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Importance: Shifting care to alternative sites when clinically appropriate may be associated with reduced US health care spending, improved access, and, in some cases, improved care outcomes. Objective: To fill 2 main gaps in the current literature on site-of-care shifts: (1) understanding the clinician perspective on appropriateness of alternative care sites, given the central role they play in referrals and patient trust and (2) considering all potential sites where care could shift and calculating net savings potential. Design, Setting, and Participants: In this survey study, physicians (MDs and DOs), nurse practitioners, physician assistants, nurse anesthetists, radiology and imaging technicians, and psychologists were surveyed from September 17 to November 22, 2021, about potential shifts of care from the hospital setting to alternative sites. Participants were selected by the survey firm Intellisurvey to provide broad representation across all specialties of interest. A minimum of 34 clinicians responded to each question. Data were analyzed from April 2022 through October 2023. Exposure: More than 5000 individual diagnostic and procedural codes were reviewed and sorted into 312 distinct care activities by an expert panel of physicians. Survey respondents were then provided with the 2019 claims-based distribution across sites of care for each care activity and were asked, "based on your clinical judgment, what portion of [care activity] could safely occur in each of the following sites of care, without compromising clinical outcomes?" Main Outcomes and Measures: Based on clinician-reported distributions, the total potential shift of volume from hospital-based settings to alternative sites and the associated net savings were estimated. Results: Survey respondents included 1069 practicing clinicians (386 female [36.1%]; mean [SD] years since residency of physicians, 21.0 [9.7] years; mean [SD] age of nonphysicians, 45.3 [9.4] years) across specialties, all of whom practiced more than 20 clinical hours per week. There were 794 physicians (74.3%), and the remaining 275 respondents were midlevel professionals, such as physician assistants. Among 312 care activities surveyed, respondents indicated that 10.3 percentage points (95% CI, 10.0-10.5 percentage points) of commercial and 10.9 percentage points (95% CI, 10.7-11.1 percentage points) of Medicare volume currently taking place in hospital-based settings could shift to alternative sites with today's technology without compromising clinical outcomes. Across the entire US health care system, these shifts could be associated with a reduction in overall health care consumption spending ($3â¯562â¯339â¯000â¯000â¯000) by approximately $113.8 billion ($113â¯767â¯446â¯087â¯174 [3.2%]) to $147.7 billion ($147â¯661â¯672â¯284â¯263 [4.1%]) annually. Conclusions and relevance: In this study, a substantial net savings opportunity was estimated. However, realizing this potential will require ongoing alignment among organizations, clinicians, and policymakers to overcome barriers to these shifts.
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Ahorro de Costo , Humanos , Estados Unidos , Encuestas y Cuestionarios , Masculino , Femenino , Actitud del Personal de Salud , AdultoRESUMEN
Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (GxS) interaction testing. There were 13 loci significant for GxS interactions, with the top finding in LTBP1 (RR=3.37 [2.04 - 5.56], p=1.93x10 -6 ). LTBP1 plays a role in regulating TGF-B bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression of LTBP1 between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant GxS interactions and the CP phenotype. We found significant association for LTBP1 in cell cultured fibroblasts in female probands (p=0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, and LTBP1 is a candidate risk gene, particularly in females.
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This JAMA Forum discusses dimensions of financial manipulation in health care and highlights policies that might address it.
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Atención a la Salud , Humanos , Atención a la Salud/economíaAsunto(s)
Comercio , Industria Farmacéutica , Economía Farmacéutica , Política de Salud , Preparaciones Farmacéuticas , Humanos , Comercio/economía , Comercio/legislación & jurisprudencia , Costos de los Medicamentos/legislación & jurisprudencia , Industria Farmacéutica/legislación & jurisprudencia , Industria Farmacéutica/economía , Economía Farmacéutica/legislación & jurisprudencia , Patentes como Asunto/legislación & jurisprudencia , Preparaciones Farmacéuticas/economía , Estados Unidos , United States Food and Drug Administration/economía , United States Food and Drug Administration/legislación & jurisprudencia , Política de Salud/economía , Política de Salud/legislación & jurisprudenciaRESUMEN
Telemedicine use remains substantially higher than it was before the COVID-19 pandemic, although it has fallen from pandemic highs. To inform the ongoing debate about whether to continue payment for telemedicine visits, we estimated the association of greater telemedicine use across health systems with utilization, spending, and quality. In 2020, Medicare patients receiving care at health systems in the highest quartile of telemedicine use had 2.5 telemedicine visits per person (26.8 percent of visits) compared with 0.7 telemedicine visits per person (9.5 percent of visits) in the lowest quartile of telemedicine use. In 2021-22, relative to those in the lowest quartile, Medicare patients of health systems in the highest quartile had an increase of 0.21 total outpatient visits (telemedicine and in-person) per patient per year (2.2 percent relative increase), a decrease of 14.4 annual non-COVID-19 emergency department visits per 1,000 patients per year (2.7 percent relative decrease), a $248 increase in per patient per year spending (1.6 percent relative increase), and increased adherence for metformin and statins. There were no clear differential changes in hospitalizations or receipt of preventive care.
