Atrial septal interventions during and after hybrid stage I palliation of hypoplastic left heart syndrome.

BACKGROUND: Hybrid stage I palliation (HS1P) is an alternative approach for initial palliation in hypoplastic left heart syndrome (HLHS) patients. Unlike surgical stage I palliation where atrial septectomy is routinely performed, atrial septal intervention (ASI) during HS1P is variable. In this study, we described our experience with ASI in single ventricle (SV) patients who underwent HS1P and identified factors associated with need for ASI after HS1P. METHODS: Data were retrospectively collected for all HLHS patients who underwent HS1P at our center over the past 12 years. We evaluated ASIs performed during the HS1P (intra-HS1P ASI) and ASIs performed during the period from HS1P to the subsequent surgical stage, either interval Norwood stage I or comprehensive stage II (post-HS1P ASI). Patient factors and procedural data were compared to identify factors associated with undergoing post-HS1P ASI and the impact of ASI on patient outcomes was evaluated. RESULTS: Of 50 SV patients included, 23 (46%) underwent intra-HS1P ASI and 26 (52%) underwent post-HS1P ASI. Need for post-HS1P ASI was lower among patients who had an intra-HS1P ASI as compared to those who did not (30% vs. 70%; p = 0.005). There were no significant differences in short or Midterm outcomes between patients who underwent intra-HS1P ASI or post-HS1P ASI and their counterparts. CONCLUSIONS: ASI is common both during and after HS1P but is generally well tolerated and type of ASI does not significantly impact overall patient outcomes. Our findings suggest that the current approach of individualizing management of ASI in the HS1P population is effective and safe.

Community Partnership to Co-Develop an Intervention to Promote Equitable Uptake of the COVID-19 Vaccine Among Pediatric Populations.

Objective: To describe the process of engaging community, caregiver, and youth partners in codeveloping an intervention to promote equitable uptake of the COVID-19 vaccine in non-Hispanic Black (Black) and Hispanic youth who experience higher rates of COVID-19 transmission, morbidity, and mortality but were less likely to receive the COVID-19 vaccine. Methods: A team of 11 Black and Hispanic community partners was assembled to codevelop intervention strategies with our interdisciplinary research team. We used a mixed-methods crowdsourcing approach with Black and Hispanic youth (n=15) and caregivers of Black and Hispanic youth (n=20) who had not yet been vaccinated against COVID-19, recruited from primary care clinics, to elicit perspectives on the acceptability of these intervention strategies. Results: We codeveloped five strategies: (1) community-tailored handouts and posters, (2) videos featuring local youth, (3) family-centered language to offer vaccines in the primary care clinic, (4) communication-skills training for primary care providers, and (5) use of community health workers to counsel families about the vaccine. The majority (56-96.9%) of youth and caregivers rated each of these strategies as acceptable, especially because they addressed common concerns and facilitated shared decision-making. Conclusions: Engaging community and family partners led to the co-development of culturally- and locally-tailored strategies to promote dialogue and shared decision-making about the COVID-19 vaccine. This process can be used to codevelop interventions to address other forms of public health disparities. Policy Implications: Intervention strategies that promote dialogues with trusted healthcare providers and support shared decision-making are acceptable strategies to promote COVID-19 vaccine uptake among youth from historically underserved communities. Stakeholder-engaged methods may also help in the development of interventions to address other forms of health disparities.

Sinus venosus atrial septal defect presenting with platypnea-orthodeoxia syndrome in the setting of COVID-19 infection.

Platypnea-orthodeoxia syndrome is characterised by hypoxemia and dyspnoea while upright that resolves when supine, typically associated with an interatrial communication. We present a case of platypnea-orthodeoxia syndrome associated with a sinus venosus atrial septal defect in a patient with multiple possible aetiologies of hypoxemia, including COVID-19 infection. Cardiac catheterisation with provocative maneuvers confirmed the diagnosis and symptoms resolved following defect closure. We suggest that in patients with platypnea-orthodeoxia syndrome, it is useful to obtain haemodynamic data while supine and upright.

Imaging update on gallbladder adenomyomatosis and its mimics.

