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Background: First-line treatment with pembrolizumab plus chemotherapy in recurrent and metastatic head and neck squamous cell carcinomas (HNSCC) has improved survival. However, the overall response rate with this standard of care regimen (SOC) remains limited. Interleukin (IL)-12 is a potent cytokine that facilitates the crosstalk between innate and adaptive immunity, making it crucial in the antitumor response. Alum-anchored murine IL-12 (mANK-101) has been demonstrated to elicit robust antitumor responses in diverse syngeneic models, which were correlated with increased immune effector functions and prolonged local retention of IL-12. This study investigates the therapeutic benefit of combining mANK-101 with SOC in the MOC1 and MOC2 murine HNSCC tumor models., Methods: MOC1 and MOC2 tumor-bearing C57BL/6 mice were administered with a single intratumoral injection of mANK-101 and weekly intraperitoneal injections of cisplatin and α-programmed death 1 (PD-1) for 3 weeks. For MOC1, flow cytometry and cytokine array were performed to assess the immune effector functions associated with the combinational treatment. Multiplex immunofluorescence was employed to characterize the influence of the treatment on the immune architecture in the tumors. RNA analysis was implemented for in-depth examination of the macrophage and effector populations., Results: In the MOC1 and MOC2 models, combination therapy with mANK-101, cisplatin, and α-PD-1 resulted in superior tumor growth inhibition and resulted in the highest rate of tumor-free survival when compared with treatment cohorts that received mANK-101 monotherapy or SOC treatment with α-PD-1 plus cisplatin. Furthermore, the combination therapy protected against tumor re-growth on rechallenge and controlled the growth of distal tumors. The improved therapeutic effect was associated with increased CD8 + T-cell recruitment, increased CD8 + and CD4 + activity, and repolarization of the macrophage population from M2 to M1 at the tumor site. Elevated and prolonged interferon-γ expression is central to the antitumor activity mediated by the combination therapy. In addition, the combination therapy with mANK-101+cisplatin+α-PD-1 induced the formation of tertiary lymphoid structure-like immune aggregates in the peritumoral space., Conclusion: The current findings provide a rationale for the combination of alum-tethered IL-12 with cisplatin and α-PD-1 for HNSCC., Competing Interests: Competing interests: HK and SB work for Ankyra Therapeutics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Adults with intellectual disabilities in community residential programs receive services from direct support professionals (DSPs) intended to facilitate community engagement. As part of a rate study for Washington State's Developmental Disabilities Administration on community residential services, adults in these programs were asked to provide their perspective on the quality and effectiveness of their care. Method: Twenty-five adults with intellectual disabilities were interviewed focusing on daily activities, staffing, and living situations. Interview transcripts were coded and analyzed for dominant themes. Results: Participants emphasized the desire for trustworthy, caring, and respectful DSPs; DSPs trained in behavioral management techniques made participants feel safe and supported. Nearly all participants called for greater staffing stability. Conclusions: People living in community residential programs are profoundly impacted by the stress and uncertainty of DSPs facing limited resources and high staff turnover. Stable, consistent support makes it easier for participants to engage in community integration., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The research reported in this article was supported by the Washington State Department of Social and Health Services on the direction of Washington State legislators. The authors declare that they have no direct conflicts of interest with respect to the research, authorship, and/or publication of this article and the content is solely the responsibility of the authors and does not necessarily represent the official views of the Washington State Department of Social and Health Services.

Hypothyroidism is a common endocrine disorder whose prevalence increases with age. The disease manifests itself when the thyroid gland fails to produce sufficient thyroid hormones. The disorder includes cases of congenital hypothyroidism (CH), but most cases exhibit hormonal feedback dysregulation and destruction of the thyroid gland by autoantibodies. In this study, we sought to identify causal genes for hypothyroidism in large populations. The study used the UK-Biobank (UKB) database, reporting on 13,687 cases of European ancestry. We used GWAS compilation from Open Targets (OT) and tuned protocols focusing on genes and coding regions, along with complementary association methods of PWAS (proteome-based) and TWAS (transcriptome-based). Comparing summary statistics from numerous GWAS revealed a limited number of variants associated with thyroid development. The proteome-wide association study method identified 77 statistically significant genes, half of which are located within the Chr6-MHC locus and are enriched with autoimmunity-related genes. While coding GWAS and PWAS highlighted the centrality of immune-related genes, OT and transcriptome-wide association study mostly identified genes involved in thyroid developmental programs. We used independent populations from Finland (FinnGen) and the Taiwan cohort to validate the PWAS results. The higher prevalence in females relative to males is substantiated as the polygenic risk score prediction of hypothyroidism relied mostly from the female group genetics. Comparing results from OT, TWAS, and PWAS revealed the complementary facets of hypothyroidism's etiology. This study underscores the significance of synthesizing gene-phenotype association methods for this common, intricate disease. We propose that the integration of established association methods enhances interpretability and clinical utility., 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 © 2024 Zucker, Kovalerchik, Stern, Kaufman and Linial.)

