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Rapid onset of hypercalcemia from high-grade lymphoma in the setting of HIV-related immune reconstitution inflammatory syndrome.
Hypercalcemia in HIV patients has been previously reported, but 1,25-(OH)2 vitamin D-mediated hypercalcemia, due to increased activity of extrarenal 1-alpha hydroxylase, is rarely described with HIV-related infections or malignancies. We describe a case of 1,25-(OH)2 vitamin D-mediated hypercalcemia in a patient presenting with progressive cognitive decline and weakness. Initial evaluation revealed a new diagnosis of HIV, for which he was started on antiretroviral therapy (ART). He was also noted to have mild asymptomatic hypocalcemia, likely from his acute illness and malnutrition, which was not further investigated at the time. While the patient's mental status initially improved with ART, he became progressively delirious and was found to be hypercalcemic approximately 4 weeks after the initiation of ART. Possible etiologies for hypercalcemia were vigorously evaluated, including granulomatous disease, infection, and malignancy, in the setting of suspected immune reconstitution inflammatory syndrome (IRIS), due to recent initiation of ART. Infectious workup was unrevealing, but computed tomography (CT) of the chest, abdomen, and pelvis revealed new extensive diffuse lymphadenopathy and hepatomegaly, not present on admission studies. Cytology and flow cytometry of a liver biopsy specimen revealed CD10 positive high-grade B-cell lymphoma. Chemotherapy was not pursued due to poor performance status. Over the next week, spontaneous tumor lysis developed, and the patient expired. Postmortem, his 1,25-(OH)2 vitamin D level returned as markedly elevated. Immunohistochemical staining of his liver biopsy tissue showed strong expression of CYP27B1. 1,25-(OH)2 vitamin D-mediated hypercalcemia is uncommon in a patient with newly diagnosed HIV and, in this case, was likely due to IRIS unmasking an underlying high-grade lymphoma and restoration of immune function (including T-cells and cytokine production). This case emphasizes the importance of including aggressive lymphomas, capable of progressing over days to weeks, in the evaluation of hypercalcemia in HIV patients at risk for developing IRIS and the rapid dynamic changes in mineral homeostasis that can occur with such an aggressive tumor in an immunocompromised host
Infectious Mimicry Complicates Diagnosis in Hemophagocytic Syndrome Caused by Anaplastic Large-Cell Lymphoma
Hemophagocytic syndrome (HPS) arises secondary to genetic, rheumatologic, neoplastic, and infectious causes. We discuss a patient whose presentation was consistent with systemic infection but was discovered to have HPS of unknown etiology. The presenting symptoms, as well as unremarkable malignancy and rheumatologic workups, led to the pursuit of an infectious cause, but the patient was ultimately discovered to have an occult anaplastic large-cell lymphoma (ALCL). This case demonstrates the diagnostic challenges that result from infectious mimicry in the context of HPS—first, in distinguishing noninfectious HPS from the systemic inflammation that can result from a widespread infectious process, second, in the identification of the precipitating cause of HPS. While evidence of these challenges has been suggested by the limited literature on HPS and ALCL, our case illustrates the diagnostic dilemma that arises when tissue biopsy does not quickly reveal an etiology. It is important that all physicians be aware that HPS can mimic infection and be prepared to redirect the workup when an infectious etiology for HPS cannot be identified
Data driven theory for knowledge discovery in the exact sciences with applications to thermonuclear fusion
In recent years, the techniques of the exact sciences have been applied to the analysis of increasingly complex and non-linear systems. The related uncertainties and the large amounts of data available have progressively shown the limits of the traditional hypothesis driven methods, based on first principle theories. Therefore, a new approach of data driven theory formulation has been developed. It is based on the manipulation of symbols with genetic computing and it is meant to complement traditional procedures, by exploring large datasets to find the most suitable mathematical models to interpret them. The paper reports on the vast amounts of numerical tests that have shown the potential of the new techniques to provide very useful insights in various studies, ranging from the formulation of scaling laws to the original identification of the most appropriate dimensionless variables to investigate a given system. The application to some of the most complex experiments in physics, in particular thermonuclear plasmas, has proved the capability of the methodology to address real problems, even highly nonlinear and practically important ones such as catastrophic instabilities. The proposed tools are therefore being increasingly used in various fields of science and they constitute a very good set of techniques to bridge the gap between experiments, traditional data analysis and theory formulation
A Collaboratory, Multi-Disciplinary Approach to Risk Mitigation during HIV Analytical Treatment Interruption
Analytic treatment interruptions (ATIs) are currently the standard for assessing the impact of experimental interventions aimed at inducing sustained antiretroviral therapy (ART)-free remission in trials related to HIV cure. ATIs are associated with substantial risk to both study participants and their sexual partner(s). Two documented HIV transmissions occurring in the context of ATIs have been recently reported, but recommendations for mitigating the risk of such events during ATIs are limited. We outline a practical approach to risk mitigation during ATI studies and describe strategies we are utilising in an upcoming clinical trial that may be applicable to other centres
Considerations for designing and implementing combination HIV cure trials: findings from a qualitative in-depth interview study in the United States