Radiologists across many imaging modalities commonly encounter gallbladder adenomyomatosis. The classic imaging appearances of gallbladder adenomyomatosis are well described and confirm benignity. However, in clinical practice, adenomyomatosis can be challenging to differentiate from other gallbladder pathologies that require cholecystectomy. In this article, we describe the common and uncommon appearances of gallbladder adenomyomatosis on multimodality imaging, helping differentiate adenomyomatosis from non-benign gallbladder abnormalities. Accurately differentiating adenomyomatosis from its mimics provides the surgical team with important clinical and surgical management information, improving patient outcomes.

The Sympathetic Nervous System Promotes Hepatic Lymphangiogenesis, which Is Protective Against Liver Fibrosis.

Liver is the largest lymph-producing organ. In cirrhotic patients, lymph production significantly increases concomitant with lymphangiogenesis. The aim of this study was to determine the mechanism of lymphangiogenesis in liver and its implication in liver fibrosis. Liver biopsies from portal hypertensive patients with portal-sinusoidal vascular disease (n = 22) and liver cirrhosis (n = 5) were evaluated for lymphangiogenesis and compared with controls (n = 9 and n = 6, respectively). For mechanistic studies, rats with partial portal vein ligation (PPVL) and bile duct ligation (BDL) were used. A gene profile data set (GSE77627), including 14 histologically normal liver, 18 idiopathic noncirrhotic portal hypertension, and 22 cirrhotic patients, was analyzed. Lymphangiogenesis was significantly increased in livers from patients with portal-sinusoidal vascular disease, cirrhotic patients, as well as PPVL and BDL rats. Importantly, Schwann cells of sympathetic nerves highly expressed vascular endothelial growth factor-C in PPVL rats. Vascular endothelial growth factor-C neutralizing antibody or sympathetic denervation significantly decreased lymphangiogenesis in livers of PPVL and BDL rats, which resulted in progression of liver fibrosis. Liver specimens from cirrhotic patients showed a positive correlation between sympathetic nerve/Schwann cell-positive areas and lymphatic vessel numbers, which was supported by gene set analysis from patients with noncirrhotic portal hypertension and cirrhotic patients. Sympathetic nerves promote hepatic lymphangiogenesis in noncirrhotic and cirrhotic livers. Increased hepatic lymphangiogenesis can be protective against liver fibrosis.

Augmented Reality Visualization of 3D Rotational Angiography in Congenital Heart Disease: A Comparative Study to Standard Computer Visualization.

Augmented reality (AR) visualization of 3D rotational angiography (3DRA) provides 3D representations of cardiac structures with full visualization of the procedural environment. The purpose of this study was to evaluate the feasibility of converting 3DRAs of congenital heart disease patients to AR models, highlight the workflow for 3DRA optimization for AR visualization, and assess physicians' perceptions of their use. This single-center study prospectively evaluated 30 retrospectively-acquired 3DRAs that were converted to AR, compared to Computer Models (CM). Median patient age 6.5 years (0.24-38.8) and weight 20.6 kg (3.4-107.0). AR and CM quality were graded highly. RV pacing was associated with higher quality of both model types (p = 0.02). Visualization and identification of structures were graded as "very easy" in 81.1% (n = 73) and 67.8% (n = 61) of AR and CM, respectively. Fifty-nine (66%) grades 'Agreed' or 'Strongly Agreed' that AR models provided superior appreciation of 3D relationships; AR was found to be least beneficial in visualization of aortic arch obstruction. AR models were thought to be helpful in identifying pathology and assisting in interventional planning in 85 assessments (94.4%). There was significant potential seen in the opportunity for patient/family counseling and trainee/staff education with AR models. It is feasible to convert 3D models of 3DRAs into AR models, which are of similar image quality as compared to CM. AR models provided additional benefits to visualization of 3D relationships in most anatomies. Future directions include integration of interventional simulation, peri-procedural counseling of patients and families, and education of trainees and staff with AR models.

Telehealth and Type 1 Diabetes Care During COVID-19: Perceptions From Youth of Color, Caregivers, and Health Care Providers.

