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Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mut

Unproven cell-based interventions (CBIs) emerged early in the 2000s as a particularly problematic form of unproven therapy and remain a vexing policy problem to this day. These unproven interventions can harm patients both physically and financially and can complicate the process of developing a rigorous evidence base to support the translation of novel stem cell or other cell therapies. In this concise review, we examine the emergence of unproven CBIs and the various policy approaches that have been pursued or proposed to address this problem. We review the evolution of this field over the last 2 decades and explore why these policy efforts have proven challenging. We conclude by highlighting potential directions that the field could evolve and urging continued attention to both current and future forms of unproven CBIs to minimize future risks to patients and the field and to promote the development of evidence-based cell therapies., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Periprosthetic joint infection (PJI) is a severe complication of total joint arthroplasty (TJA), occurring in approximately 1-2% of primary procedures. These infections, characterized by an overall weighted mean incidence of 0.97% for total hip arthroplasty (THA) and 1.03% for total knee arthroplasty (TKA), pose significant challenges for patients and health-care providers., Case Report: The authors present two intriguing case reports. The first involves a 64-year-old male who underwent TKA 17 months prior and presented to our outpatient clinic with clinical symptoms and laboratory findings consistent with PJI. Subsequent Streptococcus dysgalactiae culture results confirmed the diagnosis. The second case involves a 51-year-old male who presented to our outpatient clinic 2 weeks after undergoing THA, with clinical symptoms consistent with infected hematoma, which was later confirmed with positive Staphylococcus lugdunensis culture results and another infected process, occurring 3 months after the initial procedure, confirmed by positive Group B Streptococcus (Streptococcus agalactiae). Both patients reported swimming in a recreational swimming pool before and after the procedures and during the follow-up period, approximately 2-3 times a week. Those patients reported resuming their recreational swimming activities just a few days after the procedures. Although as part of post-operative wound care, we instruct all of our patients not to get the wound wet for the 1st days after surgery, to our knowledge swimming activities are not included in the various risk factors for developing a PJI, nor are the bacteria mentioned above associated with aquagenic infection., Conclusion: Although swimming activity has not been identified as a known risk factor for PJI, it is important for physicians to maintain a high clinical suspicion for delayed or late infections in patients who engage in swimming activities. Further investigations are warranted to determine the potential role of recreational swimming activities as a risk factor for PJI after TJA., Competing Interests: Conflict of Interest: Nil, (Copyright: © Indian Orthopaedic Research Group.)

Total knee replacement (TKR) surgery carries with it significant surgical trauma and activates complex inflammatory pathways, which initially assist healing. However, impaired regulation of inflammatory pathways can cause tissue damage and postoperative complications. The vagus nerve regulates inflammation, the activity of which is indexed by heart-rate variability (HRV), which predicts postoperative pain, longer hospitalization and improved recovery during the postoperative period. The present study examined the relationship between presurgical HRV, inflammation and complications after TKR. The present study assessed data from 41 patients undergoing TKR. A retrospective design was used, where preoperative electrocardiograms were scanned to determine HRV. Outcome measures included inflammation [C-reactive protein (CRP) levels] over four postoperative days, length of stay (LOS), and complications. Preoperative HRV predicted the trajectory of postoperative CRP levels. The low HRV group demonstrated higher overall postoperative CRP and a longer time to recover than patients with high HRV. Furthermore, the magnitude of inflammatory decline between postoperative days two and four was associated with LOS. However, HRV did not predict postoperative complications. In conclusion, patients with lower presurgical vagal activity had a worse postoperative inflammatory profile than those with high vagal tone. In the age of personalized medicine, such findings may have implications for identifying and preparing patients before surgery., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024, Spandidos Publications.)

Objective: To determine if immediate plate fixation of open tibial plafond fractures has a negative effect on soft tissue complications and increases the risk of deep infection., Design: This was a single-institution retrospective cohort study performed at level-1 trauma center. All patients with open OTA/AO 43C plafond fractures treated over 20-year period with follow-up until fracture union or development of deep infection. Ninety-nine of 333 identified patents met the inclusion criteria. The intervention was operative treatment of open tibial plafond fractures. The main outcome measurements were return to operating room for deep infection, nonunion, and below knee amputation., Results: The overall rate of complications was 52%. Gender, body mass index, tobacco use, diabetes, ASA classification, time to OR from injury, wound location, and associated fibula fracture were not associated with deep infection. There was a significant difference in Gustilo-Anderson fracture grade among infected versus non-infected (P = 0.04). There was no significant difference in postoperative infection rates between patients treated with external fixation, external fixation and limited plate fixation, and plate fixation alone during initial surgery (P = 0.64)., Conclusion: It is well established that open pilon fractures have a high incidence for postoperative infection and development of complications such as nonunion. As these injuries have poor clinical outcomes, any additional measures to prevent infection and soft tissue complications should be utilized. In appropriately selected cases, both immediate plate fixation and immediate limited plate fixation with external fixation at the time of I&D do not appear to elevate risk of deep infection., Level of Evidence: Therapeutic Level III., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Skin-to-skin (STS) care may contribute to mother-to-infant vertical microbial transmission by enriching the preterm infant's microbiome., Purpose: The purpose of this observational study was to define the impact of increased STS care duration on vertical microbial transmission and consequently modulate oral and intestinal microbial balance., Methods: Postpartum women and their preterm infants, 31 to 34 weeks' gestation (n = 25), were recruited for this study. Using 16S rRNA sequencing, we compared α- and β-diversity with the Shannon and Chao indexes and nonmetric multidimensional scaling, respectively, and relative abundance of microbial communities, which refers to the percentage of specific organisms in a community, from mother's chest skin, preterm infant's oral cavity, and preterm infant's stool samples. Effects of STS care on vertical transmission were determined by comparing oral and stool microbial population of preterm infants who received low exposure (<40 minutes) with that of preterm infants who received high exposure (>60 minutes)., Results: Microbial composition, diversity, and relative abundance were different across the 3 sites. Oral microbial richness was less and stool richness was greater among the preterm infants in the high STS care group. Oral and intestinal microbial diversity and composition were different between the groups, with the relative abundance of Gemella and Aggregatibacter genera and Lachnospiraceae family significantly greater in the stool of the high STS care group., Implications for Practice: Results suggest that STS care may be an effective method to enhance microbial communities among preterm infants., (Copyright © 2023 by The National Association of Neonatal Nurses.)

