Endoscopic sleeve gastroplasty (ESG) is an endolumenal, organ-sparing therapy for obesity, with wide global adoption. We aimed to explore the efficacy and safety of ESG with lifestyle modifications ...compared with lifestyle modifications alone.
We conducted a randomised clinical trial at nine US centres, enrolling individuals aged 21–65 years with class 1 or class 2 obesity and who agreed to comply with lifelong dietary restrictions. Participants were randomly assigned (1:1·5; with stratified permuted blocks) to ESG with lifestyle modifications (ESG group) or lifestyle modifications alone (control group), with potential retightening or crossover to ESG, respectively, at 52 weeks. Lifestyle modifications included a low-calorie diet and physical activity. Participants in the primary ESG group were followed up for 104 weeks. The primary endpoint at 52 weeks was the percentage of excess weight loss (EWL), with excess weight being that over the ideal weight for a BMI of 25 kg/m2. Secondary endpoints included change in metabolic comorbidities between the groups. We used multiple imputed intention-to-treat analyses with mixed-effects models. Our analyses were done on a per-protocol basis and a modified intention-to-treat basis. The safety population was defined as all participants who underwent ESG (both primary and crossover ESG) up to 52 weeks.
Between Dec 20, 2017, and June 14, 2019, 209 participants were randomly assigned to ESG (n=85) or to control (n=124). At 52 weeks, the primary endpoint of mean percentage of EWL was 49·2% (SD 32·0) for the ESG group and 3·2% (18·6) for the control group (p<0·0001). Mean percentage of total bodyweight loss was 13·6% (8·0) for the ESG group and 0·8% (5·0) for the control group (p<0·0001), and 59 (77%) of 77 participants in the ESG group reached 25% or more of EWL at 52 weeks compared with 13 (12%) of 110 in the control group (p<0·0001). At 52 weeks, 41 (80%) of 51 participants in the ESG group had an improvement in one or more metabolic comorbidities, whereas six (12%) worsened, compared with the control group in which 28 (45%) of 62 participants had similar improvement, whereas 31 (50%) worsened. At 104 weeks, 41 (68%) of 60 participants in the ESG group maintained 25% or more of EWL. ESG-related serious adverse events occurred in three (2%) of 131 participants, without mortality or need for intensive care or surgery.
ESG is a safe intervention that resulted in significant weight loss, maintained at 104 weeks, with important improvements in metabolic comorbidities. ESG should be considered as a synergistic weight loss intervention for patients with class 1 or class 2 obesity. This trial is registered with ClinicalTrials.gov, NCT03406975.
Apollo Endosurgery, Mayo Clinic.
BackgroundAdoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of T cells with poor function or ...persistence. Toll-like receptor (TLR) agonists can invigorate antitumor T cell responses when administered directly to patients, but these responses often coincide with toxicities. We posited that TLR agonists could be repurposed ex vivo to condition T cells with remarkable potency in vivo, circumventing TLR-related toxicity.MethodsIn this study we investigated how tumor-specific murine CD8+ T cells and human tumor infiltrating lymphocytes (TILs) are impacted when expanded ex vivo with the TLR9 agonist CpG.ResultsHerein we reveal a new way to reverse the tolerant state of adoptively transferred CD8+ T cells against tumors using TLR-activated B cells. We repurposed the TLR9 agonist, CpG, commonly used in the clinic, to bolster T cell—B cell interactions during expansion for ACT. T cells expanded ex vivo from a CpG-treated culture demonstrated potent antitumor efficacy and prolonged persistence in vivo. This antitumor efficacy was accomplished without in vivo administration of TLR agonists or other adjuvants of high-dose interleukin (IL)-2 or vaccination, which are classically required for effective ACT therapy. CpG-conditioned CD8+ T cells acquired a unique proteomic signature hallmarked by an IL-2RαhighICOShighCD39low phenotype and an altered metabolic profile, all reliant on B cells transiently present in the culture. Likewise, human TILs benefitted from expansion with CpG ex vivo, as they also possessed the IL-2RαhighICOShighCD39low phenotype. CpG fostered the expansion of potent CD8+ T cells with the signature phenotype and antitumor ability via empowering a direct B–T cell interaction. Isolated B cells also imparted T cells with the CpG-associated phenotype and improved tumor immunity without the aid of additional antigen-presenting cells or other immune cells in the culture.ConclusionsOur results demonstrate a novel way to use TLR agonists to improve immunotherapy and reveal a vital role for B cells in the generation of potent CD8+ T cell-based therapies. Our findings have immediate implications in the clinical treatment of advanced solid tumors.