Background: Intratumorally delivered immunotherapies have the potential to favorably alter the local tumor microenvironment and may stimulate systemic host immunity, offering an alternative or adjunct to other local and systemic treatments. Despite their potential, these therapies have had limited success in late-phase trials for advanced cancer resulting in few formal approvals. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to determine how to design clinical trials with the greatest chance of demonstrating the benefits of intratumoral immunotherapy for patients with cancers across all stages of pathogenesis., Methods: An Intratumoral Immunotherapy Clinical Trials Expert Panel composed of international key stakeholders from academia and industry was assembled. A multiple choice/free response survey was distributed to the panel, and the results of this survey were discussed during a half-day consensus meeting. Key discussion points are summarized in the following manuscript., Results: The panel determined unique clinical trial designs tailored to different stages of cancer development-from premalignant to unresectable/metastatic-that can maximize the chance of capturing the effect of intratumoral immunotherapies. Design elements discussed included study type, patient stratification and exclusion criteria, indications of randomization, study arm determination, endpoints, biological sample collection, and response assessment with biomarkers and imaging. Populations to prioritize for the study of intratumoral immunotherapy, including stage, type of cancer and line of treatment, were also discussed along with common barriers to the development of these local treatments., Conclusions: The SITC Intratumoral Immunotherapy Clinical Trials Expert Panel has identified key considerations for the design and implementation of studies that have the greatest potential to capture the effect of intratumorally delivered immunotherapies. With more effective and standardized trial designs, the potential of intratumoral immunotherapy can be realized and lead to regulatory approvals that will extend the benefit of these local treatments to the patients who need them the most., Competing Interests: Competing interests: JJL: Researcher: AbbVie, Astellas, Astrazeneca, Bristol-Myers Squibb, Corvus, Day 1, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, XencorConsultant/Advisor/Speaker: Abbvie, Agenus, Alnylam, Atomwise, Bayer, Bristol-Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic, Synthekine, 7 Hills, Affivant, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest, Abbvie, Agenus, Amgen, Immutep, Evaxion. DD: Grants/Research Support (institutional): Arcus, Immunocore, Merck, Regeneron Pharmaceuticals, Tesaro/GSK. Consultant: ACM Bio, Ascendis, Castle, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Immunitas, Medical Learning Group (MLG), Replimmune, Trisalus, Xilio Therapeutics. CE Speakers’ Bureau: Castle Biosciences. Stockholder: None. Intellectual Property: US Patent 63/124,231, "Compositions and Methods for Treating Cancer", December 11, 2020 US Patent 63/208,719, "Compositions and Methods For Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer", June 9, 2021. AM: Owner: HiFiBio, Deka Bio, Hotspot Therapeutics, Shattuck Labs, Researcher: Astra Zeneca, BMS, Sanofi, Consultant/Advisor/Speaker: Gritstone, Innate Pharma, Neogene, Deka Bio, Hotspot therapeutics, J&J, Medicxi, Depth Charge, BiolineRx, Clover Pharma, Grey Wolf, Lytix, RedX, HiFiBio, ImCheck, Applied Materials, Takeda, Shattuck Labs, Marengo therapeutics, Pierre Fabre, Third Rock Ventures, SotioPublicly Traded Stocks: Centessa. RHA–Employee: Seven & Eight Biopharmaceuticals. Ownership Interest Less Than 5 Percent: Seven & Eight Biopharmaceuticals. NB: Consulting Fees: Novartis, Apricity, Rome Therapeutics, BreakBio, Carisma Therapeutics, CureVac, BioNTech, Gilead, Tempest Therapeutics, Boehringer Ingelheim, Contracted Research: Regeneron Pharmaceutics, Dragonfly Therapeutics, Harbour Biomed Sciences, Ownership Interest Less Than 5 Percent: BreakBio, Apricity. JDB: Researcher: Merck, Genentech, Astrazeneca, Kite/Gilead, BMS, Celldex, Oncovir, Seattle Genetics, ADC Therapeutics, Epizyme, Consultant/Advisor/Speaker: Merck, Genentech, Astrazeneca, Kite/Gilead, BMS, Seattle Genetics, ADC Therapeutics, Epizyme, Asgaard Therapeutics, Global BioAccess, SIRPant Immunotherapeutics. JC: Executive Role: UofL Health, Researcher: Amgen, Iovance, Fate, Replimune, Consultant/Advisor/Speaker: Replimune advisory board 2020-21, Royalties or Patent Beneficiary: US Patents: University of Louisville. RC: Employee: Replimune. TdB: Consultant/Advisor/Speaker: Terumo, Boston Scientific, Astra Zeneca, Nanobiotix, Quantum Surgical, Guerbet, Cook medical, Johnson & Johnson. TDdG: Patents: (1) The use of cytostatics for the accelerated differentiation of DC; WO2009019320-A2; WO2009019320-A3; AU2008285598-A1; EP2281030-A2; CA2724018-A1; US2011117051-A1. US8,470,789B2; DCprime BV. (2) Immunoglobulins binding human Vγ9VÎ’2 T cell receptors; P31885NL00. Consulting Fees: Mendus (formerly Immunicum, formerly DCPrime BV), Partner Therapeutics, GE Health, LAVA Therapeutics, Contracted Research: Idera Pharmaceuticals, Macrophage Parma, Ownership Interest Less Than 5 Percent: LAVA Therapeutics. MGF: Employee: Regeneron. GVG: Employee: Merck. Publicly Traded Stocks: Immunogen, Aveo, Beta Bionics. KJH: Researcher: AstraZeneca, Boehringer-Ingelheim, Replimune, Consultant/Advisor/Speaker: Arch Oncology, AstraZeneca, BMS, Boehringer-Ingelheim, Codiak, Eisai, Inzen, Merck-Serono, MSD, Oncolys, Pfizer, Replimune. HK: Employee: Ankyra Therapeutics. Consultant/Advisor/Speaker: Castle Biosciences, Marengo Therapeutics. CMK: Researcher: Amgen, Merck & Co., Kartos Pharmaceuticals, EMD Serono, Deciphera Pharmaceuticals, Eily lilly, Blueprint Medicines, Incyte Corporation, Clovis Oncology, BMS, Aadi Bioscience, Pfizer, Iterion Therapeutics, Springworks Therapeutics, Nektar Therapeutics, GSK, Adaptimmune, Medimmune, Bioatla, Oncternal Therapeutics, Daiichi- Sankyo Co. Traycon Pharm, Eisai. Ascentage Pharma, Hutchison Medipharma, Salarius Pharmaceuticals, Loxo Oncology, -BTG Specialty Pharmaceuticals, AStex Pharmaceuticals, Xencor, bayer healthcare, Athenex pharmaceuticals, servier, K- group Beta, Trilliium Pharmaceuticals, Ayala Pharmaceuticals, Ningbo Newbay Technology Development, Rain Therapeutics, Inhibrx, C4 Therapeutics, Foghorn Therapeutics, Theseus Pharmaceuticals, Cogent Therapeutics, Curadev PharmaRegeneron, Consultant/Advisor/Speaker: Chemocentryx, Kartos, Servier, Immunicom, Other: Spouse employed by Daichii Sankyo with stock options. ADK: Employee: Merck. KL: Employee: Marengo Therapeutics. SL: Executive Role: Big Against Cancer (Belgium), Breast Cancer Trials (Australia), International Breast Cancer Study Group (Switzerland) Researcher: Research funding to institution from Novartis, Bristol Meyers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, Astra Zeneca, Roche-Genentech and Seattle Genetics, Consultant/Advisor/Speaker: Consultant (not compensated) to Seattle Genetics, Novartis, Bristol Meyers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics and Roche-Genentech. Consultant (paid to institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, Astra Zeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly and Bristol Meyers Squibb, Role: Presenter (Speaker). GVL: Consultant/Advisor/Speaker: Consultant Advisor for Agenus, Amgen, Array Biopharma, AstraZeneca UK, Boehringer Ingelheim International, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme (Australia), Merck Sharpe & Dohme, Novartis Pharma AG, PHMR, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals. IM: Consulting Fees: Bristol-Myers Squibb, F-STAR, Alligator, Pharma Mar, AstraZeneca, Numab Therapeutics, Roche, Amunix, Gossamer, Molecular Partners, Merck-Serono, Genmab, PharmaMar, Contracted Research: Roche, Bristol-Myers Squibb, Highlight Therapeutics, Alligator, Genmab, Astrazeneca. MRM: Researcher : Roche, Astrazeneca, Novartis, Immunocore, BMS, Pfizer, Merck/MSD, Regeneron, BiolineRx, Replimune, GRAIL, Alkermes, iOx, Vaccitech, Consultant/Advisor/Speaker: Infinitopes. BN: Researcher: As a principal investigator for clinical trials sponsored by UZ Brussel, my institution received support from Novartis, Pfizer, Bayer, BMS, MSD, Pierre-Fabre, Amgen, Consultant/Advisor/Speaker: Novartis, BMS, MSD, Pfizer, Pierre-Fabre, Amgen. DJP: Consulting Fees: ViiV Healthcare, Bayer, Hoffman La Roche, EISAI, H3B, MiNa Alpha Therapeutics, DaVolterra, Fees for Non CE Services: Hoffmann La Roche, EISAI, Contracted Research: Merck Sharpe and Dohme, Bristol Myers Squibb (to institution). RAS: Researcher: Boston ScientificConsultant/Advisor/Speaker: Cook Medical, TriSalus, Replimune, Medtronic. SBS: Owner: Aperture Medical Technology, Executive Role: Aperture Medical Technology, Researcher: GE Healthcare, Johnson & Johnson, Elesta, Consultant/Advisor/Speaker: GE Healthcare, XACT Robotics, Microbot, Candel Therapeutics, Varian, Merck & Co., Royalty and Patent Beneficiary: Aperture Medical Technology, Publicly Traded Stocks: Johnson & Johnson, Poseidx Therapeutics, Motus GI, Sientra, Avadel, Lantheus. PS: Employee: Johnson & Johnson, Publicly Traded Stocks: Johnson & Johnson. SITC staff members SMW, CG, AK, NL, EG and KJ have no disclosures., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Scientific research trends and interests evolve over time. The ability to identify and forecast these trends is vital for educational institutions, practitioners, investors, and funding organizations. In this study, we predict future trends in scientific publications using heterogeneous sources, including historical publication time series from PubMed, research and review articles, pre-trained language models, and patents. We demonstrate that scientific topic popularity levels and changes (trends) can be predicted five years in advance across 40 years and 125 diverse topics, including life-science concepts, biomedical, anatomy, and other science, technology, and engineering topics. Preceding publications and future patents are leading indicators for emerging scientific topics. We find the ratio of reviews to original research articles informative for identifying increasing or declining topics, with declining topics having an excess of reviews. We find that language models provide improved insights and predictions into temporal dynamics. In temporal validation, our models substantially outperform the historical baseline. Our findings suggest that similar dynamics apply across other scientific and engineering research topics. We present SciTrends, a user-friendly webtool for predicting future publication trends for any topic covered in PubMed., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Michal Linial reports financial support was provided by 10.13039/501100003483Hebrew University of Jerusalem. Michal Linial reports a relationship with Hebrew University of Jerusalem that includes: employment. None., (© 2023 Published by Elsevier Ltd.)

