Spend less to achieve more: Economic analysis of intermittent versus continuous cetuximab in KRAS wild-type patients with metastatic colorectal cancer.

BACKGROUND: In 2014, the COIN-B clinical trial demonstrated that intermittent cetuximab (IC) was a safe alternative to continuous cetuximab (CC), with less cytotoxic chemotherapy, in first-line treatment for KRAS wild-type metastatic colorectal cancer (mCRC). Cetuximab has been available for this indication in England since 2015, but treatment breaks beyond 6 weeks were prohibited, despite real-world evidence that therapy de-escalation maintains equivalent disease control, but with superior Quality-of-Life (QoL). We performed health economic analyses of IC versus CC and used this evidence to help underpin policy change and guide clinical practice through reduction in unnecessary treatment for mCRC patients. METHODS: Employing cost-minimization analysis, we conducted partitioned survival modelling (PSM) and Markov Chain Monte-Carlo (MCMC) simulation to determine costs and quality-adjusted-life-years for IC versus CC. RESULTS: IC reduced costs by £â€¯35,763 (PSM; p < 0.001) or £â€¯30,189 (MCMC) per patient annually, while preserving treatment efficacy and enhancing QoL. Extrapolating to all mCRC patients eligible for cetuximab therapy would have generated cost savings of ~£â€¯1.2 billion over this cohort's lifetime. These data helped underpin a request to NHS England to remove treatment break restrictions in first-line mCRC therapy, which has been adopted as an interim treatment option policy in colorectal cancer during the Covid-19 pandemic. CONCLUSIONS: Our results highlight substantial cost savings achievable by treatment de-escalation, while also reinforcing the importance of therapy breaks to potentially increase tumour responsiveness and reduce treatment toxicity. Our study also highlights how health economic evidence can influence health policy, championing reduced treatment intensity approaches without compromising patient outcomes, which is of particular relevance when addressing the reduced capacity and treatment backlogs experienced during the pandemic.

Economy of Hand Motion During Cleft Palate Surgery Using a High-Fidelity Cleft Palate Simulator.

OBJECTIVE: The objectives of this study were to assess economy of hand motion of residents, fellows, and staff surgeons using a high-fidelity cleft palate simulator to (1) stratify performance for the purpose of simulator validation and (2) to estimate the learning curve. DESIGN: Two residents, 2 fellows, and 2 staff surgeons performed cleft palate surgery on a high-fidelity cleft palate simulator while their hand motion was tracked using an electromagnetic hand sensor. The time, number of hand movements, and path length of their hands were determined for 10 steps of the procedure. The magnitude of these metrics was compared among the 3 groups of participants and utilized to estimate the learning curve using curve-fitting analysis. RESULTS: The residents required the most time, number of hand movements, and path length to complete the procedure. Although the number of hand movements was closely matched between the fellows and staff, the overall total path length was shorter for the staff. Inverse curves were fit to the data to represent the learning curve and 25 and 113 simulation sessions are required to reach within 5% and 1% of the expert level, respectively. CONCLUSION: The simulator successfully stratified performance using economy of hand motion. Path length is better matched to previous level of experience compared to time or number of hand movements.

Inequality in access to cultural ecosystem services from protected areas in the Chilean biodiversity hotspot.

Experiences with nature through visits to protected areas provide important cultural ecosystem services that have the potential to strengthen pro-environmental attitudes and behavior. Understanding accessibility to protected areas and likely preferences for enjoying the benefits of nature visits are key factors in identifying ways to reduce inequality in access and inform the planning and management for future protected areas. We develop, at a regional scale, a novel social media database of visits to public protected areas in part of the Chilean biodiversity hotspot using geotagged photographs and assess the inequality of access using the home locations of the visitors and socio-economic data. We find that 20% of the population of the region make 87% of the visits to protected areas. The larger, more biodiverse protected areas were the most visited and provided most cultural ecosystem services. Wealthier people tend to travel further to visit protected areas while people with lower incomes tend to visit protected areas that are closer to home. By providing information on the current spatial flows of people to protected areas, we demonstrate the need to expand the protected area network, especially in lower income areas, to reduce inequality in access to the benefits from cultural ecosystem services provided by nature to people.