Our objectives were to evaluate the clinical efficacy of oral and intranasal administration of a commercial modified-live Salmonella Dublin vaccine in dairy calves and to determine the serologic ...response associated with these extralabel routes of administration. We conducted a randomized field trial with calves from a New York dairy farm following an outbreak of Salmonella Dublin. A total of 399 Holstein calves were allocated by pen to 3 treatment groups: oral vaccination, intranasal vaccination, and an unvaccinated control group. Administration of the vaccine through oral and intranasal routes did not have a significant effect on pneumonia incidence risk or weight gain; however, calves vaccinated orally and intranasally had lower mortality risk as compared with control calves. Among calves tested using a Salmonella Dublin ELISA, vaccination did not induce an increase in antibody production relative to control calves, indicating that oral and intranasal administration will not hinder diagnosis based on this assay.
In academia, funding for conference attendance is limited, and both students and early-career researchers are therefore only able to attend a limited number of conferences. This means that, ...typically, researchers need to choose between attending multiple local and, at times, more affordable conferences, or one or two large, expensive, international conferences. Local and less expensive conferences may be research-specific but will have a smaller audience and lower networking potential. In biological anthropology and bioarchaeology, the majority of these larger annual conferences are held in North America and Western Europe where travel and accommodation costs can be very high for those outside of these regions. These costs, in addition to visa restrictions, reduce the diversity of participants at academic conferences, skewing attendance to students and researchers from the host countries. Not only does this disadvantage individuals outside of the typical host-countries, but it also limits the breadth of academic dialogue, with inclusion in academic conferences determined all too often by financial resources rather than academic value. This paper discusses the demographics and lack of diversity at some of these large conferences and the factors that are known to limit international conference travel. It then presents the benefits of digital presentation methods using Digital Dilemma 2018 as a case study for how digital presentation methods can be combined with physical presentations at minimal cost and time. We hope that this will encourage more conferences to offer a digital presentation option in the future.
The coronavirus disease 2019 (COVID-19) global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to place an immense burden on societies and health care ...systems. A key component of COVID-19 control efforts is serological testing to determine the community prevalence of SARS-CoV-2 exposure and quantify individual immune responses to prior SARS-CoV-2 infection or vaccination. Here, we describe a laboratory-developed antibody test that uses readily available research-grade reagents to detect SARS-CoV-2 exposure in patient blood samples with high sensitivity and specificity. We further show that this sensitive test affords the estimation of viral spike-specific IgG titers from a single sample measurement, thereby providing a simple and scalable method to measure the strength of an individual's immune response. The accuracy, adaptability, and cost-effectiveness of this test make it an excellent option for clinical deployment in the ongoing COVID-19 pandemic.
Serological surveillance has become an important public health tool during the COVID-19 pandemic. Detection of protective antibodies and seroconversion after SARS-CoV-2 infection or vaccination can help guide patient care plans and public health policies. Serology tests can detect antibodies against past infections; consequently, they can help overcome the shortcomings of molecular tests, which can detect only active infections. This is important, especially when considering that many COVID-19 patients are asymptomatic. In this study, we describe an enzyme-linked immunosorbent assay (ELISA)-based qualitative and quantitative serology test developed to measure IgG and IgA antibodies against the SARS-CoV-2 spike glycoprotein. The test can be deployed using commonly available laboratory reagents and equipment and displays high specificity and sensitivity. Furthermore, we demonstrate that IgG titers in patient samples can be estimated from a single measurement, enabling the assay's use in high-throughput clinical environments.