In fiscal year 2020, new national Medicare payment models were implemented in the two most common post-acute care settings (i.e., skilled nursing facilities (SNFs) and home health agencies (HHAs)), which were followed by the emergence of COVID-19. Given concerns about the unintended consequence of these events, this study protocol will examine how organizations responded to these policies and whether there were changes in SNF and HHA access, care delivery, and outcomes from the perspectives of leadership, staff, patients, and families. We will conduct a two-phase multiple case study guided by the Institute of Medicine's Model of Healthcare Systems. Phase I will include three cases for each setting and a maximum of fifty administrators per case. Phase II will include a subset of Phase I organizations, which are grouped into three setting-specific cases. Each Phase II case will include a maximum of four organizations. Semi-structured interviews will explore the perspectives of frontline staff, patients, and family caregivers (Phase II). Thematic analysis will be used to examine the impact of payment policy and COVID-19 on organizational operations, care delivery, and patient outcomes. The results of this study intend to develop evidence addressing concerns about the unintended consequences of the PAC payment policy during the COVID-19 pandemic.

PANDAS, or pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, is a neuropsychiatric disease seen in children that presents with prevailing symptoms of obsessive-compulsive disorder (OCD), tic disorder, or both. These symptoms appear suddenly following a streptococcal infection, such as strep throat or scarlet fever. The antibodies formed to eradicate the streptococcal infection have been shown to alter central dopamine signaling. In spite of being acknowledged in the medical community for the last two to three decades, PANDAS is a disorder that goes unnoticed by many healthcare professionals. Unfortunately, even with correct diagnosis and utilization of commonly prescribed pharmacotherapy and psychotherapy, medical management can often be ineffective at treating the neuropsychiatric symptoms. Here, we describe a case of a 15-year-old male who presented to the primary care office with complaints of episodic behavioral changes that would occur multiple times daily. The general symptoms were centered around body dysmorphia where the patient became obsessed with fixed portions of food and became highly focused on only specific food types. The symptoms would exacerbate and progress with a dire need to burn calories, leading the patient to damage carpeted areas in the home due to regular and fanatical pacing. The patient underwent trials with serotonergic pharmacotherapy with little to no relief of the psychiatric symptoms. After discussion with his primary care physician, the patient underwent trial management with antidopaminergic therapy that resulted in significant neurological and psychiatric improvement. The use of antidopaminergic pharmacotherapy to target the induction of D1 and D2 dopamine receptors was efficacious in this patient; however, it warrants additional research with a larger sample to determine its effectiveness in the treatment of this psychiatric condition., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Hefelfinger et al.)

Objective: To systematically map the existing evidence on self-perceived health among adults aged 60 and older in Latin America and the Caribbean, describe the use of the single-item measure of self-perceived health with this population, and identify gaps in the existing literature., Methods: Following PRISMA Extension for Scoping Reviews guidelines, eight databases were searched for publications that were published between 2009 and 2019 and reported self-perceived health of adults over 60 years old in Latin America and the Caribbean. Data on study characteristics, sample characteristics, and the use and analysis of the self-perceived health measure were charted., Results: The database and secondary searches identified 516 articles. After removing duplicates and assessing titles and abstracts for inclusion, 263 full-text articles were assessed for eligibility using the inclusion criteria and an additional 89 articles were excluded. Ultimately, 174 articles were included in the scoping review. Studies included participants from 17 countries in the region, led in frequency by Brazil with 120 articles. The self-perceived health question most often included a five-category response scale (130), and response options were predominantly divided into two (86) or three (48) categories for analysis., Conclusions: Information on the health and social needs of people aged 60 and older across Latin America and the Caribbean, particularly their perceptions of health, is limited. We highlight the need to expand research throughout the region, include particularly vulnerable populations, utilize data from longitudinal and qualitative studies, and call for transparency in how questions and responses are worded and analyzed. This review serves to inform future studies, programs, and policies directed at this population.

Objective: Diabetic foot ulcers of the first ray result from several distinct biomechanical mechanisms related to anatomical deformities, which must be addressed if surgical offloading is contemplated. The objective of this study was to create a classification of the anatomical deformities of first-ray ulcers that could lead to better standardization of treatment and reporting., Methods: The authors performed a file review of patients with diabetic neuropathy diagnosed with first-ray ulcers over a period of 3 years in an outpatient setting. Anatomical deformities were diagnosed clinically and reported with ulcer location. The primary classification was the metatarsophalangeal joint, the interphalangeal joint, and the distal phalanx., Results: Records for 59 patients (mean age, 62 years) with University of Texas A1 and A2 ulcers were reviewed. Mean ulcer duration was 2 months. The more common deformities were hallux valgus (41%), hallux valgus interphalangeus (14%), and hallux malleus (20%), and these were primarily associated with metatarsophalangeal, interphalangeal joint, and tip-of-toe ulcers, respectively (P < .0001)., Conclusions: By classifying ulcer locations, the relevant corrective surgery may be chosen. Although some prophylactic procedures may be safe and effective, prophylactic hallux valgus correction in the diabetic foot requires further study., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Lower extremity ulcers (LEUs) are associated with a decline in patients' quality of life (QoL). Better healthcare availability in remote regions, facilitated by telemedicine (TM), may improve patient wellbeing. The aim of this study was to compare the QoL of patients treated via synchronous video TM with that of patients treated with standard face-to-face (FTF) care., Method: The study was performed in a large health services provider in Israel (Maccabi Healthcare Services). TM was used in four remote locations; the FTF method was applied in two regional clinics. The treatment protocol was performed by a nurse and supervised by the regional physician in both treatment modes. A validated Wound-QoL questionnaire in Hebrew was used to assess patient outcomes., Results: A total of 83 patients were treated via TM and 94 patients were treated FTF. The mean QoL for patients treated via TM was 0.546±0.249 compared with 0.507±0.238 for the FTF group. A similarity relating to outcomes in both treatment methods was demonstrated by a difference of 0.039 (95% confidence interval -0.33-0.111) and p=0.291. The probability of the difference being within the limits of the interval in a replicated study was 83.4%. The equivalence/non-inferiority was established within the accepted Δ=0.12 range., Conclusion: The results indicated no reduced QoL for patients with LEUs treated with telemedicine versus with standard FTF care., Declaration of Interest: The authors have no conflicts of interest.

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC., Competing Interests: Competing interests: JIC: speakers bureau: Bristol Myers Squibb (BMS), Merck; unpaid consultant, Clinigen Group; BC: research support: Clinigen, AstraZeneca, Galectin Therapeutics, consulting DMC: Merck, honoraria: BMS, Prometheus, travel: BMS, Agonox; EJD: research support: BMS, Incyte, Karyopharm, Genentech; HK: employee of Immuneering, consulting Replimune, SapVax; AAm: speakers bureau: BMS, Merck, Regeneron, Bioarray, research support: BMS, Merck, Exelixis, consultant: Novartis; AAl: consultant: AstraZeneca, Merck, Pfizer, BMS, travel expenses: Merck, BMS, research support: Genetech, BMS, Merck, Prometheus, Mirati, AstraZeneca, Roche, Bayer, Progenics, Astellas, Arcus, Harpoon Celgene, Janssen; TFL: research support: Abraxis, Acceleron, Amgen, Argos, AstraZeneca, Aveo, Biovex, BMS, Eisai, Lilly, GlaxoSmithKline, Roche, Immatics, Merck, Novartis, Pfizer, Prometheus, Synta, Threshold, Millenium, Tracon, Cerulean, EMD Serono, Macrogenics, Peloton, Iovance, Medimmune, Dynavax, consulting—Prometheus; RH: no disclosures; GPM: no disclosures; UV: consulting: BMS, Merck, Exelixis, Bayer, research support: BMS, Exelixis; DBJ: consulting: Array, BMs, Janssen, Merck, Novartis, research support: BMS, Incyte; RLW: no disclosures; PHW: no disclosures; JPD: consulting: Clinigen, Prometheus, DMCs: Merck, BMS, Eisai, Nektar, Iovance, Amgen., (© American Federation for Medical Research 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: The current opioid injection drug use epidemic has been associated with an increase in hepatitis C virus infections among women of childbearing age in the United States, but changes in hepatitis B virus (HBV) infections have not been studied., Methods: A retrospective analysis of HBV statuses among women of childbearing age nationally and by state was conducted, utilizing the Quest Diagnostics database. Rates of HBV in women born before and after the implementation of universal HBV vaccination recommendations were determined., Results: We identified 8 871 965 women tested for HBV from 2011-2017. Nationally, the annual rate of acute HBV infections was stable, but rates increased in Kentucky, Alabama, and Indiana (P < .03). The national prevalence of new, chronic HBV diagnoses decreased significantly, from 0.83% in 2011 to 0.19% in 2017 (P < .0001), but increased in Mississippi, Kentucky, and West Virginia (P ≤ .05). A declining prevalence of HBV seroprotection was evident over time, especially within the birth-dose cohort (which dropped from 48.5% to 38.5%; P < .0001)., Conclusions: National rates of newly diagnosed acute and chronic HBV infections declined or were stable overall, but increased significantly in specific Appalachian states. The HBV vaccine is effective in decreasing infections, but seroprotection wanes over time. These trends in new infections may be related to increased injection drug use and highlight potential gaps in HBV vaccine protection., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The recent global pandemic has placed a high priority on identifying drugs to prevent or lessen clinical infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused by Coronavirus disease-2019 (COVID-19)., Methods: We applied two computational approaches to identify potential therapeutics. First, we sought to identify existing FDA approved drugs that could block coronaviruses from entering cells by binding to ACE2 or TMPRSS2 using a high-throughput AI-based binding affinity prediction platform. Second, we sought to identify FDA approved drugs that could attenuate the gene expression patterns induced by coronaviruses, using our Disease Cancelling Technology (DCT) platform., Results: Top results for ACE2 binding iincluded several ACE inhibitors, a beta-lactam antibiotic, two antiviral agents (Fosamprenavir and Emricasan) and glutathione. The platform also assessed specificity for ACE2 over ACE1, important for avoiding counterregulatory effects. Further studies are needed to weigh the benefit of blocking virus entry against potential counterregulatory effects and possible protective effects of ACE2. However, the data herein suggest readily available drugs that warrant experimental evaluation to assess potential benefit. DCT was run on an animal model of SARS-CoV, and ranked compounds by their ability to induce gene expression signals that counteract disease-associated signals. Top hits included Vitamin E, ruxolitinib, and glutamine. Glutathione and its precursor glutamine were highly ranked by two independent methods, suggesting both warrant further investigation for potential benefit against SARS-CoV-2., Conclusions: While these findings are not yet ready for clinical translation, this report highlights the potential use of two bioinformatics technologies to rapidly discover existing therapeutic agents that warrant further investigation for established and emerging disease processes.

