RESUMO
Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.
Assuntos
Antivirais/administração & dosagem , Sistemas de Liberação de Medicamentos , Hepatite C Crônica/tratamento farmacológico , Animais , Antivirais/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Carbamatos , Análise Custo-Benefício , Modelos Animais de Doenças , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/economia , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Fluorenos/administração & dosagem , Fluorenos/farmacocinética , Hepacivirus/efeitos dos fármacos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Cirrose Hepática/tratamento farmacológico , Modelos Animais , Pirrolidinas , Ribavirina/administração & dosagem , Ribavirina/farmacocinética , Sofosbuvir/administração & dosagem , Sofosbuvir/farmacocinética , Suínos , Valina/análogos & derivadosRESUMO
BACKGROUND: Patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) show a significant response to checkpoint inhibitor therapies, but the economic impact of these therapies is unknown. A decision analytic model was used to explore the effectiveness and cost burden of MSI-H/dMMR mCRC treatment. METHODS: The treatment of hypothetical patients with MSI-H/dMMR mCRC was simulated in 2 treatment scenarios: a third-line treatment and an exploratory first-line treatment. The treatments compared were nivolumab, ipilimumab and nivolumab, trifluridine and tipiracil (third-line treatment), and mFOLFOX6 and cetuximab (first-line treatment). Disease progression, drug toxicity, and survival rates were based on the CheckMate 142, study of TAS-102 in patients with metastatic colorectal cancer refractory to standard chemotherapies (RECOURSE), and Cancer and Leukemia Group B/Southwest Oncology Group 80405 trials. The analyzed outcomes included survival (life-years), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Ipilimumab with nivolumab was the most effective strategy (10.69 life-years and 9.25 QALYs for the third line; 10.69 life-years and 9.44 QALYs for the first line) in comparison with nivolumab (8.21 life-years and 6.76 QALYs for the third line; 8.21 life-years and 7.00 QALYs for the first line), trifluridine and tipiracil (0.74 life-years and 0.07 QALYs), and mFOLFOX6 and cetuximab (2.72 life-years and 1.63 QALYs). However, neither checkpoint inhibitor therapy was cost-effective in comparison with trifluridine and tipiracil (nivolumab ICER, $153,000; ipilimumab and nivolumab ICER, $162,700) or mFOLFOX6 and cetuximab (nivolumab ICER, $150,700; ipilimumab and nivolumab ICER, $158,700). CONCLUSIONS: This modeling analysis found that both single and dual checkpoint blockade could be significantly more effective for MSI-H/dMMR mCRC than chemotherapy, but they were not cost-effective, largely because of drug costs. Decreases in drug pricing and/or the duration of maintenance nivolumab could make ipilimumab and nivolumab cost-effective. Prospective clinical trials should be performed to explore the optimal duration of maintenance nivolumab.
Assuntos
Antineoplásicos Imunológicos/economia , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/economia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Análise Custo-Benefício , Reparo de Erro de Pareamento de DNA , Custos de Medicamentos , Feminino , Fluoruracila/economia , Fluoruracila/uso terapêutico , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/economia , Leucovorina/economia , Leucovorina/uso terapêutico , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Nivolumabe/economia , Compostos Organoplatínicos/economia , Compostos Organoplatínicos/uso terapêutico , Anos de Vida Ajustados por Qualidade de VidaAssuntos
Duodeno/parasitologia , Infecções por HTLV-I/diagnóstico , Strongyloides stercoralis/isolamento & purificação , Estrongiloidíase/diagnóstico , Dor Abdominal/etiologia , Adulto , Animais , Biópsia , Diagnóstico Diferencial , Diarreia/etiologia , Duodeno/patologia , Endoscopia do Sistema Digestório , Infecções por HTLV-I/complicações , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Intestinos/diagnóstico por imagem , Intestinos/patologia , Masculino , Estômago/patologia , Estrongiloidíase/complicações , Tomografia Computadorizada por Raios X , Redução de PesoRESUMO