Objective: At the outset of the coronavirus disease 2019 (COVID-19) pandemic, health care systems rapidly implemented telehealth services to maintain continuity of type 1 diabetes care. Youth of color are more likely to have suboptimal glycemic control and may benefit most from efforts to ensure continuity of care. However, research examining the perspectives of families of youth of color regarding telehealth for pediatric type 1 diabetes care is limited. We gathered perspectives from youth of color, their caregivers, and health care providers (HCPs) on telehealth for type 1 diabetes care during COVID-19. Methods: Fifty participants (22 caregivers, 19 youth, and nine HCPs) completed semi-structured interviews conducted in English (n = 44) or Spanish (n = 6). Transcripts containing mentions of telehealth (n = 33) were included for qualitative analysis to extract themes pertaining to perceptions of type 1 diabetes care and telehealth use during COVID-19. Results: Themes related to perceptions, feasibility, and quality of telehealth diabetes care were obtained. Most families had positive perceptions of telehealth. Families and HCPs described logistical and technical challenges and noted the potential for disparities in telehealth access and use. Furthermore, caregivers and HCPs felt that the lack of in-person interaction and limited access to clinical data affected the quality of care. Conclusion: Families of youth of color with type 1 diabetes mostly had positive perceptions of telehealth but also identified issues with feasibility and quality of care. Our findings highlight a need for interventions promoting equal access to telehealth and quality care for all youth with type 1 diabetes to minimize disruptions in care.

Long-term monitoring and modeling of PAHs in capped sediments at the Grand Calumet River.

The assessment of a cap for remediation of sediments requires long-term monitoring because of the slow migration of contaminants in porous media. In this study, coring and passive sampling tools were used to assess the transport and degradation of polycyclic aromatic hydrocarbons (PAHs) in an amended cap (sand + Organoclay® PM-199) in the Grand Calumet River (Indiana, USA) during four sampling events from 2012 to 2019. Measurements of three PAHs (phenanthrene (Phe), pyrene (Pyr) and benzo[a]pyrene (BaP), representing low, medium, and high molecular weight compounds, respectively) showed a difference of at least two orders of magnitude between bulk concentrations in the native sediments and the remediation cap. Averages of pore water measurements also showed lower levels in the cap respective to the native sediments by a factor of at least 7 for Phe and 3 for Pyr. In addition, between the baseline (BL), which corresponds to observations from 2012 to 2014, and the measurements in 2019, there was a decrease in depth-averaged pore water concentrations of Phe (C2019/CBL=0.20-0.07+0.12 in sediments and 0.27-0.10+0.15 in cap) and Pyr (C2019/CBL=0.47-0.12+0.16 in sediments and 0.71-0.20+0.28 in the cap). In the case of BaP in pore water, no change was observed in native sediments (C2019/CBL=1.0-0.24+0.32) and there was an increase in the cap (C2019/CBL=2.0-0.54+0.72). Inorganic anions and estimates of pore water velocity along with measurements of PAHs were used to model the fate and transport of contaminants. The modeling suggested that degradation of Phe (t1/2=1.12-0.11+0.16 years) and Pyr (t1/2=5.34-1.8+5.3 years) in the cap is faster than migration, thus the cap is expected to be protective of the sediment-water interface indefinitely for these constituents. No degradation was noted in BaP and the contaminant is expected to reach equilibrium in the capping layer over approximately 100 years if there exists sufficient mass of BaP in the sediments and there is no deposition of clean sediment at the surface.

Timing of Balloon Atrial Septostomy in Patients with d-TGA and Association with Birth Location and Patient Outcomes.

Patients with d-looped transposition of the great arteries (d-TGA), especially those without an adequate atrial septal defect, can experience severe hypoxemia and hemodynamic compromise in the neonatal period. This can be mitigated by urgent balloon atrial septostomy (BAS). However, some patients with d-TGA are born at centers without this capability. The aim of this retrospective study of d-TGA patients who had urgent or emergent BAS at our institution between 2010 and 2021 was to evaluate time from birth to BAS for infants born at a tertiary care center as compared to those requiring transport from other institutions and to examine correlation between time to BAS and patient outcomes. Our primary outcome was time from birth to BAS. Secondary outcomes included hospital and ICU length of stay, mortality, and evidence of pulmonary or neurologic abnormalities including pulmonary hypertension, abnormal neuroimaging, or seizures. Of 96 patients, 67 (70%) were born at our institution. The median time to BAS was 4 h for patients born at our institution vs. 14.1 h for those born elsewhere (p < .0001). A longer time from birth to BAS was associated with longer ICU (r = 0.21, p = 0.046) and hospital length of stay (r = 0.24, p = 0.02) and increased likelihood of elevated right ventricular pressure on post-operative discharge echocardiogram (p = 0.01). There were no differences in mortality between the groups. Therefore, prenatal planning for patients with known d-TGA should include a delivery plan with access to urgent BAS.

