Cost and Activity Analysis of Patient Navigation for Persons With HIV: Comparing Health Department and Health Clinic Delivered Interventions.

BACKGROUND: Housing and employment are key factors in the health and well-being of people with HIV (PWH). Patient navigation programs to improve housing and employment show success in achieving viral suppression. Replicating patient navigation interventions to improve population health is needed. Understanding costs associated with patient navigation is a key next step. Therefore, the purpose of this study is to describe the costs associated with delivering patient navigator interventions in two different organizations to improve housing and employment for PWH. METHODS: We conducted a cost analysis of two models of patient navigation. Costs were collected from two sites' payroll, invoices, contracts, and receipts. Pre-implementation and implementation costs and utilization of service costs are presented. Potential reimbursement costs were calculated based on salaries from the Department of Labor. RESULTS: The health clinic's pre-implementation costs were higher ($169,133) than the health department's ($22,018). However, costs of patient navigation during the 2-year intervention were similar between health clinic and health department ($264,985 and $232,923, respectively). The health clinic reported more total time spent with clients (16,013.7 hours) than the health department (1,883.8 hours). The costs per additional person suppressed were $20,632 versus $37,810 for the health department and health clinic, respectively, which are lower than the average lifetime cost of HIV treatment. DISCUSSION: Replicability and scalability of a patient navigation intervention are possible in both health clinic and health department settings. Each site had specific costs, client needs, and other factors that required adaptations to successfully implement the intervention. Future programs should consider tailoring costs to site-specific factors to improve outcomes. Policymakers and public health officials should consider using these results to improve planning and investment in HIV treatment and prevention interventions.

Hind- and midfoot bone morphology varies with foot type and sex.

Foot type has been associated with pain, injury, and altered gait mechanics. Morphological variations in foot bones due to foot type variation may impact surgical and therapeutic treatments. The purpose of this study was to utilize principal component analysis (PCA) to determine how morphology of the hind- and midfoot bones differs among foot types and sex. The calcaneus, talus, navicular, and cuboid were segmented using previously obtained computed tomography (CT) scans and converted to surface models. The CTs were sorted into four foot types-cavus, neutrally aligned, asymptomatic planus, and symptomatic planus. Morphometric shape analysis software (Geomorph) was used to perform a PCA to determine which components varied between foot types and between sexes. The calcaneus showed planus feet of both types to have calcanei that have decreased height and increased length compared to neutrally aligned feet. The talus demonstrated increased posterior mass for cavus feet compared to neutrally aligned feet. For the navicular, symptomatic planus had a more posteriorly positioned tuberosity and were wider than asymptomatic planus feet. The cuboid did not exhibit any differences between foot types. Sex differences, found only at the talus and navicular, were subtle. PCA is an objective technique that helped elucidate differences in bone morphology between foot types and sex without needing to determine the features of interest before comparing groups. Understanding these variations can help inform diagnosis of foot pathologies and surgical protocols as well as improve computer models of the foot. Published 2018. This article is a U.S. Government work and is in the public domain in the USA. J Orthop Res 9999:1-16, 2019.

Altered Range of Motion and Plantar Pressure in Anterior and Posterior Malaligned Total Ankle Arthroplasty: A Cadaveric Gait Study.

