THA-AID: Deep Learning Tool for Total Hip Arthroplasty Automatic Implant Detection With Uncertainty and Outlier Quantification.

BACKGROUND: Revision total hip arthroplasty (THA) requires preoperatively identifying in situ implants, a time-consuming and sometimes unachievable task. Although deep learning (DL) tools have been attempted to automate this process, existing approaches are limited by classifying few femoral and zero acetabular components, only classify on anterior-posterior (AP) radiographs, and do not report prediction uncertainty or flag outlier data. METHODS: This study introduces Total Hip Arhtroplasty Automated Implant Detector (THA-AID), a DL tool trained on 241,419 radiographs that identifies common designs of 20 femoral and 8 acetabular components from AP, lateral, or oblique views and reports prediction uncertainty using conformal prediction and outlier detection using a custom framework. We evaluated THA-AID using internal, external, and out-of-domain test sets and compared its performance with human experts. RESULTS: THA-AID achieved internal test set accuracies of 98.9% for both femoral and acetabular components with no significant differences based on radiographic view. The femoral classifier also achieved 97.0% accuracy on the external test set. Adding conformal prediction increased true label prediction by 0.1% for acetabular and 0.7 to 0.9% for femoral components. More than 99% of out-of-domain and >89% of in-domain outlier data were correctly identified by THA-AID. CONCLUSIONS: The THA-AID is an automated tool for implant identification from radiographs with exceptional performance on internal and external test sets and no decrement in performance based on radiographic view. Importantly, this is the first study in orthopedics to our knowledge including uncertainty quantification and outlier detection of a DL model.

Controversial Ebola vaccine trials in Ghana: a thematic analysis of critiques and rebuttals in digital news.

BACKGROUND: Communication is of paramount importance in responding to health crises. We studied the media messages put forth by different stakeholders in two Ebola vaccine trials that became controversial in Ghana. These interactions between health authorities, political actors, and public citizens can offer key lessons for future research. Through an analysis of online media, we analyse stakeholder concerns and incentives, and the phases of the dispute, to understand how the dispute evolved to the point of the trials being suspended, and analyse what steps might have been taken to avert this outcome. METHODS: A web-based system was developed to download and analyse news reports relevant to Ebola vaccine trials. This included monitoring major online newspapers in each country with planned clinical trials, including Ghana. All news articles were downloaded, selecting out those containing variants of the words "Ebola," and "vaccine," which were analysed thematically by a team of three coders. Two types of themes were defined: critiques of the trials and rebuttals in favour of the trials. After reconciling differences between coders' results, the data were visualised and reviewed to describe and interpret the debate. RESULTS: A total of 27,460 articles, published between 1 May and 30 July 2015, were collected from nine different newspapers in Ghana, of which 139 articles contained the keywords and met the inclusion criteria. The final codebook included 27 themes, comprising 16 critiques and 11 rebuttals. After coding and reconciliation, the main critiques (and their associated rebuttals) were selected for in-depth analysis, including statements about the trials being secret (mentioned in 21% of articles), claims that the vaccine trials would cause an Ebola outbreak in Ghana (33%), and the alleged impropriety of the incentives offered to participants (35%). DISCUSSION: Perceptions that the trials were "secret" arose from a combination of premature news reporting and the fact that the trials were prohibited from conducting any publicity before being approved at the time that the story came out, which created an impression of secrecy. Fears about Ebola being spread in Ghana appeared in two forms, the first alleging that scientists would intentionally infect Ghanaians with Ebola in order to test the vaccine, and the second suggesting that the vaccine might give trial participants Ebola as a side-effect - over the course of the debate, the latter became the more prominent of the two variants. The incentives were sometimes criticised for being coercively large, but were much more often criticised for being too small, which may have been related to a misperception that the incentives were meant as compensation for the trials' risks, which were themselves exaggerated. CONCLUSION: The rumours captured through this research indicate the variety of strong emotions drawn out by the trials, highlighting the importance of understanding the emotional and social context of such research. The uncertainty, fear, and distrust associated with the trials draw from the contemporary context of the Ebola outbreak, as well as longstanding historical issues in Ghana. By analysing the debate from its inception, we can see how the controversy unfolded, and identify points of concern that can inform health communication, suggesting that this tool may be valuable in future epidemics and crises.

Diabetes Increases Median Nerve Cross-Sectional Area but Not Disease Severity in Patients with Carpal Tunnel Syndrome.