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COVID-19 , Gastos en Salud , Medicare , Telemedicina , Estados Unidos , Humanos , Telemedicina/estadística & datos numéricos , Telemedicina/economía , Medicare/economía , Medicare/estadística & datos numéricos , Gastos en Salud/estadística & datos numéricos , Calidad de la Atención de Salud , Masculino , SARS-CoV-2 , Femenino , Pandemias , Anciano , Aceptación de la Atención de Salud/estadística & datos numéricosRESUMEN
The "missing" heritability of complex traits may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. We propose a new kernel-based method called Latent Interaction Testing (LIT) to screen for genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Using simulated data, we demonstrate that LIT increases power to detect latent genetic interactions compared to univariate methods. We then apply LIT to obesity-related traits in the UK Biobank and detect variants with interactive effects near known obesity-related genes (URL: https://CRAN.R-project.org/package=lit ).
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Estudio de Asociación del Genoma Completo , Obesidad , Humanos , Obesidad/genética , Epistasis Genética , Carácter Cuantitativo Heredable , Sitios de Carácter Cuantitativo , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Pleiotropía Genética , Fenotipo , Herencia MultifactorialRESUMEN
Allele-specific methylation (ASM) is an epigenetic modification whereby one parental allele becomes methylated and the other unmethylated at a specific locus. ASM is most often driven by the presence of nearby heterozygous variants that influence methylation, but also occurs somatically in the context of genomic imprinting. In this study, we investigate ASM using publicly available single-cell reduced representation bisulfite sequencing (scRRBS) data on 608 B cells sampled from six healthy B cell samples and 1,230 cells from 11 chronic lymphocytic leukemia (CLL) samples. We developed a likelihood-based criterion to test whether a CpG exhibited ASM, based on the distributions of methylated and unmethylated reads both within and across cells. Applying our likelihood ratio test, 65,998 CpG sites exhibited ASM in healthy B cell samples according to a Bonferroni criterion (p < 8.4 × 10-9), and 32,862 CpG sites exhibited ASM in CLL samples (p < 8.5 × 10-9). We also called ASM at the sample level. To evaluate the accuracy of our method, we called heterozygous variants from the scRRBS data, which enabled variant-based calls of ASM within each cell. Comparing sample-level ASM calls to the variant-based measures of ASM, we observed a positive predictive value of 76%-100% across samples. We observed high concordance of ASM across samples and an overrepresentation of ASM in previously reported imprinted genes and genes with imprinting binding motifs. Our study demonstrates that single-cell bisulfite sequencing is a potentially powerful tool to investigate ASM, especially as studies expand to increase the number of samples and cells sequenced.
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Metilación de ADN , Leucemia Linfocítica Crónica de Células B , Sulfitos , Humanos , Metilación de ADN/genética , Alelos , Leucemia Linfocítica Crónica de Células B/genética , Funciones de Verosimilitud , Impresión Genómica/genética , Islas de CpG/genéticaRESUMEN
Importance: Increasing integration across medical services may have important implications for health care quality and spending. One major but poorly understood dimension of integration is between physician organizations and pharmacies for self-administered drugs or in-house pharmacies. Objective: To describe trends in the use of in-house pharmacies, associated physician organization characteristics, and associated drug prices. Design, Setting, and Participants: A cross-sectional study was conducted from calendar years 2011 to 2019. Participants included 20% of beneficiaries enrolled in fee-for-service Medicare Parts A, B, and D. Data analysis was performed from September 15, 2020, to December 20, 2023. Exposures: Prescriptions filled by in-house pharmacies. Main Outcomes and Measures: The share of Medicare Part D spending filled by in-house pharmacies by drug class, costliness, and specialty was evaluated. Growth in the number of physician organizations and physicians in organizations with in-house pharmacies was measured in 5 specialties: medical oncology, urology, infectious disease, gastroenterology, and rheumatology. Characteristics of physician organizations with in-house pharmacies and drug prices at in-house vs other pharmacies are described. Results: Among 8â¯020â¯652 patients (median age, 72 [IQR, 66-81] years; 4 570 114 [57.0%] women), there was substantial growth in the share of Medicare Part D spending on high-cost drugs filled at in-house pharmacies from 2011 to 2019, including oral anticancer treatments (from 10% to 34%), antivirals (from 12% to 20%), and immunosuppressants (from 2% to 9%). By 2019, 63% of medical oncologists, 20% of urologists, 29% of infectious disease specialists, 21% of gastroenterologists, and 22% of rheumatologists were in organizations with specialty-relevant in-house pharmacies. Larger organizations had a greater likelihood of having an in-house pharmacy (0.75 percentage point increase [95% CI, 0.56-0.94] per each additional physician), as did organizations owning hospitals enrolled in the 340B Drug Discount Program (10.91 percentage point increased likelihood [95% CI, 6.33-15.48]). Point-of-sale prices for high-cost drugs were 1.76% [95% CI, 1.66%-1.87%] lower at in-house vs other pharmacies. Conclusions and Relevance: In this cross-sectional study of physician organization-operated pharmacies, in-house pharmacies were increasingly used from 2011 to 2019, especially for high-cost drugs, potentially associated with organizations' financial incentives. In-house pharmacies offered high-cost drugs at lower prices, in contrast to findings of integration in other contexts, but their growth highlights a need to understand implications for patient care.