Background: Case Western Reserve University (CWRU)/University Hospitals Cleveland Medical Center in Cleveland, OH, and the University of Pittsburgh (Pitt) in Pittsburgh, PA, forged a strategic alliance to form the Rustbelt Center for AIDS Research. The Rustbelt Center for AIDS Research developed a National Institutes of Health-supported diversity, equity, and inclusion pathway initiative termed the "Rustbelt Investigators for the Next Generation (RING) Program" that provides research training experiences for Puerto Rican students that will help them pursue a biomedical research career in HIV., Setting: The RING Program provides 10-week research training experiences in different disciplines of HIV/AIDS for under-represented minority undergraduate and masters students from 4 campuses (Río Piedras, Mayagüez, Humacao, and Cayey) at the University of Puerto Rico. Mentors are drawn from both CWRU and Pitt., Results: The RING Program recently completed our first wave of recruitment. Recruitment sessions were either virtual or on site at the University of Puerto Rico campuses and included an overview presentation, a Q&A session, and in-person interviews. We interviewed 32 eligible applicants and accepted 10 into the program, of which 9 were female. Five students were matched with faculty at CWRU and 5 with faculty at Pitt., Conclusions: The RING Program is a comprehensive program in laboratory and implementation science that aims to enhance under-represented Hispanic undergraduate and masters students' passion for pursuing a biomedical research career in HIV., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There is an urgent need to increase diversity among scientific investigators in the HIV research field to be more reflective of communities highly affected by the HIV epidemic. Thus, it is critical to promote the inclusion and advancement of early-stage scholars from racial and ethnic groups underrepresented in HIV science and medicine., Methods: To widen the HIV research career pathway for early-stage scholars from underrepresented minority groups, the National Institutes of Health supported the development of the Centers for AIDS Research (CFAR) Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI). This program was created through partnerships between CFARs and Historically Black Colleges and Universities and other Minority Serving Institutions throughout the United States., Results: Seventeen CFARs and more than 20 Historically Black Colleges and Universities and Minority Serving Institutions have participated in this initiative to date. Programs were designed for the high school (8), undergraduate (13), post baccalaureate (2), graduate (12), and postdoctoral (4) levels. Various pedagogical approaches were used including didactic seminar series, intensive multiday workshops, summer residential programs, and mentored research internship opportunities. During the first 18 months of the initiative, 257 student scholars participated in CDEIPI programs including 150 high school, 73 undergraduate, 3 post baccalaureate, 27 graduate, and 4 postdoctoral students., Conclusion: Numerous student scholars from a wide range of educational levels, geographic backgrounds, and racial and ethnic minority groups have engaged in CDEIPI programs. Timely and comprehensive program evaluation data will be critical to support a long-term commitment to this unique training initiative., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The field of regenerative medicine, including cellular immunotherapies, is on a remarkable growth trajectory. Dozens of cell-, tissue- and gene-based products have received marketing authorization worldwide while hundreds-to-thousands are either in preclinical development or under clinical investigation in phased clinical trials. However, the promise of regenerative therapies has also given rise to a global industry of direct-to-consumer offerings of prematurely commercialized cell and cell-based products with unknown safety and efficacy profiles. Since its inception, the International Society for Cell & Gene Therapy Committee on the Ethics of Cell and Gene Therapy has opposed the premature commercialization of unproven cell- and gene-based interventions and supported the development of evidence-based advanced therapy products. In the present Guide, targeted at International Society for Cell & Gene Therapy members, we analyze this industry, focusing in particular on distinctive features of unproven cell and cell-based products and the use of tokens of scientific legitimacy as persuasive marketing devices. We also provide an overview of reporting mechanisms for patients who believe they have been harmed by administration of unapproved and unproven products and suggest practical strategies to address the direct-to-consumer marketing of such products. Development of this Guide epitomizes our continued support for the ethical and rigorous development of cell and cell-based products with patient safety and therapeutic benefit as guiding principles., Competing Interests: Declaration of Competing Interest Hamid R. Bidkhori is the chancellor of the Biomedical Research Ethics Committee of Academic Center for Education, Culture and Research (ACECR) - Mashhad. He is a member of the International Society for Cell & Gene Therapy (ISCT), the International Society for Extracellular Vesicles (ISEV) and the ISCT Committee on the Ethics of Cell and Gene Therapy. Rachele Ciccocioppo is a member of the Advisory Board of Takeda (Italy) for the use of mesenchymal stromal cells in fistulizing Crohn's disease. Natividad Cuende is a member of the Governing Council of the Agencia Española de Medicamentos y Productos Sanitarios (Spanish Medicine and Medical Device Agency). She is member of the ISCT Committee on the Ethics of Cell and Gene Therapy and the ISCT Legal and Regulatory Affairs Committee–Europe. She is also member of the Spanish Guarantee Committee for Donation and Use of Human Cells