Comparing Renin-Angiotensin-Aldosterone Blockade Regimens for Long-Term Chemotherapy-Related Cardiac Dysfunction: A Network Meta-Analysis.

PURPOSE: Cancer therapies including trastuzumab and anthracyclines are cardiotoxic and cause cardiac dysfunction. To prevent cardiotoxicity, pharmacological agents used in heart failure have been administered concomitantly with cardiotoxic cancer therapy, but few studies to date have performed a head-to-head comparison of these different agents. This systematic review and network meta-analysis of randomized-controlled trials aims to evaluate the efficacy of renin-angiotensin-aldosterone system (RAAS) blockers, namely angiotensin-converting enzyme inhibitors (ACE-Is), aldosterone receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), in primary prevention against chemotherapy-related cardiac dysfunction in patients receiving anthracyclines and/or trastuzumab. METHODS: A systematic search was performed in major web databases for studies from inception to 15 September 2022. A Bayesian network meta-analysis model was used to assess the relative effects of competing treatments on the primary outcomes of risk of significant decline in left ventricular ejection fraction (LVEF) and mean LVEF decline. Secondary outcomes included left ventricular diastolic function, global longitudinal strain, and cardiac biomarkers. This study is registered with PROSPERO, CRD42022357980. RESULTS AND CONCLUSION: Nineteen studies reported the effects of 13 interventions (N = 1905 patients). Only enalapril (RR 0.05, 95% CI 0.00-0.20) was associated with reduced risk of patients developing significant decline in LVEF relative to placebo. Subgroup analysis showed that the beneficial effect of enalapril was driven by protection against anthracycline-associated toxicity. In addition, no RAAS-inhibiting agents showed efficacy in protection against treatment with both anthracycline and trastuzumab. The use of RAAS inhibition therapy did not conclusively impact on other markers of cardiac function, including left ventricular diastolic function and cardiac biomarkers.

Eltrombopag as frontline treatment of aplastic anaemia in routine practice: implications on cost and efficacy.

The thrombopoietin mimetic eltrombopag (EPAG) is efficacious in clinical trials of newly diagnosed moderate (M), severe (S) and very severe (vS) aplastic anaemia (AA). Its use in routine practice and resource-constrained settings is not well described. Twenty-five men and 38 women at a median age of 54 (18-86) years with newly diagnosed AA treated consecutively in a 7-year period with EPAG (N = 6), EPAG/cyclosporine (CsA) (N = 33) and EPAG/CsA/anti-thymocyte globulin (ATG) (N = 24) were analyzed. Because EPAG was not reimbursed, peak doses ranged from 25 to 200 mg/day depending on affordability. EPAG/CsA-treated patients were older (median age: 61 years) with less severe AA (MAA, N = 15; SAA, N = 14; vSAA, N = 4), whereas EPAG/CsA/ATG-treated patients were younger (median age: 44 years) with more severe AA (MAA, N = 2; SAA, N = 12, vSAA, N = 10). The overall/trilineage response rates were 83%/50% for EPAG-treated patients; 79%/42% for EPAG/CsA-treated patients and 75%/63% for EPAG/CsA/ATG-treated patients. Adverse events included grade 1 liver derangement (N = 7) and grade 1 dyspepsia (N = 3). The 5-year overall survivals/failure-free survivals were 62%/80% for the entire cohort; 55%/75% for EPAG/CsA-treated patients and 82%/78% for EPAG/CsA/ATG-treated patients. EPAG showed robust efficacy in AA in routine practice. However, EPAG dosage and combinations remain to be optimized for AA of different severities.

Deterioration of teeth and alveolar bone loss due to chronic environmental high-level fluoride and low calcium exposure.

