Repairing DNA: a review

The promise and challenge of therapeutic genome editing

Jenifer Doudna publishes a must read review article on genome editing in Nature this week. 

Current clinical trials using the CRISPR platform aim to improve chimeric antigen receptor (CAR) T cell effectiveness, treat sickle cell disease and other inherited blood disorders, and stop or reverse eye disease. In addition, clinical trials to use genome editing for degenerative diseases including for patients with muscular dystrophy are on the horizon.

 Notably, all of the genome-editing therapeutics under development aim to treat patients through somatic cell modification. These treatments are designed to affect only the individual who receives the treatment, reflecting the traditional approach to disease mitigation. However, genome editing offers the potential to correct disease causing mutations in the germline, which would introduce genetic changes that would be passed on to future generations.

 At the time of writing, international commissions convened by the World Health Organization (WHO) and by the US National Academy of Sciences and National Academy of Medicine, together with the Royal Society, are drafting detailed requirements for any potential future clinical use.

Meanwhile, CRISPR is closer than you think.

Fig. 1: Ex vivo and in vivo genome editing to treat human disease.

Fig. 2: The genome editing toolbox.

Fig. 3: Emerging tools.

Fig. 4: Editing the human germline.

Germline genome editing under scrutiny

Societal and Ethical Impacts of Germline Genome Editing: How Can We Secure Human Rights?

Geneva Statement on Heritable Human Genome Editing: The Need for Course Correction

A CRISPR Moratorium Isn't Enough: We Need a Boycott

The Human Right to Science and the Regulation of Human Germline Engineering

The last frontier in genome editing (if it exists) is germline. The special issue of The Crispr journal on bioethics contains an article of special interest and proposes a third process for evaluating individual and societal harms: a Human Rights Impact Assessment.

Human germline alteration is possible, due in part to democratization of genetic tools required for genome editing, and international scientific and legislative bodies are developing frameworks to manage the ramifications of this technology. Common among these frameworks are two pillars: public engagement and foundational principles. These components are necessary for respecting the autonomy of individuals and for fair processes and respecting diverse values.

However, they are not sufficient for protecting the most vulnerable members of society who may not even be in a position to participate in democratic processes. We propose implementing a HRIA, which captures concerns of public health and offers an opportunity to evaluate and anticipate the societal impact of GGE iteratively as the technology advances, public sentiments evolve, and cultural contexts shift. We recognize that this will raise new challenges of how such assessments are shared and implemented and how they can be enforced. We urge regulatory bodies and policy makers to consider this assessment approach in helping to establish robust regulatory frameworks necessary for the global protection of human rights.

And the Geneva Statement on Heritable Human Genome Editing says:

No decision about whether to pursue heritable human genome modification can be legitimate without broadly inclusive and substantively meaningful public engagement and empowerment. Such deliberations may be challenging and messy. They will take time and organizing them will necessitate creativity, hard work, and significant human and financial resources. The course correction proposed here is essential to these efforts.
We must in the meantime respect the predominant policy position against pursuing heritable human genome modification, if we are to prevent individual scientists or small committees from making this momentous decision for us all. This will preserve time to cultivate an informed and engaged public that can consider and discuss the societal consequences of altering the genes of future generations and make wise, democratic decisions about the shared future we aspire to build. 

I agree.

PS. CRISPR in 2020  Two major reports on germline editing, from the National Academies/Royal Society and the World Health Organization, will be released in 2020. We hope the reports will coordinate, with all the voices of CRISPR being heard, so we can build consensual and broadly acceptable frameworks to ensure we use CRISPR responsibly, especially regarding usage in human embryos for germline editing. The public has asked for it, and the community has been working on it. The science versus society gap will be bridged.

Digital health next to you

Bringing health care to the patient: An overview of the use of telemedicine in OECD countries 

Benchmarking deployment of eHealth among general practitioners

EHEALTH TREND BAROMETER: ANNUAL EUROPEAN EHEALTH SURVEY 2019

Several reports have been recently released. I would like to highlight the first one by the OECD, it reviews the current state of telemedicine and explains what works. In my opinion we do need an assessment of cost effectiveness of telemedicine, otherwise technology driven change is not enough.

