Doxorubicin pharmacokinetics and toxicity in patients with aggressive lymphoma and hepatic impairment.

Aggressive lymphomas are curable with doxorubicin-based chemotherapy. In patients presenting with elevated serum bilirubin, doxorubicin is commonly dose reduced or delayed based on limited pharmacokinetic data. We evaluated plasma pharmacokinetics of doxorubicin and its metabolite doxorubicinol as well as toxicity in 59 patients with normal bilirubin levels and 10 patients with elevated bilirubin levels. Patients received full-dose EPOCH +/-rituximab. Median (range) age was 51 (18-75) years. Patients with elevated bilirubin levels had higher international prognostic index and poorer performance status. Although median doxorubicin clearance was lower and median plasma doxorubicin and doxorubicinol concentrations were higher in patients with elevated bilirubin levels, values were within the concentration range observed in patients with normal levels. Rates of febrile neutropenia were similar between groups, but there was greater grade 4 neutropenia and thrombocytopenia during the first but not subsequent treatment cycles in patients with elevated bilirubin. More grade 3/4 gastrointestinal and neurotoxicity occurred in patients with elevated bilirubin during the first but not subsequent cycles. Although toxicity was greater on cycle 1, the adverse effects were managed safely. These results show that empiric dose reductions of continuous infusion doxorubicin may not be necessary in patients with elevated bilirubin levels. This trial was registered at www.clinicaltrials.gov as #NCT00001337, #NCT00069238, and #NCT00005780.

Ideological assumptions of Chile's international migrant healthcare policy: A critical discourse analysis.

In the current historical moment of rewriting the Chilean Constitution, there are new hopes for producing a different socio-legal, political-economic and public health order. The Chilean case holds important implications for global health practitioners, researchers and policy-makers because it clearly shows both the impacts of neoliberal processes on a worldwide scale and neoliberal policy responses. This article contributes to the field of global health policy critical analysis by offering scrutiny of Chile's international migrant healthcare policy from the perspective of its ideological assumptions. We apply Fairclough's analytical perspective to the Chilean migrant healthcare policy, identifying its components, argumentative premises and ideological assumptions that contribute to the reproduction of the processes of social determination. It allows us to identify bias mobilisation, exclusion, and subordinate inclusion processes that systematically lead to the omission of structural processes in the social determination of migrants' healthcare, contributing to their reproduction. We conclude by problematising the place of academia in said reproduction to the extent that the concepts and premises they use remain in the ideological territory of exclusion of the structural defined by the policy, disconnecting reflection and action in the health field from collective demands.

Deported, homeless, and into the canal: Environmental structural violence in the binational Tijuana River.

INTRODUCTION: The US deports more Mexicans to Tijuana than any other borderland city. Returning involuntarily as members of a stigmatized underclass, many find themselves homeless and de-facto stateless. Subject to routinized police victimization, many take refuge in the Tijuana River Canal (El Bordo). Previous reports suggest Tijuana River water may be contaminated but prior studies have not accessed the health effects or contamination of the water closest to the river residents. METHODS: A binational, transdisciplinary team undertook a socio-environmental, mixed methods assessment to simultaneously characterize Tijuana River water quality with chemical testing, assess the frequency of El Bordo residents' water-related diseases, and trace water contacts with epidemiological survey methods (n = 85 adults, 18+) in 2019, and ethnographic methods in 2019-2021. Our analysis brings the structural violence framework into conversation with an environmental injustice perspective to documented how social forces drive poor health outcomes enacted through the environment. RESULTS: The Tijuana River water most proximate to its human inhabitants fails numerous water-quality standards, posing acute health risks. Escherichia coli values were ∼40,000 times the Mexican regulatory standard for directly contacted water. Skin infections (47%), dehydration (40%) and diarrhea (28%) were commonly reported among El Bordo residents. Residents are aware the water is contaminated and strive to minimize harm to their health by differentially using local water sources. Their numerous survival constraints, however, are exacerbated by routine police violence which propels residents and other people who inject drugs into involuntary contact with contaminated water. DISCUSSION: Human rights to drinking water, sanitation and hygiene are routinely violated among El Bordo inhabitants. This is exacerbated by violent policing practices that force unhoused deportees to seek refuge in waterways, and drive water contacts. Furthermore, US-Mexico 'free-trade' agreements drive rapid growth in Tijuana, restrict Mexican environmental regulation enforcement, and drive underinvestment in sewage systems and infrastructure.

How Should Clinicians Express Solidarity With Asylum Seekers at the US-Mexico Border?

