Moiré superlattices in twisted two-dimensional halide perovskites.

Moiré superlattices have emerged as a new platform for studying strongly correlated quantum phenomena, but these systems have been largely limited to van der Waals layer two-dimensional materials. Here we introduce moiré superlattices leveraging ultrathin, ligand-free halide perovskites, facilitated by ionic interactions. Square moiré superlattices with varying periodic lengths are clearly visualized through high-resolution transmission electron microscopy. Twist-angle-dependent transient photoluminescence microscopy and electrical characterizations indicate the emergence of localized bright excitons and trapped charge carriers near a twist angle of ~10°. The localized excitons are accompanied by enhanced exciton emission, attributed to an increased oscillator strength by a theoretically predicted flat band. This research showcases the promise of two-dimensional perovskites as unique room-temperature moiré materials.

Disparities in Offering Enrollment in Remote Patient Monitoring for COVID-19.

Introduction: Remote patient monitoring (RPM) programs are increasingly common. There is a risk that inequitable use of RPM will perpetuate existing health care disparities. We conducted a study to determine if enrollment in a COVID-19 RPM program was offered differentially across demographic groups. Methods: From March through September 2020, patients with COVID-19 were evaluated within a large academic health system with a standardized care pathway that directed providers to refer the patients for RPM. We conducted a retrospective cohort study to evaluate the effects of social vulnerability and urbanicity of residence on the odds of referral. We estimated vulnerability using the CDC social vulnerability index (SVI) and used logistic regression to determine odds ratios (ORs) for referral based on SVI and urbanicity. Results: Of 16,739 patients who had a qualifying health care encounter, 2,946 (17.6%) were referred for RPM. Patients in census tracts with higher social vulnerability were less likely to be referred than those in tracts with lower vulnerability (OR 0.73, 95% confidence interval 0.63-0.84). Patients living in Micropolitan/Large Rural Cities or Small Towns/Small Rural Towns were more likely to be referred than those in Metropolitan/Urban areas. In the full regression model, including both SVI and urbanicity, urbanicity was the strongest predictor of referral, and patients living in Metropolitan/Urban areas were the most likely to be referred. Conclusions: We found disparities in who is offered access to remote monitoring despite the use of standardized care pathways. Health systems need to evaluate how they implement RPM programs and care pathways to ensure equitable care delivery.

Synovial sarcoma with intra-abdominal metastasis causing hemoperitoneum: a case-report.

Synovial sarcoma is a rare soft tissue sarcoma which frequently involves the upper or lower extremities. Soft tissue sarcomas including synovial sarcoma have a propensity to metastasize to the lungs, and there are very few reports of metastatic lesions in other locations.Here, we report a case of a 49-year-old patient who underwent neoadjuvant chemoradiation for an upper extremity synovial sarcoma and presented approximately 4 years later with abdominal pain and hemoperitoneum and was ultimately found to have metastatic synovial sarcoma involving the greater curvature of the stomach and surrounding peri-gastric soft tissue. We describe the multidisciplinary management of this complex patient presentation and propose that expanded surveillance imaging beyond that of the local tumor resection bed and the chest may be beneficial especially in tumors with high-risk features.

Twist Angle Tuning of Moiré Exciton Polaritons in van der Waals Heterostructures.

Twisted atomically thin semiconductors are characterized by moiré excitons. Their optical signatures and selection rules are well understood. However, their hybridization with photons in the strong coupling regime for heterostructures integrated in an optical cavity has not been the focus of research yet. Here, we combine an excitonic density matrix formalism with a Hopfield approach to provide microscopic insights into moiré exciton polaritons. In particular, we show that exciton-light coupling, polariton energy, and even the number of polariton branches can be controlled via the twist angle. We find that these new hybrid light-exciton states become delocalized relative to the constituent excitons due to the mixing with light and higher-energy excitons. The system can be interpreted as a natural quantum metamaterial with a periodicity that can be engineered via the twist angle. Our study presents a significant advance in microscopic understanding and control of moiré exciton polaritons in twisted atomically thin semiconductors.

Remote Patient Monitoring for COVID-19: A Retrospective Study on Health Care Utilization.