OBJECTIVES: Health risks due to chronic exposure to highly fluoridated groundwater could be underestimated because fluoride might not only influence the teeth in an aesthetic manner but also seems to led to dentoalveolar structure changes. Therefore, we studied the tooth and alveolar bone structures of Dorper sheep chronically exposed to very highly fluoridated and low calcium groundwater in the Kalahari Desert in comparison to controls consuming groundwater with low fluoride and normal calcium levels within the World Health Organization (WHO) recommended range. MATERIALS AND METHODS: Two flocks of Dorper ewes in Namibia were studied. Chemical analyses of water, blood and urine were performed. Mineralized tissue investigations included radiography, HR-pQCT analyses, histomorphometry, energy-dispersive X-ray spectroscopy and X-ray diffraction-analyses. RESULTS: Fluoride levels were significantly elevated in water, blood and urine samples in the Kalahari group compared to the low fluoride control samples. In addition to high fluoride, low calcium levels were detected in the Kalahari water. Tooth height and mandibular bone quality were significantly decreased in sheep, exposed to very high levels of fluoride and low levels of calcium in drinking water. Particularly, bone volume and cortical thickness of the mandibular bone were significantly reduced in these sheep. CONCLUSIONS: The current study suggests that chronic environmental fluoride exposure with levels above the recommended limits in combination with low calcium uptake can cause significant attrition of teeth and a significant impaired mandibular bone quality. CLINICAL RELEVANCE: In the presence of high fluoride and low calcium-associated dental changes, deterioration of the mandibular bone and a potential alveolar bone loss needs to be considered regardless whether other signs of systemic skeletal fluorosis are observed or not.

Psychiatric morbidity in ketamine users attending counselling and youth outreach services.

BACKGROUND: No study has examined ketamine users' psychiatric morbidity using structured diagnostic instruments. The aim of this study was thus to determine the psychiatric comorbidity of community-based ketamine users using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), Axis I Disorders (SCID). METHODS: A convenience sample of 200 frequent ketamine users was recruited from community organizations in Hong Kong. Participants were screened with the Severity of Dependence Scale (SDS), Beck Depression Inventory (BDI), Anxiety subscale of the Hospital Anxiety Depression Scale (HADSA), and SCID psychotic symptoms. Those who scored above the threshold (cutoff point of 8/9 on the BDI and 4/5 on HADSA) or displayed evidence of psychotic symptoms were referred for a structured clinical interview conducted by a psychiatrist. RESULTS: One hundred and seventy participants scored above the cutoff point on 1 or more of the scales, and 115 participants attended the SCID interview. Fifty-one of these 115 participants received a psychiatric diagnosis of 1 or more comorbidities for the month preceding the interview. Mood disorders accounted for 80.4% of the diagnoses, anxiety disorders for 33.3%, and psychotic disorders for 7.8%. CONCLUSIONS: Female gender and history of psychiatric/psychological clinic attendance were significantly associated with comorbid psychiatric disorders, whereas ketamine dependence had a borderline association.

Prognostic factors in 448 newly diagnosed multiple myeloma receiving bortezomib-based induction: impact of ASCT, transplant refusal and high-risk MM.

In Hong Kong, newly diagnosed multiple myeloma (NDMM) receives bortezomib-based triplet induction. Upfront autologous stem cell transplant (ASCT) is offered to transplant eligible (TE) patients (NDMM ≤ 65 years of age), unless medically unfit (TE-unfit) or refused (TE-refused). Data was retrieved for 448 patients to assess outcomes. For the entire cohort, multivariate analysis showed that male gender (p = 0.006), international staging system (ISS) 3 (p = 0.003), high lactate dehydrogenase (LDH) (p = 7.6 × 10-7) were adverse predictors for overall survival (OS), while complete response/ near complete response (CR/nCR) post-induction (p = 2.7 × 10-5) and ASCT (p = 4.8 × 10-4) were favorable factors for OS. In TE group, upfront ASCT was conducted in 252 (76.1%). Failure to undergo ASCT in TE patients rendered an inferior OS (TE-unfit p = 1.06 × 10-8, TE-refused p = 0.002) and event free survival (EFS) (TE-unfit p = 0.00013, TE-refused p = 0.002). Among TE patients with ASCT, multivariate analysis showed that age ≥ 60 (p = 8.9 × 10-4), ISS 3 (p = 0.019) and high LDH (p = 2.6 × 10-4) were adverse factors for OS. In those with high-risk features (HR cytogenetics, ISS 3, R-ISS 3), ASCT appeared to mitigate their adverse impact. Our data reaffirmed the importance of ASCT. The poor survival inherent with refusal of ASCT should be recognized by clinicians. Finally, improved outcome with ASCT in those with high-risk features warrant further studies.