We previously reported in HEK 293T cells that silencing the mitochondrial peptidyl prolyl isomerase cyclophilin-D (Cyp-D) reduces V o 2 . We now report that in vivo Cyp-D ablation using constitutive Cyp-D knockout (KO) mice also reduces V o 2 both at rest (∼15%) and during treadmill exercise (∼12%). Yet, despite V o 2 reduction, these Cyp-D KO mice ran longer (1071 ± 77 vs. 785 ± 79 m; P = 0.002), for longer time (43 ± 3 vs. 34 ± 3 min; P = 0.004), and at higher speed (34 ± 1 vs. 29 ± 1 m/s; P ≤ 0.001), resulting in increased work (87 ± 6 vs. 58 ± 6 J; P ≤ 0.001). There were parallel reductions in carbon dioxide production, but of lesser magnitude, yielding a 2.3% increase in the respiratory exchange ratio consistent with increased glucose utilization as respiratory substrate. In addition, primary skeletal muscle cells of Cyp-D KO mice subjected to electrical stimulation exhibited higher glucose uptake (4.4 ± 0.55 vs. 2.6 ± 0.04 pmol/mg/min; P ≤ 0.001) with enhanced AMPK activation (0.58 ± 0.06 vs. 0.38 ± 0.03 pAMPK/β-tubulin ratio; P ≤ 0.01) and TBC1 (Tre-2/USP6, BUB2, Cdc16) domain family, member 1 (TBC1D1) inactivation. Likewise, pharmacological activation of AMPK also increased glucose uptake (3.2 ± 0.3 vs. 2.3 ± 0.2 pmol/mg/min; P ≤ 0.001). Moreover, lactate and ATP levels were increased in these cells. Taken together, Cyp-D ablation triggered an adaptive response resulting in increased exercise capacity despite less oxygen utilization associated with increased glucose uptake and utilization involving AMPK-TBC1D1 signaling nexus.-Radhakrishnan, J., Baetiong, A., Kaufman, H., Huynh, M., Leschinsky, A., Fresquez, A., White, C., DiMario, J. X., Gazmuri, R. J. Improved exercise capacity in cyclophilin-D knockout mice associated with enhanced oxygen utilization efficiency and augmented glucose uptake via AMPK-TBC1D1 signaling nexus.

Hepatic fibrosis and advanced fibrosis in particular is the strongest predictor of liver-related outcomes and mortality among nonalcoholic steatohepatitis (NASH) patients. Understanding prevalence and predictors of NASH with advanced fibrosis is critical for healthcare resource planning. Using a large U.S. clinical laboratory database from 10/1/2017-9/30/2018, adults negative for hepatitis B and hepatitis C and after excluding for alcoholic liver disease and pregnancy were evaluated for prevalence of F3 and F4 fibrosis using a systematic algorithm of five fibrosis-4 (FIB-4) criteria: Criteria 1 (≥F3: >2.67), Criteria 2 (2.674.12), Criteria 3 (2.673.15), Criteria 4 (3.253.5), Criteria 5 (3.254.12). Metabolic co-morbidities evaluated included decreased high density lipoprotein (<40 mg/dL men, <50 mg/dL women), high triglycerides (≥150 mg/dL), elevated hemoglobin A1C (≥6.5%). Parallel analyses of patients with specific NAFLD/NASH ICD-9/10 codes from 10/1/2013-9/30/2018 were performed. Multivariate logistic regression models evaluated for predictors of ≥F3 fibrosis. Among patients with NAFLD/NASH ICD-9/10 codes, ≥F3 prevalence ranged from 4.35% - 6.90%, and F4 prevalence ranged from 2.52%- 3.67%. Increasing metabolic co-morbidities was associated with higher risk of ≥F3 fibrosis. Compared to NASH patients without metabolic co-morbidities, NASH with four concurrent metabolic co-morbidities had higher risk of ≥F3 (OR 1.56, 95% CI 1.40-1.73, p<0.001). In summary, prevalence of NASH with advanced fibrosis among U.S. adults was as high as 6.90% and prevalence of NASH with cirrhosis was as high as 3.67%, representing 5.18 million and 2.75 million, respectively, when using an estimate of 75 million U.S. adults with NAFLD. Co-morbid metabolic abnormalities were associated with higher risk of advanced fibrosis among NASH patients., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Robert Wong: research grants, consulting, advisory board, speaker’s bureau – Gilead Sciences; research grants – Abbvie; speaker’s bureau – Salix, Bayer; research grant – AASLD Foundation; Tram Tran: employee and stocks – Gilead Sciences; Harvey Kaufman: None; Justin Niles: None; Robert Gish: consulting, advisor - Abbot, AbbVie, Alexion, Arrowhead, Bayer AG, Biocollections, Bristol-Myers Squibb Company, Contravir, Eiger, Enyo, eStudySite, Genentech, Gilead Sciences, HepaTX, HepQuant, Hoffmann-LaRoche Ltd., Intellia, Intercept, Ionis Pharmaceuticals, Janssen, MedImmune, Merck, Prometheus, Quest, Shionogi, Transgene, Trimaran; Scientific/clinical Advisory Boards -AbbVie, Merck, Arrowhead, Bayer, Contravir, Dova Pharmaceuticals, Eiger, Enyo, Janssen, Medimmune, Janssen/J&J, Intercept, Shionogi, Spring Bank; Clinical trials – eStudySite. Chair Clinical Advisory Board – Arrowhead; Data Safety Monitoring Board – Ionis; Speaker’s bureau – AbbVie, Alexion, Bayer, BMS, Gilead Sciences Inc., Merck; Minor stock shareholder - Athenex, Triact, Synageva, RiboSciences, CoCrystal; Stock options – Arrowhead, Eiger. The above competing interests statement and funding do not alter our adherence to all PLOS ONE policies on sharing data and materials.

