Impact on Quality during In-Use Preparation of an Antibody Drug Conjugate with Eight Different Closed System Transfer Device Brands.

The aim of this study was to investigate the in-use compatibility of eight commercially available closed system transfer device brands (CSTDs) with a formulated model antibody drug conjugate (ADC). Overall, in-use simulated dosing preparation applying the CSTD systems investigated raised concerns for several product quality attributes. The incompatibilities observed were mainly associated with increased visible and subvisible particles formation as well as significant changes in holdup volumes. Visible and subvisible particles contained heterogeneous mixtures of particle classes, with the majority of subvisible particles associated with silicone oil leaching from CSTD systems during simulated dose preparation upon contact with the ADC formulation. These observations demonstrate that CSTD use may adversely impact product quality and delivered dose which could potentially lead to safety and efficacy concerns during administration. Other product quality attributes measured including turbidity, color, ADC recovery, and purity by size exclusion HPLC, did not show relevant changes. It is therefore strongly recommended to test and screen the compatibility of CSTDs with the respective ADC, in a representative in-use simulated administration setting, during early CMC development, i.e., well before the start of clinical studies, to include information about compatibility and to ensure that the CSTD listed in the manuals of preparation for clinical handling has been thoroughly assessed before human use.

Predictors of one year pressure injury outcomes in hospitalized spinal cord injured veterans with one stage 3 or 4 pressure injury.

OBJECTIVE: The purpose of this study is to investigate predictors of pressure injury (PrI) outcomes at one year after discharge for Veterans with spinal cord injury (SCI) hospitalized with a Stage 3 or 4 PrI. DESIGN/SETTING/PARTICIPANTS: This is a retrospective medical record review from one VA Health Care System SCI unit. Participants were Veterans with traumatic or non-traumatic SCI admitted with one Stage 3 or 4 pelvic PrI treated medically (e.g. without flap surgery). Logistic models were used to select the significant predictors of PrI healing outcomes. OUTCOME MEASURE: One year after discharge wound outcomes (healed vs non-healed) for Veterans with SCI hospitalized with a Stage 3 or 4 PrI. RESULTS: A total of 62 hospitalizations were included for analyses resulting in 33 healed and 29 non-healed PrIs. Three significant predictors of non-healed PrI outcomes included use of pressure mapping during hospitalization, greater PrI depth, and usage of alginate dressings. Two significant predictors of healed PrI outcomes included the use of animal-based tissue and hydrocolloid dressings. Area under curve of this logistic regression model was 79.98%. CONCLUSION: The clinical decision of having a patient pressure mapped predicts that the PrI may not heal at one year of discharge. Pressure mapping protocol correlated with another variable that could not serve as a predictor by itself, including using powered pressure relief techniques. The three PrI treatment predictors may represent characteristics of the PrI itself, rather than the efficacy of the product. Further investigation on these clinical decision-making factors is warranted to ensure efficient and cost-effective treatment strategies for individuals with SCI hospitalized with PrIs.

Utilisation of skin blood flow as a precursor for pressure injury development in persons with acute spinal cord injury: A proof of concept.

People with spinal cord injury (SCI) are at high risk of developing a pressure injury. It is unclear why some people with SCI develop pressure injury while others with similar predisposing risk factors do not during acute hospitalisation. This may hinder healthcare utilisation to prevent pressure injuries. The purpose of the study was to examine the proof-of-concept objective bedside skin blood flow measurements before a pressure injury develops in spinal cord injured patients during acute hospitalisation. This was an observational study. All participants had acute traumatic SCI and were pressure injury-free upon enrollment. Skin blood flow patterns were collected at both heels under two circumstances: localised pressure for reactive hyperemia, and localised heating for heat hyperemia. Our results showed that reactive and heat hyperemia were successfully induced in all eleven participants. Two participants developed pressure injury and nine did not have pressure injury at discharge. Heat hyperemia was smaller in participants with pressure injury. No difference was observed in reactive hyperemia between the groups. In conclusion, skin blood flow measurements could be obtained at bedside during acute hospitalisation of SCI for the purpose of research. Further examination of a larger group is warranted to determine clinical use of heat hyperemia pattern as predictor for pressure injury development.

Healthcare utilization and outcomes of spinal cord injured veterans with stage 3-4 pressure injuries.