Evaluating the role of a hospital pharmacist in a cardiac day ward.

OBJECTIVES: To evaluate the role of clinical pharmacists in cardiac day wards. METHODS: A service evaluation was conducted during 24 February 2020-27 March 2020 to assess the role of clinical pharmacists for all patients admitted to an Australian tertiary hospital cardiac day ward. KEY FINDINGS: Overall, 297 patients were included. Medication review occurred for 80% (237/297) and a best possible medication history was obtained for 65% (193/297) of patients. Acceptance of interventions for medication-related problems was 93% (84/90). When compared with medication plans outlined in standard catheterisation laboratory documentation without pharmacist input, a pharmacist medication review resulted in increased documentation of medication plans in the patient's medical record at the time of discharge (20% (1/5) versus 95% (142/150), P < 0.001). CONCLUSION: Pharmacists can optimise the medication management of patients in cardiac day wards by performing medication review, and facilitating implementation and communication of medication changes at hospital discharge to patients and primary healthcare providers.

Depression and anxiety in older adults with cancer: Systematic review and meta-summary of risk, protective and exacerbating factors.

OBJECTIVE: To systematically evaluate the risk factors of depression and anxiety in older adults with cancer. METHOD: This PRISMA-adherent systematic review (PROSPERO CRD42022372747) involved a systematic database search for prospective and retrospective cohort studies. RESULTS: We included 33 cohort studies with 31 evaluating depression and seven evaluating anxiety. Systematic synthesis yielded various protective and exacerbating factors for depression and anxiety amongst older adults with cancer. These factors span a range of domains: (1) Cancer and associated treatment-related factors; (2) Medical, physical and functional factors; (3) Demographic factors and; (4) Social and lifestyle factors. At the individual-level, the most significant factors were the presence of chronic medical comorbidities, having pre-existing psychological symptoms, and poor baseline physical and functional status. Within the social unit, the degree of social support and presence of a partner were most significant. CONCLUSION: The deleterious impact comorbid psychological symptoms can have on older adults with cancer can be profound. In this review, we highlight a range of protective and exacerbating factors identified from cohort studies that may enable policymakers to tailor and individualise interventions to manage depression, anxiety and associated burden in this vulnerable population. The relative paucity of studies evaluating anxiety highlights an important research gap.

An updated analysis of hepatitis C virus genotypes and subtypes based on the complete coding region.

BACKGROUND: The hepatitis C virus (HCV) genomic database is expanding rapidly. AIMS: There is a need to provide an updated phylogenetic tree analysis based on the complete coding region of HCV. METHODS: All available HCV complete genome sequences in the HCV databases available through October 2010 were analyzed. RESULTS: The assignment of all known complete sequences up-to-date confirmed the previous six major genotypes and one new sequence, which have been provisionally assigned as subtype 7a. New recombinant forms of HCV, although uncommon, have been detected and were found to have different crossover points. CONCLUSION: This updated analysis based on the complete region of HCV confirmed the validity of the previously assigned genotypes/subtypes and provided an up-to-date reference for future basic research and clinical studies.

Extreme hyperferritinemia without associated HLH in a patient with T-cell lymphoma.

Extreme hyperferritinemia has historically been associated with a short list of rare diagnoses, including hemophagocytic lymphohistiocytosis (HLH). However, hyperferritinemia is not specific for HLH in the adult population. Among other more common causes, T-cell lymphoma and other malignancies warrant evaluation prior to considering more rare diagnoses.

