Challenge trials for a Hepatitis C vaccine

 The Journal Clinical Infectious Diseases has a special supplement on challenge trials (human infection trials) of a Hep C vaccine (now that Hep C is a curable disease):

Volume 77, Issue Supplement_3, 15 August 2023

Controlled Human Infection Model for HCV Vaccine Development

SUPPLEMENT ARTICLES

Controlled Human Infection Model for Hepatitis C Virus Vaccine Development: Is It Time to Be Real? 

T Jake Liang and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Page S215, https://doi.org/10.1093/cid/ciad343

• Hepatitis C virus (HCV) elimination has been a goal of the public health and scientific communities since its identification in 1989. Despite the advance and availability of highly effective antiviral regimens to treat HCV infection, it is unlikely that global HCV elimination can be achieved without an effective preventive vaccine. Because of the lack of appropriate animal models for preclinical testing and the perception that highly effective treatments would suffice in addressing the global burden of HCV, HCV vaccine development has not been a high priority. To accelerate vaccine development, the concept of a controlled human infection model (CHIM) for HCV has been proposed, in which healthy human volunteers would be deliberately infected with HCV for the purpose of testing the efficacy of candidate vaccines. This concept of challenge studies is not new and has been applied to more than 25 infectious agents, including the cholera vaccine, for which all efficacy data that served as the basis for regulatory approval were obtained from CHIM studies. Without a CHIM strategy, HCV vaccine development may not be feasible. In a recent phase 2 randomized controlled trial, over 900 people who inject drugs were screened to enroll 548 individuals to receive a T-cell–based HCV vaccine candidate or placebo. After a monumental effort that took over 6 years to complete, the trial documented 75 incident HCV infections overall, with only 45 included in the final analysis, and showed no protection against initial infection or progression to chronicity with the vaccine. While this study demonstrated that vaccine testing in the at-risk population can be done, future testing of additional HCV vaccine candidates using a similar pathway may be impractical in light of the duration and cost. With the ability to cure those who do not clear the virus, HCV CHIM is now a conceivable approach that could be a critically important, if not necessary, intermediate stage of vaccine development. HCV CHIM could de-risk vaccine candidates, accelerate development, reduce cost, and allow the selection of more promising candidates for further testing in larger clinical trials. CHIM may conceivably be used for larger phase 2/3 efficacy trials as a basis for clinical approval. In developing such a model, many challenges and questions must be addressed. In this Supplement issue, we, the editors of this Supplement commissioned various articles written by respective subject matter experts who provide their perspectives and opinions on these challenges and questions, ranging from the source of viral inoculum and the safety of transient HCV infection to the perspective of potential volunteers and the ethics of CHIM. While we strive to be data-driven and evidence-based, some of the opinions represent the views of the authors of each article and may be controversial. Ultimately, we hope these perspectives will enable fulsome discussion about the feasibility of HCV CHIM and lead to the development of well-designed clinical protocols.

  Supplement sponsorship. This article appears as part of the supplement “Controlled Human Infection Model for HCV Vaccine Development,” sponsored by Toronto General Research Institute, United States National Institutes of Health, Johns Hopkins University, the Canadian Institutes of Health Research (CIHR), and the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of CIHR (HPC-178912) and the Public Health Agency of Canada.

• View article

Ethics of Controlled Human Infection Studies With Hepatitis C Virus 

Annette Rid and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S216–S223, https://doi.org/10.1093/cid/ciad382

• Global elimination of hepatitis C virus (HCV) will be difficult to attain without an effective HCV vaccine. Controlled human infection (CHI) studies with HCV were not considered until recently, when highly effective treatment became available. However, now that successful treatment of a deliberate HCV infection is feasible, it is imperative to evaluate the ethics of establishing a program of HCV CHI research. Here, we evaluate the ethics of studies to develop an HCV CHI model in light of 10 ethical considerations: sufficient social value, reasonable risk–benefit profile, suitable site selection, fair participant selection, robust informed consent, proportionate compensation or payment, context-specific stakeholder engagement, fair and open collaboration, independent review and oversight, and integrated ethics research. We conclude that it can be ethically acceptable to develop an HCV CHI model. Indeed, when done appropriately, developing a model should be a priority on the path toward global elimination of HCV.

• View article 
• Supplementary data

Volunteering for Infection: Participant Perspectives on a Hepatitis C Virus Controlled Human Infection Model 

Jake D Eberts and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S224–S230, https://doi.org/10.1093/cid/ciad350

The perspectives of former challenge study participants and a survey of other potential volunteers can inform the design of hepatitis C virus controlled human infection models, including on topics such as transparency, volunteer safety and risk, and compensation.

• Ethical human subjects research requires participants to be treated safely and respectfully, yet much bioethical debate takes place without participants. We aim to address this gap in the context of controlled human infection model (CHIM) research. Based upon our own experience as study participants, and bolstered by a survey of 117 potential hepatitis C virus CHIM participants, we present ideas to inform efficient, ethical, and scientifically useful study design. We advocate for full protocol transparency, higher compensation, commitment to the rapid dissemination of study results, and proactive efforts to detail risk-minimization efforts as early as possible in the recruitment process, among other measures. We encourage researchers to proactively partner with volunteer advocacy organizations that promote collective representation of volunteers to maximize their agency, and guard against ethical issues arising from healthy human subjects research.