and Tissues of the Spanish Ministry of Science and Innovation. She is not paid for these roles. Bambi Grilley is affiliated with QBRegulatory Consulting LLC that has provided regulatory affairs and project management support to AlloVir, Marker Therapeutics, LOKON Pharma, Tessa Therapeutics and March Biosciences. She is a member of ISCT and its Ethics of Cell and Gene Therapy (ECGT) Committee and is the incoming Chief Regulatory Officer of ISCT. She is not paid for her roles in ISCT. Conflict of interest is managed in accordance with Baylor College of Medicine policy and oversight. Laertis Ikonomou has written an expert report in a class action lawsuit filed against a business selling unproven “stem cell”-based interventions, and wrote the report on a pro bono basis. He is a member of the ISCT and the International Society for Stem Cell Research (ISSCR) and the chair of the ISCT Committee on the Ethics of Cell and Gene Therapy. He is not paid for these roles. Conflict of interest is managed in accordance with University at Buffalo policy and oversight. Aaron D. Levine is a member of ISCT and its ECGT committee. He is not paid for these roles. Levine's research program is supported by the National Science Foundation (NSF) (Grant No. EEC-1648035). Bruce Levine has received compensation for serving on the scientific advisory boards of Akron Bio, Avectas, Immuneel, Immusoft, In8bio, Ori Biotech, Oxford Biomedica, UTC Therapeutics and Vycellix. He has received compensation for consulting for GSK. He has received compensation and equity from Capstan Therapeutics as a co-founder and member of the Scientific Advisory Board. As co-founder of Tmunity Therapeutics, he received equity. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight. Megan Munsie is a member of the International Society for Stem Cell Research and its Ethics Committee and Public Policy Committee. She is also the President of the Australasian Society for Stem Cell Research. Munsie's research program is supported by the Novo Nordisk Foundation Center for Stem Cell Medicine (NNF21CC0073729). John E. J. Rasko: employment: Royal Prince Alfred Hospital; consultancy and honoraria: Rarecyte, Gilead, Roche, Novartis, Bluebird Bio, Spark therapeutics, Cynata, Pfizer; equity: Genea; shareholder: Rarecyte, Woke; DSMB: Diamond Fanconi anemia trial; research funding: National Health and Medical Research Council (NHMRC), New South Wales Cancer Council, Cancer Institute NSW (CINSW), Therapeutic Innovation Australia, Philanthropic foundations; Chair, Gene Technology Technical Advisory Committee, Office of The Gene Technology Regulator, Australian Government. Leigh Turner served as a compensated expert witness for the US government in a criminal case and as a pro bono expert witness in a class action lawsuit. He is a member of ISCT and its ECGT committee. He is also a member of the International Society for Stem Cell Research and its Ethics Committee and Membership Committee. Turner's research program is supported by the Pew Charitable Trusts. Daniel J. Weiss served as a compensated expert witness for the US government in a criminal case and as a pro bono expert witness in a class action lawsuit. He is a member of ISCT and its ECGT committee and is former Chief Scientific Officer of the ISCT. He is not paid for his roles in the ISCT. Dr. Weiss has received compensation for consulting with Mesoblast Inc., NextCell Inc., United Therapeutics. Inc. and Vertex Inc. Conflict of interest is managed in accordance with University of Vermont policy and oversight. Patricia J. Zettler reports serving as a consultant to the US Food & Drug Administration. All the other authors have no commercial, proprietary, or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Despite the rising prevalence of arthroplasty and aging population, limited data exist regarding differences in periprosthetic fracture clinical outcomes compared with native counterparts. This study compares differences in hospital treatment, morbidity, and mortality associated with periprosthetic distal femur fractures at an urban level 1 trauma center. We retrospectively reviewed all adult AO/OTA type 33 fractures (526) that presented to our institution between 2009 and 2018. In total, 54 native and 54 periprosthetic fractures were matched by age and gender. We recorded demographics, operative measures, length of stay (LOS), discharge disposition, and mortality. We used McNemar's and paired t -tests for analysis where appropriate ( p  < 0.05) (IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY; IBM Corp.). The average age at injury was 74 years ± 12 (native) compared with 73 years ± 12 (periprosthetic). After 1:1 matching, the groups had similar body mass index (31.01 vs. 32.98, p  = 0.966 for native and periprosthetic, respectively) and mechanisms of injury with 38 native and 44 periprosthetic ( p  = 0.198) fractures from low-energy falls. Both groups had 51/54 fractures managed with open reduction internal fixation with a locking plate. The remaining were managed via amputation or intramedullary nail fixation. Mean operative time (144 minutes (±64) vs. 132 minutes (±62), p  = 0.96) and estimated blood loss (319 mL (±362) vs. 289 mL (±231), p  = 0.44) were comparable between the native and periprosthetic groups, respectively. LOS: 9 days ± 7 (native) versus 7 days ± 5 (periprosthetic, p  = 0.31); discharge disposition (to skilled nursing facility/rehab): n  = 47 (native) versus n  = 43 (periprosthetic, p  = 0.61); and mortality: n  = 6 (native) versus n  = 8 (periprosthetic, p  = 0.55). No significant differences were observed. We found no statistical differences in morbidity and mortality in periprosthetic distal femur fractures treated over 10 years at a level 1 trauma center. Native and periprosthetic AO/OTA type 33 distal femur fractures are serious injuries with similar outcomes at a level 1 trauma center., Competing Interests: None declared., (Thieme. All rights reserved.)

