The Association between Factor XI Deficiency and the Risk of Bleeding, Cardiovascular, and Venous Thromboembolic Events.
Thrombosis and haemostasis
The objective of this study was to assess the relationship between factor XI (FXI) deficiency and the risks of bleeding and cardiovascular (CV) events. We conducted a retrospective cohort study using data from Maccabi Healthcare Services (MHS). We identified adults with FXI deficiency (severe: <15%, partial: 15 to <50%, any deficiency: <50%) that had been tested for FXI between 2007 and 2018 and matched to patients from the general MHS population. We estimated 10-year risks of outcomes using the Kaplan-Meier approach. Using Cox proportional hazards regression, we compared outcomes among patients with versus without FXI deficiency. Less than 10% of patients tested for FXI activity had activity levels <50% (mean age: 39 years; 72.2% females). Compared with the general population, patients with any FXI deficiency were at higher risk of severe bleeding (adjusted hazard ratio [aHR]: 2.56, 95% confidence interval [CI]: 1.13-5.81; 10-year risk: 1.90%, 95% CI: 0.50-3.20% vs. 0.90%, 95% CI: 0.50-1.30%) and clinically relevant nonsevere bleeding (CRNSB) (aHR: 1.45, 95% CI: 1.08-1.97; 10-year risk: 11.60%, 95% CI: 8.30-14.80% vs. 9.20%, 95% CI: 8.00-10.40%). Severe FXI deficiency was associated with a greater risk of CRNSB. While few CV events ( = 2) and venous thromboembolisms (VTE) ( = 1) were observed in the FXI overall deficient group, there was a nonsignificant negative association between any FXI deficiency and CV events (aHR: 0.55; 95% CI: 0.13-2.36) and VTEs (aHR: 0.45; 95% CI: 0.06-3.47). Overall FXI deficiency was associated with an increased risk of severe bleeding and CRNSB. Further research is warranted to explore the lower risk of CV and VTE among patients with FXI deficiency compared with the general population.
10.1055/s-0041-1735971
Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling.
eLife
The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03-69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03-69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03-69. Transcription profiling identified the upregulation of proapoptotic gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03-69 led to an in vivo compatible compound MYF-03-176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.
10.7554/eLife.78810
10. Complex regional pain syndrome.
Pain practice : the official journal of World Institute of Pain
INTRODUCTION:Complex regional pain syndrome (CRPS) is a clinical disorder that can develop following surgery or trauma. Based on the most prominent underlying pathophysiological mechanisms, CRPS can be classified into different subtypes, namely inflammatory, nociplastic/neuropathic, vasomotor, and motor. Depending on the subtype, personalized treatment can be applied. If conservative treatments are insufficient or ineffective, more invasive treatments may be recommended. This article provides an overview of the most recent insights into CRPS and discusses the most common invasive treatments. METHODS:The literature regarding interventional treatments for CRPS has been systematically reviewed and summarized. RESULTS:Bisphosphonates are effective in treating the inflammatory subtype, while ketamine can provide pain relief for the nociplastic/neuropathic subtype. Sympathetic blocks are effective in addressing vasomotor disturbances. For patients with refractory symptoms, neurostimulation is a viable option due to its multimechanistic properties for all subtypes. End-of-line motor disturbances may benefit from intrathecal baclofen. CONCLUSIONS:CRPS is a debilitating condition with an unpredictable course. The effectiveness of treatment varies from patient to patient. When conservative approaches prove insufficient, gradual progression to invasive treatments based on the underlying subtype is recommended.
10.1111/papr.13413
Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses.
Blood
ABSTRACT:Outcomes are poor in triple-class-exposed (TCE) relapsed and refractory multiple myeloma (R/RMM). In the phase 3 KarMMa-3 trial, patients with TCE R/RMM and 2 to 4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary end point; 13.3 vs 4.4 months; P < .0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median was 41.4 (95% CI, 30.9 to not reached [NR]) vs 37.9 (95% CI, 23.4 to NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI, 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE R/RMM. This trial was registered at www.ClinicalTrials.gov as #NCT03651128.
10.1182/blood.2024024582
Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review.
Frontiers in immunology
TL1A, also called TNFSF15, is a member of tumor necrosis factor family. It is expressed in different immune cell, such as monocyte, macrophage, dendritic cell, T cell and non-immune cell, for example, synovial fibroblast, endothelial cell. TL1A competitively binds to death receptor 3 or decoy receptor 3, providing stimulatory signal for downstream signaling pathways, and then regulates proliferation, activation, apoptosis of and cytokine, chemokine production in effector cells. Recent findings showed that TL1A was abnormally expressed in autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, primary biliary cirrhosis, systemic lupus erythematosus and ankylosing spondylitis. and studies further demonstrated that TL1A was involved in development and pathogenesis of these diseases. In this study, we comprehensively discussed the complex immunological function of TL1A and focused on recent findings of the pleiotropic activity conducted by TL1A in inflammatory autoimmune disease. Finish of the study will provide new ideas for developing therapeutic strategies for these diseases by targeting TL1A.
10.3389/fimmu.2022.891328
Underutilization of Mineralocorticoid Antagonists in Patients With Heart Failure With Reduced Ejection Fraction.
Journal of the American College of Cardiology
BACKGROUND:It is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF). OBJECTIVES:In this study, we sought to evaluate the safety and efficacy of eplerenone according to duration of HFrEF. METHODS:In the EMPHASIS-HF trial, 3 patient groups were created according to HFrEF duration: <1 year, 1 to <5 years, and ≥5 years. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Outcomes were adjusted for prespecified prognostic variables and examined with the use of Cox regression models. RESULTS:The numbers of patients in each group were: 975, <1 year; 769, 1 to <5 years; and 988, ≥5 years. Patients with longer-standing HF were older and more frequently had cardiovascular and noncardiovascular comorbidities. The rate of the primary outcome (per 100 person-years) increased with HFrEF duration: 9.8 (95% CI: 8.4-11.4) for <1 year, 13.5 (95% CI: 11.6-15.7) for 1 to <5 years, and 17.6 (95% CI: 15.6-19.8) for ≥5 years. The benefits of eplerenone were consistent across HF duration: HRs for the primary outcome were 0.57 (95% CI: 0.42-0.79) for <1 year, 0.81 (95% CI: 0.60-1.10) for 1 to <5 years, and 0.61 (95% CI: 0.48-0.78) for ≥5 years; P = 0.24. The absolute benefit was greatest in the longest-duration group: the number needed to treat for the primary outcome was 14 for <1 year, 13 for 1 to <5 years, and 10 for ≥5 years duration. CONCLUSIONS:Patients with longer-standing HFrEF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent regardless of HFrEF duration. (A Comparison of Outcomes in Patients in NYHA Class II Heart Failure When Treated With Eplerenone or Placebo in Addition to Standard Heart Failure Medicines [EMPHASIS-HF]; NCT00232180).
