and the sum of parabens (Σparabens) in association with breast cancer incidence using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), and with mortality using Cox regression to estimate hazard ratios (HRs) and 95% CIs. We evaluated multiplicative effect measure modification using cross-product terms in nested models. Results: The highest (vs lowest) quintiles of urinary methylparaben, propylparaben, and Σparabens were associated with risk of breast cancer with ORs ranging from 1.31 to 1.50. Methylparaben, propylparaben, and Σparabens were also associated with all-cause mortality HRs ranging from 0.68 to 0.77. Associations for breast cancer incidence were more pronounced among women with BMI

Granulomatous Orchitis secondary to lymphatic filiarisis is a rare diagnosis within the United States. We report a case of a 22yo Male from Sri Lanka, with a new onset scrotal swelling and palpable right testicular mass. Ultrasound identified a 1 cm right testicular mass with signs of tunica albuginea invasion. A right inguinal radical orchiectomy was performed and pathology showed Filarial orchitis. This report describes the detailed history, physical exam, and diagnostic workup and treatment options for a rare entity for acute scrotal pathology.

A 71-year-old woman with suspected endometrial cancer underwent robotic-assisted hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, and infracolic omentectomy revealing a stage II uterine carcinosarcoma with components of serous adenocarcinoma and undifferentiated spindle cell sarcoma. There was no evidence of distant metastasis at the time of surgery. However pelvic washings were positive for malignant cells. She received adjuvant chemotherapy and vaginal cuff brachytherapy. Forty months later she developed a subcutaneous mass at the location of previous port site which was confirmed to be recurrence of the uterine primary. She subsequently developed additional distant metastases to the abdominal wall, lungs, and bone. Port site metastasis (PSM) was the earliest indicator of disseminated metastatic disease in this patient. We review challenges in the management of patients with PSM and propose that PSM be considered as a sign of systemic disease even when presenting as an apparently isolated recurrence.

We hypothesize that occupational exposure to PCBs is associated with a reduction in central dopamine (DA) similar to changes previously seen in PCB exposed adult non-human primates. To test that hypothesis, we used [123I]β-CIT SPECT imaging to estimate basal ganglia DA transporter density in former capacitor workers. Women, but not men, showed an inverse relationship between lipid-adjusted total serum PCB concentrations and DA transporter densities in the absence of differences in serum PCB concentrations. These sex differences may reflect age-related reductions in the levels of gonadal hormones since these hormones have been shown experimentally to alter response to DA neurotoxicants. These findings may aid in better understanding the roles that sex and age play in modifying central DA function following exposure, not only to PCBs, but also to other DA neurotoxicants as well as further elucidating the role of gonadal hormones in influencing the initiation and/or progression of neurodegenerative disorders.

Tirapazamine (TPZ) [3-amino -1,2,4-benzotriazine 1,4-dioxide, SR4233, WIN 59075, and Tirazone™] is a novel anticancer drug that is selectively activated by the low oxygen environment in solid tumors. By killing the radioresistant hypoxic cells, TPZ potentiates the antitumor efficacy of fractionated irradiation of transplanted tumors in mice. As this cell kill is closely correlated with TPZ-induced DNA damage, we investigated whether human head and neck cancers would show DNA damage similar to that seen in mouse tumors following TPZ administration. TPZ-induced DNA damage in both transplanted tumors in mice and in neck nodes of 13 patients with head and neck cancer was assessed using the alkaline comet assay on cells obtained from fine-needle aspirates. The oxygen levels of the patients' tumors were also measured using a polarographic oxygen electrode. Cells from the patients' tumors showed DNA damage immediately following TPZ administration that was comparable to, or greater than, that seen with transplanted mouse tumors. The heterogeneity of DNA damage in the patients' tumors was greater than that of individual mouse tumors and correlated with tumor hypoxia. The similarity of TPZinduced DNA damage in human and rodent tumors suggests that tirapazamine should be effective when added to radiotherapy or to cisplatin-based chemotherapy in head and neck cancers.