Assessing Technical Performance and Determining the Learning Curve in Cleft Palate Surgery Using a High-Fidelity Cleft Palate Simulator.

BACKGROUND: This study assessed technical performance in cleft palate repair using a newly developed assessment tool and high-fidelity cleft palate simulator through a longitudinal simulation training exercise. METHODS: Three residents performed five and one resident performed nine consecutive endoscopically recorded cleft palate repairs using a cleft palate simulator. Two fellows in pediatric plastic surgery and two expert cleft surgeons also performed recorded simulated repairs. The Cleft Palate Objective Structured Assessment of Technical Skill (CLOSATS) and end-product scales were developed to assess performance. Two blinded cleft surgeons assessed the recordings and the final repairs using the CLOSATS, end-product scale, and a previously developed global rating scale. RESULTS: The average procedure-specific (CLOSATS), global rating, and end-product scores increased logarithmically after each successive simulation session for the residents. Reliability of the CLOSATS (average item intraclass correlation coefficient (ICC), 0.85 ± 0.093) and global ratings (average item ICC, 0.91 ± 0.02) among the raters was high. Reliability of the end-product assessments was lower (average item ICC, 0.66 ± 0.15). Standard setting linear regression using an overall cutoff score of 7 of 10 corresponded to a pass score for the CLOSATS and the global score of 44 (maximum, 60) and 23 (maximum, 30), respectively. Using logarithmic best-fit curves, 6.3 simulation sessions are required to reach the minimum standard. CONCLUSIONS: A high-fidelity cleft palate simulator has been developed that improves technical performance in cleft palate repair. The simulator and technical assessment scores can be used to determine performance before operating on patients.

Objective Assessment of the Unilateral Cleft Lip Nasal Deformity Using Three-Dimensional Stereophotogrammetry: Severity and Outcome.

BACKGROUND: Optimization of care to correct the unilateral cleft lip nasal deformity is hampered by lack of objective measures to quantify preoperative severity and outcome. The purpose of this study was to develop a consensus standard of nasal appearance using three-dimensional stereophotogrammetry; determine whether anthropometric measurements could be used to quantify severity and outcome; and determine whether preoperative severity predicts postoperative outcome. METHODS: The authors collected facial three-dimensional images of 100 subjects in three groups: 45 infants before cleft lip repair; the same 45 infants after cleft lip repair; and 45 children aged 8 to 10 years with previous repairs. Five additional age-matched unaffected control subjects were included in each group. Seven expert surgeons ranked images in each group according to nasal appearance. The rank sum score was used as consensus standard. Anthropometric analysis was performed on each image and compared to the rank sum score. Preoperative rank and anthropometric measurements were compared to postoperative rank. RESULTS: Interrater and intrarater reliability was excellent (intraclass correlation coefficient, >0.76; Pearson correlation, >0.75) on each of the three image sets. Columellar angle, nostril width ratio, and lateral lip height ratio were highly correlated with preoperative severity and moderately correlated with postoperative nasal appearance. Postoperative outcome was associated with preoperative severity (rank and anthropometric measurement). CONCLUSIONS: Consensus ranking of preoperative severity and postoperative outcome can be achieved on three-dimensional images. Preoperative severity predicts postoperative outcomes. Columellar angle, nostril width ratio, and lateral lip height ratio are objective measures that correlate with consensus ratings by surgeons at multiple ages.

Infant Robotic Cleft Palate Surgery: A Feasibility Assessment Using a Realistic Cleft Palate Simulator.

BACKGROUND: A surgical robot offers enhanced precision, visualization, and access and the potential to improve outcomes in cleft palate surgery. The goal of this study was to investigate the feasibility of using the da Vinci robot for cleft palate repair in infants using a cleft palate simulator test bed. METHODS: A high-fidelity cleft palate simulator was developed that allows performance of a robotic cleft palate repair procedure. A complete cleft palate repair was performed with the da Vinci Si with 5-mm instruments and the da Vinci Xi with 8-mm instruments. The advantages of the robotic approach were assessed in comparison with using standard instruments. For each system, arm repositioning, collisions, instrument and endoscope excursion, wrist orientation, and vision were compared for 12 steps of the repair. RESULTS: The cleft palate simulator provided a reproducible platform for testing robotic cleft palate surgery. The advantages of the robotic approach were the ability to articulate a miniature wrist intraorally with superior visualization, increased ambidexterity, and improved ergonomics compared with using standard instruments. Cleft palate repair with the Xi was superior to the Si with respect to arm repositioning, instrument collisions and excursion, and wrist orientation. However, Xi performance remained suboptimal because of the larger instruments. CONCLUSIONS: Robotic cleft palate repair using the da Vinci system offers advantages compared with the traditional approach. Cleft palate repair is more feasible with the Xi and 8-mm instruments. However, performance is limited by the instrumentation, which requires modification to ensure safety and efficacy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Investing in Obesity Treatment: Kaiser Permanente's Approach to Chronic Disease Management.