Vitamin E, Alpha-Tocopherol, and Its Effects on Depression and Anxiety: A Systematic Review and Meta-Analysis.

BACKGROUND: Recently, it has been discovered that anti-inflammatory and anti-oxidative pathways play a role in depression and anxiety. Lower serum levels of antioxidants, such as vitamin E, have been implicated in both depression and anxiety. METHODS: This PROSPERO-registered systematic review (Reference: CRD42021260058) is reported according to PRISMA guidelines. PubMed, EMBASE, CENTRAL, PsycINFO, and CINAHL were searched from inception to June 2021. RESULTS: Twelve studies were included in this systematic review, and nine in meta-analysis of vitamin E versus placebo. For depression, meta-analysis of 354 participants showed a standardised mean difference of -0.88 (95% CI: -1.54, -0.21; I2 = 87%) favouring vitamin E. For anxiety, meta-analysis of 306 participants showed a standardised mean difference of -0.86 (95% CI: -2.11, 0.40; I2 = 95%) favouring vitamin E. Three of the studies involved a pure comparison of vitamin E against placebo, while others included constituents such as omega-3 fatty acids. Nine of the studies were at low risk of bias, two had some concerns, and one was at high risk of bias. CONCLUSION: Vitamin E supplementation has shown inconclusive results in ameliorating both depression and anxiety. Containing a reassuring safety profile and low cost, future studies would be of promise, and they would benefit from both larger sample sizes and from excluding other constituents, such as omega-3 fatty acids, from experimental and comparator arms.

Hepatic expression of cell proliferation markers and growth factors in giant cell hepatitis: implications for the pathogenetic mechanisms involved.

OBJECTIVES: The aim of this study is to determine whether amitotic division or nuclear proliferation is involved in the formation of giant cells (GCs) in giant cell hepatitis (GCH). PATIENTS AND METHODS: Liver sections from 18 pediatric patients with idiopathic infantile GCH and 12 patients with postinfantile GCH were evaluated for the expression of proliferating cell nuclear antigen (PCNA) and human histone 3 (H3) mRNA, transforming growth factor-alpha (TGF-α), TGF-ß1, hepatocyte growth factor (HGF), and epidermal growth factor receptor (EGFR). RESULTS: Proliferation markers were detected in 1% to 80% in the nuclei of GC and non-GC hepatocytes in 10 of 18 (56%) infantile GCH biopsies and 11 of 12 (92%) postinfantile GCH biopsies, but not in normal liver. The expression of proliferation markers in GCs paralleled that in non-GC hepatocytes (P < 0.05 for both markers). TGF-α and EGFR were detected in both GCs (9/29 and 4/30 patients with infantile or postinfantile GCH, respectively) and non-GC hepatocytes (15/29 and 11/30 patients with infantile or postinfantile GCH, respectively). TGF-ß1 and HGF were detected mainly in sinusoidal cells in 20 of 29 and 10 of 30 patients with infantile or postinfantile GCH, respectively; the expression of HGF was positively correlated with PCNA and H3 mRNA in non-GC hepatocytes and with H3 mRNA in GCs (P < 0.01). CONCLUSIONS: Hepatic expressions of nuclear proliferation markers and growth factors were similar in infantile and postinfantile GCH, nuclear proliferation markers were detected in both GCs and non-GC hepatocytes in a high proportion of patients, and expression of HGF correlated positively with the proliferation markers. These data indicate that nuclear proliferation may contribute to the pathogenesis of GCs in at least a proportion of patients with GCH. A model for the pathogenesis of GCH is proposed.

Investigating the effect of moisture protection on solid-state stability and dissolution of fenofibrate and ketoconazole solid dispersions using PXRD, HSDSC and Raman microscopy.