Background: Chronic ulcers pose a significant health concern and economic burden. Numerous products, including animal-derived collagen products, have been designed to provide the injured site with a biocompatible structural matrix that promotes tissue regeneration. Yet, animal-derived collagens can evoke immune responses, bear risk of disease transmission, and fail to closely mimic the function of native collagen., Objective: This study aims to assess the safety and performance of a novel flowable wound matrix, formulated from tobacco plant-purified fibrillated recombinant human type I collagen (rhCollagen), in patients with chronic lower limb ulcers., Materials and Methods: This single-arm, open-label, multicenter trial took place at 5 treatment centers. Wounds were photographed and preliminary surgical debridement was performed prior to rhCollagen application. Patients received a single application of rhCollagen to the wound bed, followed by weekly assessments of the wound., Results: Twenty patients (mean age, 63 years), presenting with a chronic ulcer of neuropathic (45%), posttraumatic (35%), postoperative (10%), and venous (10%) origin, underwent rhCollagen treatment. Initial wound area ranged between 0.2 cm3 to 9.2 cm3. At 4-weeks posttreatment, median wound area reduction was 94%. Fifteen ulcers exhibited ≥ 70% wound closure, 9 of which achieved complete closure. Only 1 participant suffered a local self-resolving wound infection. No significant device-related adverse events were reported throughout the study., Conclusions: A single, easy-to-use rhCollagen flowable gel application for chronic lower limb ulcers may promote wound closure with minimal adverse events.

Background: Lower extremities ulcers (LEU) are associated with considerable morbidity and mortality. With longer life expectancy, the prevalence of LEU in developed countries is assumed to grow, necessitating an increased demand for treatment by specialists., Objectives: To compare the effectiveness of a telemedicine video conferencing modality with the conventional face-to-face treatment of LEU., Methods: The study was conducted in conjunction with a two-million member healthcare organization in Israel (Maccabi Healthcare Services). Consecutive visits of patients to wound care specialists during a 12-month observation period reviewed in 2015 were valuated. A nurse-assisted setting was implemented during all treatment sessions. The same specialist supervised patients in both modalities., Results: A sample of 111 patients (n=55 in the telemedicine group; n=56 in the face-to-face group) with 593 visits was analyzed. No significant difference in healing of LEU (78.2% in telemedicine vs. 75.0% in face-to-face) was detected, P = 0.823. A reduced number of visits in telemedicine (4.36 ± 2.36) compared to the face-to-face care (6.32 ± 4.17) was shown, P = 0.003. Non-inferiority of telemedicine demonstrated within the Δ = 15% range limits and 80% statistical power was demonstrated., Conclusions: Compared to the usual face-to-face method, synchronous video conferencing-based telemedicine may be a feasible and efficient method for LEU management.

Introduction: With growing prevalence of lower extremity ulcers (LEU) and shortage of wound specialists, gaps in access to care may occur, particularly in remote areas. This gap can be mitigated with high-quality telemedicine (TM). This study aims to explore the effectiveness of synchronous video TM compared to the conventional face-to-face treatment (FTF)., Methods: The study was conducted at Maccabi Healthcare Services, a 2.2-million-member sick fund in Israel. We reviewed all consecutive visits of LEU patients to wound care specialists between Jan 2013 and Jun 2017. Both TM and FTF modalities were implemented using identical treatment settings with the same nurse at each location. Study endpoint was ulcer healing as assessed by the treating specialist., Results: The study population included 650 LEU cases (n TM  = 277, n FTF  = 373) and contained 5203 visits. Comparable (P = 0.475) proportions of healed ulcers (52% in TM vs. 55% in FTF) were detected. Survival analyses found a non-significant advantage of TM (0.887; 0.650-1.212) compared to FTF. The non-inferiority of TM was demonstrated within the Δ = 0.15 range limits and 80% statistical power. Trial replication probability is 0.93., Conclusions: Synchronous video-conferencing based telemedicine may be a feasible and efficient method of LEU management., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Prognostic scoring systems are used to estimate the risk of mortality from metastatic renal cell carcinoma (mRCC). Outcomes from different therapies may vary within each risk group. These survival algorithms have been applied to assess outcomes in patients receiving T-cell checkpoint inhibitory immunotherapy and tyrosine kinase inhibitor therapy, but have not been applied extensively to patients receiving high dose interleukin-2 (HD IL-2) immunotherapy., Methods: Survival of 810 mRCC patients treated from 2006 to 2017 with high dose IL-2 (aldesleukin) and enrolled in the PROCLAIM SM registry data base was assessed utilizing the International Metastatic RCC Database Consortium (IMDC) risk criteria. Median follow-up is 23.4 months (mo.) (range 0.2-124 mo.). Subgroup evaluations were performed by separating patients by prior or no prior therapy, IL-2 alone, or therapy subsequent to IL-2. Some patients were in two groups. We will focus on the 356 patients who received IL-2 alone, and evaluate outcome by risk factor categories., Results: Among the 810 patients, 721 were treatment-naïve (89%) and 59% were intermediate risk. Overall, of the 249 patients with favorable risk, the median overall survival (OS) is 63.3 mo. and the 2-year OS is 77.6%. Of 480 patients with intermediate risk, median OS is 42.4 mo., 2-year OS 68.2%, and of 81 patients with poor risk, median OS 14 mo., 2-year OS 40.4%. Among those who received IL-2 alone (356 patients), median OS is 64.5, 57.6, and 14 months for favorable, intermediate and poor risk categories respectively. Two year survival among those treated only with HD IL-2 is 73.4, 63.7 and 39.8%, for favorable, intermediate and poor risk categories respectively., Conclusions: Among mRCC patients treated with HD IL-2, all risk groups have median and 2-year survival consistent with recent reports of checkpoint or targeted therapies for mRCC. Favorable and intermediate risk (by IMDC) patients treated with HD IL-2 have longer OS compared with poor risk patients, with most durable OS observed in favorable risk patients. Favorable risk patients treated with HD IL-2 alone have a 2-year OS of 74%. These data continue to support a recommendation for HD IL-2 for patients with mRCC who meet eligibility criteria., Trial Registration: PROCLAIM, NCT01415167 was registered with ClinicalTrials.gov on August 11, 2011, and initiated for retrospective data collection until 2006, and prospective data collection ongoing since 2011.

The slow healing process and high recurrence rate of lower extremity ulcerations (LEU) impose a considerable medical and economic burden and affect quality of life (QoL). Analyses of LEU-related QoL in Israel are limited due to lack of a validated Hebrew disease-specific evaluation instrument. The aim of this study was to validate the disease-specific Hebrew "Wound QoL" questionnaire. The validation of the "Wound QoL" disease-specific instrument, translated from English to Hebrew, was based on a comparison with the valid Hebrew version of the SF12v.2 health-related questionnaire. The convenience sample for the "Wound QoL" validation (n = 32) was obtained from patient populations in the Maccabi Health Services' outpatient clinics at the northern and southern parts of Israel. The study was conducted between June and September 2017. Face/construct validity was accepted by specialists' consensus. Internal consistency assessed by Cronbach's α was .893. Concurrent validity reflected by Pearson's correlations between the tools was in the range of 0.830 to 0.950. The Wound QoL Hebrew version is a valid and reliable instrument suitable for implementation in an Israeli cultural environment., (© 2018 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Juvenile probation officers (JPOs) are increasingly using risk/needs assessments to evaluate delinquency risk, identify criminogenic needs and specific responsivity factors, and use this information in case planning. Justice-involved youth are exposed to traumatic events and experience traumatic stress symptoms at a high rate; such information warrants attention during the case planning process. The extent to which JPOs identify specific responsivity factors, in general, and trauma history, specifically, when scoring risk/need assessments is understudied. In the current study, 147 JPOs reviewed case vignettes that varied by the adolescents' gender (male vs. female), traumatic event exposure (present vs. absent), and traumatic stress symptoms (present vs. absent), and then scored the YLS/CMI and developed case plans based on that information. JPOs who received a vignette that included trauma information identified a higher number of trauma-specific responsivity factors on the YLS/CMI. Despite an overall high needs match ratio (57.2%), few JPOs prioritized trauma as a target on case plans. The findings underscore the importance of incorporating trauma screening into risk/needs assessment and case planning. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Objective: Oxygen plays a central role in wound healing. Recent technological advances have miniaturised oxygen delivery systems, with novel topical oxygen therapy allowing patients to receive oxygen therapy 24 hours a day while remaining completely mobile. Here we aim to examine the efficacy and safety of continuous topical oxygen diffusion in a 'real-world' setting., Methods: Topical oxygen therapy (TOT) was evaluated in patients with chronic, non-healing wounds in a tertiary referral specialist clinic., Results: The mean wound duration before TOT was 15 months. Regardless of treatment duration, in this previously non-healing group complete wound closure was observed in 32% of the total patients treated with the TOT device. However, optimal wound healing occurred when the device was used for >25 days, with an 83% wound area reduction and 47% wound closure rate seen in venous leg ulcers (VLUs) and a 74% reduction and a 57% wound closure rate in arterial foot ulcers., Conclusion: Use of TOT in chronic wounds stimulates a healing state. In our study, almost half of the previously non-healing wounds closed.

ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy.

Objective: To evaluate high-performing cochlear implant patients' performance on AzBio sentence testing., Methods: Retrospective review of prospectively collected database at a tertiary care hospital. Unilateral cochlear implant patients with AzBio testing were included. The primary outcome of interest was AzBio performance scores in quiet and at +10 and +5 decibels signal to noise (dB S/N)., Results: One hundred eighty five subjects met inclusion criteria with scores for AzBio in quiet, 114 at +10 dB S/N, and 66 at +5 dB S/N. Linear mixed effects models showed performance significantly correlated with time since activation in all conditions (8.4%/yr; p < 0.0001). Strong correlations between mean performance in quiet and at +10 dB S/N (r = 0.77, p < 0.0001), and between +10 and +5 dB S/N (r = 0.73, p < 0.0001) were found. The correlation between quiet and +5 dB S/N (r = 0.45, p = 0.01) was less robust. Shapiro-Wilks test of normality found only +10 dB S/N to correspond to a normal distribution. Skew analysis demonstrated values of -0.64, -0.11, and 0.8 for quiet, +10 dB S/N, and +5 dB S/N, respectively., Conclusions: AzBio scores at +10 dB S/N show a strong correlation with, but avoid the ceiling effects that limit the usefulness of testing in quiet for high performing cochlear implant users, making it the preferred test in this population. Significant complexities exist in the study of outcomes in cochlear implant recipients, and there is no single test that is ideal for the entirety of this population.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Using commercial laboratory data, we found 80% of 29382 young persons currently infected with hepatitis C virus lived >10 miles from a syringe services program. The median distance was 37 miles, with greater distances in rural areas and Southern and Midwestern states. Strategies to improve access to preventive services are warranted., (Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: In Ontario, Canada, patients who lack decision-making capacity and have no family or friends to act as substitute decision-makers currently rely on the Office of the Public Guardian and Trustee to consent to long-term care (nursing home) placement, but they have no legal representative for other placement decisions., Objectives: We highlight the current gap in legislation for difficult transition cases involving unrepresented patients and provide a novel framework for who ought to assist with making these decisions and how these decisions ought to be made., Research Design: This paper considers models advanced by Volpe and Steinman with regard to who ought to make placement decisions for unrepresented patients, as well as current ethical models for analyzing how these decisions should be made., Participants and Research Context: We describe an anonymized healthcare transition case to illustrate the fact that there is no legally recognized decision-maker for placement destinations other than long-term care facilities and to show how this impacts all stakeholders., Ethical Considerations: The case provided is an anonymized vignette representing a typical transition case involving an unrepresented patient., Findings: As a result of a gap in provincial legislation, healthcare providers usually determine the appropriate placement destination without a clear framework to guide the process and this can cause significant moral distress., Discussion: We argue for a team decision-making approach in the short term, and a legislative change in the long-term, to respect the patient voice, evaluate benefit and risk, enhance collaboration between healthcare providers and patients, and promote social justice. We believe that our approach, which draws upon the strengths of interprofessional teams, will be of interest to all who are concerned with the welfare and ethical treatment of the patients for whom they care., Conclusions: One of the main strengths of our recommendation is that it provides all members of the healthcare team (including nurses, social workers, therapists, and others) an increased opportunity to advocate on behalf of unrepresented patients., (© The Author(s) 2015.)

Background: The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important., Methods: A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board., Results: Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0-10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing., Conclusion: Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability., Implications for Practice: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (©AlphaMed Press.)

Shockwave therapy is used in medicine due to its ability to stimulate healing processes. The application of orthodontic force evokes an inflammatory reaction resulting in tooth movement. Shockwave therapy might have an effect on both inflammatory and periodonal ligament cytokine profiles. Our aim was to evaluate the fluctuations of different inflammatory cytokines after orthodontic force induction with and without shockwave therapy. An orthodontic appliance was applied between the rats' molars and incisors. In conjunction with the commencement of orthodontic force, the rats were treated with a single episode of 1000 shock waves and the gingival crevicular fluid was collected for 3 days. The expression and concentration of different cytokines was evaluated by a commercial 4-multiplex fluorescent bead-based immunoassay. The level of all cytokines displayed a similar trend in both shockwave-treated and untreated groups; the concentration peaked on the first day and declined thereafter. In all cases, however, the cytokine levels were smaller in the shockwave-treated than in untreated animals; a significant difference was found for sRANKL and borderline difference for IL-6 on Day 1. We conclude that shockwave therapy during the induction of orthodontic tooth movement influences the expression of inflammatory cytokines.

Talimogene laherparepvec (T-VEC) is the first-in-class oncolytic virus immunotherapy for the treatment of cancer and was generated from an attenuated, recombinant herpes simplex virus. T-VEC has demonstrated therapeutic activity in melanoma patients and is being tested in a number of other cancers alone and in combination with standard cancer therapeutics and other immunotherapy agents. This review will discuss the current landscape of melanoma, the construction and application of T-VEC for melanoma along with other indications for T-VEC, as well as highlight some of the novel challenges with oncolytic virus immunotherapy as it enters into clinical practice., (Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.)

Objective: To identify and understand the barriers to equitable care within health care settings that women of ethnic minorities encounter in Latin America and to examine possible strategies for mitigating the issues., Methods: This was a comprehensive review of the literature from 2000-2015 available from the online databases PubMed, Google Scholar, EBSCOhost, and SciELO in Spanish, English, and Portuguese, using a keyword search that included the Region and country names., Results: Health provider discrimination against Indigenous and Afrodescendant women is a primary barrier to quality health care access in Latin America. Discrimination is driven by biases against ethnic minority populations, women, and the poor in general. Discriminatory practices can manifest as patient-blaming, purposeful neglect, verbal or physical abuse, disregard for traditional beliefs, and the non-use of Indigenous languages for patient communication. These obstacles prevent delivery of appropriate and timely clinical care, and also produce fear of shame, abuse, or ineffective treatment, which, in addition to financial barriers, deter women from seeking care., Conclusions: To ensure optimal health outcomes among Indigenous and Afrodescendant women in Latin America, the issue of discrimination in health care settings needs to be understood and addressed as a key driver of inequitable health outcomes. Strategies that target provider behavior alone have limited impact because they do not address women's needs and the context of socioeconomic inequality in which intra-hospital relations are built.

Background and Objective: Extracorporeal shock wave therapy has been used in various clinical conditions as a result of its ability to stimulate healing processes in acute and chronic inflammatory states. Orthodontic force application triggers an inflammatory reaction in the periodontal tissue surrounding the involved teeth, resulting in tooth movement. Preliminary work revealed that extracorporeal shock wave therapy increased the expression of the inflammatory cytokines involved. Our aim was to investigate the expression of inflammatory cytokines in the periodontal tissues following orthodontic force induction, with and without shock wave therapy, in experimental rats., Material and Methods: An orthodontic appliance was fabricated and applied between the molars and the incisors of adult Wistar rats. In conjunction with orthodontic force commencement, the rats were treated with a single episode of 1000 shock waves. Every day, during the 3 d of the study, rats were killed and the immunolocalization of RANKL, interleukin (IL)-1β, IL-6 and tumor necrosis factor-alpha was evaluated., Results: The percentage of the area staining positively for all inflammatory cytokines during the first 2 d decreased statistically significantly more in the shock wave-treated group compared with the nontreated control group. On the first day, the percentage of the area staining positively for IL-1β and RANKL on the compression side peaked in both groups, with a sequential rise in the number of TRAP-positive cells., Conclusion: The induction of shock wave therapy during orthodontic tooth movement influences the expression of different inflammatory cytokines in the tissue and might alter the expected periodontal remodeling rate., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Leflunomide is a novel immunomodulatory drug prescribed for treating rheumatoid arthritis. It inhibits the activity of protein tyrosine kinases and dihydroorotate dehydrogenase, a rate-limiting enzyme in the pyrimidine nucleotide synthesis pathway. Here, we report that A77 1726, the active metabolite of leflunomide, inhibited the phosphorylation of ribosomal protein S6 and two other substrates of S6K1, insulin receptor substrate-1 and carbamoyl phosphate synthetase 2, in an A375 melanoma cell line. A77 1726 increased the phosphorylation of AKT, p70 S6 (S6K1), ERK1/2, and MEK through the feedback activation of the IGF-1 receptor-mediated signaling pathway. In vitro kinase assay revealed that leflunomide and A77 1726 inhibited S6K1 activity with IC50 values of approximately 55 and 80 μM, respectively. Exogenous uridine partially blocked A77 1726-induced inhibition of A375 cell proliferation. S6K1 knockdown led to the inhibition of A375 cell proliferation but did not potentiate the antiproliferative effect of A77 1726. A77 1726 stimulated bromodeoxyuridine incorporation in A375 cells but arrested the cell cycle in the S phase, which was reversed by addition of exogenous uridine or by MAP kinase pathway inhibitors but not by rapamycin and LY294002 (a phosphoinositide 3-kinase inhibitor). These observations suggest that A77 1726 accelerates cell cycle entry into the S phase through MAP kinase activation and that pyrimidine nucleotide depletion halts the completion of the cell cycle. Our study identified a novel molecular target of A77 1726 and showed that the inhibition of S6K1 activity was in part responsible for its antiproliferative activity. Our study also provides a novel mechanistic insight into A77 1726-induced cell cycle arrest in the S phase.