10.1016/j.jacc.2023.06.021
Consistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs.
Nature communications
Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival as well as key differences between preclinical procurement and immunosuppression and clinical standards-of-care. Notably, no studies of solid organ pig-to-NHP transplantation have achieved xenograft survival longer than one month without CD40/CD154 costimulatory blockade, which is not currently an FDA-approved immunosuppression strategy. We now present consistent survival in consecutive cases of pig-to-NHP kidney xenotransplantation, including long-term survival after >3 hours of xenograft cold preservation time as well as long-term survival using FDA-approved immunosuppression. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation. Moreover, long-term survival without CD40/CD154 costimulatory blockade may provide important insights for immunosuppression regimens to be considered for first-in-human clinical trials.
10.1038/s41467-024-47679-6
Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model.
Proceedings of the National Academy of Sciences of the United States of America
Brain insulin signaling controls peripheral energy metabolism and plays a key role in the regulation of mood and cognition. Epidemiological studies have indicated a strong connection between type 2 diabetes (T2D) and neurodegenerative disorders, especially Alzheimer's disease (AD), linked via dysregulation of insulin signaling, i.e., insulin resistance. While most studies have focused on neurons, here, we aim to understand the role of insulin signaling in astrocytes, a glial cell type highly implicated in AD pathology and AD progression. To this end, we created a mouse model by crossing 5xFAD transgenic mice, a well-recognized AD mouse model that expresses five familial AD mutations, with mice carrying a selective, inducible insulin receptor (IR) knockout in astrocytes (iGIRKO). We show that by age 6 mo, iGIRKO/5xFAD mice exhibited greater alterations in nesting, Y-maze performance, and fear response than those of mice with the 5xFAD transgenes alone. This was associated with increased Tau (T231) phosphorylation, increased Aβ plaque size, and increased association of astrocytes with plaques in the cerebral cortex as assessed using tissue CLARITY of the brain in the iGIRKO/5xFAD mice. Mechanistically, in vitro knockout of IR in primary astrocytes resulted in loss of insulin signaling, reduced ATP production and glycolic capacity, and impaired Aβ uptake both in the basal and insulin-stimulated states. Thus, insulin signaling in astrocytes plays an important role in the control of Aβ uptake, thereby contributing to AD pathology, and highlighting the potential importance of targeting insulin signaling in astrocytes as a site for therapeutics for patients with T2D and AD.
10.1073/pnas.2220684120
HBV/HDV Co-Infection: Epidemiological and Clinical Changes, Recent Knowledge and Future Challenges.
Sagnelli Caterina,Sagnelli Evangelista,Russo Antonio,Pisaturo Mariantonietta,Occhiello Laura,Coppola Nicola
Life (Basel, Switzerland)
Several investigations have been published on Hepatitis Delta Virus (HDV) infection in recent years, from which we have drawn the salient data to provide readers with useful information to improve their knowledge on the subject. HDV genotypes 5-8 have been recently imported to Western countries from central Africa, whose clinical relevance deserves further investigation. Ongoing HDV replication has been identified as an independent predictor of progression to cirrhosis and HCC for patients with HDV chronic hepatitis (HDV-CH). Long-term treatments of HDV-CH with standard or pegylated interferon alfa (peg-IFN-α) have all been unsatisfactory, leading to a sustained virological response (SVR) only in 20-30% of patients treated, faced with a poor tolerability and frequent serious adverse reactions; the addition of HBV nucleo(s)tide analogues to peg-IFN- α did not improve the rate of SVR. The improved knowledge of the HDV life cycle has allowed the development of direct acting agents towards key-points of the HDV life cycle, namely bulevirtide, lonafarnib and nucleic acid polymers. Preliminary data have shown that these drugs are more effective than interferon-based therapies, but adverse reactions are also common, which however seem toned down in combination therapy with other antivirals.
10.3390/life11020169
Human Health and Ocean Pollution.