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Enfermedades Transmisibles , Farmacias , Médicos , Estados Unidos , Humanos , Anciano , Femenino , Masculino , Estudios Transversales , MedicareRESUMEN
This JAMA Forum discusses the good and bad of innovation in health care delivery, tax policy, an escrow account for failure, and state monitoring.
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Atención a la SaludRESUMEN
BACKGROUND: Identification of rare variants involved in complex, polygenic diseases like Crohn's disease (CD) has accelerated with the introduction of whole exome/genome sequencing association studies. Rare variants can be used in both diagnostic and therapeutic assessments; however, since they are likely to be restricted to specific ancestry groups, their contributions to risk assessment need to be evaluated outside the discovery population. Prior studies implied that the three known rare variants in NOD2 are absent in West African and Asian populations and only contribute in African Americans via admixture. METHODS: Whole genome sequencing (WGS) data from 3418 African American individuals, 1774 inflammatory bowel disease (IBD) cases, and 1644 controls were used to assess odds ratios and allele frequencies (AF), as well as haplotype-specific ancestral origins of European-derived CD variants discovered in a large exome-wide association study. Local and global ancestry was performed to assess the contribution of admixture to IBD contrasting European and African American cohorts. RESULTS: Twenty-five rare variants associated with CD in European discovery cohorts are typically five-fold lower frequency in African Americans. Correspondingly, where comparisons could be made, the rare variants were found to have a predicted four-fold reduced burden for IBD in African Americans, when compared to European individuals. Almost all of the rare CD European variants were found on European haplotypes in the African American cohort, implying that they contribute to disease risk in African Americans primarily due to recent admixture. In addition, proportion of European ancestry correlates the number of rare CD European variants each African American individual carry, as well as their polygenic risk of disease. Similar findings were observed for 23 mutations affecting 10 other common complex diseases for which the rare variants were discovered in European cohorts. CONCLUSIONS: European-derived Crohn's disease rare variants are even more rare in African Americans and contribute to disease risk mainly due to admixture, which needs to be accounted for when performing cross-ancestry genetic assessments.
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Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Enfermedad de Crohn/genética , Predisposición Genética a la Enfermedad , Enfermedades Inflamatorias del Intestino/genética , Negro o Afroamericano/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , BlancoRESUMEN
This JAMA Forum discusses resiliency, telehealth, the health care labor force, and public health in the context of the health system changes occurring since the start of the COVID-19 pandemic.
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COVID-19 , Atención a la Salud , Humanos , Atención a la Salud/tendenciasRESUMEN
Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n = 435), and subtype-specific risks for any cleft soft palate (CSP), (n = 259) and any cleft hard palate (CHP) (n = 125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p = 4.24 × 10-8) associated with CHP. One gene at this locus, angiopoietin-like 2 (ANGPTL2), plays a role in osteoblast differentiation. It is expressed both in craniofacial tissue of human embryos and developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p < 5 × 10-6), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios for the 20 loci were most similar across all 3 groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either subtype. We also found nominal evidence of replication (p < 0.05) for 22 SNPs previously associated with orofacial clefts. Our study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.