BACKGROUND & AIMS: Although treatment of T1a esophageal adenocarcinoma (EAC) is shifting from esophagectomy to endoscopic therapy, T1b EACs are considered too high risk to be treated endoscopically. We investigated the effectiveness and cost effectiveness of esophagectomy vs endoscopic therapy for T1a and T1b EACs, and the effects of age and comorbidities, using a decision analytic Markov model. METHODS: We developed a model to simulate a hypothetical cohort of men 75 years old with Charlson comorbidity index scores of 0 and either T1aN0M0 or T1bN0M0 EAC, as a base case. We used the model to compare the effects of esophagectomy vs serial endoscopic therapy. We performed sensitivity analyses based on age at diagnosis of 60-85 years, comorbidity indices of 0-2, and utilities. Post-procedure cancer-specific mortality was derived from the Surveillance, Epidemiology, and End Results Medicare database. RESULTS: In the T1a base case, esophagectomy yielded more unadjusted life years than endoscopic therapy (6.97 vs 6.81), but fewer quality-adjusted life years (QALYs, 4.95 for esophagectomy vs 5.22 for endoscopic therapy). In the T1b base case, esophagectomy yielded more unadjusted life years than endoscopic therapy (5.73 vs 5.01) and QALYs (4.07 vs 3.85 for endoscopic therapy), but was not cost effective (incremental cost-effectiveness ratio $156,981). Sensitivity analyses showed endoscopic therapy optimized QALYs for patients more than 80 years old with a comorbidity index of 1 or 2, or if the ratio of post-esophagectomy to post-endoscopic therapy utilities was below 0.875. CONCLUSION: In a Markov model, we showed that endoscopic therapy of T1a EAC yields more QALYs and is more cost effective than esophagectomy for patients of all ages and comorbidity indices tested. In contrast, selection of therapy for T1b EAC depends on age and comorbidities, due to surgical mortality and the competing risk of non-cancer death.
Assuntos
Adenocarcinoma/cirurgia , Técnicas de Apoio para a Decisão , Endoscopia/métodos , Neoplasias Esofágicas/cirurgia , Procedimentos Cirúrgicos Operatórios/métodos , Idoso , Análise Custo-Benefício , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients. METHODS: We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK). FINDINGS: We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing. CONCLUSIONS: We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients. FUNDING: This work was supported by MIT's Karl van Tassel (1925) Career Development Professorship and Department of Mechanical Engineering and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.
Assuntos
Sistemas de Liberação de Medicamentos , Fluoruracila , Medicina de Precisão , Fluoruracila/farmacocinética , Fluoruracila/administração & dosagem , Coelhos , Animais , Sistemas de Liberação de Medicamentos/métodos , Medicina de Precisão/métodos , Humanos , Infusões Intravenosas , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/administração & dosagemRESUMO
Simplification of complex medication regimens in polypharmacy positively contributes to treatment adherence and cost-effective improved health outcomes. Even though fixed dose combination (FDC) drug products are the only currently available single dose poly-pill regimens, the lack of flexibility in dose adjustment of a single drug in the combination limits their efficacy. To fill the existing gap in drug dose personalization and simplification of complex medication regimens commonly encountered in the treatment of cardiovascular disease, tuberculosis, and tapering of corticosteroid therapy, a modular titratable polypill approach that simultaneously addresses both aspects is proposed. The polypill consists of modular units that contain different drugs at incremental or decremental doses to be assembled in a single titratable polypill at the required dose for each drug through a stacking or interlocking process. The variable dose (VD) modular tablets are subjected to quality control tests and found to comply to pharmacopeia's acceptance criteria and requirements specified in the respective drug monographs. A cost-effectiveness analysis is conducted supporting the VD strategy as cost-effective compared to the FDC strategy and more effective and less expensive than standard of care. The VD approach stands to enable pill burden reduction, ease of administration, enhancement of treatment adherence, and potential cost-saving benefits.