• View article 
• Supplementary data

First Do No Harm? Modeling Risks and Benefits of Challenge Trials for Hepatitis C Vaccine DevelopmentGet access

Alyssa Bilinski and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S231–S237, https://doi.org/10.1093/cid/ciad379

• Background

  In 2019, about 58 million individuals were chronically infected with hepatitis C virus. Some experts have proposed challenge trials for hepatitis C virus vaccine development.

  Methods

  We modeled incremental infections averted through a challenge approach, under varying assumptions regarding trial duration, number of candidates, and vaccine uptake. We computed the benefit-risk ratio of incremental benefits to risks for challenge versus traditional approaches. We also benchmarked against monetary costs of achieving incremental benefits through treatment.

  Results

  Our base case assumes 3 vaccine candidates, each with an 11% chance of success, corresponding to a 30% probability of successfully developing a vaccine. Given this probability, and assuming a 5-year difference in duration between challenge and traditional trials, a challenge approach would avert an expected 185 000 incremental infections with 20% steady-state uptake compared to a traditional approach and 832 000 with 90% uptake (quality-adjusted life-year benefit-risk ratio, 72 000 & 323 000). It would cost at least $92 million and $416 million, respectively, to obtain equivalent benefits through treatment. BRRs vary considerably across scenarios, depending on input assumptions.

  Conclusions

  Benefits of a challenge approach increase with more vaccine candidates, faster challenge trials, and greater uptake.

• View article 
• Supplementary data
• **********
  Earlier:

  Monday, May 15, 2023

  Eliminating Hepatitis C, now that there's a cure (even though it's expensive

  and here are my posts on challenge trials (and Covid vaccines).

Twenty Years of Marginal Revolution--econ blog pioneers

Economics in the 21st Century has blossomed, including new ways for economists to earn our livings.  Together with and alongside of that have come new ways for economists to communicate, among ourselves and with the wider public.  One of those ways is via blogs, and perhaps the most significant and most general interest economics blog has been Marginal Revolution, by Alex Tabarrok and Tyler Cowen. Yesterday MR marked its 20th anniversary.

Twenty Years of Marginal Revolution! by  Alex Tabarrok, August 23, 2023

"Who would have guessed that after twenty years Tyler and I would still be writing Marginal Revolution! Thanks especially to Tyler, we have had multiple new posts every single day for twenty years!"

Before pig kidneys can be transplanted into human patients...

 Here's a paper in the Lancet suggesting some of the work that remains before pig kidneys can be transplanted into human patients:

Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study, by Prof Alexandre Loupy, MD PhD, Valentin Goutaudier, MD MSc, Alessia Giarraputo, PhD, Fariza Mezine, MSc, Erwan Morgand, PhD, Blaise Robin, MSc, Karen Khalil, PharmD, Sapna Mehta, MD, Brendan Keating, PhD, Amy Dandro, MSc, Anaïs Certain, MSc, Pierre-Louis Tharaux, MD PhD, Prof Navneet Narula, MD, Prof Renaud Tissier, DVM PhD, Sébastien Giraud, PhD, Prof Thierry Hauet, MD PhD, Prof Harvey I Pass, MD, Aurélie Sannier, MD PhD, Ming Wu, MD, Adam Griesemer, MD, David Ayares, PhD, Vasishta Tatapudi, MD, Jeffrey Stern, MD, Prof Carmen Lefaucheur, MD PhD, Prof Patrick Bruneval, MD, Massimo Mangiola, PhD, Prof Robert A Montgomery, MD PhD, August 17, 2023 DOI:https://doi.org/10.1016/S0140-6736(23)01349-

"Background: Cross-species immunological incompatibilities have hampered pig-to-human xenotransplantation, but porcine genome engineering recently enabled the first successful experiments. However, little is known about the immune response after the transplantation of pig kidneys to human recipients. We aimed to precisely characterise the early immune responses to the xenotransplantation using a multimodal deep phenotyping approach.

...

"Interpretation: Despite favourable short-term outcomes and absence of hyperacute injuries, our findings suggest that antibody-mediated rejection in pig-to-human kidney xenografts might be occurring. Our results suggest specific therapeutic targets towards the humoral arm of rejection to improve xenotransplantation results."

********

Yesterday:

Wednesday, August 23, 2023

Transplanted pig kidney functions for a week in brain dead patient

Transplanted pig kidney functions for a week in brain dead patient

 Here's a report on a kidney from a genetically engineered pig, that was transplanted into a brain dead patient maintained on a ventilator, and which functioned successfully for seven days.  I'm beginning to think it's possible that xenotransplants of pig kidneys may be available for living patients in my lifetime.

Locke JE, Kumar V, Anderson D, Porrett PM. Normal Graft Function After Pig-to-Human Kidney Xenotransplant. JAMA Surg. Published online August 16, 2023. doi:10.1001/jamasurg.2023.2774

"Thirty-seven million adults in the US have chronic kidney disease (CKD), many of whom will ultimately progress to end-stage kidney disease (ESKD). Kidney transplant is the gold-standard therapy for patients with ESKD, yet annually, only 25 000 individuals receive a kidney. The gap between supply and demand is so vast that 40% of listed patients die within 5 years while waiting for a kidney transplant. Although xenotransplant represents 1 potential solution for the kidney shortage, previous reports of pig-to-human kidney xenotransplant using a preclinical human brain death model have shown xenograft urine production but not creatinine clearance, a necessary function to sustain life.1,2 Thus, no study to date has shown the ability of a xenograft to provide life-sustaining kidney function in a human.