Introduction: Data are limited on the effectiveness of remote patient monitoring (RPM) for acute illnesses, including COVID-19. We conducted a study to determine if enrollment in a COVID-19 RPM program was associated with better outcomes. Methods: From March through September 2020, patients with respiratory symptoms and presumptive COVID-19 were referred to the health system's COVID-19 RPM program. We conducted a retrospective cohort study comparing outcomes for patients enrolled in the RPM (n = 4,435) with those who declined enrollment (n = 2,742). Primary outcomes were emergency room, hospital, and intensive care unit admissions, and death. We used logistic regression to adjust for demographic differences and known risk factors for severe COVID-19. Results: Patients enrolled in the RPM were less likely to have risk factors for severe COVID-19. There was a significant decrease in the odds of death for the group enrolled in the RPM (adjusted odds ratio [OR] = 0.50; 95% confidence interval [CI], 0.30-0.83) and a nonsignificant decrease in the odds of the other primary outcomes. Increased number of interactions with the RPM significantly decreased the odds of hospital admission (OR = 0.92; 95% CI, 0.88-0.95). Conclusions: COVID-19 RPM enrollment was associated with decreased odds of death, and the more patients interacted with the RPM, the less likely they were to require hospital admission. RPM is a promising tool that has the potential to improve patient outcomes for acute illness, but controlled trials are necessary to confirm these findings.

The future of orthopaedic surgical education: Where do we go now?

INTRODUCTION: COVID-19 will undoubtedly change the future landscape of medical and surgical education. The economic and environmental advantages of virtual learning are clear, while access to a wider range of resources and subject specialists makes the adoption of virtual learning within surgical education an attractive prospect. AIMS: This literature review aims to evaluate evidence on the effectiveness of virtual education in orthopaedics and how we might implement positive changes to educational practice in the future, as a result of lessons learned during the COVID-19 pandemic. METHODOLOGY: We performed a review of the literature reporting on efficacy of learning outcomes achieved as a result of virtual education within orthopaedic surgery. Electronic searches were performed using NICE healthcare databases from the date of inception to March 2021. Relevant studies were identified, data extracted, and qualitative synthesis performed. RESULTS: 14 manuscripts with a total of 1548 participants (orthopaedic trainees or medical students) were included for analysis. Nine studies (n = 1109) selected compared e-learning to conventional learning material (control group). All nine studies reported significantly higher outcome scores for e-learning participants compared to control participants (p < 0.001 to p < 0.05). The remaining studies compared blended e-learning approaches or evaluated pre/post intervention improvements in learning outcomes. All studies demonstrated a significant improvement in learning outcomes (p < 0.0001 to p < 0.01). The majority of studies (64%) used a blended approach. No studies were identified reporting efficacy of webinars or videoconferencing within orthopaedic education. CONCLUSION: A blended approach, combining virtual teaching, face-to-face instruction and distance learning tools, based on the evidence we have provided, would improve the quality of knowledge reception and retention, and learner satisfaction. However, in order to be successful, it is vital that these educational programmes are designed with the needs of the learner in mind, and an awareness of best practice for virtual teaching and learning.

The introduction of day-case total knee arthroplasty in a national healthcare system: A review of the literature and development of a hospital pathway.

INTRODUCTION: As we now drive to reinitiate our full capacity elective services in an attempt to tackle an ever-growing demand for lower limb arthroplasty, this pandemic has presented rare opportunities to revise and re-engage elective arthroplasty pathways aimed at improving patient care and healthcare efficiency. AIMS: We present the development of an evidence-based multidisciplinary perioperative care pathway for day-case total knee arthroplasty (TKA) in a United Kingdom National Health Service (NHS) institution, in conjunction with a review of the literature upon which the protocol is founded. METHODOLOGY: We performed a review of the literature reporting complication or readmission rates at ≥30 day postoperative following day-case TKA. Electronic searches were performed using four databases from the date of inception to November 2020. Relevant studies were identified, data extracted, and qualitative synthesis performed. RESULTS: 13 manuscripts with a total of 3370 day-case TKAs, defined as discharged on the same-calendar-day of surgery, were included in analysis. Mean 90-day complication rates (8.31% [range, 0-16.3%] vs 9.49% [range, 0-13.1%], respectively) and readmission rates (2.71% [range, 0-10.0%] vs 3.41% [range, 0-9.9%], respectively) were equivocal between day-case and inpatient TKA. The overall rate of successful same-calendar-day discharge was 95.8%. Our evaluation and critique of the evidence-based literature identifies day-case TKA to be safe, effective and economical, benefitting both patients and healthcare systems alike. CONCLUSION: We further validate the introduction of our institutional Elective Day Surgery Arthroplasty Pathway (EDSAP) based on the evidence presented. Careful patient selection paralleled with well-defined care pathways are essential for successful introduction of day-case TKA into the NHS.