Assuntos
Doenças Cardiovasculares , Medicina de Precisão , Humanos , Combinação de Medicamentos , Doenças Cardiovasculares/tratamento farmacológicoRESUMO
BACKGROUND AND AIMS: Informed consent should allow patients the appropriate time and conditions to make decisions about their care. However, consent is often obtained immediately prior to a colonoscopy. We conducted a quality improvement study to assess how a preprocedure consent video 2 days prior to an outpatient colonoscopy impacts patient satisfaction. METHODS: Patients undergoing outpatient colonoscopy at a large academic medical center opted in to a text messaging platform for procedural information. Our intervention was an informed consent video 2 days before the colonoscopy. Our primary outcome was a composite patient satisfaction score. Pre and postintervention scores were compared using ordinal or multinomial logistic models to calculate odds ratios (OR) or relative risk ratios and 95% confidence intervals (CI), adjusting for age and sex. RESULTS: 1109 and 1452 patients completed ≥1 survey question in the pre and postintervention phases, respectively. Overall patient satisfaction did not differ between groups [OR for a 1-point increment in satisfaction score between post- vs pre-intervention groups = 1.05; 95% CI: 0.90-1.22; P = .51]. Compared to preintervention, postintervention respondents were more likely to report higher satisfaction with time available to talk with their physician (OR of a 1-point increase in individual question response = 1.29; 95% CI: 1.09-1.54; P = .004). Compared to preintervention, more physicians in the postintervention phase rated satisfaction with consent process efficiency as "very satisfied" or "satisfied" (P < .001). CONCLUSION: An informed consent video prior to colonoscopy resulted in similar overall patient satisfaction. However, post-intervention, patients were more likely to report sufficient time to talk with their physician, and physicians reported higher satisfaction with consent efficiency.
RESUMO
Gastrointestinal-based drug delivery is considered the preferred mode of drug administration owing to its convenience for patients, which improves adherence. However, unique characteristics of the gastrointestinal tract (such as the digestive environment and constraints on transport across the gastrointestinal mucosa) limit the absorption of drugs. As a result, many medications, in particular biologics, still exist only or predominantly in injectable form. In this Review, we examine the fundamentals of gastrointestinal drug delivery to inform clinicians and pharmaceutical scientists. We discuss general principles, including the challenges that need to be overcome for successful drug formulation, and describe the unique features to consider for each gastrointestinal compartment when designing drug formulations for topical and systemic applications. We then discuss emerging technologies that seek to address remaining obstacles to successful gastrointestinal-based drug delivery.
Assuntos
Sistemas de Liberação de Medicamentos , Trato Gastrointestinal , Fármacos Gastrointestinais , HumanosRESUMO
Maintaining an ample supply of personal protective equipment continues to be a challenge for the healthcare industry, especially during emergency situations and times of strain on the supply chain. Most critically, healthcare workers exposed to potential airborne hazards require sufficient respiratory protection. Respirators are the only type of personal protective equipment able to provide adequate respiratory protection. However, their ability to shield hazards depends on design, material, proper fit, and environmental conditions. As a result, not all respirators may be adequate for all scenarios. Additionally, factors including user comfort, ease of use, and cost contribute to respirator effectiveness. Therefore, a careful consideration of these parameters is essential for ensuring respiratory protection for those working in the healthcare industry. Here respirator design and material characteristics are reviewed, as well as properties of airborne hazards and potential filtration mechanisms, regulatory standards of governmental agencies, respirator efficacy in the clinical setting, attitude of healthcare personnel toward respiratory protection, and environmental and economic considerations of respirator manufacturing and distribution.
