Does it pay to pay? A comparison of the benefits of open-access publishing across various sub-fields in biology.

Authors are often faced with the decision of whether to maximize traditional impact metrics or minimize costs when choosing where to publish the results of their research. Many subscription-based journals now offer the option of paying an article processing charge (APC) to make their work open. Though such "hybrid" journals make research more accessible to readers, their APCs often come with high price tags and can exclude authors who lack the capacity to pay to make their research accessible. Here, we tested if paying to publish open access in a subscription-based journal benefited authors by conferring more citations relative to closed access articles. We identified 146,415 articles published in 152 hybrid journals in the field of biology from 2013-2018 to compare the number of citations between various types of open access and closed access articles. In a simple generalized linear model analysis of our full dataset, we found that publishing open access in hybrid journals that offer the option confers an average citation advantage to authors of 17.8 citations compared to closed access articles in similar journals. After taking into account the number of authors, Journal Citation Reports 2020 Quartile, year of publication, and Web of Science category, we still found that open access generated significantly more citations than closed access (p < 0.0001). However, results were complex, with exact differences in citation rates among access types impacted by these other variables. This citation advantage based on access type was even similar when comparing open and closed access articles published in the same issue of a journal (p < 0.0001). However, by examining articles where the authors paid an article processing charge, we found that cost itself was not predictive of citation rates (p = 0.14). Based on our findings of access type and other model parameters, we suggest that, in the case of the 152 journals we analyzed, paying for open access does confer a citation advantage. For authors with limited budgets, we recommend pursuing open access alternatives that do not require paying a fee as they still yielded more citations than closed access. For authors who are considering where to submit their next article, we offer additional suggestions on how to balance exposure via citations with publishing costs.

Recommendations for procurement of starting materials by apheresis for advanced therapy medicinal products.

Activities involved in the production of certain advanced therapy medicinal products (ATMPs) require standardized approaches to mononuclear cell procurement to ensure the highest product quality, safety and process efficiency. These aims must be achieved while meeting regulatory and accreditation requirements for the procurement of mononuclear cells as starting materials. Mononuclear cells constitute the starting materials for many ATMPs, and this article sets out recommendations for procurement by clinical apheresis, addressing the variation among existing working practices and different manufacturers' requirements that currently poses a challenge when managing multiple different protocols.

A Novel Small Molecule Inhibits Hepatitis C Virus Propagation in Cell Culture.

Hepatitis C virus (HCV) can cause acute and chronic infection that is associated with considerable liver-related morbidity and mortality. In recent years, there has been a shift in the treatment paradigm with the discovery and approval of agents that target specific proteins vital for viral replication. We employed a cell culture-adapted strain of HCV and human hepatoma-derived cells lines to test the effects of our novel small-molecule compound (AO13) on HCV. Virus inhibition was tested by analyzing RNA replication, protein expression, and virus production in virus-infected cells treated with AO13. Treatment with AO13 inhibited virus spread in cell culture and showed a 100-fold reduction in the levels of infectious virus production. AO13 significantly reduced the level of viral RNA contained within cell culture fluids and reduced the cellular levels of HCV core protein, suggesting that the compound might act on a late step in the viral life cycle. Finally, we observed that AO13 did not affect the release of infectious virus from infected cells. Docking studies and molecular dynamics analyses suggested that AO13 might target the NS5B RNA polymerase, however, real-time RT-PCR analyses of cellular levels of HCV RNA showed only an ∼2-fold reduction in viral RNA levels in the presence of AO13. Taken together, this study revealed that AO13 showed consistent, but low-level antiviral effect against HCV, although the mechanism of action remains unclear. IMPORTANCE The discovery of curative antiviral drugs for a chronic disease such as HCV infection has encouraged drug discovery in the context of other viruses for which no curative drugs currently exist. Since we currently face a novel virus that has caused a pandemic, the need for new antiviral agents is more apparent than ever. We describe here a novel compound that shows a modest antiviral effect against HCV that could serve as a lead compound for future drug development against other important viruses such as SARS-CoV-2.

Clinical Adoption of Advanced Therapies: Challenges and Opportunities.

As the cell and gene therapy field matures the powerful therapeutic potential of these innovative therapies is starting to be shown, particularly in the fields of oncology and childhood immune deficiency diseases. However, as more therapies enter late stage clinical trials, advances and innovation are required in manufacturing, logistics, regulation, reimbursement and the healthcare setting to ensure that systems are in place to support wider clinical adoption of these promising treatments. A window of opportunity exists to implement new methodologies for best practice in both the ability to manufacture products reproducibly at scale, as well as ensuring healthcare systems are not overwhelmed by the variety and complexity of these new therapies and the additional burden they will place on already stretched facilities. If all interested parties work together it will be possible for the sector to develop the necessary processes, skilled staff and infrastructure needed as more treatments move from clinical trial to marketed products.