Enhanced dissolution of poorly soluble active pharmaceutical ingredients (APIs) in amorphous solid dispersions often diminishes during storage due to moisture-induced re-crystallization. This study aims to investigate the influence of moisture protection on solid-state stability and dissolution profiles of melt-extruded fenofibrate (FF) and ketoconazole (KC) solid dispersions. Samples were kept in open, closed and Activ-vials(®) to control the moisture uptake under accelerated conditions. During 13-week storage, changes in API crystallinity were quantified using powder X-ray diffraction (PXRD) (Rietveld analysis) and high sensitivity differential scanning calorimetry (HSDSC) and compared with any change in dissolution profiles. Trace crystallinity was observed by Raman microscopy, which otherwise was undetected by PXRD and HSDSC. Results showed that while moisture protection was ineffective in preventing the re-crystallization of amorphous FF, KC remained X-ray amorphous despite 5% moisture uptake. Regardless of the degree of crystallinity increase in FF, the enhanced dissolution properties were similarly diminished. Moisture uptake above 10% in KC samples also led to re-crystallization and significant decrease in dissolution rates. In conclusion, eliminating moisture sorption may not be sufficient in ensuring the stability of solid dispersions. Analytical quantification of API crystallinity is crucial in detecting subtle increase in crystallinity that can diminish the enhanced dissolution properties of solid dispersions.

The licorice flavonoid isoliquiritigenin suppresses phorbol ester-induced cyclooxygenase-2 expression in the non-tumorigenic MCF-10A breast cell line.

Cyclooxygenase (COX) is the rate-limiting enzyme for the conversion of prostaglandins from arachidonic acid. Upregulation of COX-2 has been well documented during tumorigenesis and metastasis of breast cancer. Isoliquiritigenin (ILN), a flavonoid isolated from licorice (the rhizomes of GLYCYRRHIZA GLABRA, a member of the bean plant family), is known to be a potential suppressor of COX-2 expression. This study focuses on phorbol ester-induced COX-2 expression in the non-tumorigenic MCF-10A cells. Real-time PCR and Western blotting indicated that ILN at 5 microM or above significantly inhibited phorbol 12-myristate 13-acetate (PMA)-induced COX-2 expression in the breast cells. The activated PKC alpha appeared to be not affected, whereas its downstream mitogen-activated protein kinase (MAPK) ERK-1/2 was deactivated. ERK can activate the transcriptional factor binding of AP-1 or CRE, which can be located at the COX-2 promoter region (- 72/- 53). Electrophoretic mobility shift assays illustrated that ILN suppressed DNA binding at this region. The shifted bands could be competed off with consensus sequences of AP-1 and CRE, and the supershift assay demonstrated that CREB-1 instead of c-Jun was responsible for the binding. This study showed that ILN downregulated PMA-induced COX-2 expression by modulating ERK-1/2 signaling, a finding that may be relevant to the disease prevention properties of licorice.

Expression of Src and FAK in hepatocellular carcinoma and the effect of Src inhibitors on hepatocellular carcinoma in vitro.

The expressions of c-Src and focal adhesion kinase (FAK) were studied in 65 Chinese patients with hepatocellular carcinoma (HCC) by immunohistochemistry using rabbit monoclonal antibodies. Expressions of total Src, an active form of Src, and FAK were found in 44/65 (67.7%), 36/45 (55.4%), and 33/56 (58.9%) HCC cases, respectively. There was a good correlation between the expression of total Src, active form of Src, and FAK in these HCC cases (P < 0.001). Expression of Src was not correlated to any clinical parameters, cancer cell phenotypic markers, and pathologic features apart from a positive correlation with alpha-fetoprotein (P < 0.01). The expression of FAK was correlated with earlier onset and the expression of Ki-67 but not proliferating cell nuclear antigen (PCNA) in these HCC cases. Four liver-cancer-derived cell lines (three derived from HCC and one from hepatoblastoma) were then tested with inhibitors against Src. A small molecule, KX2-391, designed to target the substrate binding pocket of Src, was found to have more broad-spectrum activity and better potency than Dasatinib, an adenosine triphosphate (ATP)-competitive inhibitor in vitro. Our data indicates that Src and FAK expression are both elevated and active in Chinese patients with HCC and that Src may play a key role in supporting HCC progression. Src antagonism with specific inhibitors may be an attractive treatment paradigm for patients with HCC.