PPP2 syndrome type R5D, or Jordan's syndrome, is a neurodevelopmental disorder caused by pathogenic missense variants in PPP2R5D , a β-subunit of the Protein Phosphatase 2A (PP2A). The condition is characterized by global developmental delays, seizures, macrocephaly, ophthalmological abnormalities, hypotonia, attention disorder, social and sensory challenges often associated with autism, disordered sleep, and feeding difficulties. Among affected individuals, there is a broad spectrum of severity, and each person only has a subset of all associated symptoms. Some, but not all, of the clinical variability is due to differences in the PPP2R5D genotype. These suggested clinical care guidelines for the evaluation and treatment of individuals with PPP2 syndrome type R5D are based on data from 100 individuals reported in the literature and from an ongoing natural history study. As more data are available, particularly for adults and regarding treatment response, we anticipate that revisions to these guidelines will be made., (© 2023 Levine and Chung; Published by Cold Spring Harbor Laboratory Press.)

Patient interest in non-trial access pathways to investigational cell-and gene-based interventions, such as expanded access in the USA, is increasing, while the regulatory and business environments for non-trial access in the cell and gene therapy field are shifting. Against this background, in 2022 the International Society for Cell & Gene Therapy (ISCT) established a Working Group on Expanded Access to identify practical, ethical, and regulatory issues emerging from the use (and possible misuse) of the expanded access pathway in the cell and gene therapy field. In this Short Report, the Working Group sets the stage for its future activities by analyzing the history of expanded access and identifying three examples of questions that we anticipate arising as uses of expanded access for investigational cell and gene-based interventions increase and evolve., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Tightly regulated communication between the gastrointestinal epithelium and immune cells in the underlying lamina propria is critical for immune homeostasis and inflammation. IL-17C, produced by epithelial cells after exposure to inflammatory stimuli, facilitates cell-to-cell communication by promoting inflammatory responses in Th17 cells. In this study, we demonstrate that Th17-derived cytokines TNF-α, IL-17A, and IL-22 synergistically enhance IL-17C expression in both human-transformed colonic epithelial cell lines and primary non-inflammatory bowel disease colonic epithelial spheroids. This synergistic expression requires activation of the transcription factor NF-κB downstream of the TNF-α stimulus, evidenced by the reduction of IL-17C expression in the presence of an IκBα inhibitor. IL-17A and IL-22 enhance IL-17C expression through the activation of the transcription factor AP-1 in a p38 MAPK-dependent manner. Colonic spheroids derived from uninvolved epithelial of ulcerative colitis patients stimulated with TNF-α, IL-17A, and IL-22 show muted responses compared with non-inflammatory bowel disease spheroids, and inflamed spheroids yielded more IL-17C expression in the presence of TNF-α, and no response to IL-22 stimulation. Altogether, a role for IL-17C in activating Th17 cells combined with our findings of Th17-derived cytokine-driven synergy in the expression of IL-17C identifies a novel inflammatory amplification loop in the gastrointestinal tract between epithelial cells and Th17 cells., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Biomaterials--from implanted iron teeth in the second century to intraocular lenses, artificial joints, and stents today--have long been used clinically. Today, biomaterials researchers and biomedical engineers are pushing beyond these inert synthetic alternatives and incorporating complex multifunctional materials to control biological interactions and direct physiological processes. These advances are leading to novel strategies for targeted drug delivery, drug screening, diagnostics and imaging, gene therapy, tissue regeneration, and cell transplantation. While the field has survived ethical transgressions in the past, the rapidly expanding scope of biomaterials science, combined with the accelerating clinical translation of this diverse field calls for urgent attention to the complex and challenging ethical dilemmas these advances pose. This perspective responds to this call, examining the intersection of research ethics -- the sets of rules, principles and norms guiding responsible scientific inquiry -- and ongoing advances in biomaterials. While acknowledging the inherent tensions between certain ethical norms and the pressures of the modern scientific and engineering enterprise, we argue that the biomaterials community needs to proactively address ethical issues in the field by, for example, updating or adding specificity to codes of ethics, modifying training programs to highlight the importance of ethical research practices, and partnering with funding agencies and journals to adopt policies prioritizing the ethical conduct of biomaterials research. Together these actions can strengthen and support biomaterials as its advances are increasingly commercialized and impacting the health care system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hunckler and Levine.)

Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ICMJE forms for all authors are available online.