Human Papillomavirus Impact on Temporal Treatment Trends in Oropharyngeal Carcinoma: 2010-2016.

INTRODUCTION: The study objective was to identify practice patterns in oropharyngeal cancer management from 2010 to 2016 among human papillomavirus (HPV)-associated and non-HPV-associated oropharyngeal squamous-cell carcinoma (OPSCC) patients. METHODS: The National Cancer Database was utilized to identify OPSCC patients from 2010 to 2016. Frequency distributions and multivariable analyses were generated to identify practice patterns and predictors of treatment modality. RESULTS: A total of 35,956 patients with nonmetastatic OPSCC were included. HPV status was not associated with a treatment modality preference. At academic centers, the proportion of HPV-associated OPSCC patients versus non-HPV-associated OPSCC patients undergoing surgical management was similar (35.7%; 35.9%). Community cancer programs treated patients less often surgically but with no significant treatment preference based on HPV status. Within each facility type, HPV status was not a predictor of surgical or nonsurgical management. CONCLUSION: HPV association does not appear to significantly influence treatment modality preference among OPSCC patients. The proportion of OPSCC patients undergoing surgical treatment declined from 2010 to 2016.

Tubing determination in an hematology oncology clinic.

United States Pharmacopeia (USP) Chapter <800> for hazardous drug (HD) handling in healthcare settings requires HD be primed intravenously with a non-HD solution prior to dispensing. This review details our clinic's algorithm for determining tubing needs for medications used in an hematology oncology clinic. Factors to consider are volume, irritant and vesicant properties, and compatibility with hydration solution.

Blood vessel epicardial substance reduces LRP6 receptor and cytoplasmic ß-catenin levels to modulate Wnt signaling and intestinal homeostasis.

Blood vessel epicardial substance (BVES, otherwise known as POPDC1) is an integral membrane protein known to regulate tight junction formation and epithelial-mesenchymal transition. BVES is underexpressed in a number of malignancies, including colorectal cancer. BVES loss leads to activation of the Wnt pathway, suggesting that decreased BVES expression functionally contributes to tumorigenesis. However, the mechanism by which BVES modulates Wnt signaling is unknown. Here, we confirm that BVES loss increases ß-catenin protein levels, leads to Wnt pathway activation in a ligand-independent fashion and coordinates with Wnt ligand to further increase Wnt signaling. We show that BVES loss increases levels and activation of the Wnt co-receptor, LRP6, in cell lines, murine adenoma tumoroids and human-derived colonoids. We also demonstrate that BVES interacts with LRP6. Finally, murine tumor modeling using a Wnt-driven genetic model and a chemically induced model of colorectal carcinogenesis demonstrate that BVES loss increases tumor multiplicity and dysplasia. Together, these results implicate BVES as an inhibitor of Wnt signaling, provide one of the first examples of a tight junction-associated protein regulating Wnt receptor levels, and expand the number of putative molecular targets for therapeutic intervention in colorectal cancer.

The TORC1-activated Proteins, p70S6K and GRB10, Regulate IL-4 Signaling and M2 Macrophage Polarization by Modulating Phosphorylation of Insulin Receptor Substrate-2.

