Biologic Therapies for the Treatment of Knee Osteoarthritis: An Updated Systematic Review.

BACKGROUND: Use of "orthobiologics" continues to expand for patients who have knee osteoarthritis (OA). We sought to perform a systemic review of biologic therapies relative to comparative groups, including the following: (1) platelet-rich plasma (PRP); (2) bone marrow-derived mesenchymal stem cells (BMSCs); (3) adipose-derived mesenchymal stem cells (ADSCs); and (4) amniotic-derived mesenchymal stem cells (AMSCs). We assessed the following: (1) study methodologies; (2) cell preparations and formulations; (3) patient-reported outcome scores (PROMs); and (4) structural changes. METHODS: PubMed, Cochrane Library, and Embase databases were queried (2013-2021) to conduct a systematic review of biologic therapies for knee OA, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eighty-two studies were included: PRP (51); BMSC (15); ADSC (11); and AMSC (5). Study evaluations were made using the Modified Coleman Methodology Score. PROMs included the Western Ontario and McMaster Universities Arthritis Index and the Visual Analog Scale. Structural change evaluations included ultrasounds, radiographs, or magnetic resonance imaging. RESULTS: PRP comprised a majority of the studies (n = 51), most with "fair" to "good" Modified Coleman Methodology Score. Studies had variable cell preparations and formulations, with comparison study results leading to inconsistent PROMs, and structural changes. A limited number of studies were included for BMSC, ADSC, and AMSC, all with similar findings to PRP. CONCLUSION: Available literature evaluating "orthobiologics" for knee OA remain nonsuperior to comparison cohorts. Higher level studies with larger sample sizes and improved methodologies are warranted to suggest differences. Despite a growth of "orthobiologics" in clinics, this updated systematic review highlights the uncertain efficacy for use in knee OA.

Pros and Cons of Physician Aid in Dying.

The question of a physician's involvement in aid in dying (or "assisted suicide") is being debated across the country. This article adopts no one position because its authors hold contrasting views. It aims instead to articulate the strongest arguments in favor of aid in dying and the strongest arguments opposed. It also addresses relevant terminology and reviews the history of its legalization in the United States.

Futile Treatment and Conquering Death.

Pragmatically speaking, there is a stronger case for using the language of "futility" than "potentially appropriate" for end-of-life care. The latter obscures the reality of death as a part of human life. Do patients die because death always wins in the end? Or do they die because physicians run out of ways to treat them? In the end, modern medicine has made the conquest of death its de facto goal. That is a fundamental error, one which the language of "potentially appropriate" is unwittingly supportive of.

Where Has It Gone?: Writing, Loss, and Old Age.

Along with many others who have done research and writing on aging over the years, I was drawn to the topic by its social and economic importance. I could not help realizing in some vague way that I would one day become old myself. That thought tended to get brushed away, pushed under the rug along with other stray musings. All that began to change when I hit my 80s, intensifying even more as I went from 85 to 87. I was given an intensified introduction to doctors, disease, operations, and scans-and fear and anxiety. I also lost all interest in writing, my favorite activity. This is my story, which fortunately required writing.

What is it to do good ethics?

Much of my work in bioethics over the years has been throwing off ethics as pursued in the analytical tradition. I believe the field should steer clear of the rigid style of hyper-rationalist ethics and a reduction of ethics to a search for rules and principles. It should be open to a full range of influence, in style and substance, of literature, history and the social sciences. It should take in the full range of human life, individual and social.

Can the social sciences save bioethics?

John Evans proposes some ways in which the social sciences can improve bioethics: by recognizing that it is a profession, that it embrace the four principles advanced by Beauchamp and Childress over the years, and that ethical commissions and committees make use of social science research to determine and use the values of the public. All three of these proposals are challenged.

Obesity: chasing an elusive epidemic.

Obesity in America is so widespread and such a product of our culture that combating it is nearly impossible. We need to change almost everything about the way we live, more or less simultaneously. In order to succeed, an edgier strategy is needed.

Triple stimulus-responsive polypeptide nanoparticles that enhance intratumoral spatial distribution.

To address the limited tumor penetration of nanoparticle drug delivery vehicles, we report the first pH-responsive polypeptide micelle that dissociates at the low extracellular pH of solid tumors. This histidine-rich elastin-like polypeptide block copolymer self-assembles at 37 °C into spherical micelles that are stabilized by Zn(2+) and are disrupted as the pH drops from 7.4 to 6.4. These pH-sensitive micelles demonstrate better in vivo penetration and distribution in tumors than a pH-insensitive control.

A highly parallel method for synthesizing DNA repeats enables the discovery of 'smart' protein polymers.

Robust high-throughput synthesis methods are needed to expand the repertoire of repetitive protein-polymers for different applications. To address this need, we developed a new method, overlap extension rolling circle amplification (OERCA), for the highly parallel synthesis of genes encoding repetitive protein-polymers. OERCA involves a single PCR-type reaction for the rolling circle amplification of a circular DNA template and simultaneous overlap extension by thermal cycling. We characterized the variables that control OERCA and demonstrated its superiority over existing methods, its robustness, high-throughput and versatility by synthesizing variants of elastin-like polypeptides (ELPs) and protease-responsive polymers of glucagon-like peptide-1 analogues. Despite the GC-rich, highly repetitive sequences of ELPs, we synthesized remarkably large genes without recursive ligation. OERCA also enabled us to discover 'smart' biopolymers that exhibit fully reversible thermally responsive behaviour. This powerful strategy generates libraries of repetitive genes over a wide and tunable range of molecular weights in a 'one-pot' parallel format.