Annals of global health
Background:Pollution - unwanted waste released to air, water, and land by human activity - is the largest environmental cause of disease in the world today. It is responsible for an estimated nine million premature deaths per year, enormous economic losses, erosion of human capital, and degradation of ecosystems. Ocean pollution is an important, but insufficiently recognized and inadequately controlled component of global pollution. It poses serious threats to human health and well-being. The nature and magnitude of these impacts are only beginning to be understood. Goals:(1) Broadly examine the known and potential impacts of ocean pollution on human health. (2) Inform policy makers, government leaders, international organizations, civil society, and the global public of these threats. (3) Propose priorities for interventions to control and prevent pollution of the seas and safeguard human health. Methods:Topic-focused reviews that examine the effects of ocean pollution on human health, identify gaps in knowledge, project future trends, and offer evidence-based guidance for effective intervention. Environmental Findings:Pollution of the oceans is widespread, worsening, and in most countries poorly controlled. It is a complex mixture of toxic metals, plastics, manufactured chemicals, petroleum, urban and industrial wastes, pesticides, fertilizers, pharmaceutical chemicals, agricultural runoff, and sewage. More than 80% arises from land-based sources. It reaches the oceans through rivers, runoff, atmospheric deposition and direct discharges. It is often heaviest near the coasts and most highly concentrated along the coasts of low- and middle-income countries. Plastic is a rapidly increasing and highly visible component of ocean pollution, and an estimated 10 million metric tons of plastic waste enter the seas each year. Mercury is the metal pollutant of greatest concern in the oceans; it is released from two main sources - coal combustion and small-scale gold mining. Global spread of industrialized agriculture with increasing use of chemical fertilizer leads to extension of Harmful Algal Blooms (HABs) to previously unaffected regions. Chemical pollutants are ubiquitous and contaminate seas and marine organisms from the high Arctic to the abyssal depths. Ecosystem Findings:Ocean pollution has multiple negative impacts on marine ecosystems, and these impacts are exacerbated by global climate change. Petroleum-based pollutants reduce photosynthesis in marine microorganisms that generate oxygen. Increasing absorption of carbon dioxide into the seas causes ocean acidification, which destroys coral reefs, impairs shellfish development, dissolves calcium-containing microorganisms at the base of the marine food web, and increases the toxicity of some pollutants. Plastic pollution threatens marine mammals, fish, and seabirds and accumulates in large mid-ocean gyres. It breaks down into microplastic and nanoplastic particles containing multiple manufactured chemicals that can enter the tissues of marine organisms, including species consumed by humans. Industrial releases, runoff, and sewage increase frequency and severity of HABs, bacterial pollution, and anti-microbial resistance. Pollution and sea surface warming are triggering poleward migration of dangerous pathogens such as the species. Industrial discharges, pharmaceutical wastes, pesticides, and sewage contribute to global declines in fish stocks. Human Health Findings:Methylmercury and PCBs are the ocean pollutants whose human health effects are best understood. Exposures of infants to these pollutants through maternal consumption of contaminated seafood can damage developing brains, reduce IQ and increase children's risks for autism, ADHD and learning disorders. Adult exposures to methylmercury increase risks for cardiovascular disease and dementia. Manufactured chemicals - phthalates, bisphenol A, flame retardants, and perfluorinated chemicals, many of them released into the seas from plastic waste - can disrupt endocrine signaling, reduce male fertility, damage the nervous system, and increase risk of cancer. HABs produce potent toxins that accumulate in fish and shellfish. When ingested, these toxins can cause severe neurological impairment and rapid death. HAB toxins can also become airborne and cause respiratory disease. Pathogenic marine bacteria cause gastrointestinal diseases and deep wound infections. With climate change and increasing pollution, risk is high that infections, including cholera, will increase in frequency and extend to new areas. All of the health impacts of ocean pollution fall disproportionately on vulnerable populations in the Global South - environmental injustice on a planetary scale. Conclusions:Ocean pollution is a global problem. It arises from multiple sources and crosses national boundaries. It is the consequence of reckless, shortsighted, and unsustainable exploitation of the earth's resources. It endangers marine ecosystems. It impedes the production of atmospheric oxygen. Its threats to human health are great and growing, but still incompletely understood. Its economic costs are only beginning to be counted.Ocean pollution can be prevented. Like all forms of pollution, ocean pollution can be controlled by deploying data-driven strategies based on law, policy, technology, and enforcement that target priority pollution sources. Many countries have used these tools to control air and water pollution and are now applying them to ocean pollution. Successes achieved to date demonstrate that broader control is feasible. Heavily polluted harbors have been cleaned, estuaries rejuvenated, and coral reefs restored.Prevention of ocean pollution creates many benefits. It boosts economies, increases tourism, helps restore fisheries, and improves human health and well-being. It advances the Sustainable Development Goals (SDG). These benefits will last for centuries. Recommendations:World leaders who recognize the gravity of ocean pollution, acknowledge its growing dangers, engage civil society and the global public, and take bold, evidence-based action to stop pollution at source will be critical to preventing ocean pollution and safeguarding human health.Prevention of pollution from land-based sources is key. Eliminating coal combustion and banning all uses of mercury will reduce mercury pollution. Bans on single-use plastic and better management of plastic waste reduce plastic pollution. Bans on persistent organic pollutants (POPs) have reduced pollution by PCBs and DDT. Control of industrial discharges, treatment of sewage, and reduced applications of fertilizers have mitigated coastal pollution and are reducing frequency of HABs. National, regional and international marine pollution control programs that are adequately funded and backed by strong enforcement have been shown to be effective. Robust monitoring is essential to track progress.Further interventions that hold great promise include wide-scale transition to renewable fuels; transition to a circular economy that creates little waste and focuses on equity rather than on endless growth; embracing the principles of green chemistry; and building scientific capacity in all countries.Designation of Marine Protected Areas (MPAs) will safeguard critical ecosystems, protect vulnerable fish stocks, and enhance human health and well-being. Creation of MPAs is an important manifestation of national and international commitment to protecting the health of the seas.
10.5334/aogh.2831
A fluoroscopic grid in supine total hip arthroplasty: improving cup position, limb length, and hip offset.
Gililland Jeremy M,Anderson Lucas A,Boffeli Shannon L,Pelt Christopher E,Peters Christopher L,Kubiak Erik N
The Journal of arthroplasty
We hypothesized that use of a novel fluoroscopic grid would decrease operative time and component positioning variability during anterior supine total hip arthroplasty (THA). We reviewed 99 anterior supine THAs: 39 using a fluoroscopic grid, and 60 using fluoroscopy alone. Goals were cup abduction of 40° ± 10° and limb length and hip offset within 10 mm of the contralateral side. Surgical time was decreased in the study group (79 vs 94 minutes, P = .002). In the study group, more components met the goal for cup abduction (97% vs 83%, P = .046), limb length (100% vs 88%, P = .04), hip offset (85% vs 67%, P = .047), and all 3 combined (82% vs 52%, P = .002). We demonstrated decreased component positioning variability during anterior supine THA with assistance of a fluoroscopic grid.
10.1016/j.arth.2012.03.027
2020 White Paper on Recent Issues in Bioanalysis: Vaccine Assay Validation, qPCR Assay Validation, QC for CAR-T Flow Cytometry, NAb Assay Harmonization and ELISpot Validation ( - Recommendations on Immunogenicity Assay Strategies, NAb Assays, Biosimilars and FDA/EMA Immunogenicity Guidance/Guideline, Gene & Cell Therapy and Vaccine Assays).