Lung M2 macrophages are regulators of airway inflammation, associated with poor lung function in allergic asthma. Previously, we demonstrated that IL-4-induced M2 gene expression correlated with tyrosine phosphorylation of the insulin receptor substrate-2 (IRS-2) in macrophages. We hypothesized that negative regulation of IRS-2 activity after IL-4 stimulation is dependent upon serine phosphorylation of IRS-2. Herein, we describe an inverse relationship between tyrosine phosphorylation (Tyr(P)) and serine phosphorylation (Ser(P)) of IRS-2 after IL-4 stimulation. Inhibiting serine phosphatase activity increased Ser(P)-IRS-2 and decreased Tyr(P)-IRS-2 leading to reduced M2 gene expression (CD200R, CCL22, MMP12, and TGM2). We found that inhibition of p70S6K, downstream of TORC1, resulted in diminished Ser(P)-IRS-2 and prolonged Tyr(P)-IRS-2 as well. Inhibition of p70S6K increased expression of CD200R and CCL22 indicating that p70S6K negatively regulates some, but not all, human M2 genes. Knocking down GRB10, another negative regulatory protein downstream of TORC1, enhanced both Tyr(P)-IRS-2 and increased expression of all four M2 genes. Furthermore, GRB10 associated with IRS-2, NEDD4.2 (an E3-ubiquitin ligase), IL-4Rα, and γC after IL-4 stimulation. Both IL-4Rα and γC were ubiquitinated after 30 min of IL-4 treatment, suggesting that GRB10 may regulate degradation of the IL-4 receptor-signaling complex through interactions with NEDD4.2. Taken together, these data highlight two novel regulatory proteins that could be therapeutically manipulated to limit IL-4-induced IRS-2 signaling and polarization of M2 macrophages in allergic inflammation.

BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation.

Blood vessel epicardial substance (BVES/Popdc1) is a junctional-associated transmembrane protein that is underexpressed in a number of malignancies and regulates epithelial-to-mesenchymal transition. We previously identified a role for BVES in regulation of the Wnt pathway, a modulator of intestinal stem cell programs, but its role in small intestinal (SI) biology remains unexplored. We hypothesized that BVES influences intestinal stem cell programs and is critical to SI homeostasis after radiation injury. At baseline, Bves(-/-) mice demonstrated increased crypt height, as well as elevated proliferation and expression of the stem cell marker Lgr5 compared to wild-type (WT) mice. Intercross with Lgr5-EGFP reporter mice confirmed expansion of the stem cell compartment in Bves(-/-) mice. To examine stem cell function after BVES deletion, we used ex vivo 3D-enteroid cultures. Bves(-/-) enteroids demonstrated increased stemness compared to WT, when examining parameters such as plating efficiency, stem spheroid formation, and retention of peripheral cystic structures. Furthermore, we observed increased proliferation, expression of crypt-base columnar "CBC" and "+4" stem cell markers, amplified Wnt signaling, and responsiveness to Wnt activation in the Bves(-/-) enteroids. Bves expression was downregulated after radiation in WT mice. Moreover, after radiation, Bves(-/-) mice demonstrated significantly greater SI crypt viability, proliferation, and amplified Wnt signaling in comparison to WT mice. Bves(-/-) mice also demonstrated elevations in Lgr5 and Ascl2 expression, and putative damage-responsive stem cell populations marked by Bmi1 and TERT. Therefore, BVES is a key regulator of intestinal stem cell programs and mucosal homeostasis. Stem Cells 2016;34:1626-1636.

Nebulized Fentanyl in Acute Pain: A Systematic Review.

OBJECTIVE: To provide a systematic review of the current role of nebulized fentanyl in acute pain and potentially other conditions. DATA SOURCES: A MEDLINE literature search inclusive of the dates 1946 to May 2016 was performed using the following search terms: fentanyl and administration, inhaled Excerpta Medica was searched from 1980 to May 2016 using the following search terms: exp fentanyl/inhalation drug administration Additionally, Web of Science was searched using the terms fentanyl and pain inclusive of 1945 to May 2016. STUDY SELECTION AND DATA EXTRACTION: We utilized the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to select English language, human primary literature, review articles, and supporting data assessing the efficacy of nebulized fentanyl in acute pain. DATA SYNTHESIS: Seven clinical trials have demonstrated no difference in efficacy between nebulized fentanyl and intravenous (IV) opioids. Few adverse effects were reported; however, the trials were of short duration. Nebulized fentanyl appeared to be a rapid-acting analgesic that does not require IV access. CONCLUSION: Evidence suggests that nebulized fentanyl is as effective as IV opioids in the treatment of acute pain, with relatively few adverse effects. However, questions remain about the extemporaneous preparation of fentanyl nebulized solution, the variability in nebulization devices, and ensuring consistent drug delivery to distal airways in the clinical setting. The abuse potential of nebulized fentanyl should also be considered.

Gay and Bisexual Men's Willingness to Use a Self-Collected Anal Cancer Screening Test.