The Global Alliance for iPSC Therapies (GAiT).

The Global Alliance for iPSC Therapies (GAiT) is a new initiative to support the implementation and clinical application of therapies derived from pluripotent stem cells to the benefit of patients globally. GAiT's mission is to serve as a central, international resource for those organisations developing therapies from clinical-grade induced pluripotent stem cells, and to support the expansion of this nascent field. With the support of its international partners, GAiT already has an early position on manufacturing, regulatory and quality standards. This article details GAiT's development, its mission and structure, as well as how, and by whom, it is funded. The article ends with brief overview of current and upcoming activities.

Safety profile of autologous macrophage therapy for liver cirrhosis.

Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 107, 108 or up to 109 cells. Leukapheresis and macrophage infusion were well tolerated with no transfusion reactions, dose-limiting toxicities or macrophage activation syndrome. All participants were alive and transplant-free at one year, with only one clinical event recorded, the occurrence of minimal ascites. The primary outcomes of safety and feasibility were met. This study informs and provides a rationale for efficacy studies in cirrhosis and other fibrotic diseases.

Allogeneic Ex Vivo Expanded Corneal Epithelial Stem Cell Transplantation: A Randomized Controlled Clinical Trial.

Limbal stem cell deficiency (LSCD) is a disease resulting from the loss or dysfunction of epithelial stem cells, which seriously impairs sight. Autologous limbal stem cell transplantation is effective in unilateral or partial bilateral disease but not applicable in total bilateral disease. An allogeneic source of transplantable cells for use in total bilateral disease can be obtained from culture of donated cadaveric corneal tissue. We performed a controlled multicenter study to examine the feasibility, safety, and efficacy of allogeneic corneal epithelial stem cells in the treatment of bilateral LSCD. Patients were randomized to receive corneal epithelial stem cells cultured on amniotic membrane (AM): investigational medicinal product (IMP) or control AM only. Patients received systemic immunosuppression. Primary endpoints were safety and visual acuity, secondary endpoint was change in composite ocular surface score (OSS). Sixteen patients were treated and 13 patients completed all assessments. Safety was demonstrated and 9/13 patients had improved visual acuity scores at the end of the trial, with no significant differences between IMP and control groups. Patients in the IMP arm demonstrated significant, sustained improvement in OSS, whereas those in the control arm did not. Serum cytokine levels were measured during and after the period of immune suppression and we identified strongly elevated levels of CXCL8 in the serum of patients with aniridia, which persisted throughout the trial. This first randomized control trial of allogeneic corneal epithelial stem cells in severe bilateral LSCD demonstrates the feasibility and safety of this approach. Stem Cells Translational Medicine 2019;8:323-331.

Quality control guidelines for clinical-grade human induced pluripotent stem cell lines.

Use of clinical-grade human induced pluripotent stem cell (iPSC) lines as a starting material for the generation of cellular therapeutics requires demonstration of comparability of lines derived from different individuals and in different facilities. This requires agreement on the critical quality attributes of such lines and the assays that should be used. Working from established recommendations and guidance from the International Stem Cell Banking Initiative for human embryonic stem cell banking, and concentrating on those issues more relevant to iPSCs, a series of consensus workshops has made initial recommendations on the minimum dataset required to consider an iPSC line of clinical grade, which are outlined in this report. Continued evolution of this field will likely lead to revision of these guidelines on a regular basis.

Anticipating the clinical adoption of regenerative medicine: building institutional readiness in the UK.

This perspective paper examines the challenges of implementing regenerative medicine (RM) therapies within hospitals and clinics. Drawing on recent work in the social sciences, the paper highlights dynamics within existing healthcare systems that will present both hindrances and affordances for the implementation of new RM technologies within hospitals and clinics. The paper argues that identifying suitable locations for cell- and gene-therapy treatment centers requires an assessment of their institutional readiness for RM. Some provisional criteria for assessing institutional readiness are outlined, and the paper will suggest that it is necessary to begin developing a program for the phased introduction of RM in the longer term.

Attitudinal and behavioral differences between cigarette users who do and do not identify as "smokers".