Migrants along the US-Mexico border have been subjected to transnational violence created by international policy, militaristic intervention, and multinational organizational administration of border operations. The COVID-19 pandemic compounded migrants' vulnerabilities and provoked several logistical and ethical problems for US-based clinicians and organizations. This commentary examines how the concept of transnational solidarity facilitates analysis of clinicians' and migrants' shared historical and structural vulnerabilities. This commentary also suggests how actions implemented by one organization in Tijuana, Mexico, could be scaled more broadly for care of migrants and asylum seekers in other transnational health care settings.

Los migrantes en la frontera entre EE. UU. y México han sufrido violencia transnacional por parte de la policía internacional, la intervención militar y la administración organizativa multinacional de las operaciones fronterizas. La pandemia de la COVID-19 agravó las vulnerabilidades de los migrantes y provocó varios problemas logísticos y éticos para los médicos y las organizaciones estadounidenses. Este comentario examina de qué manera el concepto de solidaridad transnacional facilita el análisis de los médicos y las vulnerabilidades históricas y estructurales compartidas de los migrantes. También, sugiere cómo las acciones implementadas por una organización en Tijuana, México, podrían aplicarse a mayor escala para la atención de los migrantes y solicitantes de asilo en otros entornos de atención médica transnacional.

Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL.

PURPOSE: CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. PATIENTS AND METHODS: We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. RESULTS: Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. CONCLUSION: With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.

The Influence of Sex and Ancestry on Three-Dimensional Palate Shape.

ABSTRACT: Modern human palate shape has been reported to vary by sex and ancestry, but limitations in the methods used to quantify shape and in population coverage have led to inconsistent findings. In the present study, the authors aim to characterize the effects of sex and ancestry on normal-range three-dimensional palate shape through landmark-based morphometrics.Three-dimensional digital dental casts were obtained and landmarked from 794 adults of European (n = 429), African (n = 295), and East Asian (n = 70) ancestry. Principal component analysis was conducted to identify patterns of shape variation present in our cohort, and canonical variates analysis was performed to test for shape differences between sexes and ancestries.Principal component analysis showed that 3 principal components, explaining 76.52% of variance, linked higher palatal vault with either a relative reduction in anteroposterior or mediolateral dimensions. Canonical variates analysis showed that males had wider and shorter palates with more posteriorly located maximum vault depth than females. Individuals of African ancestry, having higher vaults with more posteriorly located maximal depths, also had wider and shorter palates, whereas individuals of European ancestry had narrower and longer palates with more anteriorly located maximum vault depths. Individuals of East Asian ancestry showed the shallowest vaults.It was found that both sex and ancestry influence palate shape, suggesting a possible genetic component underlying this variation. Additionally, our findings indicate that vault height tends to co-vary with anteroposterior or mediolateral dimensions. Further investigation of these morphological patterns may shed light on possible links to common congenital anomalies such as orofacial clefting.

Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis.

Tsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce populations of insect pollinator species. Here we present a promising, environment-friendly alternative to current insecticides that targets the insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded and eliminated. RNA interference (RNAi) of either the first two enzymes in the tyrosine degradation pathway (tyrosine aminotransferase (TAT) and 4-hydroxyphenylpyruvate dioxygenase (HPPD)) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, oral administration of NTBC to bumblebees did not affect their survival. Using a novel mathematical model, we show that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current disease elimination programmes.

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21.

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.

Structural vulnerability and new perspectives in social medicine on the health of immigrants: Interview with James Quesada and Seth M. Holmes. / La vulnerabilidad estructural y las nuevas perspectivas en medicina social sobre la salud de los migrantes: entrevista a James Quesada y Seth M. Holmes.

A decade ago, a number of English-speaking authors focused mainly on the analysis and intervention of processes of social determination of health of migrants developed the concept of structural vulnerability as a way to combat individualism, biologism, the invisibilization of processes of structural determination and the blaming of victims. As part of the historical contributions of social medicine, the current developments of the structural vulnerability approach have been disconnected from the discussions of the collective health movement and Latin American social medicine in general, among other reasons due to linguistic barriers associated with the scarcity of publications in Spanish. The present interview, conducted with two of the primary representatives of the structural vulnerability approach, investigates its historical origins and seeks to explore the specific contributions that are being made today, as a way to bring them closer to Spanish-speaking readers and so enable dialogue with the proposals of Latin American social medicine.