Acceptability and Feasibility of eSCCIP: Results From a Pilot Study of the Electronic Surviving Cancer Competently Intervention Program.

BACKGROUND: Providing high-quality psychosocial care to parents and other primary caregivers of children with cancer (henceforth referred to as caregivers) is important, given the numerous challenges associated with a pediatric cancer diagnosis and the increased risk for negative psychosocial sequelae among caregivers. The Electronic Surviving Cancer Competently Intervention Program (eSCCIP) is a psychosocial eHealth intervention for caregivers, developed using an iterative, user-centered process. METHOD: eSCCIP was tested in a single-arm pilot trial at Nemours Children's Hospital, Delaware (NCT05333601). The primary outcomes were intervention acceptability and feasibility, assessed via enrollment and retention targets, and item-level acceptability ratings. Enrollment and retention targets of 45% were set based on previous work, and an item-level acceptability threshold of 80% was set. A secondary exploratory analysis was conducted examining acute distress, anxiety, symptoms of post-traumatic stress, and family functioning. RESULTS: 44 caregivers enrolled in the study and 31 completed. The intervention was rated favorably by completers, with over 80% of the sample selecting "mostly true" or "very true" for all items of the eSCCIP Evaluation Questionnaire, which was used to assess acceptability and feasibility. Enrollment and retention rates were 54% and 70%, respectively. Exploratory psychosocial outcomes showed statistically significant decreases from pre-intervention to post-intervention for overall symptoms of post-traumatic stress disorder (PTSD), cluster D symptoms of PTSD (negative mood and cognitions), and anxiety. Small-moderate effect sizes were observed for all psychosocial outcomes of interest. CONCLUSIONS: eSCCIP is an acceptable and feasible intervention for caregivers. Results are promising regarding reductions in symptoms of post-traumatic stress and anxiety.

Understanding disparities in post-operative mortality for Indigenous patients.

There is an urgent need for high-quality evidence regarding post-operative mortality among Indigenous peoples. Our group recently published a national audit of 4,000,000 procedures conducted between 2005-2017, which identified considerable disparities in post-operative mortality between Indigenous Maori and non-Indigenous New Zealanders. Understanding the primary drivers of these disparities-for Maori, but likely also other Indigenous populations worldwide-requires us to consider the multiple levels at which these drivers might arise. To that end, in this paper we breakdown these drivers in detail, conceptualising these drivers as operating in layers with each factor leading to the next. These layers include structural factors, care system factors, care process factors, care team factors and patient factors. Each of these factors are presented within a framework that can be used to begin to understand them - with a view to rousing action and inspiring intervention to address inequities in post-operative outcomes experienced by Indigenous peoples.

Spectroscopic studies of 7,8-diacetoxy-4-methylcoumarin and 7,8-dipentynoyl-4-methylcoumarin binding with calreticulin.

Calreticulin (CRT) is a protein found mainly in the endoplasmic reticulum (ER) that maintains calcium levels and controls protein folding, but has recently been found at the cell surface, cytoplasm, and in the extracellular matrix. CRT participates in multiple physiological processes such as gene expression, the immune response, and cancer. Calreticulin has been shown to autoacetylate with the binding of preferred ligand 7,8-diacetoxy-4-methylcoumarin (DAMC). This project aims to develop a chemical biology approach to investigate importance of CRT acylating abilities on its nonendoplasmic reticulum functions by targeting the downstream substrates of CRT acetylation. Our goal was to use CRT to transfer a pentynoyl tag (using a novel ligand, DPeMC) to its substrates, which can then be used as a handle for protein identification. Molecular modelling using available data in the literature was used to approximate the binding interface between CRT and the acylation ligands. Molecular Operating Environment (MOE) software was used to perform sequence alignment, simulated annealing, positional refinement, and blind docking of acylated coumarins with the CRT model. Docking studies pointed to the P domain as the most thermodynamically and sterically favourable region for acylated coumarin binding with tryptophan residue 200 within the active site on CRT. Absorption and fluorescence spectra of all coumarin compounds in ethanol:PBS (1:9 v/v) solution were investigated. Stern-Volmer quenching constant (KSV ), binding constant (K), and number of binding sites (n) of each coumarin compound with CRT was determined. Our studies demonstrated that acyl coumarin compounds bind to CRT using a dynamic quenching mechanism, bind to a single binding site on the P domain, and that the protein-ligand interaction is spontaneous and exothermic.