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Labio Leporino , Fisura del Paladar , Humanos , Animales , Ratones , Fisura del Paladar/epidemiología , Estudio de Asociación del Genoma Completo , Labio Leporino/epidemiología , Factores de Riesgo , Proteína 2 Similar a la AngiopoyetinaRESUMEN
Genome-wide association studies of complex traits frequently find that SNP-based estimates of heritability are considerably smaller than estimates from classic family-based studies. This 'missing' heritability may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. To circumvent these challenges, we propose a new method to detect genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Our approach, Latent Interaction Testing (LIT), uses the observation that correlated traits with shared latent genetic interactions have trait variance and covariance patterns that differ by genotype. LIT examines the relationship between trait variance/covariance patterns and genotype using a flexible kernel-based framework that is computationally scalable for biobank-sized datasets with a large number of traits. We first use simulated data to demonstrate that LIT substantially increases power to detect latent genetic interactions compared to a trait-by-trait univariate method. We then apply LIT to four obesity-related traits in the UK Biobank and detect genetic variants with interactive effects near known obesity-related genes. Overall, we show that LIT, implemented in the R package lit, uses shared information across traits to improve detection of latent genetic interactions compared to standard approaches.
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As one of the most common structural birth defects, orofacial clefts (OFCs) have been studied for decades, and recent studies have demonstrated that there are genetic differences between the different phenotypic presentations of OFCs. However, the contribution of rare genetic variation genome-wide to different subtypes of OFCs has been understudied, with most studies focusing on common genetic variation or rare variation within targeted regions of the genome. Therefore, we used whole-genome sequencing data from the Gabriella Miller Kids First Pediatric Research Program to conduct a gene-based burden analysis to test for genetic modifiers of cleft lip (CL) vs cleft lip and palate (CLP). We found that there was a significantly increased burden of rare variants in SEC24D in CL cases compared to CLP cases (p = 6.86 [Formula: see text] 10-7). Of the 15 variants within SEC24D, 53.3% were synonymous, but overlapped a known craniofacial enhancer. We then tested whether these variants could alter predicted transcription factor binding sites (TFBS), and found that the rare alleles destroyed binding sites for 9 transcription factors (TFs), including Pax1 (p = 0.0009), and created binding sites for 23 TFs, including Pax6 (p = 6.12 [Formula: see text] 10-5) and Pax9 (p = 0.0001), which are known to be involved in normal craniofacial development, suggesting a potential mechanism by which these synonymous variants could have a functional impact. Overall, this study indicates that rare genetic variation may contribute to the phenotypic heterogeneity of OFCs and suggests that regulatory variation may also contribute and warrant further investigation in future studies of genetic variants controlling risk to OFC.
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Labio Leporino , Fisura del Paladar , Niño , Humanos , Labio Leporino/genética , Fisura del Paladar/genética , Alelos , Sitios de Unión , Proteínas de Transporte VesicularRESUMEN
In this the first of an anticipated four paper series, fundamental results of quantitative genetics are presented from a first principles approach. While none of these results are in any sense new, they are presented in extended detail to precisely distinguish between definition and assumption, with a further emphasis on distinguishing quantities from their usual approximations. Terminology frequently encountered in the field of human genetic disease studies will be defined in terms of their quantitive genetics form. Methods for estimation of both quantitative genetics and the related human genetics quantities will be demonstrated. While practitioners in the field of human quantitative disease studies may find this work pedantic in detail, the principle target audience for this work is trainees reasonably familiar with population genetics theory, but with less experience in its application to human disease studies. We introduce much of this formalism because in later papers in this series, we demonstrate that common areas of confusion in human disease studies can be resolved be appealing directly to these formal definitions. The second paper in this series will discuss polygenic risk scores. The third paper will concern the question of "missing" heritability and the role interactions may play. The fourth paper will discuss sexually dimorphic disease and the potential role of the X chromosome.
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Most complex human traits differ by sex, but we have limited insight into the underlying mechanisms. Here, we investigated the influence of biological sex on protein expression and its genetic regulation in 1,277 human brain proteomes. We found that 13.2% (1,354) of brain proteins had sex-differentiated abundance and 1.5% (150) of proteins had sex-biased protein quantitative trait loci (sb-pQTLs). Among genes with sex-biased expression, we found 67% concordance between sex-differentiated protein and transcript levels; however, sex effects on the genetic regulation of expression were more evident at the protein level. Considering 24 psychiatric, neurologic and brain morphologic traits, we found that an average of 25% of their putatively causal genes had sex-differentiated protein abundance and 12 putatively causal proteins had sb-pQTLs. Furthermore, integrating sex-specific pQTLs with sex-stratified genome-wide association studies of six psychiatric and neurologic conditions, we uncovered another 23 proteins contributing to these traits in one sex but not the other. Together, these findings begin to provide insights into mechanisms underlying sex differences in brain protein expression and disease.