In the United States, most new cases of human immunodeficiency virus (HIV) belong to the at-risk group of gay and bisexual men. Developing therapies to reverse viral latency and prevent spread is paramount for the HIV cure agenda. In gay and bisexual men, a major, yet poorly characterized, route of HIV entry is via transport across the colonic epithelial barrier. While colonic tears and paracellular transport contribute to infection, we hypothesize that HIV entry through the colonic mucosa proceeds via a process known as transcytosis, involving (i) virion binding to the apical surface of the colonic epithelium, (ii) viral endocytosis, (iii) transport of virions across the cell, and (iv) HIV release from the basolateral membrane. Using Caco-2 colonic epithelial cells plated as a polarized monolayer in transwells, we characterized the mechanism of HIV transport. After exposing the monolayer to HIV apically, reverse transcription quantitative PCR (RT-qPCR) of the viral genome present in the basolateral chamber revealed that transport is dose dependent, cooperative, and inefficient, with released virus first detectable at 12 h. Inefficiency may be associated with >50% decline in detectable intracellular virus that correlates temporally with increased association of the virion with lysosomal-associated membrane protein 1 (LAMP-1+) endosomes. Microscopy revealed green fluorescent protein (GFP)-labeled HIV within the confines of the epithelial monolayer, with no virus detectable between cells, suggesting that viral transport is transcellular. Treatment of the monolayer with endocytosis inhibitors, cholesterol reducing agents, and small interfering RNA (siRNA) to caveolin showed that viral endocytosis is mediated by caveolin-coated endosomes contained in lipid rafts. These results indicate that HIV transport across the intestinal epithelial barrier via transcytosis is a viable mechanism for viral spread and a potential therapeutic target. IMPORTANCE Despite the success of combination antiretroviral therapy in suppressing HIV replication and the emergence and effectiveness of PrEP-based prevention strategies, in 2018, 37,968 people in the United States received a new HIV diagnosis, accompanied by 15,820 deaths. While the annual number of new diagnoses decreased 7% from 2014 to 2018, 14% of people with HIV did not know they were infected. Gay and bisexual men accounted for 69% of all HIV diagnoses and 83% of diagnoses among males. Due to the scope of the HIV epidemic, determining and understanding precise routes of infection and the mechanisms of viral spread are paramount to ending the epidemic. Since transcellular transport of HIV across an intact colonic epithelial barrier is poorly understood, our overall goal is to characterize the molecular events involved in HIV transcytosis across the intestinal epithelial cell.

Percutaneous iliosacral screw fixation and transsacral fixation are challenging procedures requiring extensive knowledge of sacral anatomy to avoid damaging nearby neurovascular structures. Greater knowledge of anatomical screw trajectory and size allowances would be helpful to guide surgical placement. An anatomical study of 40 cadaveric sacra in specimens ages 18-65 was performed. Three-dimensional surface scans were obtained, and computer modeling software was used to simulate a 7.3 mm diameter screw with 1 mm buffer inserted orthogonal to the sacroiliac joint in the pelvic inlet and outlet views. Transsacral screws were also inserted into S1 and S2 vertebrae. For screws orthogonal to the sacroiliac joint, the overall mean screw insertion angle was 4.1° ± 7.5° (range, -18.3° to 22.0°) in the inlet view in the posterior to anterior direction, and 21.7° ± 5.1° (range, 8.2°-36.3°) in the outlet view in the caudal to cranial direction. Before breaching the sacrum, the range of sacral tunnel lengths was between 31.1 and 70.1 mm with a range of diameters between 9.3 and 13.3 mm. Transsacral screws inserted into either the S1 or S2 vertebrae did not breach the sacrum in 40% (16/40) at each level. 30% (12/40) of sacra could not safely accommodate both S1 and S2 transsacral screws. There is an initial screw insertion angle range of -4° to 12° in the inlet view and 16°-27° in the outlet view. There was always adequate size to accept a 7.3 mm or larger screw., (© 2021 American Association of Clinical Anatomists.)

The significant morbidity and mortality of coronavirus disease 19 (COVID-19) prompted a global race to develop new therapies. These include interventions using cell- or cell-derived products, several of which are being tested in well-designed, properly controlled clinical trials. Yet, the search for cell-based COVID-19 treatments has also been fraught with hyperbolic claims; flouting of crucial regulatory, scientific, and ethical norms; and distorted communication of research findings. In this paper, we critically examine ethical issues and public communication challenges related to the development of cell-based therapeutics for COVID-19. Drawing on the lessons learned from this ongoing process, we argue against the rushed development of cell-based interventions. We conclude by outlining ways to improve the ethical conduct of cell-based clinical investigations and public communication of therapeutic claims., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Residual systemic inflammation and mucosal immune dysfunction persist in people living with HIV, despite treatment with combined anti-retroviral therapy, but the underlying immune mechanisms are poorly understood. Here we report that the altered immune landscape of the oral mucosa of HIV-positive patients on therapy involves increased TLR and inflammasome signaling, localized CD4 + T cell hyperactivation, and, counterintuitively, enrichment of FOXP3 + T cells. HIV infection of oral tonsil cultures in vitro causes an increase in FOXP3 + T cells expressing PD-1, IFN-γ, Amphiregulin and IL-10. These cells persist even in the presence of anti-retroviral drugs, and further expand when stimulated by TLR2 ligands and IL-1β. Mechanistically, IL-1β upregulates PD-1 expression via AKT signaling, and PD-1 stabilizes FOXP3 and Amphiregulin through a mechanism involving asparaginyl endopeptidase, resulting in FOXP3 + cells that are incapable of suppressing CD4 + T cells in vitro. The FOXP3 + T cells that are abundant in HIV-positive patients are phenotypically similar to the in vitro cultured, HIV-responsive FOXP3 + T cells, and their presence strongly correlates with CD4 + T cell hyper-activation. This suggests that FOXP3 + T cell dysregulation might play a role in the mucosal immune dysfunction of HIV patients on therapy., (© 2021. The Author(s).)