Factors shaping the abundance and diversity of the gut archaeome across the animal kingdom.

Archaea are common constituents of the gut microbiome of humans, ruminants, and termites but little is known about their diversity and abundance in other animals. Here, we analyse sequencing and quantification data of archaeal and bacterial 16S rRNA genes from 250 species of animals covering a large taxonomic spectrum. We detect the presence of archaea in 175 animal species belonging to invertebrates, fish, amphibians, birds, reptiles and mammals. We identify five dominant gut lineages, corresponding to Methanobrevibacter, Methanosphaera, Methanocorpusculum, Methanimicrococcus and "Ca. Methanomethylophilaceae". Some archaeal clades, notably within Methanobrevibacter, are associated to certain hosts, suggesting specific adaptations. The non-methanogenic lineage Nitrososphaeraceae (Thaumarchaeota) is frequently present in animal samples, although at low abundance, but may have also adapted to the gut environment. Host phylogeny, diet type, fibre content, and intestinal tract physiology are major drivers of the diversity and abundance of the archaeome in mammals. The overall abundance of archaea is more influenced by these factors than that of bacteria. Methanogens reducing methyl-compounds with H2 can represent an important fraction of the overall methanogens in many animals. Together with CO2-reducing methanogens, they are influenced by diet and composition of gut bacteria. Our results provide key elements toward our understanding of the ecology of archaea in the gut, an emerging and important field of investigation.

Perceptions of support in shelter environments for caregivers and young children experiencing family homelessness.

BACKGROUND: Young children who stay with their families in homeless shelters face chronic challenges related to extreme poverty and acute risks from stressful events surrounding the loss of housing and move to shelter. These adversities increase the likelihood of a range of poor developmental outcomes. Consistent with the risk and resilience perspective, however, many children who experience family homelessness succeed, functioning as well or better than their non-homeless peers. As such, efforts to support resilience should consider how best to enhance protective factors, such as supportive environments within shelter settings. METHODS: With data from 60 caregivers of children ages birth to 5 years recruited from family shelters, we assessed caregivers' perceptions of community support as well as child and family well-being in terms of recent adverse experiences, parenting stress, access to social support, and child social-emotional functioning. RESULTS: Many caregivers experiencing family homelessness perceived negative aspects of the shelters where they were staying with their children. Furthermore, children whose caregivers had more negative perceptions of the shelter environment displayed worse social-emotional functioning, even when accounting for differences in parenting stress, recent family adversity, and other sources of social support. CONCLUSIONS: Because young children rely on their caregivers as primary resources for nurturance and support, we encourage family homelessness service providers to work in partnership with caregivers to create more inclusive and empowering practices within the shelter context. Doing so is likely to improve children's developmental outcomes and the overall well-being of the families.

Non-enzymatic glycoxidation linked with nutrition enhances the tumorigenic capacity of prostate cancer epithelia through AGE mediated activation of RAGE in cancer associated fibroblasts.

The molecular implications of food consumption on cancer etiology are poorly defined. The rate of nutrition associated non-enzymatic glycoxidation, a reaction that occurs between reactive carbonyl groups on linear sugars and nucleophilic amino, lysyl and arginyl groups on fats and proteins, is rapidly increased by food cooking and manufacturing processes. In this study, we assign nutrition-associated glycoxidation with significant oncogenic potential, promoting prostate tumor growth, progression, and metastasis in vivo. Advanced glycation end products (AGEs) are the final irreversible product of non-enzymatic glycoxidation. Exogenous treatment of prostate tumor cells with a single AGE peptide replicated glycoxidation induced tumor growth in vivo. Mechanistically, receptor for AGE (RAGE) deficiency in the stroma inhibited AGE mediated tumor growth. Functionally, AGE treatment induced RAGE dimerization in activated fibroblasts which sustained and increased the migratory potential of tumor epithelial cells. These data identify a novel nutrition associated pathway that can promote a tissue microenvironment conducive for aggressive tumor growth. Targeted and/or interventional strategies aimed at reducing AGE bioavailability as a consequence of nutrition may be viewed as novel chemoprevention initiatives.