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Estudio de Asociación del Genoma Completo , Caracteres Sexuales , Femenino , Masculino , Humanos , Encéfalo , Herencia Multifactorial , FenotipoRESUMEN
OBJECTIVE: To investigate primary care practice ownership and specialist-use patterns for commercially insured children with disabilities. DATA SOURCES AND STUDY SETTING: A national commercial claims database and the Health Systems and Provider Database from 2012 to 2016 are the data sources for this study. STUDY DESIGN: This cross-sectional, descriptive study examines: (1) the most visited type of pediatric primary care physician and practice (independent or system-owned); (2) pediatric and non-pediatric specialist-use patterns; and (3) how practice ownership relates to specialist-use patterns. DATA COLLECTION/EXTRACTION METHODS: This study identifies 133,749 person-years of commercially insured children with disabilities aged 0-18 years with at least 24 months of continuous insurance coverage by linking a national commercial claims data set with the Health Systems and Provider Database and applying the validated Children with Disabilities Algorithm. PRINCIPAL FINDINGS: Three-quarters (75.9%) of children with disabilities received their pediatric primary care in independent practices. Nearly two thirds (59.6%) used at least one specialist with 45.1% using nonpediatric specialists, 28.8% using pediatric ones, and 17.0% using both. Specialist-use patterns varied by both child age and specialist type. Children with disabilities in independent practices were as likely to see a specialist as those in system-owned ones: 57.1% (95% confidence interval [95% CI] 56.7%-57.4%) versus 57.3% (95% CI 56.6%-58.0%), respectively (p = 0.635). The percent using two or more types of specialists was 46.1% (95% CI 45.4%-46.7%) in independent practices, comparable to that in systems 47.1% (95% CI 46.2%-48.0%) (p = 0.054). However, the mean number of specialist visits was significantly lower in independent practices than in systems-4.0 (95% CI 3.9%-4.0%) versus 4.4 (95% CI 4.3%-4.6%) respectively-reaching statistical significance with p < 0.0001. CONCLUSIONS: Recognizing how privately insured children with disabilities use pediatric primary care from pediatric and nonpediatric primary care specialists through both independent and system-owned practices is important for improving care quality and value.
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Background: Paclitaxel is widely used for the treatment of metastatic breast cancer (MBC). However, it has a low oral bioavailability due to gut extrusion caused by P-glycoprotein (P-gp). Oral paclitaxel (oPAC) may be more convenient, less resource-intensive, and more tolerable than its intravenous form. Encequidar (E) is a first-in-class, minimally absorbed, gut-specific oral P-gp inhibitor that facilitates the oral absorption of paclitaxel. Objectives: To investigate the pharmacokinetics (PK), overall response rate (ORR), and safety of weekly oral paclitaxel with encequidar (oPAC + E) in patients with advanced breast cancer. Design: This is a multicenter, single-arm, open-label study in six medical centers in Taiwan. Methods: Patients with advanced breast cancer were administered 205 mg/m2 oPAC and 12.9 mg E for 3 consecutive days weekly for up to 16 weeks. Plasma samples were collected at weeks 1 and 4. PK, ORR, and safety were evaluated. Results: In all, 28 patients were enrolled; 27 had MBC; 23 had prior chemotherapy; and 14 had ⩾2 lines of prior chemotherapy. PK were evaluable in 25 patients. Plasma paclitaxel area under the curve (AUC)(0-52 h) at week 1 (3419 ± 1475 ng h/ml) and week 4 (3224 ± 1150 ng h/ml) were equivalent. Best overall response in 28 evaluable patients was partial response (PR) in 11 (39.3%), 13 (46.4%) stable disease (SD), and 1 (3.6%) with progressive disease (PD). No patient achieved complete response (CR). The clinical benefit rate (CR + PR + SD) was 85.7%. Major adverse events among the 28 treated patients were grade 3 neutropenia (25%), grade 4 neutropenia (18%), with febrile neutropenia in 4%, and grade 3 diarrhea (4%). No treatment-related deaths occurred. Grade 2 peripheral neuropathy occurred in 1 (4%) patient and grade 3 peripheral neuropathy in 1 (4%) patient. Conclusions: oPAC + E produced a consistent therapeutic plasma paclitaxel exposure during treatment. There was a high rate of radiologically assessed clinical benefit, and a low rate of neurotoxicity which may provide advantages over IV paclitaxel. Registration: ClinicalTrials.gov Identifier: NCT03165955.
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This JAMA Forum discusses 5 observations about the possible effects of artificial intelligence on medicine.