BACKGROUND: Pressure injuries (PI) are a significant source of morbidity for individuals with spinal cord injury/disease (SCI/D). They are also associated with significant healthcare resource utilization including prolonged hospitalizations. However, the long-term outcomes in terms of wound recurrence-free survival, hospital readmission rates, and all-cause mortality in this population remain largely unknown. OBJECTIVE: To examine the clinical characteristics, healthcare utilization and outcomes of SCI Veterans hospitalized at the VA North Texas Health Care System (VANTHCS) SCI inpatient unit with stage 3 and 4 PI, and compare these between those who received a myocutaneous flap surgery (flap patients (FP)) and those treated medically (non-flap patients (NFP)). METHODS: A retrospective chart review was conducted of all adult patients admitted to the VANTHCS SCI/D unit with stage 3 or 4 pelvic PI between 1/1/2013 and 12/31/2018. Healthcare utilization and outcome information was extracted for pre-specified time points. RESULTS: 78 patients met criteria (113 hospitalizations; 27 FP; 51 NFP). Average length of stay (LOS) was 122 days; FP had a significantly higher LOS than NFP (P = 0.01). Average number of consults was 24. Estimated cost per hospitalization was $175,198. Readmission rate within 30 days was 12.39%. The mortality rate within 1 year of discharge was 21.57% for NFP, as opposed to 3.70% in the FP group. Only 5.00% of NFP wounds were healed at discharged with sustained healing at 1 year, significantly less than FP wounds (55.26%, P < 0.01). CONCLUSIONS: Despite the high investment in terms of healthcare utilization, outcomes in terms of wound healing are poor. Additionally, nearly 22% of NFP died within one year of discharge. This calls into question the utility of prolonged hospitalizations for PI in the SCI/D population in terms of wound treatment efficacy, healthcare costs, and patient morbidity/mortality.

Assessing Skin Blood Flow and Interface Pressure in Patients With Spinal Cord Injury Provided an Alternating Pressure Overlay: A Cross-sectional Study

The effects of an alternating pressure (AP) overlay on the skin are not fully understood. PURPOSE: This study was conducted among persons with spinal cord injury (SCI) to examine skin blood flow (SBF) and interface pressure (IP) during and after AP overlay use. METHODS: In this cross-sectional, repeated measures study, persons eligible for participation were clinic outpatients from a large metropolitan area in the midwest United States who were 18 to 65 years old with a SCI with a neurologic level of injury at T10 or above for more than 1 year and used a wheelchair for primary mobility. Persons with a current pressure injury, diabetes mellitus, and/or hypertension or other vascular or pulmonary diseases were excluded. Data regarding age, gender, body mass index (BMI), duration of SCI, and American Spinal Injury Association Impairment Scale scores were collected. The experimental study involved 3 protocols: the AP protocol (participants lay supine for 40 minutes on an operating room [OR] pad with a low-profile AP that used a 10-minute inflation-deflation cycle); the post-AP protocol (participants lay on the 2-inch foam OR pad for 40 minutes), with 30 minutes of rest in between; and the control protocol, comprised of 40-minutes of laying supine on the OR pad. Each participant served as his/her own control. Outcome variables included 1) peak IP (the highest value among adjoining sensors located at the highest pressure point); 2) averaged IP (the averaged value of the sensors), calculated from pressure mapping system data from the sacrum and left heel; and SBF, measured using a laser Doppler flowmetry system. Descriptive analyses were performed for all variables to determine need for parametric or nonparametric analyses. The mean value of peak IP, averaged IP among inflation and deflation cycles of AP, and post-AP and control protocols were compared using repeated measures analysis of variance (ANOVA). Mean SBF among inflation and deflation cycles of AP and post-AP and control protocols were compared using the nonparametric Friedman test, and Wilcoxon signed rank tests were used to compare the SBF responses during the post-loading period. If the results of repeated measures ANOVA or Friedman tests were statistically significant, paired t tests and Wilcoxon signed rank tests were used for pairwise comparison with Bonferroni correction at alpha level 0.0125, respectively. RESULTS: Among the 15 participants (11 men, 4 women; age 41.77 ± 14.49 [range 20-62] years; BMI 26.81 ± 4.13 [range 22-37]; injury duration 17 ± 14.62 [range 1-48] years; mostly (11) African American), peak IP decreased during the AP deflation at sacrum (51.47 ± 30.18 mm Hg vs. 114.13 ± 60.97 mm Hg; P = .002) and heel (26.79 ± 12.91 mm Hg vs. 53.05 ± 18.22 mm Hg; P = 0 .001), and SBF increased at the heel (27.92 ± 32.15 vs. 10.43 ± 11.16 au; P = .006) but was not significant at the sacrum (15.54 ± 15.33 au vs. 11.96 ± 10.26 au, P = .023). Peak IP decreased during post-AP at the sacrum (104.62 ± 58.17 mm Hg; P = .002) but not at the heel (47.69 ± 16.21 mm Hg; P = .097). SBF increased during post-AP at the sacrum (15.78 ± 15.82 au; P = .012) but not at the heel (16.31 ± 29.18 au, P = .427). CONCLUSION: An AP overlay redistributed IP and increased SBF at the sacrum and heel during use, and its effect 40 minutes after removal was observed only at the sacrum. Studies, including evaluating the lasting effect of AP on weight-bearing tissue protection at different anatomical locations, are needed.