Infections with Chikungunya virus, a mosquito-borne alphavirus, cause an acute febrile syndrome often followed by chronic arthritis that persists for months to years post-infection. Neutralizing ...antibodies are the primary immune correlate of protection elicited by infection, and the major goal of vaccinations in development. Using convalescent blood samples collected from both endemic and non-endemic human subjects at multiple timepoints following suspected or confirmed chikungunya infection, we identified antibodies with broad neutralizing properties against other alphaviruses within the Semliki Forest complex. Cross-neutralization generally did not extend to the Venezuelan Equine Encephalitis virus (VEEV) complex, although some subjects had low levels of VEEV-neutralizing antibodies. This suggests that broadly neutralizing antibodies elicited following natural infection are largely complex restricted. In addition to serology, we also performed memory B-cell analysis, finding chikungunya-specific memory B-cells in all subjects in this study as remotely as 24 years post-infection. We functionally assessed the ability of memory B-cell derived antibodies to bind to chikungunya virus, and related Mayaro virus, as well as the highly conserved B domain of the E2 glycoprotein thought to contribute to cross-reactivity between related Old-World alphaviruses. To specifically assess the role of the E2 B domain in cross-neutralization, we depleted Mayaro and Chikungunya virus E2 B domain specific antibodies from convalescent sera, finding E2B depletion significantly decreases Mayaro virus specific cross-neutralizing antibody titers with no significant effect on chikungunya virus neutralization, indicating that the E2 B domain is a key target of cross-neutralizing and potentially cross-protective neutralizing antibodies.
IMPORTANCE: The first Postnatal Growth and Retinopathy of Prematurity Study (G-ROP-1) developed new screening criteria with 100% sensitivity for type 1 retinopathy of prematurity (ROP) and 30% ...reduction of infants requiring examinations in a retrospective development cohort of 7483 infants from 29 North American hospitals in 2006-2012. Infants meeting 1 or more of the following criteria undergo examinations: gestational age less than 28 weeks or birth weight less than 1051 g; weight gain less than 120 g during age 10 to 19 days, weight gain less than 180 g during age 20 to 29 days, or weight gain less than 170 g during age 30 to 39 days; or hydrocephalus. OBJECTIVE: To evaluate the generalizability of the G-ROP screening criteria in a new cohort of at-risk infants. DESIGN, SETTING, AND PARTICIPANTS: This prospective validation cohort study (G-ROP-2) was conducted at 41 hospitals in the United States and Canada (25 G-ROP-1 hospitals and 16 new hospitals) from September 8, 2015, to June 13, 2017, among 3981 premature infants at risk for ROP and with known ROP outcomes. MAIN OUTCOMES AND MEASURES: Sensitivity for Early Treatment for Retinopathy of Prematurity Study type 1 ROP and potential reduction in infants receiving examinations. RESULTS: Among the 3981 infants in the study (1878 girls and 2103 boys; median gestational age, 28 weeks range, 22-35 weeks; median birth weight, 1072 g range, 350-4080 g; 1966 white; 942 black; 321 Latino; 120 Asian; 22 Native Hawaian or Pacific Islander; and 25 American Indian or Alaskan Native), the G-ROP criteria correctly predicted 219 of 219 cases of type 1 ROP (sensitivity, 100%; 95% CI, 98.3%-100%), while reducing the number of infants undergoing examinations by 35.6% (n = 1418). In a combined G-ROP-1 and G-ROP-2 cohort of 11 463 infants, the G-ROP criteria predicted 677 of 677 cases of type 1 ROP (sensitivity, 100%; 95% CI, 99.4%-100%), reducing the number of infants receiving examinations by 32.5% (n = 3730), while current criteria (birth weight <1501 g or gestational age ≤30 weeks 0 days) predicted 674 of 677 type 1 cases (sensitivity, 99.6%; 95% CI, 98.7%-99.8%). CONCLUSIONS AND RELEVANCE: This study found that the G-ROP screening criteria were generalizable on validation and, if used clinically in the United States and Canada, could reduce the number of infants receiving examinations. The large G-ROP cohorts provide evidence-based screening criteria that have higher sensitivity and higher specificity (fewer infants receiving examinations) for type 1 ROP than currently recommended guidelines.