Desde hace una década, varios autores anglófonos, centrados principalmente en el análisis e intervención de los procesos de determinación social de la salud de los migrantes, forjaron el concepto de vulnerabilidad estructural, como una forma de combatir el individualismo, el biologismo, la invisibilización de los procesos de determinación estructural y la culpabilización de las víctimas. Siendo parte de las contribuciones históricas de la medicina social, los actuales desarrollos de la aproximación sobre la vulnerabilidad estructural han quedado desconectadas de las discusiones del movimiento de la salud colectiva y la medicina social latinoamericana en general, entre otras razones, por las barreras lingüísticas asociadas a la escasez de sus publicaciones en español. La presente entrevista, realizada a dos de sus principales representantes, indaga los orígenes históricos de dicha aproximación y busca explorar las contribuciones específicas que hoy está realizando, como una forma de acercarlas a los lectores de habla hispana, favoreciendo el diálogo con las propuestas de medicina social latinoamericanas.

Playing Well With Others: The Challenge of Academic and Community Radiology Practice Integration.

OBJECTIVE. In this article, we review models for clinical integration across the full spectrum of radiologic services in merged health systems that include both academic and community practice components. We also discuss the issues involved in the integration of disparate practice models and reward systems for both the community radiology group and the academic faculty practice group. CONCLUSION. Although we see advantages to the current trends in mergers and acquisitions within academic radiology, it remains to be seen whether academic and community practice radiology groups can truly work and play well together.

Forest giants on different evolutionary branches: Ecomorphological convergence in helicopter damselflies.

The convergent evolution of analogous features is an evolutionary process occurring independently across the tree of life. From the evolution of echolocation, prehensile tail, viviparity, or winged flight, environmental factors often drive this astonishing phenomenon. However, convergent evolution is not always conspicuous or easily identified. Giant damselflies count among the largest flying insects on Earth, and have astonishing ecologies including orb-web spider plucking and oviposition in phytotelmata. One species occurs in the Afrotropics and 18 species are found in the Neotropics. Convergent evolution was historically hypothesized based on the ecological and morphological affinities of these two geographically distant lineages but was not supported by earlier phylogenetic inferences supporting their monophyly. Using a molecular supermatrix approach and a large selection of outgroups, we revisit and reject the monophyly of Afrotropical and Neotropical giant damselflies that is otherwise supported by a morphological phylogeny. Molecular divergence time estimation suggests an origin of Afrotropical giant damselflies in the late Paleogene, and of Neotropical ones at the Cretaceous/Paleogene boundary, thereby rejecting a long-standing West Gondwana vicariance hypothesis. The strong ecological and morphological resemblances between these two independent lineages represents an astonishing case of Amphi-Atlantic tropical convergent evolution.

Increasing Effectiveness of Messages about Chemicals in Cigarette Smoke.

OBJECTIVES: Federal law requires informing the public on toxic chemicals in cigarette smoke. We sought the public's advice about communicating information about these chemicals. METHODS: Adolescents, young adults, and adults (N = 59), including smokers and non-smokers, participated in 9 focus groups that discussed inclusion of messages about toxic chemicals on cigarette packs, in media campaigns, and on a website. We transcribed, coded, and analyzed focus group audio-recordings. RESULTS: Participants had 3 suggestions for message content to increase the impact of messages about cigarette smoke chemicals. First, they wanted to see messages rotated more frequently to increase message novelty. Second, they recommended using stories and pictures to help connect people to the abstract idea of chemicals in smoke. Third, they cautioned against making messages that might seem overblown and could appeal to the rebellious nature of adolescents. Some participants mentioned that chemical information on a website might discourage people from smoking; others mentioned that people might use it to choose which brand to smoke. CONCLUSIONS: Legislation provides the impetus to design new chemical disclosure messages for cigarette packs and other media. Our findings can help increase the impact of these messages.

Evidence of olfactory deficits as part of the phenotypic spectrum of nonsyndromic orofacial clefting.

Improved understanding of the phenotypic spectrum associated with nonsyndromic orofacial clefting (OFC) has the potential to inform efforts to uncover the etiology of this complex trait. Prior studies report that individuals with OFC are characterized by impaired olfactory ability. In this study, we test whether olfactory dysfunction extends to the unaffected parents of children with OFC. The University of Pennsylvania Smell Identification Test was used to measure olfactory ability in a sample of 60 unaffected mothers and fathers with cleft-affected children. The proportion of deficit was compared with reference data obtained from published sex- and age-specific norms on more than 2700 individuals. The proportion of deficit was significantly higher in unaffected parents compared with baseline control subjects (41.7% vs 12.6%; P < 0.001). Of unaffected fathers, 41.7% displayed evidence of deficit compared with 15.1% of male control subjects (P = 0.001), whereas 41.7% of mothers exhibited deficits compared with 10.4% of female control subjects (P < 0.001). Olfactory deficits are present at a high proportion in the unaffected parents of individuals with OFC. This suggests that the deficits observed in affected cases may not simply be a secondary consequence of surgical repair and may instead be an informative phenotype reflecting underlying etiology.