RESUMO
Importance: Before the widespread implementation of robotic systems to provide patient care during the COVID-19 pandemic occurs, it is important to understand the acceptability of these systems among patients and the economic consequences associated with the adoption of robotics in health care settings. Objective: To assess the acceptability and feasibility of using a mobile robotic system to facilitate health care tasks. Design, Setting, and Participants: This study included 2 components: a national survey to examine the acceptability of using robotic systems to perform health care tasks in a hospital setting and a single-site cohort study of patient experiences and satisfaction with the use of a mobile robotic system to facilitate triage and telehealth tasks in the emergency department (ED). The national survey comprised individuals living in the US who participated in a sampling-based survey via an online analytic platform. Participants completed the national survey between August 18 and August 21, 2020. The single-site cohort study included patients living in the US who presented to the ED of a large urban academic hospital providing quaternary care in Boston, Massachusetts between April and August 2020. All data were analyzed from August to October 2020. Exposures: Participants in the national survey completed an online survey to measure the acceptability of using a mobile robotic system to perform health care tasks (facilitating telehealth interviews, acquiring vital signs, obtaining nasal or oral swabs, placing an intravenous catheter, performing phlebotomy, and turning a patient in bed) in a hospital setting in the contexts of general interaction and interaction during the COVID-19 pandemic. Patients in the cohort study were exposed to a mobile robotic system, which was controlled by an ED clinician and used to facilitate a triage interview. After exposure, patients completed an assessment to measure their satisfaction with the robotic system. Main Outcomes and Measures: Acceptability of the use of a mobile robotic system to facilitate health care tasks in a hospital setting (national survey) and feasibility and patient satisfaction regarding the use of a mobile robotic system in the ED (cohort study). Results: For the national survey, 1154 participants completed all acceptability questions, representing a participation rate of 35%. After sample matching, a nationally representative sample of 1000 participants (mean [SD] age, 48.7 [17.0] years; 535 women [53.5%]) was included in the analysis. With regard to the usefulness of a robotic system to perform specific health care tasks, the response of "somewhat useful" was selected by 373 participants (37.3%) for facilitating telehealth interviews, 350 participants (35.0%) for acquiring vital signs, 307 participants (30.7%) for obtaining nasal or oral swabs, 228 participants (22.8%) for placing an intravenous catheter, 249 participants (24.9%) for performing phlebotomy, and 371 participants (37.1%) for turning a patient in bed. The response of "extremely useful" was selected by 287 participants (28.7%) for facilitating telehealth interviews, 413 participants (41.3%) for acquiring vital signs, 192 participants (19.2%) for obtaining nasal or oral swabs, 159 participants (15.9%) for placing an intravenous catheter, 167 participants (16.7%) for performing phlebotomy, and 371 participants (37.1%) for turning a patient in bed. In the context of the COVID-19 pandemic, the median number of individuals who perceived the application of robotic systems to be acceptable for completing telehealth interviews, obtaining nasal and oral swabs, placing an intravenous catheter, and performing phlebotomy increased. For the ED cohort study, 51 individuals were invited to participate, and 41 participants (80.4%) enrolled. One participant was unable to complete the study procedures because of a signaling malfunction in the robotic system. Forty patients (mean [SD] age, 45.8 [2.7] years; 29 women [72.5%]) completed the mobile robotic system-facilitated triage interview, and 37 patients (92.5%) reported that the interaction was satisfactory. A total of 33 participants (82.5%) reported that their experience of receiving an interview facilitated by a mobile robotic system was as satisfactory as receiving an in-person interview from a clinician. Conclusions and Relevance: In this study, a mobile robotic system was perceived to be acceptable for use in a broad set of health care tasks among survey respondents across the US. The use of a mobile robotic system enabled the facilitation of contactless triage interviews of patients in the ED and was considered acceptable among participants. Most patients in the ED rated the quality of mobile robotic system-facilitated interaction to be equivalent to in-person interaction with a clinician.