Telemedicine services have the potential to improve effectiveness, efficiency and equity in health care, helping policy makers respond to increasing patient demands and needs. However, telemedicine interventions can also introduce new risks and amplify existing inequalities. In order for countries to maximise the benefits and limit the risks, telemedicine services need to improve the quality of care and provide clear benefits for patients. Telemedicine programmes that do not have benefits for patients are not worth pursuing and detract attention from other more effective interventions.

Josep Segú - Central Park

Health services research as a data science

Health Services Evaluation
Health Services Information: Key Concepts and Considerations in Building Episodes of Care from
Administrative Data
Assessing health systems

The provision of relevant, accurate, and timely performance information can play a pivotal role in ensuring the health system is able to deliver effective and efficient health services. Through its capacity to secure accountability in the health system, to determine appropriate treatment paths for patients, and to plan for future service patterns and structures, information can be used to identify and implement potential improvements in service delivery

AI in clinical decision making

International evaluation of an AI system for breast cancer screening

Artificial intelligence is capable of surpassing human experts in breast cancer prediction. You can check it in Nature:

 To assess its performance in the clinical setting, we curated a large representative dataset from the UK and a large enriched dataset from the USA. We show an absolute reduction of 5.7% and 1.2% (USA and UK) in false positives and 9.4% and 2.7% in false negatives. We provide evidence of the ability of the system to generalize from the UK to the USA. In an independent study of six radiologists, the AI system outperformed all of the human readers: the area under the receiver operating characteristic curve (AUC-ROC) for the AI system was greater than the AUC-ROC for the average radiologist by an absolute margin of 11.5%. 

If AI outperforms radiologists, than there is no argument to delay its implementation.
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How to distort priority setting?

Biases distorting priority setting

Why priority setting in health care has so poor outcomes while relevant systems are well developed and readily available? You just have to read this article to understand it.

It starts to identify some rational and structural explanations for the discrepancy between theoretical efforts and practical outcomes in priority setting. However, even if these issues are addressed, practical priority setting may still not obtain its goals. This is because a wide range of irrational effects is hampering priority setting: biases.

Table 1. Overview of various biases and potential implications for priority setting and at which level they may be most prominent.

Bias	Potential Implications	Level
Identifiability and Singularity effect	Undermining principles	Micro
Rejection Dislike	Hamper disinvestment	Micro, meso
Failure Embarrassment effect	Overuse	Micro (primarily)
Prominence Effect (Opportunity Cost Neglect)	Non-warranted use	All
Status Quo Bias	Overuse, Underuse	All
Endowment Effect	Overuse, Underuse	Micro (primarily)
Loss Aversion	Hamper disinvestment	All
Aversion to Risk / Ambiguity	Overuse	Micro, meso
Availability Heuristics	Overuse	Micro, meso
Sacred Values and Taboo trade-offs	Undermining principles	All
Progress bias	Overuse	All
Adoption Addiction	Overuse	Micro, macro
Complexity bias	Undermining principles, overuse	Micro, meso, macro
Extension bias	Overuse	All
Asymmetry of risks and benefits	Overuse	Micro (primarily)
Positive cognitive feedback loops	Undermining principles, overuse	Micro, meso, macro
Prestige bias	Undermining principles, overuse	Micro (primarily)
Imperative of Action	Undermining principles, overuse	Micro (primarily)
Technology Placebo Effect	Undermining principles, overuse	Micro (primarily)
Imperative of Knowledge	Overuse	Micro
Competency Effect	Overuse	Micro
Multiple Replacements	Overuse	Micro
White Elephants	Overinvestment	Micro
Boys and Toys Effect	Unwarranted use	Micro

Episode based payment systems (2)

Value-based provider payment: towards a theoretically preferred design

The details of a payment system methodology are clearly described in this article. I was not surprised to confirm that the proposals we made two decades ago were in the same direction: two-part payment, fix and variable. Unfortunately nowadays we have a retrofuture system that nobody knows exactly how incentives really work. Of course, this is the first best for a discretionary behaviour by a resource allocator. This is a clear step in the wrong direction that started a decade ago. Without proper incentives, efficiency suffers, and to be clear this means less efficient healthcare for the patients. Unfortunately again, nobody cares about it.