Quantitative model of the phase behavior of recombinant pH-responsive elastin-like polypeptides.

Quantitative models are required to engineer biomaterials with environmentally responsive properties. With this goal in mind, we developed a model that describes the pH-dependent phase behavior of a class of stimulus responsive elastin-like polypeptides (ELPs) that undergo reversible phase separation in response to their solution environment. Under isothermal conditions, charged ELPs can undergo phase separation when their charge is neutralized. Optimization of this behavior has been challenging because the pH at which they phase separate, pHt, depends on their composition, molecular weight, concentration, and temperature. To address this problem, we developed a quantitative model to describe the phase behavior of charged ELPs that uses the Henderson-Hasselbalch relationship to describe the effect of side-chain ionization on the phase-transition temperature of an ELP. The model was validated with pH-responsive ELPs that contained either acidic (Glu) or basic (His) residues. The phase separation of both ELPs fit this model across a range of pH. These results have important implications for applications of pH-responsive ELPs because they provide a quantitative model for the rational design of pH-responsive polypeptides whose transition can be triggered at a specified pH.

The contested terrain of American bioethics.

Bioethics came to life in the United States in the late 1960s. As the first research center in the world devoted to bioethics. Those of us who were early in the field had to deal with a general skepticism that the field of ethics could offer useful direction and advice, and had to deal as well with resistance among physicians. As time went on various struggles emerged on the role of ethical theory, the influence of ideology on the field of bioethics, and the particular features of American culture, highly individualistic and not inclined to take on ultimate human questions. A global bioethics has emerged and the field of bioethics, despite internal struggles, continues to grow and flourish.

Comparative immunogenicity and efficacy of thermostable (lyophilized) and liquid formulation of anthrax vaccine candidate AV7909.

The anthrax vaccine candidate AV7909 is being developed as a next-generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the anthrax vaccine adsorbed (AVA) (Emergent BioSolutions Inc., Lansing, MI) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. Emergent has produced a thermostable (lyophilized) formulation of AV7909 vaccine utilizing drying technology. The purpose of the study described here was to assess the immunogenicity and efficacy of the lyophilized formulation of the AV7909 vaccine candidate as compared with the liquid formulation in the guinea pig general-use prophylaxis (GUP) model. The study also provides initial information on the relationship between the immune response induced by the thermostable formulation of the vaccine, as measured by the toxin neutralization assay (TNA), and animal survival following lethal anthrax aerosol challenge. Results demonstrated that there were no significant differences in the immunogenicity or efficacy of lyophilized AV7909 against lethal anthrax spore aerosol challenge in the guinea pig model as compared to liquid AV7909. For both vaccine formulations, logistic regression modeling showed that the probability of survival increased as the pre-challenge antibody levels increased.

Europe and the United States: contrast and convergence.

Though the health care systems of the United States and the European countries are very different, they are being buffeted by similar problems: rising health care costs caused by aging populations, technology, and rising public demand and expectations. The primary difference is that the US system is heavily privatized, whereas the European systems are heavily government run or operated. But the latter systems are increasingly open to market ideas and practices while the US is steadily being pushed toward a stronger government role. This article offers some speculation about their gradual convergence in the years ahead.

Aging: Drawing a Map for the Future.

I live on a short street in a small town, Hastings-on-Hudson, some fifteen miles up the Hudson River from New York City. Over the past decade a number of families have moved in, with about sixteen children among them. More than a bit housebound now because of old age and watching them romping about, I try to imagine what their world will be like when they have reached my present age, some eighty years from now. But I have a problem. I just can't imagine it. The demographic changes now appearing on the horizon will force unforeseeable changes. What would it have been like in 1930, when I was born, if someone then had to project the future of aging? They could not have guessed. Some momentous changes are now emerging, and they are bound to change the aging picture. What's being done to respond to those growing pressures?

Progress: Its Glories and Pitfalls.

Steven Pinker, a cognitive psychologist and linguist at Harvard and a savant of big ideas, is one of the latest to take on the idea of progress. He does it under the aegis of "enlightenment," which comes down to a kind of holy trinity of reason, science, and humanism. His new book, Enlightenment Now: The Case for Reason, Science, Humanism, and Progress, is ambitious and cantankerous and heady with hope. On the whole, Pinker makes a good case for the benefits of progress, but with an overdose of feel-good prose. His greatest failure comes in exaggerating the threats to science and in avoiding some problems altogether. He ignores its complexity, its shadows, its creation of new problems raised by its solutions to old ones. Pinker has a particular animus against bioethics, and he misses what has been, I would argue, at the heart of bioethics from its beginning fifty or so years ago. Bioethics was prompted by a new class of medical dilemmas that require a difficult balancing of harms and benefits. Most of them are still with us, and most of them are the result of the progress of postwar medical research and fast-changing clinical practices.