Assuntos
Atenção à Saúde/métodos , Serviço Hospitalar de Emergência , Hospitais , Assistência ao Paciente/métodos , Satisfação do Paciente , Robótica/métodos , Triagem , Adulto , Idoso , Boston , COVID-19 , Cateterismo , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Flebotomia , Exame Físico , Inquéritos e Questionários , TelemedicinaRESUMO
Importance: Adoption of mask wearing in response to the COVID-19 pandemic alters daily communication. Objective: To assess communication barriers associated with mask wearing in patient-clinician interactions and individuals who are deaf and hard of hearing. Design, Setting, and Participants: This pilot cross-sectional survey study included the general population, health care workers, and health care workers who are deaf or hard of hearing in the United States. Volunteers were sampled via an opt-in survey panel and nonrandomized convenience sampling. The general population survey was conducted between January 5 and January 8, 2021. The health care worker surveys were conducted between December 3, 2020, and January 3, 2021. Respondents viewed 2 short videos of a study author wearing both a standard and transparent N95 mask and answered questions regarding mask use, communication, preference, and fit. Surveys took 15 to 20 minutes to complete. Main Outcomes and Measures: Participants' perceptions were assessed surrounding the use of both mask types related to communication and the ability to express emotions. Results: The national survey consisted of 1000 participants (mean [SD] age, 48.7 [18.5] years; 496 [49.6%] women) with a response rate of 92.25%. The survey of general health care workers consisted of 123 participants (mean [SD] age, 49.5 [9.0] years; 84 [68.3%] women), with a response rate of 11.14%. The survey of health care workers who are deaf or hard of hearing consisted of 45 participants (mean [SD] age, 54.5 [9.0] years; 30 [66.7%] women) with a response rate of 23.95%. After viewing a video demonstrating a study author wearing a transparent N95 mask, 781 (78.1%) in the general population, 109 general health care workers (88.6%), and 38 health care workers who are deaf or hard of hearing (84.4%) were able to identify the emotion being expressed, in contrast with 201 (20.1%), 25 (20.5%), and 11 (24.4%) for the standard opaque N95 mask. In the general population, 450 (45.0%) felt positively about interacting with a health care worker wearing a transparent mask; 76 general health care workers (61.8%) and 37 health care workers who are deaf or hard of hearing (82.2%) felt positively about wearing a transparent mask to communicate with patients. Conclusions and Relevance: The findings of this study suggest that transparent masks could help improve communication during the COVID-19 pandemic, particularly for individuals who are deaf and hard of hearing.
Assuntos
COVID-19/prevenção & controle , Barreiras de Comunicação , Pessoal de Saúde/estatística & dados numéricos , Máscaras/estatística & dados numéricos , Relações Profissional-Paciente , Adulto , Comunicação , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos , Adulto JovemRESUMO
Continuous monitoring in the intensive care setting has transformed the capacity to rapidly respond with interventions for patients in extremis. Noninvasive monitoring has generally been limited to transdermal or intravascular systems coupled to transducers including oxygen saturation or pressure. Here it is hypothesized that gastric fluid (GF) and gases, accessible through nasogastric (NG) tubes, commonly found in intensive care settings, can provide continuous access to a broad range of biomarkers. A broad characterization of biomarkers in swine GF coupled to time-matched serum is conducted . The relationship and kinetics of GF-derived analyte level dynamics is established by correlating these to serum levels in an acute renal failure and an inducible stress model performed in swine. The ability to monitor ketone levels and an inhaled anaesthetic agent (isoflurane) in vivo is demonstrated with novel NG-compatible sensor systems in swine. Gastric access remains a main stay in the care of the critically ill patient, and here the potential is established to harness this establishes route for analyte evaluation for clinical management.
Assuntos
Injúria Renal Aguda/metabolismo , Anestésicos Inalatórios/metabolismo , Suco Gástrico/metabolismo , Isoflurano/metabolismo , Monitorização Fisiológica/métodos , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Intubação Gastrointestinal , Cetonas/metabolismo , Estômago/metabolismo , SuínosRESUMO
Cancer patients undergoing therapeutic radiation routinely develop injury of the adjacent gastrointestinal (GI) tract mucosa due to treatment. To reduce radiation dose to critical GI structures including the rectum and oral mucosa, 3D-printed GI radioprotective devices composed of high-Z materials are generated from patient CT scans. In a radiation proctitis rat model, a significant reduction in crypt injury is demonstrated with the device compared to without (p < 0.0087). Optimal device placement for radiation attenuation is further confirmed in a swine model. Dosimetric modeling in oral cavity cancer patients demonstrates a 30% radiation dose reduction to the normal buccal mucosa and a 15.2% dose reduction in the rectum for prostate cancer patients with the radioprotectant material in place compared to without. Finally, it is found that the rectal radioprotectant device is more cost-effective compared to a hydrogel rectal spacer. Taken together, these data suggest that personalized radioprotectant devices may be used to reduce GI tissue injury in cancer patients undergoing therapeutic radiation.