Patient and clinician perspectives of an integrated electronic medication prescribing and dispensing system: A qualitative study at a multisite Australian hospital network.

BACKGROUND:: While clinician attitudes towards electronic prescribing (e-prescribing) systems have been widely studied, little is known about the perspectives of patients, despite being the primary beneficiaries of these systems. OBJECTIVE:: The objective of this study is to explore and compare patient and clinician attitudes towards an integrated e-prescribing and dispensing system, in order to guide improvements in system implementation, service delivery and enhancements to system functionality. METHOD:: A cross-sectional survey was developed and administered to patients and multidisciplinary clinicians at a multisite Australian metropolitan teaching hospital network in all areas where e-prescribing was fully implemented. Participants' views on perceived impact and valued features of the e-prescribing system were elucidated. RESULTS:: Overall, 783 participants (400 patients and 383 clinicians) completed the survey. Although 98% of clinicians were aware of the transition to e-prescriptions, only 36% of patients were aware prior to the study. Over 80% of patients and clinicians perceived improvements in prescribing and dispensing safety and clinician workflow; 90% of patients were comfortable with information privacy associated with e-prescriptions; and 86% of patients preferred e-prescriptions to handwritten prescriptions. Although over 80% of patients valued features that improved access to information and medication safety, clinicians were more discerning about valued system features. CONCLUSION:: The majority of patients and clinicians reported a positive impact of e-prescribing on safety and efficiency. Both groups valued safe and effective use of medicines, although differences existed in the importance placed on key system features. A greater focus on patient engagement and communication is needed to optimise the delivery of patient-centred care.

Cellular Response to 3-D Printed Bioactive Silicate and Borosilicate Glass Scaffolds.

The repair and regeneration of loaded segmental bone defects is a challenge for both materials and biomedical science communities. Our recent work demonstrated the capability of bioactive glass in supporting bone healing and defect bridging using a rabbit femur segmental defect model without growth factors or bone marrow stromal cells (BMSCs). Here in the current work, a comprehensive in vitro evaluation of bioactive silicate (13-93) and borosilicate (2B6Sr) glass scaffolds was conducted to provide further understanding of their biological performances and to establish a correlation between in vitro and in vivo behaviors. Our in vitro evaluation using a murine MC3T3-E1 cell line confirmed the capability of both scaffolds to support cell attachment, vascular endothelial growth factor (VEGF) formation, and to stimulate mineral deposition and osteoblast marker gene expression. In particular, borosilicate (2B6Sr) glass showed a better capability in supporting the mineralization and gene expression than silicate (13-93) glass, consistent with a faster bone healing ability in vivo. The current in vitro results, combined with our previous in vivo findings, provide a strong basis for the further translational evaluation of bioactive glass scaffolds and for potential preclinical practice. © 2018 Wiley Periodicals, Inc. J. Biomed. Mater. Res. Part B, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 818-824, 2019.

Strength, toughness, and reliability of a porous glass/biopolymer composite scaffold.

Development of bioactive glass and ceramic scaffolds intended for the reconstruction of large segmental bone defects remains a challenge for materials science due to the complexities involved in clinical implantation, bone-implant reaction, implant degradation and the multiple loading modes the implants subjected to. A comprehensive evaluation of the mechanical properties of inorganic scaffolds and exploration of new ways to toughen brittle constructs are critical prior to their successful application in loaded sites. A simple and widely adopted approach involves the coating of an inorganic scaffold with a polymeric material. In this work, a systematic evaluation of the influence of a biopolymer, polycaprolactone (PCL), coating on the mechanical performance of bioactive glass scaffolds was carried out. Results from this work indicate that a biopolymer PCL coating was more effective in increasing the compressive strength and reliability of the glass scaffold under compression, but less effective in improving its flexural strength or fracture toughness. This is the first report that reveals the limited successfulness of a polymer coating in improving the toughness of strong scaffolds, suggesting that new and novel ways of toughening inorganic scaffolds should be future research directions for scaffolds applied in loaded sites. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1209-1217, 2018.