Contemporary Approaches to the Discovery and Development of Broad-Spectrum Natural Product Prototypes for the Control of Coronaviruses.

The pressing need for SARS-CoV-2 controls has led to a reassessment of strategies to identify and develop natural product inhibitors of zoonotic, highly virulent, and rapidly emerging viruses. This review article addresses how contemporary approaches involving computational chemistry, natural product (NP) and protein databases, and mass spectrometry (MS) derived target-ligand interaction analysis can be utilized to expedite the interrogation of NP structures while minimizing the time and expense of extraction, purification, and screening in BioSafety Laboratories (BSL)3 laboratories. The unparalleled structural diversity and complexity of NPs is an extraordinary resource for the discovery and development of broad-spectrum inhibitors of viral genera, including Betacoronavirus, which contains MERS, SARS, SARS-CoV-2, and the common cold. There are two key technological advances that have created unique opportunities for the identification of NP prototypes with greater efficiency: (1) the application of structural databases for NPs and target proteins and (2) the application of modern MS techniques to assess protein-ligand interactions directly from NP extracts. These approaches, developed over years, now allow for the identification and isolation of unique antiviral ligands without the immediate need for BSL3 facilities. Overall, the goal is to improve the success rate of NP-based screening by focusing resources on source materials with a higher likelihood of success, while simultaneously providing opportunities for the discovery of novel ligands to selectively target proteins involved in viral infection.

Disparities in post-operative mortality between Maori and non-Indigenous ethnic groups in New Zealand.

AIM: To describe disparities in post-operative mortality experienced by Indigenous Maori compared to non-Indigenous New Zealanders. METHODS: We completed a national study of all those undergoing a surgical procedure between 2005 and 2017 in New Zealand. We examined 30-day and 90-day post-operative mortality for all surgical specialties and by common procedures. We compared age-standardised rates between ethnic groups (Maori, Pacific, Asian, European, MELAA/Other) and calculated hazard ratios (HRs) using Cox proportional hazards regression modelling adjusted for age, sex, deprivation, rurality, comorbidity, ASA score, anaesthetic type, procedure risk and procedure specialty. RESULTS: From nearly 3.9 million surgical procedures (876,976 acute, 2,990,726 elective/waiting list), we observed ethnic disparities in post-operative mortality across procedures, with the largest disparities occurring between Maori and Europeans. Maori had higher rates of 30- and 90-day post-operative mortality across most broad procedure categories, with the disparity between Maori and Europeans strongest for elective/waiting list procedures (eg, elective/waiting list musculoskeletal procedures, 30-day mortality: adj. HR 1.93, 95% CI 1.56-2.39). CONCLUSIONS: The disparities we observed are likely driven by a combination of healthcare system, process and clinical team factors, and we have presented the key mechanisms within these factors.

Splenic-vasculature involvement is associated with poor prognosis in resected distal pancreatic cancer.

BACKGROUND: Distal pancreatic carcinoma is one of the most lethal cancers largely due to its high incidence of distant metastasis. This study aims to assess the prognostic value of splenic-vasculature involvement in resected distal pancreatic carcinoma. METHODS: In this retrospective study, we collected the clinicopathologic information of 454 patients with pancreatic cancer and performed univariate and multivariate analyses to identify factors associated with progression-free survival (PFS) and overall survival (OS), with an emphasis on the prognostic value of splenic-artery and -vein involvement. RESULTS: Univariate analysis revealed that larger tumor size, non-intraductal papillary mucinous neoplasm (non-IPMN)-associated adenocarcinoma, poor differentiation, stage pT3, nodal metastasis, lymphovascular invasion, perineural invasion, and pathologic and radiographic evidence of splenic-vein invasion were significantly associated with shorter PFS and OS (all P < 0.05). Multivariate analysis confirmed non-IPMN-associated adenocarcinoma, stage pT3, stage pN1-2, and post-operative adjuvant chemotherapy as independent risk factors for both PFS and OS, and larger tumor size and radiographic evidence of splenic-artery invasion as predictors of PFS only. CONCLUSION: Guidelines should be developed for a uniform approach with regard to the examination and reporting of the status of the splenic vasculature when dealing with distal-pancreatic-cancer specimens.