The main contribution of this paper is twofold. Inspired by the societal debate on what
stakeholders in health care should ideally strive for, as well as by existing definitions of value, we first described and further specified the concept of value, facilitating the specification of requirements in the design of VBP. We conclude that, in this respect, value is ideally conceptualised as a multifaceted concept, comprising not only high quality of care at the lowest possible costs but also efficient cooperation, innovation and health promotion. Second, starting from these value dimensions, we derived various design features of a theoretically preferred VBP model. We conclude that in order to stimulate value in a broad sense, the payment should consist of two main components that must be carefully designed. The first component is a risk-adjusted global base payment with risk-sharing elements paid to a multidisciplinary provider group for the provision of (virtually) the full continuum of care to a certain population. The second
component is a relatively low-powered variable payment that explicitly rewards aspects of value that can be adequately measured.

The time to fix the current mess has arrived.

Jordi Sàbat

Episode based payment systems

Unraveling the Complexity in the Design and Implementation of Bundled Payments: A Scoping Review of Key Elements From a Payer’s Perspective

After per case based payment systems (DRGs) everybody was waiting for a comprehensive system to measure health services activities. And instead of focusing on episodes, what happened is that bundling was the new frame. Unfortunately, after all these years bundling has not provided the answer because the scope of measurement is related to several diseases and it is not holistic.
When everybody was asking for an alternative to fee-for service, the answer was in my opinion "patient focused episodes of care", but the US government decided otherwise and protected the interests of those that leverage fee-for-service.
Therefore, now it is the time to fix this mistake and take the right  road. In this article you'll find some issues to consider when you have to design a payment system. It still talks about bundling, forget it, substitute it by episodes and it will be fine.

Our framework provides a structured overview of the principal, literature‐based elements of the design and implementation of bundled payment contracts from a payer's perspective. We identified 53 elements that involve all procurement phases and relate to actors on all levels of the health care system. A better understanding of these elements can help payers and other actors devise a strategic approach and reduce the complexity of implementing these contracts. Compared with traditional FFS models, bundled payment contracts introduce an alternative set of financial incentives that affect the entire health care system, involve almost all aspects of governance within organizations, and demand a different type of collaboration among organizations. This is what makes the design and implementation of bundled payment contracts complex and is why they should not be strategically approached by payers as merely the adoption of a new contracting model but, rather, as part of a broader transformation to a more sustainable value‐based health care system, based less on short‐term transactional negotiations and more on long‐term collaborative relationships between payers and providers.

All you need to know about molecular diagnostics

Molecular Diagnostics Fundamentals, Methods, and Clinical Applications

Current advances in health sciences are available at the same time that diagnostic technology and knowledge provide new tools. This book is specially relevant because it summarises all the current state of the art on molecular diagnostics. Therefore a good suggestion for those who want to practice precision medicine.

Table of contents:
I. Fundamentals of Molecular Biology: An Overview
1. Nucleic Acids and Proteins
2. Gene Expression and Epigenetics
II. Common Techniques in Molecular Biology
3. Nucleic Acid Extraction Methods
4. Resolution and Detection of Nucleic Acids
5. Analysis and Characterization of Nucleic Acids and Proteins
6. Nucleic Acid Amplification
7. Chromosomal Structure and Chromosomal Mutations
8. Gene Mutations
9. DNA Sequencing
III. Techniques in the Clinical Laboratory
10. DNA Polymorphisms and Human Identification
11. Detection and Identification of Microorganisms
12. Molecular Detection of Inherited Diseases
13. Molecular Oncology
14. DNA-Based Tissue Typing
15. Quality Assurance and Quality Control in the Molecular Laboratory
Appendices
A. Study Questions Answers
B. Answers to Case Studies
Glossary
Index

Tough days ahead for health policy

Sistema Nacional de Salud: retos y tareas pendientes tras la Gran Recesión

The issue of Revista ICE, a must read for the new health minister:

Presentación

Innovación tecnológica y financiación de prestaciones

La colaboración público-privada en sanidad: hasta dónde y cómo delimitar sus fronteras

Reformas pendientes en la organización de la actividad sanitaria

La atención especilizada del Sistema Nacional de Salud durante la Gran Recesión. Gasto, utilización y variabilidad en el periodo 2004-2015

Atención a la dependencia y cuidados sanitarios: obligados a entenderse

Mirando más allá de los servicios de atención sanitaria: el papel de la salud pública