Comparison of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in the serum of hypothyroxinemic and euthyroid dogs.

OBJECTIVE: To determine the profile of 14 polybrominated diphenyl ethers (PBDEs) and 23 polychlorinated biphenyls (PCBs) in serum of domestic canines and whether this was predictive of thyroid hormone status. SAMPLES: Serum samples were collected from 51 client-owned dogs visiting the University of California Davis William R. Pritchard Veterinary Medical Teaching Hospital during 2012 to 2016 for routine appointments. Fifteen dogs were diagnosed with hypothyroxinemia while 36 were euthyroid. PROCEDURES: Concentrations of PBDEs and PCBs in canine serum samples were measured by gas chromatography mass spectrometry. Logistic regression analysis was used to determine the association between the presence/absence of canine hypothyroxinemia and the serum concentration of individual PBDE or PCB congeners. RESULTS: The median concentrations of total PBDE and PCB congeners in the hypothyroxinemic group were 660 and 1,371 ng/g lipid, respectively, which were higher than concentrations detected in the control group. However, logistic regression analysis determined that current concentrations of PBDEs and PCBs in canines were not significantly associated with hypothyroxinemia. BDE 183 was the only congener showing near significance (p = 0.068). CONCLUSIONS: PBDE and PCB congeners were detected in all canine samples confirming ongoing exposure to these pollutants. Because household dogs share the human environment, they may serve as biosentinels of human exposure to these contaminants.

Macro- and micro-designed chitosan-alginate scaffold architecture by three-dimensional printing and directional freezing.

While many tissue-engineered constructs aim to treat cartilage defects, most involve chondrocyte or stem cell seeding on scaffolds. The clinical application of cell-based techniques is limited due to the cost of maintaining cellular constructs on the shelf, potential immune response to allogeneic cell lines, and autologous chondrocyte sources requiring biopsy from already diseased or injured, scarce tissue. An acellular scaffold that can induce endogenous influx and homogeneous distribution of native stem cells from bone marrow holds great promise for cartilage regeneration. This study aims to develop such an acellular scaffold using designed, channeled architecture that simultaneously models the native zones of articular cartilage and subchondral bone. Highly porous, hydrophilic chitosan-alginate (Ch-Al) scaffolds were fabricated in three-dimensionally printed (3DP) molds designed to create millimeter scale macro-channels. Different polymer preform casting techniques were employed to produce scaffolds from both negative and positive 3DP molds. Macro-channeled scaffolds improved cell suspension distribution and uptake overly randomly porous scaffolds, with a wicking volumetric flow rate of 445.6 ± 30.3 mm(3) s(-1) for aqueous solutions and 177 ± 16 mm(3) s(-1) for blood. Additionally, directional freezing was applied to Ch-Al scaffolds, resulting in lamellar pores measuring 300 µm and 50 µm on the long and short axes, thus creating micrometer scale micro-channels. After directionally freezing Ch-Al solution cast in 3DP molds, the combined macro- and micro-channeled scaffold architecture enhanced cell suspension uptake beyond either macro- or micro-channels alone, reaching a volumetric flow rate of 1782.1 ± 48 mm(3) s(-1) for aqueous solutions and 440.9 ± 0.5 mm(3) s(-1) for blood. By combining 3DP and directional freezing, we can control the micro- and macro-architecture of Ch-Al to drastically improve cell influx into and distribution within the scaffold, while achieving porous zones that mimic articular cartilage zonal architecture. In future applications, precisely controlled micro- and macro-channels have the potential to assist immediate endogenous bone marrow uptake, stimulate chondrogenesis, and encourage vascularization of bone in an osteochondral scaffold.