Evaluating the Effects of Hinge Flexibility on the Solution Structure of Antibodies at Concentrated Conditions

Employing 2 different coarse-grained models, we evaluated the effect of intramolecular domain-domain distances and hinge flexibility on the general solution structure of monoclonal antibodies (mAbs), within the context of protein-protein steric repulsion. These models explicitly account for the hinge region, and represent antibodies at either domain or subdomain levels (i.e., 4-bead and 7-bead representations, respectively). Additionally, different levels of mAb flexibility are also considered. When evaluating mAbs as rigid structures, analysis of small-angle scattering profiles showed that changes in the relative internal distances between Fc and Fab domains significantly alter the local arrangement of neighboring molecules, as well as the molecular packing of the concentrated mAb solutions. Likewise, enabling hinge flexibility in either of the mAb models led to qualitatively similar results, where flexibility increases the spatial molecular arrangement at elevated concentrations. This occurs because fluctuations in mAb quaternary structure are modulated by the close proximity between molecules at elevated concentrations (>50 mg mL^?1), yielding an increased molecular packing and osmotic compressibility. However, our results also showed that the mechanism behind this synergy between flexibility and packing strongly depends on both the level of structural detail and the number of degrees-of-freedom considered in the coarse-grained model.     

Epidemiology,clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.     

Refining amyloid complete hematological response: Quantitative serum free light chains superior to ratio

Response assessment in light chain (AL) amyloidosis is based on serum and urine monoclonal protein studies. Newly diagnosed patients (n = 373) who achieved very good partial response or complete response (CR) to first line therapy were assessed for the survival impact of each of the monoclonal protein studies. At end of therapy (EOT), negative serum/urine immunofixation (IFE) was achieved in 61% of patients, 72% achieved normal serum free light chain ratio (sFLCR), and the median involved free light chain (iFLC) and difference between involved to uninvolved light chain (dFLC) were 17 mg/L and 5 mg/L, respectively. Overall, 46% of patients achieved a CR at EOT. At EOT, iFLC ≤20 mg/L and dFLC ≤10 mg/L were additive in survival discrimination to negative serum/urine IFE and were independent predictors of overall survival. In contrast, normalization of sFLCR did not add survival discrimination to serum/urine IFE and was not independent predictor of survival. We propose a new definition for hematological CR to include serum/urine IFE negativity plus iFLC ≤20 mg/L or dFLC ≤10 mg/L, instead of the current definition of serum/urine IFE negativity and normal sFLCR. Complete response using dFLC ≤10 mg/L had the best performance in those with significant renal dysfunction and by light chain isotype, making it the preferred partner to IFE. Validation of these results in a multicenter cohort is warranted.     

Exploring Migratory Dynamics on HIV Transmission: The Case of Mexicans in New York City and Puebla,Mexico