Background & Aims: Communication between T cells and the intestinal epithelium is altered in many diseases, causing T-cell activation, depletion, or recruitment, and disruption of the epithelium. We hypothesize that activation of T cells regulates epithelial barrier function by targeting the assembly of the tight junction complex., Methods: In a 3-dimensional and 2-dimensional co-culture model of activated T cells subjacent to the basolateral surface of an epithelial monolayer, the pore, leak, and unrestricted pathways were evaluated using transepithelial resistance and flux of fluorescently labeled tracers. T cells were acutely and chronically activated by cross-linking the T-cell receptor. Tight junction assembly and expression were measured using quantitative polymerase chain reaction, immunoblot, and immunofluorescence confocal microscopy., Results: Co-culture with acutely and chronically activated T cells decreased the magnitude of ion flux through the pore pathway, which was maintained in the presence of acutely activated T cells. Chronically activated T cells after 30 hours induced a precipitous increase in the magnitude of both ion and molecular flux, resulting in an increase in the unrestricted pathway, destruction of microvilli, expansion in cell surface area, and cell death. These fluctuations in permeability were the result of changes in the assembly and expression of tight junction proteins, cell morphology, and viability. Co-culture modulated the expression of immune mediators in the epithelium and T cells., Conclusions: Bidirectional communication between T cells and epithelium mediates a biphasic response in barrier integrity that is facilitated by the balance between structural proteins partitioning in the mobile lateral phase vs the tight junction complex and cell morphology., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Over the past three decades the United States has experienced a devastating opioid epidemic. One of the many debilitating side effects of chronic opioid use is opioid-induced bowel dysfunction. We investigated the impact of methadone maintenance treatment (MMT) on the gut microbiome, the gut bacterial metabolite profile, and intestinal barrier integrity. An imbalance in key bacterial communities required for production of short-chain fatty acids (SCFAs), mucus degradation, and maintenance of barrier integrity was identified. Consistent with dysbiosis, levels of fecal SCFAs were reduced in MMT. We demonstrated that metabolites synthesized by Akkermansia muciniphila modulate intestinal barrier integrity in vitro by strengthening the pore pathway and regulating tight junction protein expression. This study provides essential information about the therapeutic potential of A. muciniphila and warrants development of new clinical strategies that aim to normalize the gut microbiome in individuals affected by chronic opioid use.

Science funders are increasingly requiring evidence of the broader impacts of even basic research. Initiatives such as NIH's CTSA program are designed to shift the research focus toward more translational research. However, tracking the effectiveness of such programs depends on developing indicators that can track the degree to which basic research is influencing clinical research. We propose a new bibliometric indicator, the TS score, that is relatively simple to calculate, can be implemented at scale, is easy to replicate, and has good reliability and validity properties. This indicator is broadly applicable in settings where the goal is to estimate the degree to which basic research is used in more applied downstream research, relative to use in basic research. The TS score should be of use for a variety of policy analysis and research evaluation purposes.

Cancer vaccines are promising adjuvant immunotherapies that can stimulate the immune system to recognize tumor-associated antigens and eliminate the residual or recurring disease. The aberrant and restricted expression of highly immunogenic cancer testis antigen NY-ESO-1 in several malignancies, including triple-negative breast cancer, melanoma, myelomas, and ovarian cancer, makes NY-ESO-1 an attractive antigenic target for cancer vaccines. This study describes a NY-ESO-1 vaccine based on a bio-inspired nanomaterial platform technology, specifically a plant virus nanoparticle. The 30 nm icosahedral plant virus cowpea mosaic virus (CPMV) displaying multiple copies of human HLA-A2 restricted peptide antigen NY-ESO-1 157-165 exhibited enhanced uptake and activation of antigen-presenting cells and stimulated a potent CD8 + T cell response in transgenic human HLA-A2 expressing mice. CD8 + T cells from immunized mice exhibited antigen-specific proliferation and cancer cell cytotoxicity, highlighting the potential application of a CPMV-NY-ESO-1 vaccine against NY-ESO-1 + malignancies., Competing Interests: The authors declare no competing financial interest.

Opioid peptides are released at sites of injury, and their cognate G protein-coupled opioid receptors (OR) are expressed on immune cells. Exposure of human circulating CD8 + T cells to selective OR agonists differentially regulates thousands of genes. Gene set enrichment analysis reveals that μ-OR more strongly regulates cellular processes than δ-OR. In TCR naive T cells, triggering μ-OR exhibits stimulatory and inhibitory patterns, yet when administered prior to TCR cross-linking, a μ-OR agonist inhibits activation. μ-OR, but not δ-OR, signaling is linked to upregulation of lipid, cholesterol, and steroid hormone biosynthesis, suggesting lipid regulation is a mechanism for immune suppression. Lipid rafts are cholesterol-rich, liquid-ordered membrane domains that function as a nexus for the initiation of signal transduction from surface receptors, including TCR and μ-OR. We therefore propose that μ-OR-specific inhibition of TCR responses in human CD8 + T cells may be mediated through alterations in lipid metabolism and membrane structure., (Copyright © 2020 The Authors.)