Assuntos
Trato Gastrointestinal/efeitos da radiação , Neoplasias Bucais/radioterapia , Impressão Tridimensional , Lesões por Radiação/prevenção & controle , Proteção Radiológica/instrumentação , Proteção Radiológica/métodos , Animais , Modelos Animais de Doenças , Trato Gastrointestinal/diagnóstico por imagem , Humanos , Mucosa/diagnóstico por imagem , Mucosa/efeitos da radiação , Órgãos em Risco , Ratos , Ratos Sprague-Dawley , Suínos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The 5-year survival rate of patients with metastatic gastric cancer (GC) is only 5%. However, trials have demonstrated promising antitumor activity for targeted therapies/immunotherapies among chemorefractory metastatic GC patients. Pembrolizumab has shown particular efficacy among patients with programmed death ligand-1 (PD-L1) expression and high microsatellite instability (MSI-H). The aim of this study was to assess the effectiveness and cost-effectiveness of biomarker-guided second-line GC treatment. METHODS: We constructed a Markov decision-analytic model using clinical trial data. Our model compared pembrolizumab monotherapy and ramucirumab/paclitaxel combination therapy for all patients and pembrolizumab for patients based on MSI status or PD-L1 expression. Paclitaxel monotherapy and best supportive care for all patients were additional comparators. Costs of drugs, treatment administration, follow-up, and management of adverse events were estimated from a US payer perspective. The primary outcomes were quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay threshold of $100,000/QALY over 60 months. Secondary outcomes were unadjusted life years (survival) and costs. Deterministic and probabilistic sensitivity analyses were performed to evaluate model uncertainty. RESULTS: The most effective strategy was pembrolizumab for MSI-H patients and ramucirumab/paclitaxel for all other patients, adding 3.8 months or 2.0 quality-adjusted months compared to paclitaxel. However, this strategy resulted in a prohibitively high ICER of $1,074,620/QALY. The only cost-effective strategy was paclitaxel monotherapy for all patients, with an ICER of $53,705/QALY. CONCLUSION: Biomarker-based treatments with targeted therapies/immunotherapies for second-line metastatic GC patients substantially improve unadjusted and quality-adjusted survival but are not cost-effective at current drug prices.
RESUMO
N95 filtering facepiece respirators (FFR) and surgical masks are essential in reducing airborne disease transmission, particularly during the COVID-19 pandemic. However, currently available FFR's and masks have major limitations, including masking facial features, waste, and integrity after decontamination. In a multi-institutional trial, we evaluated a transparent, elastomeric, adaptable, long-lasting (TEAL) respirator to evaluate success of qualitative fit test with user experience and biometric evaluation of temperature, respiratory rate, and fit of respirator using a novel sensor. There was a 100% successful fit test among participants, with feedback demonstrating excellent or good fit (90% of participants), breathability (77.5%), and filter exchange (95%). Biometric testing demonstrated significant differences between exhalation and inhalation pressures among a poorly fitting respirator, well-fitting respirator, and the occlusion of one filter of the respirator. We have designed and evaluated a transparent elastomeric respirator and a novel biometric feedback system that could be implemented in the hospital setting.
RESUMO
We generated a mouse model for hemophilia A that combines a homozygous knockout for murine factor VIII (FVIII) and a homozygous addition of a mutant human FVIII (hFVIII). The resulting mouse, having no detectable FVIII protein or activity and tolerant to hFVIII, is useful for evaluating FVIII gene-therapy protocols. This model was used to develop an effective gene-therapy strategy using the φC31 integrase to mediate permanent genomic integration of an hFVIII cDNA deleted for the B-domain. Various plasmids encoding φC31 integrase and hFVIII were delivered to the livers of these mice by using hydrodynamic tail-vein injection. Long-term expression of therapeutic levels of hFVIII was observed over a 6-month time course when an intron was included in the hFVIII expression cassette and wild-type φC31 integrase was used. A second dose of the hFVIII and integrase plasmids resulted in higher long-term hFVIII levels, indicating that incremental doses were beneficial and that a second dose of φC31 integrase was tolerated. We observed a significant decrease in the bleeding time after a tail-clip challenge in mice treated with plasmids expressing hFVIII and φC31 integrase. Genomic integration of the hFVIII expression plasmid was demonstrated by junction PCR at a known hotspot for integration in mouse liver. The φC31 integrase system provided a nonviral method to achieve long-term FVIII gene therapy in a relevant mouse model of hemophilia A.