Mechanistic Characteristics of Surface Modified Organic Semiconductor g-C3N4 Nanotubes Alloyed with Titania.

The visible-light-driven photocatalytic degradation of Bisphenol A (BPA) was investigated using the binary composite of alkaline treated g-C3N4 (HT-g-C3N4) deposited over commercial TiO2 (Evonik Degussa GmbH, Essen, Germany). The existence and contribution of both TiO2 and g-C3N4/HT-g-C3N4 in the composite was confirmed through various analytical techniques including powder X-ray diffraction (XRD), high-resolution transmission electron microscopy (HRTEM), field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), ultraviolet-visible diffuse reflectance spectra (UV-vis-DRS), and photoluminescence (PL) analysis. The results showed that the titania in the binary composite exhibited both pure rutile and anatase phases. The morphological analysis indicated that the spongy "morel-like" structure of g-C3N4 turned to nanotube form after alkaline hydrothermal treatment and thereby decreased the specific surface area of HT-g-C3N4. The low surface area of HT-g-C3N4 dominates its promising optical property and effective charge transfer, resulting in a deprived degradation efficiency of BPA two times lower than pure g-C3N4. The binary composite of HT-g-C3N4/TiO2 exhibited excellent degradation efficiency of BPA with 2.16 times higher than the pure HT-g-C3N4. The enhanced photocatalytic activity was mainly due to the promising optical band gap structure with heterojunction interface, favorable specific surface area, and good charge separation.

Time to rehabilitation in the burn population: incidence of zero onset days in the UDSMR national dataset.

A preliminary investigation of the burn rehabilitation population found a large variability of zero onset day frequency between facilities. Onset days is defined as the time from injury to inpatient rehabilitation admission; this variable has not been investigated in burn patients previously. This study explored if this finding was a facility-based phenomena or characteristic of burn inpatient rehabilitation patients. This study was a secondary analysis of Uniform Data System for Medical Rehabilitation (UDSmr) data from 2002 to 2007 examining inpatient rehabilitation characteristics among patients with burn injuries. Exclusion criteria were age less than 18 years and discharge against medical advice. Comparisons of demographic, medical and functional data were made between facilities with a high frequency of zero onset days versus facilities with a low frequency of zero onset days. A total of 4738 patients from 455 inpatient rehabilitation facilities were included. Twenty-three percent of the population exhibited zero onset days (n = 1103). Sixteen facilities contained zero onset patients; two facilities accounted for 97% of the zero onset subgroup. Facilities with a high frequency of zero onset day patients demonstrated significant differences in demographic, medical, and functional variables compared to the remainder of the study population. There were significantly more zero onset day admissions among burn patients (23%) than other diagnostic groups (0.5- 3.6%) in the Uniform Data System for Medical Rehabilitation database, but the majority (97%) came from two inpatient rehabilitation facilities. It is unexpected for patients with significant burn injury to be admitted to a rehabilitation facility on the day of injury. Future studies investigating burn rehabilitation outcomes using the Uniform Data System for Medical Rehabilitation database should exclude facilities with a high percentage of zero onset days, which are not representative of the burn inpatient rehabilitation population.

Predictors of transfer from rehabilitation to acute care in burn injuries.

BACKGROUND: Transfer to acute care from rehabilitation represents an interruption in a patient's recovery and a potential deficiency in quality of care. The objective of this study was to examine predictors of transfer to acute care in the inpatient burn rehabilitation population. METHODS: Data are obtained from Uniform Data System for Medical Rehabilitation from 2002 to 2010 for patients with a primary diagnosis of burn injury. Predictor variables include demographic, medical, and facility data. Descriptive statistics are calculated for acute and nonacute transfer patients. Logistic regression analysis is used to determine significant predictors of acute transfer within the first 3 days. A scoring system is developed to determine the risk of acute transfer. RESULTS: There were 78 acute transfers in the first 3 days of a total of 4,572 burn admissions. Functional level at admission, age, and admission classification are significant predictors of transfer to acute care (p < 0.05). Total body surface area burned and medical comorbidities were not significantly associated with acute transfer risk. A 12-point acute transfer risk scoring system was developed, which demonstrates validity. CONCLUSION: Efforts to reduce readmissions to acute care should include greater scrutiny of older, lower-functioning patients with burn injury who are evaluated for admission to inpatient rehabilitation. This acute transfer scoring system may be useful to clinicians, health care institutions, and policymakers to help predict those patients at highest risk for early transfer to the acute hospital from rehabilitation. LEVEL OF EVIDENCE: Prognostic/diagnostic study, level II.

Outcomes and predictors in burn rehabilitation.