...

"Discussion | The findings from this case series show that pigto-human xenotransplant provided life-sustaining kidney function in a deceased human with CKD. Future research in living human recipients is necessary to determine long-term xenograft kidney function and whether xenografts could serve as a bridge or destination therapy for ESKD. Because our study represents a single case, generalizability of the findings is limited. This study showcases xenotransplant as a viable potential solution to an organ shortage crisis responsible for thousands of preventable deaths annually."

Search engines as modern oracles, by Andrei Z. Broder & Preston McAfee

 Among the costs of visiting Mt. Parnassus to consult the Oracle at Delphi was that it was difficult to interpret the answers received, particularly if the questions were posed too casually.  Modern search engines are a bit like ancient oracles that way, and the resemblance may become greater as generative AI chatbots based on Large Language Models (LLMs) become part of search.

Here is some advice about how to think about all that.

Delphic Costs and Benefits in Web Search: A utilitarian and historical analysis. by Andrei Z. Broder & Preston McAfee, Google Research, August 16, 2023

Abstract: "We present a new framework to conceptualize and operationalize the total user experience of search, by studying the entirety of a search journey from an utilitarian point of view.

"Web search engines are widely perceived as “free”. But search requires time and effort: in reality there are many intermingled nonmonetary costs (e.g. time costs, cognitive costs, interactivity costs) and the benefits may be marred by various impairments, such as misunderstanding and misinformation. This characterization of costs and benefits appears to be inherent to the human search for information within the pursuit of some larger task: most of the costs and impairments can be identified in interactions with any web search engine, interactions with public libraries, and even in interactions with ancient oracles. To emphasize this innate connection, we call these costs and benefits Delphic, in contrast to explicitly financial costs and benefits.

"Our main thesis is that users’ satisfaction with a search engine mostly depends on their experience of Delphic cost and benefits, in other words on their utility. The consumer utility is correlated with classic measures of search engine quality, such as ranking, precision, recall, etc., but is not completely determined by them. To argue our thesis, we catalog the Delphic costs and benefits and show how the development of search engines over the last quarter century, from classic Information Retrieval roots to the integration of Large Language Models, was driven to a great extent by the quest of decreasing Delphic costs and increasing Delphic benefits.

"We hope that the Delphic costs framework will engender new ideas and new research for evaluating and improving the web experience for everyone."

And here's the final paragraph:

"We hope that this paper will engender new ideas for Delphic costs assessments, the measurement of Delphic costs, and means of reducing these costs. We would like to see the evaluation of web search engines move away from assessing the quality of ranking in isolation of the users’ overall search experience and personal context towards a holistic evaluation of user utility from using search engines. Moreover, this “utilitarian analysis” approach, rather than pure relevance analysis, could and should be applied to situations that do not involve explicit search, such as content feeds and recommender systems."

Return to the Econ by Joshua Gans

 Joshua Gans indulges his inner anthropologist:

Return to the Econ  by Joshua S. Gans,  August 20, 2023

Abstract: This paper revisits the Econ tribe famously documented by Leijonhufvud (1973). In half a century, the Econ have had their practices upended by technology and, for all but a few pockets of stasis, have changed their status hierarchy with new icons that are the focus of societal energy.

"In conversations with other members of the Econ, about 30 years ago, some rogue elements of Math-Econ, despite having achieved the highest levels of modl carving, made an attempt to carve modls that were actually useful and see if they “worked.” Rumour has it that they did, in fact, work and became useful in all of all things, the allocation of empty space and body parts. These elements were expelled by the Math-Econ as unworthy and left the sect with nothing but their Nobs."

Kidney disease in war-torn Sudan

 The Lancet brings us this news from Sudan.

Kidney failure in Sudan: thousands of lives at risk by Hatim A Hassan, Mohamed Hany Hafez, Valerie A Luyckx, Serhan Tuğlular, and Ali K Abu-Alfa, The Lancet, August 09, 2023DOI:https://doi.org/10.1016/S0140-6736(23)01370-3

"Sudan is one of few countries in Africa that has provided dialysis and transplantation under universal health coverage for several decades.2 Before the war, around 8000 patients required ongoing dialysis and around 4500 were living with kidney transplants (appendix). Haemodialysis was provided twice per week instead of three times per week to permit access to more patients within budget constraints.3

Haemodialysis requires continuous water, electricity, staffing, and disposable supplies. Since fighting began, dialysis services, which are mostly located in Khartoum, have been severely disrupted (appendix). Patients who can, have fled to dialysis units in other cities. Despite some units reducing haemodialysis frequency to once weekly, shortening sessions at times to 2 h, and offering appointments all day and all night, they are struggling to cope with demand. Most haemodialysis staff continue to work without being paid and are at high risk of burn-out. Egypt is accepting patients needing dialysis, but the cost and risk of the journey are prohibitively high for most.