Kaiser Permanente, an integrated health care delivery system in the USA, takes a "whole systems" approach to the chronic disease of obesity that begins with efforts to prevent it by modifying the environment in communities and schools. Aggressive case-finding and substantial investment in intensive lifestyle modification programs target individuals at high risk of diabetes and other weight-related conditions. Kaiser Permanente regions are increasingly standardizing their approach when patients with obesity require treatment intensification using medically supervised diets, prescription medication to treat obesity, or weight loss surgery.

Optimisation of a simple method to transiently transfect a CHO cell line in high-throughput and at large scale.

Transient expression of heterologous proteins in mammalian systems is a powerful way to generate protein reagents quickly. However, it has historically suffered from poor yields in comparison to methods where the recombinant gene is stably integrated into the genome and high expressing clones isolated. Transient methods have been well described for HEK-based systems. In this paper we show the use of a design of experiments (DoE) approach to quickly analyse the effect of a range of different parameters on protein expression from a CHO-based transient system. We show that this system is amenable to a very simple transfection procedure by independent direct addition of DNA and transfection reagent to the culture vessel. In addition we show that expression can be improved by reducing the temperature of the culture conditions post-transfection. The process is demonstrated to be transferrable from 3 ml cultures in deep 24-well plates through cultures in CultiFlask Bioreactors, shake flasks and up to 25 L culture in Wave Bioreactors. Data are shown to illustrate the utility of the system with a number of different classes of protein.

Impact of bariatric surgery on life expectancy in severely obese patients with diabetes: a decision analysis.

OBJECTIVE: To create a decision analytic model to estimate the balance between treatment risks and benefits for severely obese patients with diabetes. BACKGROUND: Bariatric surgery leads to many desirable metabolic changes, but long-term impact of bariatric surgery on life expectancy in patients with diabetes has not yet been quantified. METHODS: We developed a Markov state transition model with multiple Cox proportional hazards models and logistic regression models as inputs to compare bariatric surgery versus no surgical treatment for severely obese diabetic patients. The model is informed by data from 3 large cohorts: (1) 159,000 severely obese diabetic patients (4185 had bariatric surgery) from 3 HMO Research Network sites; (2) 23,000 subjects from the Nationwide Inpatient Sample; and (3) 18,000 subjects from the National Health Interview Survey linked to the National Death Index. RESULTS: In our main analyses, we found that a 45-year-old woman with diabetes and a body mass index (BMI) of 45 kg/m gained an additional 6.7 years of life expectancy with bariatric surgery (38.4 years with surgery vs 31.7 years without surgery). Sensitivity analyses revealed that the gain in life expectancy decreased with increasing BMI, until a BMI of 62 kg/m is reached, at which point nonsurgical treatment was associated with greater life expectancy. Similar results were seen for both men and women in all age groups. CONCLUSIONS: For most severely obese patients with diabetes, bariatric surgery seems to improve life expectancy; however, surgery may reduce life expectancy for the super obese with BMIs over 62 kg/m.

An assessment of risk factors associated with ifosfamide-induced encephalopathy in a large academic cancer center.