Here we report the genetic characterization of immortalized prostate epithelial cells before and after conversion to tumorigenicity using molecular cytogenetics and microarray technology. We were ...particularly interested to analyze the consequences of acquired chromosomal aneuploidies with respect to modifications of gene expression profiles. Compared with nontumorigenic but immortalized prostate epithelium, prostate tumor cell lines showed high levels of chromosomal rearrangements that led to gains of 1p, 5, 11q, 12p, 16q, and 20q and losses of 1pter, 11p, 17, 20p, 21, 22, and Y. Of 5700 unique targets on a 6.5K cDNA microarray, approximately 3% were subject to modification in expression levels; these included GRO-1, -2, IAP-1,- 2, MMP-9, and cyclin D1, which showed increased expression, and TRAIL, BRCA1, and CTNNA, which showed decreased expression. Thirty % of expression changes occurred in regions the genomic copy number of which remained balanced. Of the remainder, 42% of down-regulated and 51% of up-regulated genes mapped to regions present in decreased or increased genomic copy numbers, respectively. A relative gain or loss of a chromosome or chromosomal arm usually resulted in a statistically significant increase or decrease, respectively, in the average expression level of all of the genes on the chromosome. However, of these genes, very few (e.g., 5 of 101 genes on chromosome 11q), and in some instances only two genes (MMP-9 and PROCR on chromosome 20q), were overexpressed by > or =1.7-fold when scored individually. Cluster analysis by gene function suggests that prostate tumorigenesis in these cell line models involves alterations in gene expression that may favor invasion, prevent apoptosis, and promote growth.
Mature adipocytes store fatty acids and are a common component of tissue stroma. Adipocyte function in regulating bone marrow, skin, muscle, and mammary gland biology is emerging, but the role of ...adipocyte-derived lipids in tissue homeostasis and repair is poorly understood. Here, we identify an essential role for adipocyte lipolysis in regulating inflammation and repair after injury in skin. Genetic mouse studies revealed that dermal adipocytes are necessary to initiate inflammation after injury and promote subsequent repair. We find through histological, ultrastructural, lipidomic, and genetic experiments in mice that adipocytes adjacent to skin injury initiate lipid release necessary for macrophage inflammation. Tamoxifen-inducible genetic lineage tracing of mature adipocytes and single-cell RNA sequencing revealed that dermal adipocytes alter their fate and generate ECM-producing myofibroblasts within wounds. Thus, adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes.
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•Inhibiting dermal adipocyte lipolysis reduces inflammatory wound bed macrophages•Wound edge adipocytes dedifferentiate within hours after injury•Adipocyte lipolysis is needed for dedifferentiated adipocytes to populate wound beds•Dedifferentiated adipocytes generate wound bed myofibroblasts after injury
Using genetic mouse models and transcriptomic profiling, Shook et al. show that skin resident adipocytes undergo lipolysis to promote efficient macrophage inflammation after injury. Lipolysis also allows adipocyte-derived cells to dedifferentiate and generate diverse extracellular matrix-producing myofibroblasts in the wound bed.
Purpose: Subtotal skin electron beam therapy may be an option for patients with cutaneous lymphoma receiving radiation therapy to treat large areas of their skin but may benefit from sparing specific ...areas that may have had previous radiation therapy, are of specific cosmetic concern, and/or show no evidence of disease. We report here on the design, implementation, and dosimetric characteristics of a reusable and transparent customizable shield for use with the large fields used to deliver total skin electron beam therapy at extended distance with a conventional linear accelerator.
A shield was designed and manufactured consisting of acrylic blocks that can be mounted on a steel frame to allow patient-specific shielding. The dosimetry of the device was measured using radiochromic film.
The shield is easy to use and well-tolerated for patient treatment, providing minimal electron transmission through the shield with a sharp penumbra at the field edge, with no increase in x-ray dose. We report on the dosimetry of a commercial device that has been used to treat more than 30 patients to date.
The customizable shield is well suited to providing patient-specific shielding for subtotal skin electron beam therapy.
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