BACKGROUND: Malaligned ankle arthroplasty components have been associated with increased postoperative pain and reduced ankle range of motion. With this study, we aimed to quantify how anterior and posterior malalignment of the talar component affects foot bone kinematics and plantar pressures in a dynamic, cadaveric gait simulation. METHODS: Ten cadaveric foot specimens received a modified ankle prosthesis. Proper alignment was defined as the prosthesis being neutral to a plantigrade foot, where varus/valgus and internal/external rotation were determined using the tibial alignment guide from the prosthesis manufacturer. Axially loaded lateral radiographs were made to measure the tibiotalar ratio (TTR) preoperatively and postoperatively. Specimens were prepared for gait simulation and mounted into the robotic gait simulator. Foot bone kinematics and plantar pressures were measured for each alignment condition. RESULTS: Posterior malalignment of the talar component decreased mean sagittal-plane range of motion (p ≤ 0.0005) in the tibiotalar joint (by up to 3.9°) and in the first metatarsophalangeal joint (by up to 7.7°) and increased sagittal-plane range of motion (p ≤ 0.0005) in the calcaneocuboid joint (by up to 2.0°). Posterior malalignment increased mean transverse-plane range of motion (p ≤ 0.0005 and p = 0.012) in the tibiotalar joint (by up to 2.3°) and in the calcaneocuboid joint (by 2.3°). Posterior malalignment decreased mean peak plantar pressures (p = 0.001 and p = 0.013) under the hallux and the first metatarsal (by up to 82.1 and 110.1 kPa, respectively) and increased (p = 0.012 and p = 0.0006) peak plantar pressures under the third metatarsal and the hindfoot (by 23.0 and 47.8 kPa, respectively). Anterior malalignment decreased (p = 0.0006) mean hindfoot peak plantar pressure (by 127.7 kPa). Anterior and posterior malalignments shifted center of pressure laterally during early and late stance. The TTR weakly to moderately correlated with range-of-motion changes in the tibiotalar, calcaneocuboid, and first metatarsophalangeal joints (r ≤ 0.39) and weakly correlated with plantar pressure changes under the hindfoot, the first metatarsal, and the hallux (r ≤ 0.15). CONCLUSIONS: Anterior and posterior malalignments of the talar component altered foot bone kinematics and plantar pressures. Mild malalignments produced fewer significant differences than moderate and extreme malalignments. A greater number of significant differences were found for posterior malalignments than for anterior. The TTR weakly to moderately correlated with changes in range of motion and plantar pressures. CLINICAL RELEVANCE: The observed changes in range of motion and plantar pressures may explain why malaligned ankle arthroplasties are associated with unfavorable clinical outcomes and poor prosthesis longevity. Posterior malalignments may produce worse clinical outcomes than anterior malalignments.

Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism.

Pancreatic tumors are resistant to conventional chemotherapies. The present study was aimed at evaluating the potential of a novel plant-derived product as a therapeutic agent for pancreatic cancer (PC). The effects of an extract from the tropical tree Annona Muricata, commonly known as Graviola, was evaluated for cytotoxicity, cell metabolism, cancer-associated protein/gene expression, tumorigenicity, and metastatic properties of PC cells. Our experiments revealed that Graviola induced necrosis of PC cells by inhibiting cellular metabolism. The expression of molecules related to hypoxia and glycolysis in PC cells (i.e. HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) were downregulated in the presence of the extract. In vitro functional assays further confirmed the inhibition of tumorigenic properties of PC cells. Overall, the compounds that are naturally present in a Graviola extract inhibited multiple signaling pathways that regulate metabolism, cell cycle, survival, and metastatic properties in PC cells. Collectively, alterations in these parameters led to a decrease in tumorigenicity and metastasis of orthotopically implanted pancreatic tumors, indicating promising characteristics of the natural product against this lethal disease.

Novel combination therapy against metastatic and androgen-independent prostate cancer by using gefitinib, tamoxifen and etoposide.