Background: An increasing number of HIV cure trials involve combining multiple potentially curative interventions. Until now, considerations for designing and implementing complex combination HIV cure trials have not been thoroughly considered. Methods: We used a purposive method to select key informants for our study. Informants included biomedical HIV cure researchers, regulators, policy makers, bioethicists, and community members. We used in-depth interviews to generate ethical and practical considerations to guide the design and implementation of combination HIV cure research. We analyzed the qualitative data using conventional content analysis focused on inductive reasoning. Results: We interviewed 11 biomedical researchers, 4 community members, 2 regulators, 1 policy researcher, and 1 bioethicist. Informants generated considerations for designing and implementing combination interventions towards an HIV cure, focused on ethical aspects, as well as considerations to guide trial design, benefit/risk determinations, regulatory requirements, prioritization and sequencing and timing of interventions, among others. Informants also provided considerations related to combining specific HIV cure research modalities, such as broadly neutralizing antibodies (bNAbs), cell and gene modification products, latency-reversing agents and immune-based interventions. Finally, informants provided suggestions to ensure meaningful therapeutic improvements over standard antiretroviral therapy, overcome challenges of designing combination approaches, and engage communities around combination HIV cure research. Conclusion: The increasing number of combination HIV cure trials brings with them a host of ethical and practical challenges. We hope our paper will inform meaningful stakeholder dialogue around the use of combinatorial HIV cure research approaches. To protect the public trust in HIV cure research, considerations should be periodically revisited and updated with key stakeholder input as the science continues to advance
Ethical and practical considerations for mitigating risks to sexual partners during analytical treatment interruptions in HIV cure-related research
Background: Background: Analytical treatment interruptions (ATIs) in HIV cure-related research can result in trial participants becoming viremic with HIV, placing HIV-negative sexual partners at elevated risk of acquiring HIV. Objective: Objective:Our study aimed to generate ethical and practical considerations for designing and implementing appropriate risk mitigation strategies to reduce unintended HIV transmission events during ATIs. Methods: Methods: We conducted 21 in-depth interviews with five types of informants: bioethicists, community members, biomedical HIV cure researchers, socio-behavioral scientists/epidemiologists, and HIV care providers. We used conventional content analysis to analyze the data and generate considerations. Results: Results: Key findings include: 1) Ethical permissibility of ATI trials depends on due diligence and informed consent to mitigate risks to participants and their sexual partners; 2) Participants should receive adequate support and/or counseling if they choose to disclose ATI participation to their partners; 3) Measures to protect sexual partners of trial participants from HIV transmission during ATIs should include referral to and/or provision of pre-exposure prophylaxis, as well as other available means of preventing HIV transmission; 4) There is uncertainty regarding the appropriate management of emerging sexually transmitted infections during ATI trials and possible protection measures for multiple and/or anonymous partners of ATI trial participants. Conclusion: Conclusion: While there is no way to completely eliminate the risk of HIV transmission to sexual partners during ATIs, HIV cure trialists and sponsors should consider the ethical concerns related to the sexual partners of ATI participants. Doing so is essential to ensuring the welfare of participants, their partners and the trustworthiness of research
Bidirectional Exchanges of Medical Students Between Institutional Partners in Global Health Clinical Education Programs: Putting Ethical Principles into Practice
BackgroundOne-third of US medical students participate in global health (GH) education, and approximately one-quarter of US medical schools have structured programs that offer special recognition in GH. GH clinical electives (GHCEs) are opportunities for students to experience a medical system and culture different from their own. GHCEs are administered through institutional affiliation agreements, often between an institution in a high-income country (HIC) and one in a low- or middle-income country (LMIC). Although these agreements suggest the exchange of students in both directions, GHCEs are traditionally characterized by students from HICs traveling to LMICs.ObjectivesThe goal of this study was to investigate the availability of opportunities for students from LMICs participating in GHCEs at partner institutions in HICs and to describe the costs of these opportunities for students from LMICs.MethodsWe conducted a web-based search of 30 US institutions previously identified as having structured programs in GH. We determined which of these schools have programs that accept medical students from international schools for GHCEs, as well as the administrative requirements, types of fees, and other costs to the international student based on information available on the web. Descriptive statistics were employed for the quantitative analysis of costs.FindingsWe found that, although the majority of US institutions with structured GH programs sending students to sites abroad accept international students at their sites in the United States, nearly one-fifth of programs do not offer such opportunities for bidirectional exchange. We also characterized the substantial costs of such experiences, because this can represent a significant barrier for students from LMICs.ConclusionsAccess to GHCEs in US partner institutions should be an important underlying ethical principle in the establishment of institutional partnerships. The opportunities available to and experiences of students from LMIC partner institutions are important areas for future GH education research
Traversing the margins of corruption amidst informal economies in Amazonia
This article focuses on local idioms of extra-legal economic activity among indigenous Amazonians in eastern Peru, and its overall argument is that these idioms are part of a broader context in which indigenous people are compelled by a variety of factors to act in a seemingly corrupt manner. I further suggest that within such a context these idioms are not confined to the informal economy but are also used to refer to activities that fall within the formal economy, supporting Hart’s (2009) claim that the informal economy is a way of imagining the orthodox economy. I argue that corruption within Amazonian economies is commonly perceived by non-indigenous people as contrasting with the workings of the orthodox economy without proper consideration of the economic conditions and bureaucratic structures that give rise to it. Lastly, I argue that, here, corruption can contravene bureaucracy by restoring the humanity that Herzfeld (1993) claims bureaucracy rejects through its acts of indifference toward individuals
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