Corsaro Bart,Yang Tong-Yuan,Murphy Rocio,Sonderegger Ivo,Exley Andrew,Bertholet Sylvie,Dakappagari Naveen,Dessy Francis,Garofolo Fabio,Kierstead Lisa,Koch Holger,Sarikonda Ghanashyam,Savoie Natasha,Siggers Richard,Solstad Therese,Lu Yanmei,Milton Mark,Marshall Jean-Claude,DelCarpini Jason,Gorovits Boris,Gupta Swati,Jesaitis Lynne,Kamerud John,Kromminga Arno,Ma Anna,McNally Jim,Yan Haoheng,Wu Bonnie,Verthelyi Daniela,Kirshner Susan,Pedras-Vasconcelos Joao,Rajadhyaksha Manoj,Staack Roland F,Cherry Elana,Cludts Isabelle,Dahlbäck Madeleine,Gunn George R,Ishii-Watabe Akiko,Jawa Vibha,Kubiak Robert,Partridge Michael,Petrillo Marco,Pine Samuel O,Poetzl Johann,Song Sam,Stebbins Chris,Wu Yuling,Zhang Lucia,Kar Sumit,Liang Meina,Abhari Mohsen Rajabi,Schweighardt Becky,Stubenrauch Kay,Xu Yuanxin
Bioanalysis
The 14 edition of the Workshop on Recent Issues in Bioanalysis (14 WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14 WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by LCMS were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations on Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity). Part 1 (Innovation in Small Molecules, Hybrid LBA/LCMS & Regulated Bioanalysis), Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation) and Part 2B (Regulatory Input) are published in volume 13 of Bioanalysis, issues 4 and 5 (2020), respectively.
10.4155/bio-2021-0007
The 32nd Annual J.P. Morgan Healthcare Conference (January 13-16, 2014 - San Francisco, California, USA): Auxilium Pharmaceuticals.
Watt J
Drugs of today (Barcelona, Spain : 1998)
CEO and President Adrian Adams described Auxilium Pharmaceuticals as "the same as a Big Pharma company, only smaller." This 'specialty biopharmaceutical company' has transformed itself in the last 6 to 9 months to become the "leading men's healthcare franchise with a broad and diverse product portfolio." All of this has led to a very busy 2013, which began with the USD 600 million acquisition (Q2) and integration of Actient Pharmaceuticals, the licensing of avanafil (Stendra™) for erectile dysfunction and ended with the approval of collagenase Clostridium histolyticum (Xiaflex®) in Peyronie's disease. From a portfolio of 2 products at the beginning of 2013, Auxilium ended the year with 12.
10.1358/dot.2014.50.3.2134449
Efficacy of a -Based Vaginal Gel in Human Papillomavirus-Positive Women Older Than 40 Years: A Sub-Analysis of PALOMA Study.
Journal of personalized medicine
In the PALOMA trial, Papilocare demonstrated efficacy in repairing low-grade cervical lesions related to human papillomavirus (HPV). This sub-analysis aimed to evaluate its efficacy in repairing these cervical lesions and clearing HPV in women aged older than 40 years. This was a multicenter, randomized, open-label, parallel-group, controlled clinical trial. Patients with low-degree HPV-dependent cervical lesions receiving 6-month treatment with the vaginal gel were compared to those with a watchful waiting approach. Among the 41 women analyzed (aged 47.7 years), 31 presented high-risk (HR) oncogenic HPV subtypes, and 14 had 16-18-31 HPV genotypes. After 6 months, normalized cytology and concordant colposcopy were achieved by a greater percentage of treated women. The difference was significant in the total population (92.3% vs. 50.0%, = 0.007), and HR-HPV subpopulation (90.5% vs. 33.3%, = 0.003). In the HR HPVs-16-18-31 subpopulation, the values were 75.0% and 40.0% ( = 0.293). In the total population, 61.5% of treated patients obtained HPV clearance, compared to 50.0% in the control group. Regarding the HR-HPV subpopulation, these values were 66.7% and 44.4%, respectively. Papilocare demonstrated significant efficacy in repairing low-degree HPV-related cervical lesions and a positive trend to clear HPV in women older than 40 years old in comparison to the watchful waiting approach.
10.3390/jpm12101559
: Safe harbor landing sites for reproducible and efficient transgenesis in zebrafish.
bioRxiv : the preprint server for biology
Standard methods for transgenesis in zebrafish depend on random transgene integration into the genome followed by resource-intensive screening and validation. Targeted vector integration into validated genomic loci using phiC31 integrase-based / recombination has transformed mouse and transgenesis. However, while the phiC31 system functions in zebrafish, validated loci carrying -based landing or safe harbor sites suitable for universal transgenesis applications in zebrafish have not been established. Here, using CRISPR-Cas9, we converted two well-validated single insertion -based zebrafish transgenes with long-standing genetic stability into two landing sites, called (). Generating fluorescent reporters, -based Switch lines, CreERT2 drivers, and gene-regulatory variant reporters in the and landing site alleles, we document their suitability for transgenesis applications across cell types and developmental stages. For both landing sites, we routinely achieve 25-50% germline transmission of targeted transgene integrations, drastically reducing the number of required animals and necessary resources to generate individual transgenic lines. We document that phiC31 integrase-based transgenesis into and reproducibly results in representative reporter expression patterns in injected F0 zebrafish embryos suitable for enhancer discovery and qualitative and quantitative comparison of gene-regulatory element variants. Taken together, our new phiC31 integrase-based transgene landing sites establish reproducible, targeted zebrafish transgenesis for numerous applications while greatly reducing the workload of generating new transgenic zebrafish lines.
10.1101/2023.12.08.570868
Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study.
The Lancet. Oncology
BACKGROUND:HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification. METHODS:This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing. FINDINGS:Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%] of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients; all grade 1-2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths. INTERPRETATION:These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies. FUNDING:Zymeworks.