In this study, we evaluated, for the first time, the antiproliferative and cytotoxic effects induced by a combination of a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, with other chemotherapeutic drugs including estrogen receptor-beta (ER-beta) antagonist (tamoxifen) and topoisomerase II inhibitor (etoposide) on some metastatic prostate cancer (PC) cell lines. Immunohistochemial analyses revealed that EGFR expression was enhanced in 38% of primary prostatic adenocarcinomas (Gleason scores 4-10) as compared to the corresponding normal tissues of the same prostate gland from 32 PC patients. The RT-PCR and Western blot data have also indicated the higher expression levels of EGFR and ER-beta transcripts and proteins in metastatic LNCaP, DU145 and PC3 cells relative to nonmalignant normal prostate cells. Moreover, the results from MTT and FACS analyses revealed that the drugs, alone or in combination at lower concentrations, inhibited the growth of 17beta-estradiol (E2) plus EGF and serum-stimulated androgen-responsive LNCaP-C33 and androgen-independent LNCaP-C81, DU145 and PC3 cells. Importantly, the combined gefitinib, tamoxifen and etoposide also caused a higher rate of apoptotic death of PC cells as compared to single agents. The cytotoxic effects induced by these drugs in PC3 cells appear to be mediated through the accumulation of cellular ceramide and activation of caspase cascades via a mitochondrial pathway. These findings indicate that the combined use of inhibitors of EGF-EGFR and E2-ER-beta signaling with etoposide, which act by increasing the cellular ceramide levels and caspase activity, represents a promising strategy for a more effective treatment of metastatic PC forms.

Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells.

Although the blockade of the hedgehog cascade by using cyclopamine has been reported to inhibit the growth of some cancer cell types, few studies on the mechanism by which this drug alone or in combination with other cytotoxic agents induces its cytotoxic effect have been reported. In our study, we evaluate, for the first time, the antiproliferative and cytotoxic effects induced by a combination of selective SMO inhibitor, cyclopamine and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib on metastatic prostate cancer (PC) cells. The results revealed that cyclopamine, alone or at a lower concentration in combination with gefitinib, inhibited the growth of sonic hedgehog- (SHH), epidermal growth factor- (EGF) and serum-stimulated androgen-sensitive LNCaP-C33 and LNCaP-LN3 and androgen-independent LNCaP-C81, DU145 and PC3 cells. The antiproliferative effect of cyclopamine and gefitinib, alone or in combination, was mediated via a blockade of the PC3 cells in the G1 phase of the cell cycle. Importantly, the combined cyclopamine and gefitinib also caused a higher rate of apoptotic death of PC cells compared to single agents. The cytotoxic effect induced by these drugs in PC3 cells appears to be mediated at least, in part, via the mitochondrial pathway through the depolarization of the mitochondrial membrane and the release of cytochrome c and reactive oxygen species into the cytosol. This was also accompanied by the activation of caspase cascades, PARP cleavage and DNA fragmentation. Additionally, the combined cyclopamine and gefitinib were more effective at suppressing the invasiveness of PC3 cells through matrigel in vitro as the drugs alone. These findings indicate that the simultaneous blockade of SHH-GLI-1 and EGF-EGFR signaling, which results in the growth arrest and massive rate of apoptotic cell death, represents a promising strategy for a more effective treatment of metastatic PC forms.

Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49.

PURPOSE: Lutetium-177 (177Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both beta and gamma radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the 177Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo. METHODS: Conjugation and labeling conditions of multivalent scFv with 177Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs {dimer, sc(Fv)2; tetramer, [sc(Fv)2]2} of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with 177Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of 177Lu-labeled tetravalent [sc(Fv)2]2 construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts. RESULTS: Approximately, 90% of 177Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t1/2alpha) of 177Lu-labeled [sc(Fv)2]2 and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t1/2beta) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram (%ID/g) of the LS-174T tumor was 6.4+/-1.3 and 8.9+/-0.6 for 177Lu-labeled [sc(Fv)2]2 and IgG of CC49, respectively, in the absence of L-lysine. The corresponding values were 8.0+/-0.6 and 8.4+/-1.2 in the presence of L-lysine. Renal accumulation of [sc(Fv)2]2 was significantly (p<0.005) reduced in the presence of L-lysine. CONCLUSION: The results of this study demonstrate that the ITCB-DTPA conjugation and 177Lu-labeling of scFvs are feasible without influencing the antibody characteristics. 177Lu-labeled [sc(Fv)2]2 showed faster clearance and equivalent tumor uptake at 8 h compared with its IgG form, with a markedly reduced renal uptake in the presence of L-lysine. Therefore, 177Lu-labeled [sc(Fv)2]2 may be a potential radiopharmaceutical for the treatment of cancer.