Objective: This study aimed to investigate PDL's cytokine concentration fluctuations after induction of orthodontic force with and without extracorporeal shock wave therapy in a rat model., Materials and Methods: An orthodontic appliance was fabricated and applied between the molars and the incisors of rats. The rats were treated by a single episode of 1000 shock waves and gingival crevicular fluid was collected for 3 days. The expression and concentration of IL-1β and VEGF were evaluated by ELISA assay. On day 3 all rats were sacrificed and histologic and immunohistochemical assays were applied., Results: IL-1β concentration rose in both the treated and non treated shockwave groups on the first day, however it was statistically significantly higher in the treated group on day 2. No statistically significant difference was detected between the groups on day 3. The number/area of TRAP positive cells was higher in the non shockwave group than in the treated group. The percentage of cells expressing VEGF displayed the opposite trend. The findings regarding the immunohistochemical assay for IL-1β corresponded with those of the ELISA assay on day 3., Conclusion: The application of shockwaves during orthodontic tooth movement influences the expression of IL-1β and VEGF and may alternate the periodontal remodelling expected rate., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The importance of fungicide seed treatments on cotton was examined using a series of standardized fungicide trials from 1993 to 2004. Fungicide seed treatments increased stands over those from seed not treated with fungicides in 119 of 211 trials. Metalaxyl increased stands compared to nontreated seed in 40 of 119 trials having significant fungicide responses, demonstrating the importance of Pythium spp. on stand establishment. Similarly, PCNB seed treatment increased stands compared to nontreated seed for 44 of 119 trials with a significant response, indicating the importance of Rhizoctonia solani in stand losses. Benefits from the use of newer seed treatment chemistries, azoxystrobin and triazoles, were demonstrated by comparison with a historic standard seed treatment, carboxin + PCNB + metalaxyl. Little to no stand improvement was found when minimal soil temperatures averaged 25°C the first 3 days after planting. Stand losses due to seedling pathogens increased dramatically as minimal soil temperatures decreased to 12°C and rainfall increased. The importance of Pythium increased dramatically as minimal soil temperature decreased and rainfall increased, while the importance of R. solani was not affected greatly by planting environment. These multi-year data support the widespread use of seed treatment fungicides for the control of the seedling disease complex on cotton.

Background: DepoVax is a novel non-emulsion depot-forming vaccine platform with the capacity to significantly enhance the immunogenicity of peptide cancer antigens. Naturally processed HLA-A2 restricted peptides presented by breast, ovarian and prostate cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907., Methods: A phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose/volume cohorts in a three immunization protocol., Results: DPX-0907 was shown to be safe with injection site reactions being the most commonly reported adverse event. All breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients exhibited detectable immune responses, resulting in a 61% immunological response rate. Immune responses were generally observed in patients with better disease control after their last prior treatment. Antigen-specific responses were detected in 73% of immune responders (44% of evaluable patients) after the first vaccination. In 83% of immune responders (50% of evaluable patients), peptide-specific T cell responses were detected at ≥2 time points post vaccination with 64% of the responders (39% of evaluable patients) showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T cell memory with the ability to secrete multiple Type 1 cytokines., Conclusions: The novel DepoVax formulation promotes multifunctional effector memory responses to peptide-based tumor associated antigens. The data supports the capacity of DPX-0907 to elicit Type-1 biased immune responses, warranting further clinical development of the vaccine. This study underscores the importance of applying vaccines in clinical settings in which patients are more likely to be immune competent., Trial Registration: ClinicalTrials.gov NCT01095848.

Extracorporeal generated shock waves were introduced in medical therapy approximately 20 years ago in order to disintegrate kidney stones. Over the last 10 years, extracorporeal generated shock waves have been used to stimulate healing processes. No report to date has examined its influence on different inflammation mediators and growth factors in the periodontium. Orthodontic tooth movement is a model including the induction of an aseptic inflammation and its resolution. We conducted a preliminary study to investigate the periodontium cytokine concentration fluctuations after induction of orthodontic force with and without extracorporeal shock wave therapy (ESWT) in a rat model. An orthodontic appliance was fabricated and applied between the molars and the incisors of rats. The rats were treated by a single episode of 1000 shock waves and gingival crevicular fluid was collected for 3 days. The concentration of typical acute phase cytokines was evaluated by ELISA assay. Of the three tested cytokines, IL-1beta was the only detected cytokine along the study timeframe. IL-1beta concentration rose in both the treated and non treated shockwave groups on the first day, however it was statistically significantly higher in the treated group on day 2. On day 3, IL-1beta concentrations in both groups decreased and reached a lower level in the treated group, revealing a statistically significant difference than its level on the previous day. The application of ESWT during orthodontic force induction enhances IL-1beta production as part of mechanical forces transduction triggering a biologic response, which may contribute to accelerated periodontal remodeling and therefore foreshortening the orthodontic tooth movement period.

Background: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone., Methods: We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival., Results: The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06)., Conclusions: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).

Aim: Anal sphincter anatomy on two-dimensional endoanal -ultrasonography (EUS) does not always correlate with the clinical data. The purpose of this study was to determine whether three-dimensional (3D) measurements yield a better correlation., Method: The study group included consecutive patients who underwent 3D EUS for faecal incontinence over a 2-year period. The medical charts were reviewed for Cleveland Clinic Foundation Fecal Incontinence (CCF-FI) score and manometric pressures. Endoanal ultrasonographic images were reviewed for the presence of an external anal sphincter (EAS) defect and its extent, as determined by the radial angle, length in the sagittal plane and percentage volume deficit. Correlational analyses were performed between the clinical and imaging data., Results: Sixty-one patients of median age 53 years (range 15-82) were evaluated. Thirty-two patients had either a complete (17) or partial (15) EAS defect, and 29 patients had an intact sphincter. The CCF-FI scores were similar in patients with and without an EAS defect (12.5 ± 5.6 and 11.4 ± 5.5, respectively). The intact-sphincter group had a significantly greater EAS length (3 ± 0.4 vs 2 ± 0.62 cm, P = 0.02) and higher mean maximal squeeze pressure (MMSP; 99.7 ± 52.6 vs 66.9 ± 52.9 mmHg, P = 0.009). There were no statistically significant correlations between MMSP, CCF-FI score and EAS status on 3D EUS. Mean percentage volume of the defect was similar in patients with complete and partial tears (14.5 ± 5.5 and 17.5 ± 7.2%, P = 0.25) and showed no correlation with physiological tests or symptom scores., Conclusion: Improvements in external anal sphincter imaging have not yielded a better association with the clinical findings. The lack of clinical differences between patients with different EAS tears may reflect their similar volumetric defects., (© 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.)