10.1016/S1470-2045(22)00621-0
Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet (London, England)
BACKGROUND:Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. METHODS:In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). FINDINGS:Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. INTERPRETATION:Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. FUNDING:Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.
10.1016/S0140-6736(23)01724-5
Prevalence of cancer survivors in the United States.
Journal of the National Cancer Institute
BACKGROUND:With aging of the population and improvements in diagnosis, treatment, and supportive care, the number of cancer survivors in the United States has increased; updated prevalence estimates are needed. METHODS:Cancer prevalence on January 1, 2022, was estimated using the Prevalence Incidence Approach Model, utilizing incidence, survival, and mortality. Prevalence by age decade, sex, and time from diagnosis was calculated. The percentage of cancer survivors in the projected US population by age and sex was calculated as the ratio of the sex-specific projected prevalence to the sex-specific projected US population. RESULTS:There were an estimated 18.1 million US cancer survivors as of January 1, 2022. From 2022 to 2030, the number of US cancer survivors is projected to increase to 21.6 million; by 2040, the number is projected to be 26 million. Long-term survivors are highly prevalent; in 2022, 70% of cancer survivors had lived 5 years or more after diagnosis, and 11% of cancer survivors had lived 25 years or more after diagnosis. Among all US females aged 40-54 years, 3.6% were cancer survivors; among females aged 65-74 years, 14.5% were cancer survivors; among females aged 85 years and older, 36.4% were cancer survivors. Among all US males aged 40-54 years, 2.1% were cancer survivors; among males aged 65-74 years, 16% were cancer survivors; and among those aged 85 years and older, 48.3% were cancer survivors. CONCLUSIONS:Cancer survivors are growing in number. In the United States, most cancer survivors are long-term and very long-term survivors, representing a substantial proportion of the US population.
10.1093/jnci/djae135
Hydrocortisone in Severe Community-Acquired Pneumonia.
The New England journal of medicine
BACKGROUND:Whether the antiinflammatory and immunomodulatory effects of glucocorticoids may decrease mortality among patients with severe community-acquired pneumonia is unclear. METHODS:In this phase 3, multicenter, double-blind, randomized, controlled trial, we assigned adults who had been admitted to the intensive care unit (ICU) for severe community-acquired pneumonia to receive intravenous hydrocortisone (200 mg daily for either 4 or 7 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) or to receive placebo. All the patients received standard therapy, including antibiotics and supportive care. The primary outcome was death at 28 days. RESULTS:A total of 800 patients had undergone randomization when the trial was stopped after the second planned interim analysis. Data from 795 patients were analyzed. By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006). Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 40 of 222 (18.0%) in the hydrocortisone group and in 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among the patients who were not receiving vasopressors at baseline, such therapy was initiated by day 28 in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25.0%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82). The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups; patients in the hydrocortisone group received higher daily doses of insulin during the first week of treatment. CONCLUSIONS:Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).
10.1056/NEJMoa2215145
Pulsed electric field technology in vegetable and fruit juice processing: A review.
Food research international (Ottawa, Ont.)
The worldwide market for vegetable and fruit juices stands as a thriving sector with projected revenues reaching to $81.4 billion by 2024 and an anticipated annual growth rate of 5.27% until 2028. Juices offer a convenient means of consuming bioactive compounds and essential nutrients crucial for human health. However, conventional thermal treatments employed in the juice and beverage industry to inactivate spoilage and pathogenic microorganisms, as well as endogenous enzymes, can lead to the degradation of bioactive compounds and vitamins. In response, non-thermal technologies have emerged as promising alternatives to traditional heat processing, with pulsed electric field (PEF) technology standing out as an innovative and sustainable choice. In this context, this comprehensive review investigated the impact of PEF on the microbiological, physicochemical, functional, nutritional, and sensory qualities of vegetable and fruit juices. PEF induces electroporation phenomena in cell membranes, resulting in reversible or irreversible changes. Consequently, a detailed examination of the effects of PEF process variables on juice properties is essential. Monitoring factors such as electric field strength, frequency, pulse width, total treatment time, and specific energy is important to ensure the production of a safe and chemically/kinetically stable product. PEF technology proves effective in microbial and enzymatic inactivation within vegetable and fruit juices, mitigating factors contributing to deterioration while maintaining the physicochemical characteristics of these products. Furthermore, PEF treatment does not compromise the content of substances with functional, nutritional, and sensory properties, such as phenolic compounds and vitamins. When compared to alternative processing methods, such as mild thermal treatments and other non-thermal technologies, PEF treatment consistently demonstrates comparable outcomes in terms of physicochemical attributes, functional properties, nutritional quality, and overall safety.
10.1016/j.foodres.2024.114207
Acute Optic Neuritis: An Update on Approach and Management.
Journal of ophthalmic & vision research
This review discusses the physical examination and diagnostic tests necessary to diagnose optic neuritis (ON) and provides an update on the approach and management of acute ON. A comprehensive search of the PubMed database was conducted, limited to English-language journals and recent publications. A total of 160 articles were initially screened by title, of which 73 articles were included in the narrative synthesis. ON is an inflammation of the optic nerve that can be caused by different systemic and neurological disorders. It is commonly presented as a subacute unilateral painful vision loss, and based on its clinical manifestation, it can be classified as typical or atypical. Atypical ON is bilateral with visual acuity of worse than 20/200 or has an atypical demographic presentation for demyelination, such as a non-Caucasian male with optic disc swelling, for which neuromyelitis optica spectrum disorder (NMOSD), myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), or other etiologies should be considered. Steroids and immunosuppressants are the main treatment options for ON, and timely treatment initiation is critical to preventing irreversible vision loss, especially in atypical cases.
10.18502/jovr.v18i4.14556
Early Breast Cancer Detection Using Untargeted and Targeted Metabolomics.