Dialysis supplies have mostly run out by early August, 2023, despite dialysis sessions being reduced to weekly. A donation of supplies for a third of the patients for 3 weeks was obtained from one company. Reliance on donations of the large quantities of dialysis supplies needed for around 8000 patients is unrealistic. Dialysis supplies are not only expensive, but are bulky and costly to transport. Patients with kidney transplants are experiencing dangerous interruptions in their access to immunosuppressive medication. A reliable source of financing is urgently required to meet the needs of patients requiring dialysis and people with kidney transplants.

Support is needed to prevent adding a further layer of tragedy to this war if dialysis services cannot continue and transplant medication is not provided. Wars elsewhere pose similar threats to dialysis provision. The global health agenda must address the urgent need for transparent decision making and affordable access to vital treatments such as dialysis and transplantation during crises. Finding solutions to meet the needs of patients with kidney failure who depend on these therapies in low-resource settings in times of peace is also long overdue."

Calligraphy fan: OR and Game Theory

 Haibo Wang visited and brought me a fan, with calligraphy from his dad in Chinese characters.

Alex Chan translates:

"What is written is “運籌帷幄 博弈天下”.   運籌 is logistics (運籌學 is operations research) 博弈is gaming (and 博弈論 is  game theory)." 

"And the translation for the whole phrase is something like: strategizing and gaming the world - this is how you might describe a general." 

Kidney exchange between Portugal and Italy

 Italy-Portugal cross transplants. that click that saved two

"Thanks to a complex work of intervention planning and logistics, managed by the National Transplant Center, the Veneto Regional Transplant Center and the Portuguese institutions, the kidney of the Italian donor was removed in Vicenza and transplanted in Porto in a 41-year-old man while the Italian patient was transplanted with a kidney donated by a 36-year-old woman. The organs were harvested in the two centers simultaneously on the morning of 20 July. The Portuguese kidney arrived at Treviso airport at 2.10 pm on board a Lusitanian Air Force flight: the military delivered the organ to the regional transplant coordinator of the Veneto, Dr. Giuseppe Feltrin, receiving the Italian kidney in exchange. The 118 of Vicenza immediately transported the organ to San Bortolo where the transplantation began immediately. Both surgeries were successful and all recipients and donors went home in excellent condition."

Organ transplants between Hong Kong and mainland China: the promise and the politics

 This is a followup post to an earlier post# about the first cross border transplant in China between the mainland and Hong Kong. That's been followed by some political tensions, as reported in this forthcoming article in the American Journal of Transplantation.

A plan to save lives: Hong Kong–mainland China second-tier mutual assistance allocation. The new program between the transplant communities plays out on a backdrop of controversy and historical tension  by Lara C. Pullen, PhD, Published:July 28, 2023DOI:https://doi.org/10.1016/j.ajt.2023.07.015

"Key points:

"The transplant communities of Hong Kong and mainland China have proposed a second-tier mutual assistance allocation program that some find controversial.

• Tensions between Hong Kong and mainland China have a long and deep history.

• In 2014, the Chinese government announced a stop to obtaining organs from executed prisoners.

• Transplantation in mainland China has rapidly evolved, and people monitoring the change report that data from 10 to 15 years ago does not reflect the country’s current system."

**********

The background:

In December, the South China Morning Post carried this story about a transplant involving an organ recovered on the mainland and transplanted into a baby in Hong Kong, which was apparently the first such  transplant to cross that border:

4-month-old Hong Kong girl suffering from heart failure receives successful transplant with donated organ from mainland China, in city’s first such arrangement by Cannix Yau

One of the subheadlines is "Health Bureau notes importation of organ met relevant regulations, and hospital officials say arrangement involving mainland might be repeated in future"

***

And here's the story in the China Daily:

Securing a new lease of life By Li Bingcun | HK EDITION | Updated: 2023-03-31 15:10

"Hong Kong and the Chinese mainland have successfully carried out the first-ever cross-boundary organ-sharing operation, saving the life of an infant. The feat caps the city’s strenuous efforts to create a standing mechanism in organ sharing with the mainland to save more lives. Li Bingcun reports from Hong Kong."

***

Apparently the discussion of closer cooperation between transplant authorities in Hong Kong and the mainland is politically fraught. 

Here's a story from the Global Times that refers to some pushback from the mainland:

First organ donation between mainland and HK saves 4-month old baby By Wan Hengyi

"the acceptable heart donation for Cleo requires a donor weighing between 4.5 kilograms and 13 kilograms, and the chances of a suitable donor appearing in Hong Kong are slim to none. 

...

"COTRS initiated the allocation of a donated heart of a child with brain death due to brain trauma in the mainland on December 15. As a very low-weight donor, no suitable recipients were found after multiple rounds of automatic matching with 1,153 patients on a national waiting list for heart transplants in the COTRS system. In the end, the medical assistance human organ-sharing plan between the Chinese mainland and Hong Kong was launched.

"Some netizens from the Chinese mainland asked why a baby from Hong Kong who has not lined up in the COTRS system can get a donated heart when there is a huge shortage of donated organs in the mainland.

"In response, the organ coordinator told the Global Times that the requirements for organ donation are extremely high, noting that all the prerequisites including the conditions of the donor and recipient, the time for the organ to be transported on the road and the preparation for surgery must reach the standards before the donation can be completed.

"The COTRS system has already gone through several rounds of matching, which is done automatically by computer without human intervention, said the organ coordinator. "

...