Background and Aims: The symptomology of Crohn's disease [CD], a chronic inflammatory disease of the digestive tract, correlates poorly with clinical, endoscopic or immunological assessments of disease severity. The prevalence of CD in South America is rising, reflecting changes in socio-economic stability. Many treatment options are available to CD patients, including biological agents and corticosteroids, each of which offers variable efficacy attributed to host genetics and environmental factors associated with alterations in the gut microbiota., Methods: Based on 16S rRNA gene sequencing and taxonomic differences, we compared the faecal microbial population of Brazilian patients with CD treated with corticosteroid or anti-tumour necrosis factor [anti-TNF] immunotherapy. Faecal calprotectin and plasma sCD14 levels were quantified as markers for local and systemic inflammation, respectively., Results: Anti-TNF treatment led to an increased relative abundance of Proteobacteria and a decreased level of Bacteroidetes. In contrast, corticoid treatment was associated with an increase in the relative abundance of Actinobacteria, which has been linked to inflammation in CD. Disruption of the faecal microbiota was related to decreased bacterial diversity and composition. Moreover, the choice of clinical regimen and time since diagnosis modulate the character of the resulting dysbiosis., Conclusions: Enteric microbial populations in CD patients who have been treated are modulated by disease pathogenesis, local inflammatory microenvironment and treatment strategy. The dysbiosis that remains after anti-TNF treatment due to decreased bacterial diversity and composition abates restoration of the microbiota to a healthy state, suggesting that the identification and development of new clinical treatments for CD must include their capacity to normalize the gut microbiota., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Design: Since intestinal immunity and the microbiome are disrupted in HIV disease, we studied the abundance of innate immune sensors, Toll-like receptors (TLRs), in the mucosa of participants with viremia, prior to antiretroviral therapy (ART), immune success (>500 CD4 T cells/μl after 2 years of ART; suppressed viremia), and immune failure (<350 CD4 T cells/μl after 2 years of ART; suppressed viremia). We hypothesized that disruption of intestinal TLR abundance and location provides a mechanism behind persistent inflammation., Methods: Immunofluorescence for TLR3, TLR4, and TLR9 on paraffin embedded biopsies from uninfected, viremic, immune success, and immune failure colons was imaged by deconvolution microscopy and quantified with MetaMorph software. Plasma levels of C-reactive protein, IL-6, and intestinal fatty-acid binding protein (I-FABP) were correlated with TLR expression., Results: Viremic participants have significantly higher levels of TLR3 and TLR9 on surface epithelium and in crypts when compared with uninfected controls. TLR3 is further elevated in immune failure and immune success. TLR9 abundance remains elevated in immune failure and is normalized in immune success. TLR9 expression in the crypt and lamina propria positively associates with C-reactive protein and IL-6 and negatively with I-FABP. TLR4 is significantly lower on surface epithelium and higher in crypts in viremic. Its expression in the lamina propria positively correlates with IL-6 and negatively correlates with I-FABP., Conclusion: Mucosal TLR imbalance and deregulation, and the resulting mucosal TLR desensitization and hypervigilance, remain after suppressive ART, in the presence or absence of T-cell recovery, likely contributing to chronic systemic inflammation.

Endogenous opioid peptides are released at sites of injury, and their cognate G protein-coupled opioid receptors (ORs) are expressed on immune cells. Although drugs of misuse appropriate ORs, conflicting reports indicate immunostimulatory and immunosuppressive activity, in that opioid users have elevated infection risk, opioids activate innate immune cells, and opioids attenuate inflammation in murine T cell-mediated autoimmunity models. The i.v. use of drugs transmits bloodborne pathogens, particularly viruses, making the study of CD8 + T cells timely. From a cohort of nonuser controls and methadone users, we demonstrate, via t-Stochastic Neighbor Embedding and k-means cluster analysis of surface marker expression, that chronic opioid use alters human CD8 + T cell subset balance, with notable decreases in T effector memory RA + cells. Studying global CD8 + T cell populations, there were no differences in expression of OR and several markers of functionality, demonstrating the need for finer analysis. Purified CD8 + T cells from controls respond to opioids ex vivo by increasing cytoplasmic calcium, a novel finding for OR signal transduction, likely because of cell lineage. CD8 + T cells from controls exposed to μ-OR agonists ex vivo decrease expression of activation markers CD69 and CD25, although the same markers are elevated in μ-OR-treated cells from methadone users. In contrast to control cells, T cell subsets from methadone users show decreased expression of CD69 and CD25 in response to TCR stimulus. Overall, these results indicate a direct, selective role for opioids in CD8 + T cell immune regulation via their ability to modulate cell responses through the opioid receptors and TCRs., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Background Aims: Autologous cell therapy (AuCT) is an emerging therapeutic treatment that is undergoing transformation from laboratory- to industry-scale manufacturing with recent regulatory approvals. Various challenges facing the complex AuCT manufacturing and supply chain process hinder the scale out and broader application of this highly potent treatment., Methods: We present a multiscale logistics simulation framework, AuCT-Sim, that integrates novel supply chain system modeling algorithms, methods, and tools. AuCT-Sim includes a single facility model and a system-wide network model. Unique challenges of the AuCT industry are analyzed and addressed in AuCT-Sim. Decision-supporting tools can be developed based on this framework to explore "what-if" manufacturing and supply chain scenarios of importance to various cell therapy stakeholder groups., Results: Two case studies demonstrate the decision-supporting capability of AuCT-Sim where one investigates the optimal reagent base stocking level, and the other one simulates a reagent supply disruption event. These case studies serve as guidelines for designing computational experiments with AuCT-Sim to solve specific problems in AuCT manufacturing and supply chain., Discussion: This simulation framework will be useful in understanding the impact of possible manufacturing and supply chain strategies, policies, regulations, and standards informing strategies to increase patient access to AuCT., (Copyright © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Case: We present the case of a 15-year-old girl who has a history of Ponseti casting followed by Achilles tenotomies for congenital clubfeet as an infant and subsequently suffered an acute traumatic midsubstance Achilles tendon rupture on the left and midsubstance Achilles tendinosis on the right., Conclusions: Traumatic pediatric Achilles ruptures are rare. There are no prior reported cases in patients with a history of Achilles tenotomy, despite it being a described potential complication. This case highlights the potential for an Achilles rupture years after tenotomy and presents surgical repair as a satisfactory treatment option for Achilles ruptures in adolescents.