OBJECTIVE: The current research aimed to understand differences in smoking-related identity among college students and to illustrate the distinct characteristics of nonidentified smokers (NIS). PARTICIPANTS: Students from 2 colleges in Massachusetts (N = 538; April 2016). METHODS: Respondents reported by online survey whether or not they had smoked a cigarette in the past 30 days and if they self-identified as smokers. Nonsmokers (NIS) and identified smokers (IS) were then compared on their smoking attitudes and behavior. RESULTS: NIS made up 12.5% of the sample and 64% of all tobacco users. NIS perceived themselves as less addicted and were more confident in their ability to quit smoking. They also were less likely to smoke alone, buy their own cigarettes, or have friends who smoked. CONCLUSIONS: College health officials can best motivate NIS to quit smoking by focusing on peer norms and the potential of long-term addiction.

Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14-15 September 2015.

This paper summarizes the proceedings of a workshop held at Trinity Hall, Cambridge to discuss comparability and includes additional information and references to related information added subsequently to the workshop. Comparability is the need to demonstrate equivalence of product after a process change; a recent publication states that this 'may be difficult for cell-based medicinal products'. Therefore a well-managed change process is required which needs access to good science and regulatory advice and developers are encouraged to seek help early. The workshop shared current thinking and best practice and allowed the definition of key research questions. The intent of this report is to summarize the key issues and the consensus reached on each of these by the expert delegates.

Setting Up a Haplobank: Issues and Solutions.

The development of induced pluripotent stem cells offers the possibility of the scalable manufacture of cellular therapies for regenerative medicine. Moreover, donors can be selected on the basis of major transplant antigen systems to match the widest possible number of recipients worldwide, reducing the likely risk of immunological rejection and the degree of immune suppression or tolerance required. If such cell lines are to be broadly available, there will need to be mutual recognition of common standards across different jurisdictions. Extensive international collaboration will be required around issues such as determination of the optimal homozygous human leukocyte antigens (HLA) panel, donor selection, screening and consent, good manufacturing practice (GMP), standards and quality control and regulatory legislation. The challenges in establishing a global GMP induced pluripotent stem cell (iPSC) haplobank are formidable. We argue that now is the time to attempt to reach international agreement around common standards for GMP iPSC manufacture before the field develops in a fragmented manner.

Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease.

Epstein-Barr virus (EBV) is associated with several malignancies, including post-transplant lymphoproliferative disorder (PTLD). Conventional treatments for PTLD are often successful, but risk organ rejection and cause significant side effects. EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from peripheral blood lymphocytes provide an alternative treatment modality with few side effects, but autologous CTLs are difficult to use in clinical practice. Here we report the establishment and operation of a bank of EBV-specific CTLs derived from 25 blood donors with human leucocyte antigen (HLA) types found at high frequency in European populations. Since licensure, there have been enquiries about 37 patients, who shared a median of three class I and two class II HLA types with these donors. Cells have been infused into ten patients with lymphoproliferative disease, eight of whom achieved complete remission. Neither patient with refractory disease was matched for HLA class II. Both cases of EBV-associated non-haematopoietic sarcoma receiving cells failed to achieve complete remission. Thirteen patients died before any cells could be issued, emphasizing that the bank should be contacted before patients become pre-terminal. Thus, this third party donor-derived EBV-specific CTL cell bank can supply most patients with appropriately matched cells and most recipients have good outcomes.

Determination of the lysozyme deposit curve in soft contact lenses.

PURPOSE: To determine lysozyme deposition as a function of time in soft, high-water content, ionic (group IV) contact lenses. METHODS: ACUVUE lenses were worn on an extended-wear basis (15 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 1 day, 2 day, and so forth, up to 11 consecutive days). New lenses were dispensed at the beginning of each lens-wear period. After each wear cycle, lenses were analyzed for lysozyme deposition by high performance liquid chromatography. RESULTS: Lysozyme rapidly accumulated on lenses (15 minutes approximately 55 microg/lens) and reached a plateau level by day 6 ( approximately 1300 microg/lens). Most patients in the study showed a plateau range between 1200 and 1400 microg/lens. Six-month and 12-month follow-up studies with ACUVUE lenses showed minimal variation at the 5-day wear time point between the initial, sixth, and 12th month results. CONCLUSIONS: This study measured the rate of lysozyme buildup on lenses over time and demonstrated that lysozyme levels associated with group IV lenses reached a plateau after approximately 1 week of extended wear. Little variability was seen in lens lysozyme deposition up to 1 year later. The information derived from this study concerning the rate and variability of deposition has implications for the design and interpretation of cleaning studies and contact lens performance evaluations.