"As of the end of October 2022, a total of 42,500 donors had donated more than 126,300 large organs in China, according to Guo Yanhong, director of the medical emergency department of the NHC."

******

Here's a story from the Guardian, about political concerns on the Hong Kong side:

Hongkongers opt out of organ registry ‘amid fear of Chinese donations’      by Amy Hawkins

"Thousands of Hongkongers have opted out of the city’s organ donor registry, seemingly as a form of subtle protest against proposals to establish deeper medical ties with mainland China.

...

"The trigger appears to have been a life-saving operation carried out in December on a four-month-old baby girl in Hong Kong, who was in need of a heart transplant. When a local match could not be found, a heart was transferred from a child who had suffered brainstem death in mainland China.

...

"Since the baby’s heart transplant, authorities have discussed the idea of establishing a mutual assistance registry with mainland China to facilitate future donations. That would be yet another erosion of the boundary between China and Hong Kong, which was supposed to remain largely autonomous from Beijing until 2047.

"Earlier this month, local news outlet Ming Pao reported that there had been discussion on social media among Hongkongers who did not want their organs donated to patients in mainland China."

********

China has a population approaching 1.5 Billion people, and Hong Kong is a city of about 7.5 Million people, so my guess is that HK is too small to have an efficient self-contained transplant system, and could benefit from being integrated into the mainland's system.

********

#Here's my earlier (contemporaneous) post:

Tuesday, January 10, 2023

Cross-border transplantation between China and Hong Kong

Argentine presidential politics, and monetary markets for kidneys

 The Financial Times reports on the surprising primary election performance of a far right candidate, Javier Milei.

Argentina radical rightwinger shakes up presidential race with primary win. by Ciara Nugent

"Javier Milei, a radical libertarian economist and outsider candidate, unexpectedly won Argentina’s primary poll, indicating a strong shift to the right as the South American country prepares to vote in a presidential election.

"Milei, a former television personality and one-term congressional representative who has called for extreme austerity and dollarising Argentina’s economy, won 30.1 per cent of the vote on Sunday, surpassing pollsters’ average forecast of 20 per cent, with 96 per cent of votes counted.

"That put his Freedom Advances party ahead of centre-right force Together for Change, with 28.3 per cent, and the ruling populist coalition Union for the Homeland, whose candidate is centrist economy minister Sergio Massa, which earned 27.2 per cent."

**********

I'm not a close follower of Argentine politics, but his name rang a bell, and reminded me that I had blogged about him in connection of his support for markets for kidneys. (There's no indication that was an issue in the presidential primaries...)

Wednesday, June 15, 2022

An unusual Argentine presidential candidate supports a monetary market for kidneys

Affirmative action in Brazilian universities: guest post by Inácio Bó

 Recent legislation in Brazil addresses university admissions with affirmative action that targets multiple characteristics that individuals may have (in different combinations), namely income, ethnicity, and the type of institution at which they studied. Early attempts to implement such a system produced undesirable outcomes, but recent legislation, informed by market design, is on the path to correcting this. Below, Inácio Bó brings us up to date:

Guest blog post by Inácio Bó

For many decades, Brazilian’s federal universities were—and still are— the top higher education institutions in the country. They had, however, a contradictory combination of circumstances: all of them were public-funded and tuition-free, but their students were overwhelmingly from a minority white higher socio-economic class. In response to that, in 2012 congress passed legislation mandating affirmative action in the access of all such institutions.

Orhan Aygün and I were at that time classmates pursuing our PhD in economics at Boston College. We spent days and weeks looking at the details of the structure of the rules for implementing the law, trying to better understand it. While working on some examples, we noticed that there could in principle be situations that were at odds with the intended objective of the law. Under some circumstances, black and low-income candidates would be rejected from positions where white and high-income candidates would be accepted, despite the former having higher entry-level exam grades than the latter. This  would be an outcome that goes in the opposite direction from the intended objective of helping black and low-income students attend these institutions.

The reason for this problem lies on the method used for implement the affirmative action law in the universities. Seats in each program in each university were split into groups of seats, including “open seats”, “black candidates”, “low-income candidates”, and “black and low-income candidates”. When applying for a program, a candidate would choose one of the alternatives for which she is eligible. The top candidates among those applying for each set of seats, ranked by their grade in a national exam, would be accepted. This method might, however, result in different levels of competition for different seats in the same program, resulting for example in tougher requirements for acceptance for “black and low-income” candidates than for “black” candidates, even if on average low-income candidates have lower grades overall.

In a paper published in the AEJ:Micro in 2021 (Aygün, Orhan, and Inácio Bó. 2021. "College Admission with Multidimensional Privileges: The Brazilian Affirmative Action Case." American Economic Journal: Microeconomics, 13 (3): 1-28.), we showed how this problem can be solved while still satisfying the text and spirit of the affirmative action law in Brazil with small changes in the way by which candidates are selected. (The idea is to order slot-specific priorities so that candidates with protected characteristics can compete for all of those slots for which their characteristics qualify them.) The paper also shows “smoking gun” evidence that these “unfair rejections” were taking place, showing that programs where the cutoff grades for acceptance for each subset of seats were compatible with these rejections constituted almost half of the programs offered across the nation.