OBJECTIVE: We investigated gay and bisexual men's willingness to self-administer an anal cancer screening test at home. METHODS: We conducted 2 national, online cross-sectional surveys of self-identified gay and bisexual men: Study I in 2009 with men ages 20 to 59 (n = 306) and Study II in 2013 with men ages 18 to 26 (n = 428). We used multivariate logistic regression analyses to determine variables associated with willingness to self-administer the screening test. RESULTS: Most men were willing to self-administer an anal cancer screening test (78% Study I; 67% Study II). In Study I, willingness was higher among men who trusted anal Paps to find treatable cancer (adjusted odds ratio [aOR] = 1.47; 95% CI, 1.04-2.09) and who believed that men who have sex with men should be screened for anal cancer between 1 and 3 years vs. other intervals (aOR = 2.19; 95% CI, 1.17-4.10). In Study II, willingness was higher among men who perceived greater likelihood of anal cancer (aOR = 1.57; 95% CI, 1.12-2.20). Their most common concerns were not performing the test correctly and inaccuracy of results. CONCLUSIONS: Many gay and bisexual men were willing to self-administer anal cancer screening tests at home. If routine screening is warranted, self-collected home testing could improve participation.

Role of PTEN in basal cell derived lung carcinogenesis.

Lung adenocarcinoma (AdC) and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes, however, most genetic mouse models of lung cancer produce predominantly, if not exclusively, AdC. Whether this is secondary to targeting mutations to the distal airway cells or to the use of activating Kras mutations that drive AdC formation is unknown. We previously showed that targeting Kras(G12D) activation and transforming growth factor ß receptor type II (TGFßRII) deletion to airway basal cells via a keratin promoter induced formation of both lung AdC and SCC. In this study we assessed if targeting phosphatase and tensin homologue (PTEN) deletion to airway basal cells could initiate lung tumor formation or increase lung SCC formation. We found that PTEN deletion is capable of initiating both lung AdC and SCC formation when targeted to basal cells and although PTEN deletion is a weaker tumor initiator than Kras(G12D) with low tumor multiplicity and long latency, tumors initiated by PTEN deletion were larger and displayed more malignant conversion than Kras(G12D) initiated tumors. That PTEN deletion did not increase lung SCC formation compared to Kras(G12D) activation, suggests that the initiating genetic event does not dictate tumor histology when genetic alterations are targeted to a specific cell. These studies also confirm that basal cells of the conducting airway are capable of giving rise to multiple NSCLC tumor types.

Operative Repair of Hamstring Injuries From the Jackling Position in Rugby.

Background: The jackling position within rugby has not been previously described as a mechanism for proximal hamstring injuries. Hypothesis: Acute surgical repair of proximal hamstring avulsion injuries sustained from the jackling contact position enables a return to a previous level of sporting activity with low risk of recurrence. Study Design: Case series; Level of evidence, 4. Methods: This study included 54 professional rugby players (mean age, 26 ± 4.8 years) who underwent acute primary surgical repair of complete, proximal hamstring avulsion injuries. The mean follow-up time was 17 months (range, 12-24 months). Mean isometric hamstring strength and function testing was performed at 3 months and 1 year after repair. Results: Of the 54 players, 51 (94.4%) returned to their preinjury level of sporting activity. The mean time from surgical repair to full sporting activity was 7 months (range, 4-12 months). No patients had recurrence of the primary injury. At 1 year postoperatively, patients had significantly restored mean isometric hamstring muscle strength when compared with the uninjured leg at 0° (98.4% ± 2.8%), 15° (95.9% ± 2.9%), and 45° (92.9% ± 4.1%); improved Lower Extremity Functional Score (78.0 ± 2.0); and improved Marx activity rating score (14.3 ± 1.5) (P < .001 for all). Conclusion: Acute surgical repair of proximal hamstring avulsion injuries caused by the contact jackling position produced a high return to preinjury level of sporting activity, increased muscle strength, and improved functional outcome scores, with a low risk of recurrence at short-term follow-up.

The relationship between LDH and GLIM criteria for cancer cachexia: Systematic review and meta-analysis.