Diseño institucional y buen gobierno: avances y reformas pendientes

Crisis económica y salud: lecciones aprendidas y recomendaciones para el futuro

Physicians in society

ELS METGES A LA SOCIETAT CATALANA CONTEMPORÀNIA
Borja de Riquer i Permanyer

125th anniversary of Barcelona College of Physicians

The public option for population health improvement

Addressing Social Determinants to Improve Population Health
Integrating Social Care into the Delivery of Health Care: Moving Upstream to Improve the Nation’s Health
The Public Option How to Expand Freedom, Increase Opportunity, and Promote Equality

This is what JAMA article says about population health

While health care organizations may not be equipped to address each of the root causes of their patients’ conditions, they need to broaden their perspective on how to address social determinants of health and use their expertise to influence initiatives on education, housing, employment, and other important health related social issues that take place beyond their immediate clinical purview.

"Need to broaden their perspective", this is the message for health care organizations according to the articoe. I'm not so sure about it. The message is not only for health care organizations, it is for public policies. This is much more difficult to address when there is not a public option for the whole population. A new book sheds light on this topic for the US policy.

PS. The Limits of Private Action: What the Past 40 Years Taught Us About the Perils of Unregulated Markets
PS. There Should Be a Public Option for Everything

How altruistic behaviors reduce pain

Altruistic behaviors relieve physical pain

That's it. You'll find the details in PNAS article:

For centuries, scientists have pondered why people would incur personal costs to help others and the implications for the performers themselves. While most previous studies have suggested that those who perform altruistic actions receive direct or indirect benefits that could compensate for their cost in the future, we offer another take on how this could be understood. We examine how altruistic behaviors may influence the performers’ instant sensation in unpleasant situations, such as physical pain. We find consistent behavioral and neural evidence that in physically threatening situations acting altruistically can relieve painful feelings in human performers. These findings shed light on the psychological and biological mechanisms underlying human prosocial behavior and provide practical insights into pain management.

Parov Stelar 

Fighting against techno-eugenics

A Chinese scientist who shocked the medical community last year when he said he had illegally created the world's first gene-edited babies has been sentenced to three years in prison by a court in southern China.
He Jiankui announced in November 2018 that he had used a powerful technique called CRISPR on a human embryo to edit the genes of twin girls. He said he modified a gene with the intention of protecting the girls against HIV, the virus that causes AIDS. Many scientists expressed concerns about possible unintended side effects of the genetic changes that could be passed down to future generations.
Last fall, He also indicated there might be another pregnancy involving a gene-edited embryo. The court indicated that three genetically edited babies have been born.
The closed court in Shenzhen found He and two colleagues guilty of illegal medical practice by knowingly violating the country's regulations and ethical principles with their experiments, Xinhua news agency reported. It also ordered He to pay a fine of about $430,000.

Such unethical medical behavior is the worst news of 2019. And this article explained last June the reasons:

The link between CCR5 and HIV is fairly well studied. Disabling CCR5 removes the doorway HIV uses to enter and infect cells, but it does so only for some strains of HIV; there are others that don’t need CCR5. Further, the genetic sequence He’s edits produced does not match this well-studied variant of CCR5; in fact, it has never been observed in humans or animals. In other words, no one has any idea whether the variant with which Lulu and Nana are now living will affect HIV immunity or anything else.
That’s a key issue: Genes don’t do just one thing. Most illnesses and traits are influenced by dozens, hundreds, even thousands of DNA variations. Each of our roughly 20,000 genes is linked to many different aspects of our physiology and health. So what else does CCR5 do? A variant that provides protection against HIV also seems to increase susceptibility to a number of more common diseases, like flu and West Nile virus.
CCR5 has also been linked to brain function, which led to some sensational headlines and media speculation that the gene-edited babies might have enhanced brains. There are likely myriad other processes to which CCR5 contributes that we don’t know about yet. To that point: before the recent study, no one had researched whether the CCR5 mutation resulted in better or worse health over a person’s lifetime.
The CCR5 story illustrates a flaw in the logic that underlies gene editing. Efforts to change one gene to affect one illness in a future person ignore the fact that health is the result of infinitely complex interactions within and outside a person’s body. In most cases, the presence or absence of a particular genetic variant is not the sole determinant of a disease or condition.

And this article reminds us that, despite the appearance of agreement, ethical questions that have surrounded human germline editing for years have yet to be properly addressed.

Unnatural Selection: Season 1 | Main Trailer | Netflix