While the article gained praise in the academic economic community, our hopes that it would reach the policymakers in Brazil were initially dashed. Despite having the chance of personally visiting the Ministry of Education in 2015 for two weeks, my attempts to talk with those in power were unsuccessful, and people to whom I explained some of our findings deemed its contents “critical of the government”.

 Especially in light of the political developments that took place in Brazil in the years that followed, I had mostly moved on from my hopes of seeing the changes we proposed being implemented.

Things started to change, however, around May of 2022. The staff from the office of representative Tábata Amaral, who is a prominent young politician with a focus on education, were having talks with Ursula Mello, now a professor at the Department of Economics at PUC-Rio in Rio de Janeiro, about some aspects of the affirmative action law related to her work. Given her knowledge about the AEJ:Micro paper, Ursula suggested that I join the discussions. A meeting where this happened even ended up in the press (https://www1.folha.uol.com.br/educacao/2022/05/pesquisadores-defendem-novo-algoritmo-no-sisu-para-nao-prejudicar-cotistas.shtml).

Adriano Senkevics, her co-author in related papers who works at the INEP—an agency connected to the Brazilian Ministry of Education in charge of evaluating educational systems—also joined.

In these discussions, it became clear that if we wanted our ideas to have any chance of gaining traction, we needed to write a policy-oriented paper, focused on the current Brazilian specifics, in Portuguese, and with policy-makers as the audience—not academics.

Adriano and I worked together in that project, now with a much more detailed dataset. We tailored the proposal to the updated law, which also included reservations for candidates with disabilities, and were finally able to quantify the negative impact of the failures we identified. Our estimates indicate that, in the selection process of 2019, at least ten thousand students were “unfairly rejected” from their applications, with more than 8 thousand being left unmatched to any university despite having an exam grade high enough to be accepted for less restrictive reserved seats. These numbers greatly exceeded our expectations, and made a clear political case for a change. The working paper went out in January of 2023 (“Proposal to change the rules for the occupation of quotas in the student entrance to federal institutions of higher education,” by Inácio Bó and Adriano Souza Senkevics).

While the theoretical arguments were already in the AEJ:Micro paper, the proposal had a greater and faster impact in the corridors of the Brazilian capital. Articles in the main newspapers in the country reported on the findings and the proposal (https://oglobo.globo.com/brasil/educacao/enem-e-vestibular/noticia/2023/03/quase-650-candidatos-para-uma-vaga-maiores-concorrencia-do-sisu-estao-entre-os-alunos-cotistas.ghtml

, https://oglobo.globo.com/brasil/antonio-gois/coluna/2023/02/reformar-o-sisu.ghtml

, https://www1.folha.uol.com.br/colunas/rodrigo-zeidan/2023/04/desenhando-mercados.shtml )

People were openly sharing the article on twitter with members of the ministry of education

(https://twitter.com/thiamparo/status/1621189953785839617?s=20 ,

https://twitter.com/mgaldino/status/1621008428763332612?s=20 ). We could feel the momentum.

In the months that followed, I started having regular interactions with members of the Ministry of Education. The text and zoom discussions involved technical and political aspects of changes in the law, which extended beyond the specific changes we suggested.

Different variations of the changes and some alternative proposals were considered. I had to run simulations while flying to deliver them before a meeting that the secretary had with the minister. I also had the incredible experience of joining a meeting at the “Casa Civil”—a department somewhat comparable to the prime minister in a parliamentary system—with the presence of secretaries from multiple ministries , where I presented our proposal and discussed some details and scenarios. Around that time, and without our knowledge, a senator presented a bill explicitly based on our proposal (https://www25.senado.leg.br/web/atividade/materias/-/materia/156995 ).

By the end of June, our belief that the changes would be implemented became stronger. Since our proposal was (by design) already compatible with the quotas law, its implementation could be done even in the absence of new legislation, and there was clear interest on the part of those in charge for making it happen.

A momentous event in this journey, however, took place on August 9th.

Because of a series of political circumstances, an urge to pass a renewed law for the affirmative action led to a bill proposed by Representative Dandara—the first member of congress who herself benefitted from the quotas law—to be brought to the floor for a vote.

Among other changes, it made the affirmative action policy permanent, changed the order in which seats are filled, and included text that should, in the following secondary legislation, include text that describes our proposal. As if emotions were not high enough, we had urgent calls to send the text of our proposal to members in the floor of congress minutes before the vote took place. And this resulted in the photo below, showing Dandara giving a speech before the vote, with a page from our paper in her hand.

The journey is not yet over. The bill must still pass the senate, and the legislation with the implementation details will follow. But I learned that these changes are made of so many steps that one has to choose one as the turning point. We believe that this is a good one.

The INEP (National Institute of Educational Studies and Research) thinks so too: (https://www.gov.br/inep/pt-br/assuntos/noticias/linha-editorial/inep-contribui-com-atualizacao-da-lei-de-cotas)

The high out-of-pocket cost of donating a kidney. By Martha Gershun

 Martha Gershun continues to write eloquently about the obstacles to kidney donation.  

Here she is in Stat:

The high out-of-pocket cost of donating a kidney. By Martha Gershun 

"Five years have now passed since I donated my kidney, and both Deb and I are doing well....