Weak fluctuations about the rigid equilibrium structure of ordered molecular bridges drive charge transfer in donor-bridge-acceptor systems via quantum unfurling, which differs from both hopping and ballistic transfer, yet static disorder (low frequency motions) in the bridge is shown to induce a change of mechanism from unfurling to hopping when local fluctuations along the molecular bridge are uncorrelated. Remarkably, these two different transport mechanisms manifest in similar charge-transfer rates, which are nearly independent of the molecular bridge length. We propose an experimental test for distinguishing unfurling from hopping in DNA models with different helix directionality. A unified formulation explains the apparent similarity in the length dependence of the transfer rate despite the difference in the underlying transport mechanisms.

Aim: To examine how the geographic distribution of pluripotent and adult stem cell research publications within the USA differs from other areas of biomedical research., Materials & Methods: Publication count data for pluripotent stem cell research, adult stem cell research and a comparison group representative of biomedical research more broadly were collected and analyzed for each US state from 2009 to 2016., Results: The distribution of pluripotent stem cell research differed from the other fields with overperformance in pluripotent stem cell research observed in California, as well as Wisconsin, Massachusetts, Maryland and Connecticut., Conclusion: Our analysis suggests that permissive state stem cell policy may be one of the several factors contributing to strong state performance in pluripotent stem cell research.

Businesses marketing unproven stem cell interventions proliferate within the U.S. and in the larger global marketplace. There have been global efforts by scientists, patient advocacy groups, bioethicists, and public policy experts to counteract the uncontrolled and premature commercialization of stem cell interventions. In this commentary, we posit that medical societies and associations of health care professionals have a particular responsibility to be an active partner in such efforts. We review the role medical societies can and should play in this area through patient advocacy and awareness initiatives., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

This corrects the article DOI: 10.1038/nbt.4015.

Objective: To study cross-border reproductive care (CBRC) by assessing the frequency and nature of assisted reproductive technology (ART) care that non-U.S. residents receive in the United States., Design: Retrospective study of ART cycles reported to the Centers for Disease Control and Prevention's National ART Surveillance System (NASS) from 2006 to 2013., Setting: Private and academic ART clinics., Patient(s): Patients who participated in ART cycles in the United States from 2006 to 2013., Intervention(s): None., Main Outcome Measure(s): Frequency and trend of ART use in the U.S. by non-U.S. residents, countries of residence for non-U.S. residents, differences by residence status for specific ART treatments received, and the outcomes of these ART cycles., Result(s): A total of 1,271,775 ART cycles were reported to NASS from 2006 to 2013. The percentage of ART cycles performed for non-U.S. residents increased from 1.2% (n = 1,683) in 2006 to 2.8% (n = 5,381) in 2013 (P<.001), with treatment delivered to residents of 147 countries. Compared with resident cycles, non-U.S. resident cycles had higher use of oocyte donation (10.6% vs. 42.6%), gestational carriers (1.6% vs. 12.4%), and preimplantation genetic diagnosis or screening (5.3% vs. 19.1%). U.S. resident and non-U.S. resident cycles had similar embryo transfer and multiple birth rates., Conclusion(s): This analysis showed that non-U.S. resident cycles accounted for a growing share of all U.S. ART cycles and made higher use of specialized treatment techniques. This study provides important baseline data on CBRC in the U.S. and may also prove to be useful to organizations interested in improving access to fertility treatments., (Copyright © 2017 American Society for Reproductive Medicine. All rights reserved.)

The intestinal epithelium is a major site for the conversion of dietary β-carotene to retinaldehyde by the enzyme BCO1. The majority of retinaldehyde is further metabolized to retinol (vitamin A), esterified and packaged into triacylglycerol-rich chylomicrons for bodily distribution. Some serve on-site for the synthesis of retinoic acid, a hormone-like compound, which exerts pleiotropic and dominant effects on gastrointestinal immunity. We report here that the intestine-specific homeobox protein ISX is critical to control the metabolic flow of β-carotene through this important branching point of vitamin A metabolism. This transcription factor represses Bco1 gene expression in response to retinoic acid signaling. In ISX-deficient mice, uncontrolled Bco1 gene expression led to increased retinoid production in the intestine. Systemically, this production resulted in highly elevated hepatic retinoid stores. In the intestine, it increased the expression of retinoic acid-inducible target genes such as Aldh1a2 , Dhrs3 , and Ccr9 The β-carotene-inducible disruption of retinoid homeostasis affected gut-homing and differentiation of lymphocytes and displayed morphologically in large lymphoid follicles along the intestine. Furthermore, it was associated with an infiltration of the pancreas by gut-derived lymphocytes that manifested as a pancreatic insulitis with β-islet cell destruction and systemic glucose intolerance. Thus, our study identifies an important molecular interlink between diet and immunity and indicates that vitamin A homeostasis must be tightly controlled by ISX to maintain immunity and tolerance at the intestinal barrier., Competing Interests: The authors declare no conflict of interest.

Gestational surrogacy policy in the USA varies by state, but information on state differences is lacking. This study used data from the National Assisted Reproductive Technology Surveillance System from 2010 to 2014 to calculate state differences in gestational carrier cycle characteristics. Of the 662,165 in-vitro fertilization cycles in the USA between 2010 and 2014, 16,148 (2.4%) used gestational carriers. Non-USA residents accounted for 18.3% of gestational carrier cycles, and 29.1% of gestational carrier cycles by USA residents were performed in a state other than the state of residence of the intended parent. USA gestational surrogacy practice varies by state, potentially impacting patients' access to surrogacy services.