PURPOSE: Ifosfamide-induced encephalopathy is a neurotoxic adverse effect of ifosfamide chemotherapy. The objective of this study was to determine the incidence of encephalopathy in patients with lymphoma and sarcoma receiving ifosfamide chemotherapy and assess for potential risk factors that influence the incidence of encephalopathy. METHODS: A retrospective study of sarcoma and lymphoma patients receiving ifosfamide chemotherapy was performed at the participating institutions. Enrollment began 1 July 2011 and continued chronologically backwards until 100 sarcoma and 100 lymphoma patients were enrolled. Identification of ifosfamide-induced encephalopathy events was performed by reviewing provider documentation of ifosfamide infusions. Logistic regression was employed to determine associations between risk factors and ifosfamide-induced encephalopathy events. RESULTS: Of the 200 patients enrolled, 29 (14.5%) patients experienced encephalopathy. Ifosfamide-induced encephalopathy occurred more frequently in the sarcoma population than the lymphoma population (24 vs. 5 patients, p < 0.001). In addition to cancer type, prior use of cisplatin, concomitant opioids, and use of CYP2B6 inhibitors remained as significant variables in the multivariate model conferring a 12.47, 2.81, and 5.17 increased odds of experiencing encephalopathy, respectively. The odds of experiencing encephalopathy were 9.0 and 1.37 times higher for a one-unit increase in serum creatinine and hemoglobin, respectively, and 0.15 times lower for a one-unit increase in albumin. CONCLUSIONS: This is the first study to demonstrate that patients with sarcoma experienced ifosfamide-induced encephalopathy more often than those with lymphoma. For all patients, predisposing factors for ifosfamide-induced encephalopathy included previous cisplatin exposure, concomitant opioids and CYP2B6 inhibitors. Laboratory values that increased ifosfamide-induced encephalopathy risk included low serum albumin, increased serum creatinine, and increased hemoglobin.

Quantitative assessment of Tet-induced oxidation products of 5-methylcytosine in cellular and tissue DNA.

Recent studies showed that Ten-eleven translocation (Tet) family dioxygenases can oxidize 5-methyl-2'-deoxycytidine (5-mdC) in DNA to yield the 5-hydroxymethyl, 5-formyl and 5-carboxyl derivatives of 2'-deoxycytidine (5-HmdC, 5-FodC and 5-CadC). 5-HmdC in DNA may be enzymatically deaminated to yield 5-hydroxymethyl-2'-deoxyuridine (5-HmdU). After their formation at CpG dinucleotide sites, these oxidized pyrimidine nucleosides, particularly 5-FodC, 5-CadC, and 5-HmdU, may be cleaved from DNA by thymine DNA glycosylase, and subsequent action of base-excision repair machinery restores unmethylated cytosine. These processes are proposed to be important in active DNA cytosine demethylation in mammals. Here we used a reversed-phase HPLC coupled with tandem mass spectrometry (LC-MS/MS/MS) method, along with the use of stable isotope-labeled standards, for accurate measurements of 5-HmdC, 5-FodC, 5-CadC and 5-HmdU in genomic DNA of cultured human cells and multiple mammalian tissues. We found that overexpression of the catalytic domain of human Tet1 led to marked increases in the levels of 5-HmdC, 5-FodC and 5-CadC, but only a modest increase in 5-HmdU, in genomic DNA of HEK293T cells. Moreover, 5-HmdC is present at a level that is approximately 2-3 and 3-4 orders of magnitude greater than 5-FodC and 5-CadC, respectively, and 35-400 times greater than 5-HmdU in the mouse brain and skin, and human brain. The robust analytical method built a solid foundation for dissecting the molecular mechanisms of active cytosine demethylation, for measuring these 5-mdC derivatives and assessing their involvement in epigenetic regulation in other organisms and for examining whether these 5-mdC derivatives can be used as biomarkers for human diseases.

Developing effective physician leaders: changing cultures and transforming organizations.

In this article, the authors discuss the problematic issue of transformational change in the face of cultural conflict between the worlds of clinical care and organizational leadership, and describe a case study of organizational cultural change facilitated through a physician leadership development program. A locally developed physician leadership program can be extremely effective at both improving physicians' leadership skills and increasing understanding of the strategic goals and direction of the organization. The transformational change required for physicians to develop and appreciate business and leadership skills can be supported and encouraged in a leadership development program that includes the components of careful curriculum design, program monitoring, and opportunities to apply new skills in practice. For Columbus Children's Hospital, Columbus, Ohio, this organizational transformational change effort was successfully achieved when a new medical leadership development program helped academic and community physicians to become involved in organizational leadership. The authors describe the background and development of this program and provide results of their evaluation of the program, with discussion of future extensions to the program.