"My husband and I are comfortable financially. We could afford the $5,000 in gasoline, hotels, and food for the 19 nights we spent travelling to the Mayo Clinic for my medical evaluation, surgery, recovery, and six-month follow-up visit. Our children are grown and our parents are gone, so we had no child care or elder care expenses (though we did have to pay a cat sitter for the time we travelled). And neither of us had to forgo any wages: At 61, I had already retired from paid work, and the generous PTO policy at the nonprofit where my husband was CEO covered the 128 hours of work he missed to travel with me and help with my recovery.

 "We did not qualify for assistance from the National Living Donor Assistance Center (NLDAC), because my recipient’s income was more than 300% of the current Health and Human Services (HHS) Poverty Guidelines (this has recently been raised to 350%). In fact, my recipient generously insisted on reimbursing us for our out-of-pocket expenses. This is not considered direct compensation for an organ, so is legal under the National Organ Transplant Act (NOTA).

But all of that was just our good fortune. What about potential organ donors without our resources? It is very easy to imagine someone in a low-wage hourly job who wants to donate a kidney to their sister, a married mother of two, who, along with her spouse, has an annual household income slightly above $105,000, which is 350% of the current HHS Poverty Guidelines. That potential donor, unable to access help from NLDAC, would be unable to afford the out-of-pocket expenses or lost wages. There would be no living donation; the patient would remain on the kidney transplant waiting list, along with 93,000 others.

Every living kidney donor saves private insurance or Medicare significant expense — experts estimate between $250,000 and $500,000 over the lifetime cost of dialysis for each kidney patient they help. Every living kidney donor enables the hospital and the surgeons, nephrologists, nurses, and other staff who work there to earn money for their transplant work. But the kidney donor — the one person who gives away a part of their body to make this miracle possible — is forced to incur financial losses to participate.

Recognizing this problem, New York state recently passed the Living Donor Support Act, the first law that provides living organ donors in the United States reimbursement for donation-related expenses, including lost wages, travel, lodging, and child care.

"Congress just revised the 1984 law that set up the United Network for Organ Sharing (UNOS) as the sole contract holder to run the country’s organ transplant system. Hopefully, this will have a tremendous impact on the way the system procures, allocates, and distributes organs from deceased donors. A better functioning transplant system, with improved technology and a better process for wait list management, could help living donors, but this legislation does nothing to help living donors overcome the financial barriers to organ donation.

...

"Individuals should not have to pay out of their own pocket to save someone else’s life."

Fall workshops in Mathematics and Computer Science of Market and Mechanism Design

 Here's an update on the three scheduled workshops connected to the SLMath (formerly MSRI) semester focus on market and mechanism design. (There will be two in September and one in November.)

"Mathematics and Computer Science of Market and Mechanism Design" Register for Fall 2023 Workshops at SLMath (MSRI) in Berkeley, California and Online     In recent years, economists and computer scientists have collaborated with mathematicians, operations research experts, and practitioners to improve the design and operations of real-world marketplaces. Such work relies on robust feedback between theory and practice, inspiring new mathematics closely linked – and directly applicable – to market and mechanism design questions. Established researchers, postdoctoral fellows, and graduate students are invited to join world-renowned mathematicians, computer scientists, economists, and other experts at these hybrid events at the Simons Laufer Mathematical Sciences Institute (SLMath, formerly MSRI) in Berkeley, California.   September 7-8, 2023: Connections Workshop Organizers: Michal Feldman (Tel-Aviv University), Nicole Immorlica* (Microsoft Research) The Connections Workshop will consist of invited talks from leading researchers at all career stages in the field of market design. Particular attention will be paid to real-world applications. There will also be an AMA (Ask Me Anything) session focused on career paths with highly visible individuals in the field, and a social event intended to help workshop attendees network with each other.   Register for the Connections Workshop   September 11-15, 2023: Introductory Workshop Organizers: Scott Kominers (Harvard Business School), Paul Milgrom (Stanford University), Alvin Roth (Stanford University), Eva Tardos (Cornell University) The workshop will open with overview/perspective talks on algorithmic game theory and the theory and practice of market design; the afternoon will feature a panel on active research areas in the field (again, at the overview level). The next 2 days will consist of introductory mini-course and tutorials, on topics such as game theory, matching, auctions, and mechanism design. The following day will focus on applicable tools and technology, such as lattice theory, limit methods, continuous optimization, and extremal graph theory. The workshop will conclude with a panel discussion on major open problems.   Register for the Introductory Workshop   November 6-9, 2023: Algorithms, Approximation, and Learning in Market and Mechanism Design Organizers: Martin Bichler (Technical University of Munich), Péter Biró* (KRTK, Eotvos Lorand Research Network) The workshop is aimed at exploring core subjects in the field of market and mechanism design, such as the design of non-convex auction markets, the design of matching markets with preferences, algorithmic mechanism design, and learning in games and markets. These topics are interrelated and deeply rooted in mathematics and computer science. Each day of the 4-day workshop is devoted to one of these topics with talks by leading scholars in the field and panel discussions on major open problems.    Register for the November Workshop   Registration is open for both in-person and online-only attendees through each workshop's scheduled dates. Those who plan to attend via Zoom will receive workshop links in advance of the event. For assistance with registration questions, contact coord@slmath.org. SLMath workshops are free of charge to attend, thanks to the generous support of our funders, including the National Science Foundation and the Alfred P. Sloan Foundation.