INTRODUCTION: Cancer cachexia is a clinical condition characterized by recognizable "sickness behaviors" accompanied by loss of lean body tissue. The Global Leadership on Malnutrition (GLIM) has proposed phenotypic (unintentional weight loss, low body mass index and low muscle mass) and aetiologic (reduced food intake and inflammation or disease burden) diagnostic criteria. Recent work has suggested serum lactate dehydrogenase (LDH) might represent a 3rd aetiologic criteria. Little is known of its relationship with GLIM. A systematic review and meta-analysis of their comparative prognostic value and association was performed. METHODS: A search of electronic databases (PubMed, Medline, Ovid, Cochrane) up to February 2023 was used to identify studies that compared the prognostic value of LDH and components of the GLIM criteria in cancer. An analysis of the relationship between LDH and the components of GLIM was undertaken where this data was available. RevMan 5.4.1 was used to perform a meta-analysis for each diagnostic criteria that had 3 or more studies which reported hazard ratios with a 95 per cent confidence interval for overall survival (OS). RESULTS: A total of 119 studies were reviewed. Advanced lung cancer was the most studied population. Included in the meta-analysis were 6 studies (n=2165) on LDH and weight loss, 17 studies (n=7540) on LDH and low BMI, 5 studies (n=758) on LDH and low muscle mass, 0 studies on LDH and food intake and 93 studies (n=32,190) on LDH and inflammation. There was a significant association between elevated serum LDH and each of low BMI (OR 1.39, 1.09 - 1.77; p=0.008), elevated NLR (OR 2.04, 1.57 - 2.65; p<0.00001) and elevated CRP (OR 2.58, 1.81 - 3.67; p<0.00001). There was no association between elevated serum LDH and low muscle mass. Only one study presented data on the association between LDH and unintentional weight loss. Elevated LDH showed a comparative OS (HR 1.86, 1.57 - 2.07; p<0.00001) to unintentional weight loss (HR 1.57, 1.23 - 1.99; p=0.0002) and had a similar OS (HR 2.00, 1.70 - 2.34; p<0.00001) to low BMI (HR 1.57, 1.29-2.90; p<0.0001). LDH also showed an OS (HR 2.25, 1.76 - 2.87; p<0.00001) congruous with low muscle mass (HR 1.93, 1.14 - 3.27; p=0.01) and again, LDH conferred as poor an OS (HR 1.77, 1.64-1.90; p<0.00001) as elevated NLR (HR 1.61, 1.48 - 1.77; p<0.00001) or CRP (HR 1.55, 1.43 - 1.69; p<0.00001). CONCLUSION: Current literature suggests elevated serum LDH is associated with inflammation in cancer (an aetiologic GLIM criterion), however more work is required to establish the relationship between LDH and the phenotypic components of GLIM. Additionally, elevated serum LDH appears to be a comparative prognosticator of overall survival in cancer when compared to the GLIM criteria.

Biomarker endpoints in cancer cachexia clinical trials: Systematic Review 5 of the cachexia endpoint series.

Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety-nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C-reactive protein (n = 22, 42.3%), interleukin-6 (n = 16, 30.8%) and tumour necrosis factor-α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor 1 (IGF-1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP-3, IGF-1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.

Evaluation of the in vitro cytotoxicity of cross-linked biomaterials.

This study evaluated the in vitro cytotoxicity of poly(propylene fumarate) (PPF). PPF is an aliphatic biodegradable polymer that has been well characterized for use in bone tissue engineering scaffolds. Four different cell types, human mesenchymal stem cells (hMSC), fibroblasts (L929), preosteoblasts (MC3T3), and canine mesenchymal stem cells (cMSC), were used to evaluate the cytotoxicity of PPF. These cell types represent the tissues that PPF would interact with in vivo as a bone tissue scaffold. The sol fraction of the PPF films was measured and then utilized to estimate cross-linking density. Cytotoxicity was evaluated using XTT assay and fluorescence imaging. Results showed that PPF supported similar cell metabolic activities of hMSC, L929, MC3T3, and cMSC compared to the noncytotoxic control, high-density polyethylene (HDPE) and were statistically different than those cultured with the cytotoxic control, a polyurethane film containing 0.1% zinc diethyldithiocarbamate (ZCF). Results showed differing cellular responses to ZCF, the cytotoxic control. The L929 cells had the lowest cell metabolic activity levels after exposure to ZCF compared to the cell metabolic activity levels of the MC3T3, hMSC, or cMSC cells. Qualitative verification of the results using fluorescence imaging demonstrated no change in cell morphology, vacuolization, or detachment when cultured with PPF compared to HDPE or blank media cultures. Overall, the cytotoxicity response of the cells to PPF was demonstrated to be similar to the cytotoxic response of cells to known noncytotoxic materials (HDPE).