Wei Yiping,Jasbi Paniz,Shi Xiaojian,Turner Cassidy,Hrovat Jonathon,Liu Li,Rabena Yuri,Porter Peggy,Gu Haiwei
Journal of proteome research
Breast cancer (BC) is a common cause of morbidity and mortality, particularly in women. Moreover, the discovery of diagnostic biomarkers for early BC remains a challenging task. Previously, we [Jasbi et al. 2019, 1105, 26-37] demonstrated a targeted metabolic profiling approach capable of identifying metabolite marker candidates that could enable highly sensitive and specific detection of BC. However, the coverage of this targeted method was limited and exhibited suboptimal classification of early BC (EBC). To expand the metabolome coverage and articulate a better panel of metabolites or mass spectral features for classification of EBC, we evaluated untargeted liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) data, both individually as well as in conjunction with previously published targeted LC-triple quadruple (QQQ)-MS data. Variable importance in projection scores were used to refine the biomarker panel, whereas orthogonal partial least squares-discriminant analysis was used to operationalize the enhanced biomarker panel for early diagnosis. In this approach, 33 altered metabolites/features were detected by LC-QTOF-MS from 124 BC patients and 86 healthy controls. For EBC diagnosis, significance testing and analysis of the area under receiver operating characteristic (AUROC) curve identified six metabolites/features [ethyl ()-3-hydroxyhexanoate; caprylic acid; hypoxanthine; and 358.0018, 354.0053, and 356.0037] with < 0.05 and AUROC > 0.7. These metabolites informed the construction of EBC diagnostic models; evaluation of model performance for the prediction of EBC showed an AUROC = 0.938 (95% CI: 0.895-0.975), with sensitivity = 0.90 when specificity = 0.90. Using the combined untargeted and targeted data set, eight metabolic pathways of potential biological relevance were indicated to be significantly altered as a result of EBC. Metabolic pathway analysis showed fatty acid and aminoacyl-tRNA biosynthesis as well as inositol phosphate metabolism to be most impacted in response to the disease. The combination of untargeted and targeted metabolomics platforms has provided a highly predictive and accurate method for BC and EBC diagnosis from plasma samples. Furthermore, such a complementary approach yielded critical information regarding potential pathogenic mechanisms underlying EBC that, although critical to improved prognosis and enhanced survival, are understudied in the current literature. All mass spectrometry data and deidentified subject metadata analyzed in this study have been deposited to Mendeley Data and are publicly available (DOI: 10.17632/kcjg8ybk45.1).
10.1021/acs.jproteome.1c00019
Pediatric low-grade gliomas.
Journal of child neurology
Pediatric low-grade gliomas encompass a heterogeneous set of tumors of different histologies. Cerebellar pilocytic astrocytomas occur most frequently followed by supratentorial diffuse fibrillary astrocytomas. Recent research has implicated activation of the RAS/RAF/MEK pathway in tumorigenesis of these tumors. Surgery is the mainstay of therapy. Overall survival rates for patients whose tumors are completely resected are 90% or greater, 10 years from diagnosis. Conversely, most optic pathway/hypothalamic, deep midline, and brain stem gliomas have minimal potential for resection; these tumors can be difficult to treat and deserve special attention. Combination chemotherapy is currently recommended as front-line adjuvant treatment for progressive or recurrent tumors. Second-line radiotherapy can also improve overall survival but is associated with more frequent and significant neurocognitive, endocrine, and other long-term toxicities.
10.1177/0883073809342005
Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial.
Nature medicine
For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.
10.1038/s41591-024-02808-y
Management of Mechanical Prosthetic Heart Valve Thrombosis: JACC Review Topic of the Week.
Journal of the American College of Cardiology
Mechanical prosthetic heart valves, though more durable than bioprostheses, are more thrombogenic and require lifelong anticoagulation. Mechanical valve dysfunction can be caused by 4 main phenomena: 1) thrombosis; 2) fibrotic pannus ingrowth; 3) degeneration; and 4) endocarditis. Mechanical valve thrombosis (MVT) is a known complication with clinical presentation ranging from incidental imaging finding to cardiogenic shock. Thus, a high index of suspicion and expedited evaluation are essential. Multimodality imaging, including echocardiography, cine-fluoroscopy, and computed tomography, is commonly used to diagnose MVT and follow treatment response. Although surgery is oftentimes required for obstructive MVT, other guideline-recommended therapies include parenteral anticoagulation and thrombolysis. Transcatheter manipulation of stuck mechanical valve leaflet is another treatment option for those with contraindications to thrombolytic therapy or prohibitive surgical risk or as a bridge to surgery. The optimal strategy depends on degree of valve obstruction and the patient's comorbidities and hemodynamic status on presentation.
10.1016/j.jacc.2023.03.412
Clinical application of planar puncture template-assisted computed tomography-guided percutaneous biopsy for small pulmonary nodules.
Ji Zhe,Wang Guan,Chen Baoming,Zhang Yuwei,Zhang Li,Gao Fuchun,Chai Shude,Huo Bin,Zheng Guangjun,Huo Xiaodong,Wang Baoming,Zhu Xudong,Meng Dan,Liu Lejun,Zhu Rui,Han Mingyong,Zhang Ying,Zhang Kaixian,Wang Junjie
Journal of cancer research and therapeutics
AIMS:The aims of this study were to evaluate the clinical application of planar puncture template (PPT) in computed tomography (CT)-guided percutaneous needle lung biopsy. SUBJECTS AND METHODS:A total of 56 patients with small pulmonary nodules who received CT-guided percutaneous lung biopsy assisted by PPT were included in the study. Five steps were included in the study: fixing position, CT scanning and designing needle pathway, installing navigation system and template, puncturing fixation needle, and performing biopsy needle insertion and biopsy. The success rate of puncture, pathological results, and complications were analyzed. In addition, the factors that influenced the success rate and complications were analyzed. RESULTS:Biopsy was successfully completed in all 56 patients. The nodule diameter was 0.45-3 cm. The fixation needle technique was applied in 47 cases. Biopsy was performed 1 time in 50% of patients and 2 times in 38% of patients. For pathology, only one case showed no positive result, with a puncture success rate of 98%. The diagnostic rate of malignant tumor was 73%. For complications, the incidence of needle tract bleeding was 68%, the incidence of pneumothorax was 30%, and the thoracic drainage was required in two patients. Hemoptysis was observed in two cases. Univariate analysis: The nodule size was related to both the rate of 1-time biopsy and incidence of complications. Smaller nodule was relevant to lower rate of 1-time biopsy (P = 0.01) and higher incidence of complications (P < 0.05). The fixation needle was related to 1-time biopsy rate. The 1-time biopsy rate was significantly higher in patients with fixation needle than those without fixation needle (P = 0.001). Meanwhile, no significant difference was observed in the incidence of complications in different number of fixation needles (P > 0.05). CONCLUSIONS:PPT-assisted lung biopsy technology can provide high success rate and low complication incidence. It would be helpful to make the puncture procedures more standard for better clinical applications.