Repugnance watch: British satire considers cellular agriculture in human meat

In The Conversation:

The British Miracle Meat: how banning repugnant choices obscures the real issue of poverty  by Renaud Foucart

"A provocative Channel 4 satirical programme, The British Miracle Meat, has led to hundreds of complaints to media regulator Ofcom. The mockumentary depicts ordinary Britons facing the cost of living crisis selling thin slices of their tissue to an innovative factory that uses it to grow lab meat.

The show was inspired by Jonathan Swift’s satire A Modest Proposal (1726), in which the author of Gulliver’s Travels suggests poor Irish people sell their children for food. The Channel 4 show’s creators wanted to make viewers think about the effects of the cost of living crisis, as well as the future of food.

Viewers were left baffled, however, seeing the show as promoting cannibalism. In the UK, it is illegal to sell human organs and other tissues. But in economics, we teach our students the theory of “repugnant markets” – those in which disgust or distaste lead governments to ban certain transactions rather than tackling the underlying economic reasons for them."

Freezing (and then carefully warming) donor organs breaks the organ transplant time barrier (for rats, for the time being)

 Here's a note in Nature Reviews Nephrology pointing out the longer term promise of the recent successful freezing, thawing, and transplantation of rat kidneys.

Cryopreservation breaks the organ transplant time barrier by Marlon J. A. de Haan & Ton J. Rabelink, in Nature Reviews Nephrology (2023)

"The pressing issue of organ shortages for transplantation is fuelled by the rising incidence of kidney failure and the declining quality of organs from an ageing donor pool. However, the main bottleneck in organ transplantation is time; indeed, the current clinical standard for kidney preservation necessitates immediate transplantation following organ recovery1. This urgency often results in suboptimal matches between donors and recipients. Cryopreservation has emerged as a potential solution to this challenge. Such an approach would enable organs to be preserved in a suspended state for extended periods and ready for transplantation on demand. The prospect of long-term banking of cryopreserved organs holds promise for transforming organ transplantation into an elective procedure, thereby enhancing donor–recipient matching, improving equity in access, optimizing patient preparation, refining transplant tolerance protocols, increasing organ utilization and improving graft and patient survival. However, even though cryopreservation has successfully been used to store human embryos, extending the process to preserve whole organs has remained a scientific aspiration — until now. A study by Han et al. introduces an approach to cryopreservation that seemingly extends the shelf life of organs indefinitely2."

...

"By rapidly cooling rat kidneys to –150°C, Han et al. were able to halt the biological clock of the organs, effectively inducing a glass-like state — a process known as vitrification2 (Fig. 1). Specifically, the researchers perfused a cocktail of cryoprotective agents (CPAs) and iron oxide nanoparticles into the organ’s vasculature, which they followed by rapid cooling to ultralow temperatures to achieve a state of vitrification. This vitrified kidney, with its hard, smooth, glasslike appearance, was then transferred to a –150°C freezer for long-term banking. When these kidneys were later rewarmed and transplanted into nephrectomized recipients, they regained life-sustaining renal function. The rewarming stage poses more challenges to the process of cryopreservation: it requires both speed to avoid ice formation during devitrification and uniformity to prevent thermal stresses and mechanical cracks. Here, the iron oxide nanoparticles had a crucial role. Placing the vitrified kidney in a coil that generates electromagnetic fields activates these nanoparticles, generating heat. This innovative approach enabled rapid rewarming at an impressive rate of approximately 72 °C per minute throughout the entire organ, ensuring uniform warming rather than limiting warming to the organs’ surface. This ground-breaking milestone marks an extraordinary achievement in ‘reviving’ a complex organ like the kidney and is the culmination of decades of research into methods to prevent the destructive formation of ice during the cooling process, minimize toxicity from CPAs, and enable fast and uniform rewarming3.

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Wednesday, June 28, 2023

Freezing, thawing and transplanting a rat kidney: a first step towards organ banking

Ned Brooks on Coalition to Modify NOTA

Ned Brooks (about whom I've often blogged) is putting his eloquence and organizational skills to the task of increasing organ donation by allowing organ donors to be compensated. Below is a short video of an address he gave to the National Kidney Donation Organization (NKDO) which he founded, about his new effort, the Coalition to Modify NOTA.

 

Here's a copy of the email that came with the video:

To the NKDO Membership:   Thank you for your responses to the survey asking if NKDO should support the Coalition to Modify NOTA (CMN), formed by non-directed donors Ned Brooks, Elaine Perlman and Cody Maynard.   87% of our membership supports the mission statement of CMN as follows:   The Coalition to Modify NOTA (ModifyNOTA.org) is created in response to the inability of the current system to adequately address the crisis of kidney failure in the United States. The National Organ Transplant Act of 1984 prohibits the compensation of organ donors.   The current system of deceased donations and voluntary living donation is grossly inadequate to the task of completely ending the shortage of transplant kidneys and saving the lives of patients in kidney failure who are dying unnecessarily each year.  We believe that the solution to this crisis is to have the government compensate donors in a manner that is neither exploitative nor coercive. The Coalition to Modify NOTA seeks the modification of the National Organ Transplant Act to allow such government compensation.   Watch this presentation on the Coalition to Modify NOTA by Ned Brooks.   To sign your name in support of the Mission Statement, please go to Join the Coalition.   Kind regards,   Matt Cavanaugh, CEO and President