The objective of this paper is to explore ethical issues in the provision of transitional care. Using five case studies a number of ethical issues in transition and transition care are discussed. These issues include: 1) preserving, promoting and ensuring dignity and respect for patients; 2) fostering and supporting the trusting relationships that young people and their parents have for pediatric providers to their new adult providers by using a graduated system of transfer; 3) recognizing graduated capacity; 4) promoting autonomy and self-management; 5) duties of beneficence and non-maleficence; 6) truthtelling; 7) duty to provide developmentally appropriate care; and 8) duty of pediatric providers to advocate for transitioning patients in the adult system. Attention to the ethical issues surrounding these complex cases has the potential to positively influence a successful transition to adult-oriented health care.

Introduction: Treatment options for patients with fecal incontinence (FI) are limited, and surgical treatments can be associated with high rates of infection and other complications. One treatment, sacral nerve stimulation (SNS), is approved for FI in Europe. A large multicenter trial was conducted in North America and Australia to assess the efficacy of SNS in patients with chronic fecal incontinence. The aim of this report was to analyze the infectious complication rates in that trial., Methods: Adult patients with a history of chronic fecal incontinence were enrolled into this study. Those patients who fulfilled study inclusion/exclusion criteria and demonstrated greater than two FI episodes per week underwent a 2-week test phase of SNS. Patients who showed a > or = 50% reduction in incontinent episodes and/or days per week underwent chronic stimulator implantation. Adverse events were reported to the sponsor by investigators at each study site and then coded. All events coded as implant site infection were included in this analysis., Results: One hundred twenty subjects (92% female, 60.5 +/- 12.5 years old) received a chronically implanted InterStim Therapy device (Medtronic, Minneapolis, MN, USA). Patients were followed for an average of 28 months (range 2.2-69.5). Thirteen of the 120 implanted subjects (10.8%) reported infection after the chronic system implant. One infection spontaneously resolved and five were successfully treated with antibiotics. Seven infections (5.8%) required surgical intervention, with infections in six patients requiring full permanent device explantation. The duration of the test stimulation implant procedure was similar between the infected group (74 min) and the non-infected group (74 min). The average duration of the chronic neurostimulator implant procedure was also similar between the infected (39 min) and non-infected group (37 min). Nine infections occurred within a month of chronic system implant and the remaining four infections occurred more than a year from implantation. While the majority (7/9) of the early infections was successfully treated with observation, antibiotics, or system replacement, all four of the late infections resulted in permanent system explantation., Conclusion: SNS for FI resulted in a relatively low infection rate. This finding is especially important because the only other Food and Drug Administration-approved treatment for end-stage FI, the artificial bowel sphincter, reports a much higher rate. Combined with its published high therapeutic success rate, this treatment has a positive risk/benefit profile.

Background: Sacral nerve stimulation has been approved for use in treating urinary incontinence in the United States since 1997, and in Europe for both urinary and fecal incontinence (FI) since 1994. The purpose of this study was to determine the safety and efficacy of sacral nerve stimulation in a large population under the rigors of Food and Drug Administration-approved investigational protocol., Methods: Candidates for SNS who provided informed consent were enrolled in this Institutional Review Board-approved multicentered prospective trial. Patients showing > or =50% improvement during test stimulation received chronic implantation of the InterStim Therapy (Medtronic; Minneapolis, MN). The primary efficacy objective was to demonstrate that > or =50% of subjects would achieve therapeutic success, defined as > or =50% reduction of incontinent episodes per week at 12 months compared with baseline., Results: A total of 133 patients underwent test stimulation with a 90% success rate, and 120 (110 females) of a mean age of 60.5 years and a mean duration of FI of 6.8 years received chronic implantation. Mean follow-up was 28 (range, 2.2-69.5) months. At 12 months, 83% of subjects achieved therapeutic success (95% confidence interval: 74%-90%; P < 0.0001), and 41% achieved 100% continence. Therapeutic success was 85% at 24 months. Incontinent episodes decreased from a mean of 9.4 per week at baseline to 1.9 at 12 months and 2.9 at 2 years. There were no reported unanticipated adverse device effects associated with InterStim Therapy., Conclusion: Sacral nerve stimulation using InterStim Therapy is a safe and effective treatment for patients with FI.

The biological cascade of fracture healing is intimately linked to the muscle envelope. It further depends on the preservation of stable, perpetual axial micromovements. The current study was designed to demonstrate that high molecular weight bioactive substances diffuse from the muscle envelope to initiate osteoinductive activity at experimental fracture sites. Forty-eight rats underwent an experimental fracture of the left tibia and stabilization with an intramedullary 20-gauge needle. The animals were divided into 4 groups (A-D) of 12 rats each according to the post-fracture treatment. In group A (control) no additional treatment was applied following fracture and intramedullary fixation. In groups B, C, and D, a nitrocellulose membrane of various sizes was wrapped around the fracture, separating the periosteum from the muscle envelope. The groups differed by the membrane pore size, allowing passage of the following molecular sizes: 50 kilodaltons (kDa), 12 to 14 kDa, and 3.5 kDa in groups B, C, and D, respectively. Four animals in each group were sacrificed 2, 5, and 10 weeks after the procedure for radiographic and histological evaluation of fracture healing. Radiographic evaluation revealed a decreased rate of bone synthesis that correlated with the nitrocellulose pore size. Morphological and functional analysis of the bone explants indicated poorly healed fractures in groups B, C, and D. Direct contact between fractured bone and its muscle envelope is essential for the biological sequence of new bone formation. The extent of obstruction between the fracture and its muscle envelope correlates with the delay in fracture healing.

Objective: This study evaluated a psychosocial screening intervention that offers cancer patients counselling. The assumption underlying the intervention was that barriers are often present that hamper patients' awareness of and active request for psychosocial care. An active yet unobtrusive approach was hypothesized to improve accessibility to psychosocial services., Methods: In a sequential cohort design, patients newly admitted to the oncology department of an academic hospital were assigned to a usual care group (n=50) or a screening group (n=79). A retrospective, medical records group (n=89) was also included. At baseline and 4 weeks following discharge, the usual care and screening groups completed mental health and quality of life questionnaires., Results: Half the screening group actually wanted and received counselling. At follow-up, the screening group reported significantly less pain, better mental health and better physical and role functioning than the usual care group., Conclusion: The face-to-face screening intervention appears an effective means of identifying patients interested in obtaining formal psychosocial counselling, and may result in improvements in physical and mental health outcomes., Practice Implications: This screening intervention may be particularly useful for hospitals that prefer a personal approach to psychosocial screening, but do not have sufficient resources to interview every new patient.

Background: The purpose of this study was to determine if a cognitive task analysis (CTA) could capture steps and decision points that were not articulated during traditional teaching of a colonoscopy., Methods: Three expert colorectal surgeons were videotaped performing a colonoscopy. After the videotapes were transcribed, the experts participated in a CTA. A 26-step procedural checklist and a 16-step cognitive demands table was created by using information obtained in the CTA. The videotape transcriptions were transposed onto the procedural checklist and cognitive demands table to identify steps and decision points that were omitted during traditional teaching., Results: Surgeon A described 50% of "how-to" steps and 43% of decision points. Surgeon B described 30% of steps and 25% of decisions. Surgeon C described 26% of steps and 38% of cognitive decisions., Conclusions: By using CTA, we were able to identify relevant steps and decision points that were omitted during traditional teaching by all 3 experts.

Attempts to enhance patients' immune responses to malignancies have been largely unsuccessful. We now describe an immune-escape mechanism mediated by the inhibitory receptor Ig-like transcript 3 (ILT3) that may be responsible for such failures. Using a humanized SCID mouse model, we demonstrate that soluble and membrane ILT3 induce CD8(+) T suppressor cells and prevent rejection of allogeneic tumor transplants. Furthermore, we found that patients with melanoma, and carcinomas of the colon, rectum, and pancreas produce the soluble ILT3 protein, which induces the differentiation of CD8(+) T suppressor cells and impairs T cell responses in MLC. These responses are restored by anti-ILT3 mAb or by depletion of soluble ILT3 from the serum. Immunohistochemical staining of biopsies from the tumors and metastatic lymph nodes suggests that CD68(+) tumor-associated macrophages represent the major source of soluble ILT3. Alternative splicing, resulting in the loss of the ILT3 transmembrane domain, may contribute to the release of ILT3 in the circulation. These data suggest that ILT3 depletion or blockade is crucial to the success of immunotherapy in cancer. In contrast, the inhibitory activity of soluble ILT3 on T cell alloreactivity in vitro and in vivo suggests the potential usefulness of rILT3 for immunosuppressive treatment of allograft recipients or patients with autoimmune diseases.