10.4103/jcrt.JCRT_1017_17
A first-in-human, randomized study of the safety, pharmacokinetics and pharmacodynamics of povetacicept, an enhanced dual BAFF/APRIL antagonist, in healthy adults.
Clinical and translational science
Therapeutic agents targeting the tumor necrosis factor (TNF) superfamily cytokines B-cell activating factor (BAFF, BLyS) and/or A PRoliferation Inducing Ligand (APRIL) have demonstrated clinical effectiveness in multiple autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis, and immunoglobulin A nephropathy (IgAN). However, their clinical utility can often be limited by incomplete and/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN-303; TACI vTD-Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild-type TACI-Fc or BAFF- or APRIL-specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models. In this first-in-human study in healthy adults, povetacicept was well-tolerated as single ascending doses of up to 960 mg administered intravenously or subcutaneously. Dose-dependent pharmacokinetics were observed. Coverage of BAFF and APRIL was observed for 2-3 weeks and ≥4 weeks after doses of 80 mg and ≥240 mg, respectively. Maximal pharmacodynamic effects were observed at dose levels ≥80 mg for a single dose, associated with on-target reductions in antibody-secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease-related biomarker galactose-deficient-immunoglobulin A1 (Gd-IgA1), and were superior to results reported for wild-type TACI-Fc. These data strongly support further development of povetacicept for the treatment of B-cell-mediated automimmune diseases.
10.1111/cts.70055
Durvalumab With or Without Tremelimumab in Combination With Chemotherapy in First-Line Metastatic NSCLC: Five-Year Overall Survival Outcomes From the Phase 3 POSEIDON Trial.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
INTRODUCTION:The primary analysis (median follow-up 34.9 mo across all arms) of the phase 3 POSEIDON study revealed a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR and ALK wild-type metastatic NSCLC (mNSCLC). D+CT had a trend for OS improvement versus CT that did not reach statistical significance. This article reports prespecified OS analyses after long-term follow-up (median >5 y). METHODS:A total of 1013 patients were randomized (1:1:1) to T+D+CT, D+CT, or CT, stratified by tumor cell programmed cell death ligand-1 (PD-L1) expression (≥50% versus <50%), disease stage (IVA versus IVB), and tumor histologic type (squamous versus nonsquamous). Serious adverse events were collected during follow-up. RESULTS:After a median follow-up of 63.4 months across all arms, T+D+CT had sustained OS benefit versus CT (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.64-0.89; 5-y OS: 15.7% versus 6.8%). OS improvement with D+CT versus CT (HR = 0.84, 95% CI: 0.72-1.00; 5-y OS: 13.0%) was consistent with the primary analysis. OS benefit with T+D+CT versus CT remained more pronounced in nonsquamous (HR = 0.69, 95% CI: 0.56-0.85) versus squamous (HR = 0.85, 95% CI: 0.65-1.10) mNSCLC. OS benefit with T+D+CT versus CT was still evident regardless of PD-L1 expression, including patients with PD-L1 tumor cell less than 1%, and remained evident in STK11-mutant (nonsquamous), KEAP1-mutant, and KRAS-mutant (nonsquamous) mNSCLC. No new safety signals were identified. CONCLUSIONS:After a median follow-up of more than 5 years, T+D+CT had durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease.
10.1016/j.jtho.2024.09.1381
Assembling the climate story: use of storyline approaches in climate-related science.
Global challenges (Hoboken, NJ)
Storylines are introduced in climate science to provide unity of discourse, integrate the physical and socioeconomic components of phenomena, and make climate evolution more tangible. The use of this concept by multiple scholar communities and the novelty of some of its applications renders the concept ambiguous nonetheless, because the term hides behind a wide range of purposes, understandings, and methodologies. This semi-systematic literature review identifies three approaches that use storylines as a keystone concept: scenarios-familiar for their use in IPCC reports-discourse-analytical approaches, and physical climate storylines. After screening peer-reviewed articles that mention climate and storylines, 270 articles are selected, with 158, 55, and 57 in each category. The results indicate that each scholarly community works with a finite and different set of methods and diverging understandings. Moreover, these approaches have received criticism in their assembly of storylines: either for lacking explicitness or for the homogeneity of expertise involved. This article proposes that cross-pollination among the approaches can improve the usefulness and usability of climate-related storylines. Among good practices are the involvement of a broader range of scientific disciplines and expertise, use of mixed-methods, assessment of storylines against a wider set of quality criteria, and targeted stakeholder participation in key stages of the process.
10.1002/gch2.202200183
Sustained growth-promoting effects of vosoritide in children with achondroplasia from an ongoing phase 3 extension study.
Med (New York, N.Y.)