Puberty and plexiform neurofibroma tumor growth in patients with neurofibromatosis type I.

OBJECTIVE: To assess the relationship between pubertal progression and change in plexiform neurofibroma (PN) burden over time in pediatric and young adult patients with neurofibromatosis type 1 and PNs. STUDY DESIGN: Analyses accounted for sex, age, race, and chemotherapy. Forty-one patients with neurofibromatosis type 1 (15 female and 26 male patients) were studied at the National Institutes of Health. Tanner stage, testosterone, progesterone, estradiol, insulin-like growth factor -1, luteinizing hormone, and follicle-stimulating hormone were assessed. Tumor volume was measured using magnetic resonance imaging and lesion detection software developed locally. Patients were divided into 2 groups based on whether they were actively progressing through puberty (n = 16) or were peripubertal (n = 25) and were followed for an average of 20 months. Tumor growth rates in the puberty and peripubertal group were analyzed for a subset of patients. RESULTS: There was no statistically significant difference in tumor burden change over time (cm(2)/kg per month) between the pubertal and peripubertal groups (-0.16 ± 0.34 vs 0.03 ± 1.8, P = .31) and in the PN growth rates before and during puberty (P = .90). Change in tumor volume/patient weight/time did not correlate with testosterone change/time in males or estradiol change/time in females. CONCLUSION: These findings support that hormonal changes of puberty do not accelerate PN growth. Additional long-term follow-up of patients is necessary to further characterize the interaction between puberty and tumor growth.

Do celebrity cancer diagnoses promote primary cancer prevention?

OBJECTIVE: Celebrity cancer diagnoses generate considerable media coverage of and increase interest in cancer screening, but do they also promote primary cancer prevention? METHODS: Daily trends for smoking cessation-related media (information-availability) and Google queries (information-seeking) around Brazilian President and smoker Lula da Silva's laryngeal cancer diagnosis announcements were compared to a typical period and several cessation awareness events. RESULTS: Cessation media coverage was 163% (95% confidence interval, 54-328) higher than expected the week after the announcement but returned to typical levels the second week. Cessation queries were 67% (95% confidence interval, 40-96) greater the week after Lula's announcement, remaining 153% (95% confidence interval, 121-188), 130% (95% confidence interval, 101-163) and 71% (95% confidence interval, 43-100) greater during the second, third, and fourth week after the announcement. There were 1.1 million excess cessation queries the month after Lula's announcement, eclipsing query volumes for the week around New Years Day, World No Tobacco Day, and Brazilian National No Smoking Day. CONCLUSION: Just as celebrity diagnoses promote cancer screening, they may also promote primary prevention. Discovery of this dynamic suggests the public should be further encouraged to consider primary (in addition to the usual secondary) cancer prevention around celebrity diagnoses, though more cases, cancers, and prevention behaviors must be explored.

"Is it worth risking your life?" Ethnography, risk and death on the U.S.-Mexico border.

Every year, several hundred people die attempting to cross the border from Mexico into the United States, most often from dehydration and heat stroke though snake bites and violent assaults are also common. This article utilizes participant observation fieldwork in the borderlands of the US and Mexico to explore the experience of structural vulnerability and bodily health risk along the desert trek into the US. Between 2003 and 2005, the ethnographer recorded interviews and conversations with undocumented immigrants crossing the border, border patrol agents, border activists, borderland residents, and armed civilian vigilantes. In addition, he took part in a border crossing beginning in the Mexican state of Oaxaca and ending in a border patrol jail in Arizona after he and his undocumented Mexican research subjects were apprehended trekking through the borderlands. Field notes and interview transcriptions provide thick ethnographic detail demonstrating the ways in which social, ethnic, and citizenship differences as well as border policies force certain categories of people to put their bodies, health, and lives at risk in order for them and their families to survive. Yet, metaphors of individual choice deflect responsibility from global economic policy and US border policy, subtly blaming migrants for the danger - and sometimes death - they experience. The article concludes with policy changes to make US-Mexico labor migration less deadly.