Advances in burn care in recent decades have resulted in a growing population of burn survivors and an increased need for inpatient rehabilitation. Burn survivors who require inpatient rehabilitation typically experience severe and complicated injuries. The purpose of this study is to examine burn rehabilitation outcomes and their predictor variables. Data are obtained from the Uniform Data System for Medical Rehabilitation from 2002 to 2007. Inclusion criterion is primary diagnosis of burn injury. Predictor variables include demographic, medical, and facility data. Outcome measures are length of stay efficiency, FIM® gain, community discharge, and FIM® discharge of at least 78. Linear and logistic regression analyses are used to determine significant predictors of outcomes. There are 2920 patients who meet inclusion criteria. The mean age of the population is 51 years, 33% of the population is female, 73% is Caucasian, and 40% are married. The median TBSA decile is 20 to 29%. The population exhibits a mean FIM® gain of 28 and length of stay efficiency of 2.1. A majority of the population is discharged to the community (76%) and has a FIM® discharge of at least 78 (81%). Significant predictors of outcomes in burn rehabilitation include age, FIM® admission, onset days, employment status, and marital status. Inpatient rehabilitation is critical to community reintegration of burn survivors. Survivors who are young, married, employed, and higher functioning at the time of admission to rehabilitation demonstrate the best outcomes. This research will help assess the rehabilitation potential of burn survivors and inform resource allocation.

Reliability of tumor primary cultures as a model for drug response prediction: expression profiles comparison of tissues versus primary cultures from colorectal cancer patients.

PURPOSE: Since primary tumor cells from patients have been used as a model for assessment of drug response for individual patients, this study aims to evaluate the reliability of such a model in colorectal cancer (CRC) in predicting the response of tumor tissues through comparison of their expression profiles. METHODS: Establishment of primary cultures from tissues obtained surgically from CRC patients allowed us to study the gene expression differences between normal and tumor tissues as well as primary cultures derived from the tumor mass. The tissues comparison highlights the molecular characteristics of tumors, while the comparison between primary tumor cells versus normal and tumor tissues allowed us to identify alterations associated with the establishment of culture. Genes-drug association analyses allowed us to fine-tune our expectations while using primary culture as a model for drug assessment. RESULTS: Comparison between tumor cultures and original tissues through functional analyses showed the deregulations caused by culture establishment. Investigating the impact of such changes in genes-drug associations to identify the potential alterations in drug response, we found that primary cultures may have increased susceptibility toward paclitaxel, but reduced susceptibility toward analogues of fluorouracil compared with original tumors. CONCLUSIONS: Response of primary tumor cells toward different drugs is not linearly associated to tumor tissues. Our results highlight the importance to account for the discrepancy in responses between the primary tumor cells and original counterparts in order to provide clinicians with important insights to improve selection of drugs for individual patients based on in vitro assays.

Regulation of hTERT by BCR-ABL at multiple levels in K562 cells.

BACKGROUND: The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at multiple levels in K562 cells. METHODS: Molecular techniques such as over expression, knockdown, real-time PCR, immunoprecipitation, western blotting, reporter assay, confocal microscopy, telomerase assays and microarray were used to suggest that hTERT expression and activity is modulated by BCR-ABL at multiple levels. RESULTS: Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL negative cells). We also demonstrated that the transcription factor STAT5a plays a critical role in hTERT gene regulation in K562 cells. Knockdown of STAT5a, but not STAT5b, resulted in a marked downregulation of hTERT mRNA level, TA and hTERT protein level in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec. CONCLUSIONS: Our data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the hTERT gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients.

Analytical solutions of coupled-mode equations for multiwaveguide systems, obtained by use of Chebyshev and generalized Chebyshev polynomials.

A novel approach is proposed for obtaining the analytical solutions of the coupled-mode equations (CMEs); the method is applicable for an arbitrary number of coupled waveguides. The mathematical aspects of the CMEs and their solution by use of Chebyshev polynomials are discussed. When mode coupling between only adjacent waveguides is considered (denoted weak coupling), the first and second kinds of the usual Chebyshev polynomials are appropriate for evaluating the CMEs for linearly distributed and circularly distributed multiwaveguide systems, respectively. However, when one is considering the coupling effects between nonadjacent waveguides also (denoted strong coupling), it is necessary to use redefined generalized Chebyshev polynomials to express general solutions in a form similar to those for the weak-coupling case. As concrete examples, analytical solutions for 2 x 2, 3 x 3, and 4 x 4 linearly distributed directional couplers are obtained by the proposed approach, which treats the calculation as a nondegenerate eigenvalue problem. In addition, for the 3 x 3 circularly distributed directional coupler, which gives rise to a degenerate eigenvalue problem, an analytical solution is obtained in an improved way. Also, for comparison and without loss of generality, to clarify the difference between the two coupling cases, analytical solutions for a 5 x 5 circularly distributed directional coupler are obtained by use of the usual and the redefined generalized Chebyshev polynomials.