Migration and population movement are increasingly viewed as important factors associated with HIV transmission risk. With growing awareness of the potential impact of migration on HIV transmission, several perspectives have emerged that posit differing dynamics of risk. We considered available data on the role of migration on HIV transmission among Mexican migrants in New York City and Puebla, Mexico. Specifically, we examined 3 distinct models of migratory dynamics of HIV transmission—namely, the structural model, the local contextual model, and the interplay model. In doing so, we reframed current public health perspectives on the role of migration on HIV transmission.The epidemiological literature related to Latinos and HIV in the United States highlights geographic disparities in disease burden.1 HIV/AIDS cases among Latinos are clustered geographically, such that Latinos experience increased vulnerability as a function of residence in high-risk physical and geographic areas.2 Recent trends in HIV infection demonstrate that Latino mobility and migratory patterns are potentially associated with increased HIV incidence.3 As a result, several key dynamics to account for the role of migration and HIV transmission have emerged in recent literature. However, to adequately address the current HIV epidemic among Latinos, greater consideration of each of these mechanisms and enhanced attention to the role of geography and migration is warranted.4 Recent findings increasingly draw attention to the role of population mixing and movement, geography, and other physical spaces as important factors for understanding Latino HIV disparities.5 We build upon this work by examining the available empirical literature on HIV and migration in relation to the social structures and contexts in which risk behavior takes place. Specifically, we explored 3 mechanisms for the impact of migration on HIV transmission through the case of Mexican migrants in New York City (NYC) and Puebla.As the epicenter of the HIV/AIDS epidemic in the United States, NYC is one such high-risk geographic area.6 New York City has an incidence rate 3 times the national average and the highest number of AIDS cases relative to any other metropolitan city.6 Latinos in the city are disproportionately affected by the disease and are twice as likely to be diagnosed with HIV/AIDS compared with non-Hispanic Whites.7 Furthermore, although Latinos account for approximately 25% of the population in NYC, they represent 33% of NYC persons living with HIV/AIDS (PLWHA).8,9 Among NYC Latinos, HIV occurs primarily among adults through high-risk sexual behavior and intravenous drug use.10 Specifically, Latino men who have sex with men (MSM) constitute the majority of cases (40%), followed by injection drug users (27%).10 These data suggest that in NYC, Latino MSM and intravenous drug users bear the burden of HIV disease. However, a significant proportion of Latina women in NYC infected with HIV are exposed through high-risk sexual activity (67%) and represents a steady proportion of new HIV diagnoses among women in recent years.11HIV/AIDS is of particular concern among Latinos as they are more likely to experience delays in access to care, which results in adverse health outcomes. For example, Latinos, particularly Mexicans with low levels of acculturation, are less likely to obtain an HIV test.12 Those who are diagnosed often experience rapid progression to AIDS, suggesting that many Latinos are diagnosed late in their infection.6 In 2011, for example, 31% of Latinos diagnosed with HIV in NYC were concurrently diagnosed with AIDS, compared with only 15% of Whites.11 Late diagnosis puts Latinos at greater health risks because they do not receive the benefits of early antiretroviral treatment.13 In addition to late diagnosis and delayed treatment, obstacles in access to HIV treatment for Latinos include lack of a designated routine health care provider and adequate health insurance.14Increasingly, the Latino population in NYC has undergone important demographic changes.15 Specifically, migratory changes have shifted the composition of the Latino population in NYC, introducing new Latino subgroups to a geographic area of heightened HIV risk. Traditionally, the Latino population in NYC has been classified as largely stemming from the Caribbean—specifically, Puerto Rico and the Dominican Republic. However, Mexicans, whose US migration patterns have traditionally been associated with the areas of the Southwest, are increasingly moving to NYC, a nontraditional receiving community.For example, the Mexican population in NYC in 2010 was more than 5 times what it was in 1990.16 In 1990, an estimated 56 700 Mexicans were living in NYC; by 2000, this number grew to 180 000, and later to 325 000 in 2010.16 Foreign-born males with less than a high-school education represent the bulk of the Mexican population growth and a significant portion of this population attains employment in NYC.15 By 2024, it is predicted that Mexicans will be the most populous Latino ethnic subgroup in the largest city of the United States.17 One notable feature of NYC’s Mexican community is that nearly half (45%) originates from the state of Puebla in east-central Mexico, although other sources suggest far higher proportions (more than 70%).18 Data from the American Community Survey demonstrate that Mexican-born persons are geographically clustered in specific target communities, predominantly the Bronx and Queens (Figure 1).19Open in a separate windowFIGURE 1—Foreign-born from Mexico by Public Use Microdata Areas in New York City: 2006–2008.Note. PUMA = Public Use Microdata Area.Source. US Census Bureau.20     

Learning from preventable deaths: exploring case record reviewers' narratives using change analysis

Objective

To determine if applying change analysis to the narrative reports made by reviewers of hospital deaths increases the utility of this information in the systematic analysis of patient harm.

Design

Qualitative analysis of causes and contributory factors underlying patient harm in 52 case narratives linked to preventable deaths derived from a retrospective case record review of 1000 deaths in acute National Health Service Trusts in 2009.

Participants

52 preventable hospital deaths.

Setting

England.

Main outcome measures

The nature of problems in care and contributory factors underlying avoidable deaths in hospital.

Results

The change analysis approach enabled explicit characterisation of multiple problems in care, both across the admission and also at the boundary between primary and secondary care, and illuminated how these problems accumulate to cause harm. It demonstrated links between problems and underlying contributory factors and highlighted other threats to quality of care such as standards of end of life management. The method was straightforward to apply to multiple records and achieved good inter-rater reliability.

Conclusion

Analysis of case narratives using change analysis provided a richer picture of healthcare-related harm than the traditional approach, unpacking the nature of the problems, particularly by delineating omissions from acts of commission, thus facilitating more tailored responses to patient harm.