BACKGROUND:Vosoritide is a C-type natriuretic peptide analog that addresses an underlying pathway causing reduced bone growth in achondroplasia. Understanding the vosoritide treatment effect requires evaluation over an extended duration and comparison with outcomes in untreated children. METHODS:After completing ≥6 months of a baseline observational growth study and 52 weeks in a double-blind, placebo-controlled study (ClinicalTrials.gov: NCT03197766), participants were eligible to continue treatment in an open-label extension (ClinicalTrials.gov: NCT03424018) wherein all received 15 μg/kg vosoritide daily. Data from the CLARITY achondroplasia study provided an external untreated control population and reference data. FINDINGS:The population comprised 119 participants. Annualized growth velocity with vosoritide was similar to the average-stature population before puberty. The mean (SD) differences in annualized growth velocity across each integer age (6-16 years) between treated and untreated children were 1.84 (0.38) cm/year in boys and 1.44 (0.63) cm/year in girls. Three-year comparisons of treated versus untreated children demonstrated an additional height gain of 5.75 cm (95% confidence interval [CI]: 4.93, 6.57) with vosoritide. A significant improvement in upper-to-lower body segment ratio at 3 years of treatment was observed for participants with assessments at age <11 (females) and <12 years (males) versus population-level, age-matched, untreated controls (p = 0.0087). The arm span-to-standing height ratio remained consistent with untreated participants. Vosoritide had a favorable safety profile with continuous treatment for up to 6 years (464.05 person years of exposure). No long-term harms or deaths were observed. CONCLUSIONS:Vosoritide treatment was well tolerated and had sustained growth-promoting effects in children with achondroplasia treated for up to 6 years. FUNDING:This work was funded by BioMarin Pharmaceutical.
10.1016/j.medj.2024.11.019
Durability of Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Booster Vaccine Protection Against Omicron Among Healthcare Workers With a Vaccine Mandate.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
BACKGROUND:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has spread rapidly throughout the world since being identified in South Africa in November 2021. Few studies have assessed primary series and booster vaccine effectiveness against Omicron among US healthcare workers. METHODS:We conducted a test-negative case-control design to estimate BNT162b2 and mRNA1273 primary vaccination and booster effectiveness against SARS-CoV-2 infection and symptomatic coronavirus disease 2019 during an Omicron surge among employees of the University of Pennsylvania Health System. The study period was between 1 July 2021 and 5 April 2022. We defined the Delta period as 1 July to 12 December 2021 and the Omicron period as beginning 12 December 21. RESULTS:Our sample included 14 520 tests (2776 [19%] positive)-7422 (506 [7%] positive) during Delta and 7098 (2270 [32%] positive) during Omicron. Benchmarked against Delta, the vaccine effectiveness of 2 vaccine doses was lower during Omicron, with no significant protection against infection. Booster doses added significant protection, although they also showed reduced effectiveness during Omicron. Compared with findings in employees who had received 2 vaccine doses, 3 doses of BNT162b2 had a relative effectiveness of 50% (95% confidence interval, 42%-56%) during Omicron, relative to 78% (63%-87%) during Delta; 3 doses of mRNA1273 had a relative effectiveness of 56% (45%-65%) during Omicron, relative to 96% (82%-99%) during Delta. Restricting the sample to symptomatic tests yielded similar results to our primary analysis. After initial waning in BNT162b2 booster protection against infection, it remained largely stable for ≥16 weeks after vaccination. CONCLUSIONS:Our findings provide a strong rationale for boosters among healthcare workers in the Omicron era.
10.1093/cid/ciac454
Fifty ways to improve presentations in urology.
Monzó Gardiner J I,Secin F P,González Enguita C
Actas urologicas espanolas
BACKGROUND:Our profession permanently demands intercommunication of medical knowledge among colleagues; either in small environments such as hospitals or at larger ones such as congresses or academic courses. New technologies such as PowerPoint® are not developed enough to provide good presentations, and its employment does not always grant effective results. OBJECTIVE:In order to improve our academic presentations, we present several tools that may help us avoid the most common mistakes. EVIDENCE ACQUISITION:Literature search in PubMed and Google Scholar. We have divided the analysis into 3 sections: structure of the presentation, slide design, presentation to the audience. Each section includes a list of 50 short tips. RESULTS:Fifty tips following the study objectives. CONCLUSIONS:The scientific evidence that supports the information on how to improve presentations is mostly based on expert opinions. However, almost every work agrees that presentations must use simple structures which does not make them less scientific; their content must be developed for a specific audience, and it must be the speaker, not the slides, who captures the audience attention. Making a simple and didactic presentation of complex content supported by multimedia tools is one of the speaker's highest intellectual challenges of these days.
10.1016/j.acuro.2019.08.001
The scientific basis of combination therapy for chronic hepatitis B functional cure.
Nature reviews. Gastroenterology & hepatology
Functional cure of chronic hepatitis B (CHB) - or hepatitis B surface antigen (HBsAg) loss after 24 weeks off therapy - is now the goal of treatment, but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories: those that reduce viral replication, those that reduce antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleos(t)ide analogues and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, rationale exists for the use of combinations of all three therapy types. Monitoring during therapy is important not just to predict HBsAg loss but also to understand mechanisms of HBsAg loss using viral and immunological biomarkers, and in selected cases intrahepatic sampling. We consider various paths to functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available.
10.1038/s41575-022-00724-5
A whole-slide foundation model for digital pathology from real-world data.
Nature
Digital pathology poses unique computational challenges, as a standard gigapixel slide may comprise tens of thousands of image tiles. Prior models have often resorted to subsampling a small portion of tiles for each slide, thus missing the important slide-level context. Here we present Prov-GigaPath, a whole-slide pathology foundation model pretrained on 1.3 billion 256 × 256 pathology image tiles in 171,189 whole slides from Providence, a large US health network comprising 28 cancer centres. The slides originated from more than 30,000 patients covering 31 major tissue types. To pretrain Prov-GigaPath, we propose GigaPath, a novel vision transformer architecture for pretraining gigapixel pathology slides. To scale GigaPath for slide-level learning with tens of thousands of image tiles, GigaPath adapts the newly developed LongNet method to digital pathology. To evaluate Prov-GigaPath, we construct a digital pathology benchmark comprising 9 cancer subtyping tasks and 17 pathomics tasks, using both Providence and TCGA data. With large-scale pretraining and ultra-large-context modelling, Prov-GigaPath attains state-of-the-art performance on 25 out of 26 tasks, with significant improvement over the second-best method on 18 tasks. We further demonstrate the potential of Prov-GigaPath on vision-language pretraining for pathology by incorporating the pathology reports. In sum, Prov-GigaPath is an open-weight foundation model that achieves state-of-the-art performance on various digital pathology tasks, demonstrating the importance of real-world data and whole-slide modelling.
10.1038/s41586-024-07441-w