Background: Ultrasonography (US) is a useful diagnostic modality for diagnosis of carpal tunnel syndrome (CTS). Diabetes mellitus is increasingly prevalent and is a risk factor for CTS. Given the increasing use of US in the diagnosis of CTS, our goal was to evaluate the influence of diabetes on CTS severity and the cross-sectional area (CSA) of the median nerve in patients with CTS. Methods: Patients with clinically diagnosed CTS were seen in the outpatient setting from October 2014 to February 2021. Median nerve CSA and patient reported severity measures were obtained: Boston Carpal Tunnel Syndrome Questionnaire (BCTSQ) and CTS-6. For patients with diabetes, additional parameters were collected including most recent A1c, insulin pharmacotherapy, and polypharmacy. Results: Ninety-nine patients (122 nerves) without diabetes and 55 patients (82 nerves) with diabetes were recruited for the study. Patients in the diabetes group were more obese and older and had a significantly increased median nerve CSA compared with patients without diabetes. Obesity was associated with higher median nerve CSA in all patients but not in patients with diabetes. There was no difference in disease severity in patients with and without diabetes as reported by BCTSQ or CTS-6 scores. In patients with diabetes, there was significantly decreased median nerve CSA with A1c of 6.5 or higher and a trend to decreased CSA with polypharmacy. There was no influence of insulin therapy on median nerve CSA. Conclusion: Diabetes is associated with higher median nerve CSA in patients with CTS of similar disease severity. The increased median nerve CSA in patients with diabetes may be reflective of diabetes-related microvascular changes. Interestingly, the trend to decreased median nerve CSA in patients with suboptimal diabetic control (A1c ≥ 6.5) may suggest eventual degenerative changes to the median nerve. In summary, clinicians should be cautious with interpreting a larger median nerve CSA as more severe CTS in patients with diabetes. Level of Evidence: Level 3 Diagnostic.

Patients Prefer Ultrasound to Nerve Conduction Studies for the Diagnosis of Carpal Tunnel Syndrome.

Background: The net promoter score (NPS) allows analysis of patient satisfaction and preference between treatment and/or diagnostic testing. Electrodiagnostic testing (EDX) and ultrasound (US) are commonly used diagnostic tests for carpal tunnel syndrome. Although EDX is reliable for diagnosing carpal tunnel syndrome (CTS), it can be uncomfortable and inconvenient for patients. We aimed to determine whether patients preferred US or EDX studies for the diagnosis of CTS, using the NPS. Methods: Seventy-five patients presenting to the clinic for evaluation of CTS complaints who had EDX were prospectively studied. US evaluation of the median nerve was then completed at time of evaluation. Patient satisfaction was determined by asking, "how likely are you to recommend this procedure to a friend or relative?" for both EDX and US. Patient demographics, comorbidities, CTS-6 questionnaire (CTS-6), and functionality assessed through patient-reported qDASH were also recorded. Results: Sixty-five patients were included in the study. Most patients did not have any comorbidities and were nonsmokers. The gender composition was similar, and the average age of the enrolled patients was 58. The NPS for US was significantly higher than EDX (P < 0.0001). Patients with diabetes mellitus rated their EDX experience significantly lower than those without diabetes mellitus. Conclusions: Patients are more likely to recommend US instead of EDX in the evaluation of CTS complaints. This allows for shared decision-making between the patient and provider if ordering diagnostic testing for CTS.

Real-World Performance of a Comprehensive Genomic Profiling Test Optimized for Small Tumor Samples.

PURPOSE: Tissue-based comprehensive genomic profiling (CGP) is increasingly used for treatment selection in patients with advanced cancer; however, tissue availability may limit widespread implementation. Here, we established real-world CGP tissue availability and assessed CGP performance on consecutively received samples. MATERIALS AND METHODS: We conducted a post hoc, nonprespecified analysis of 32,048 consecutive tumor tissue samples received for StrataNGS, a multiplex polymerase chain reaction (PCR)-based comprehensive genomic profiling (PCR-CGP) test, as part of an ongoing observational trial (NCT03061305). Sample characteristics and PCR-CGP performance were assessed across all tested samples, including exception samples not meeting minimum input quality control (QC) requirements (< 20% tumor content [TC], < 2 mm2 tumor surface area [TSA], DNA or RNA yield < 1 ng/µL, or specimen age > 5 years). Tests reporting ≥ 1 prioritized alteration or meeting TC and sequencing QC were considered successful. For prostate carcinoma and lung adenocarcinoma, tests reporting ≥ 1 actionable or informative alteration or meeting TC and sequencing QC were considered actionable. RESULTS: Among 31,165 (97.2%) samples where PCR-CGP was attempted, 10.7% had < 20% TC and 59.2% were small (< 25 mm2 tumor surface area). Of 31,101 samples evaluable for input requirements, 8,089 (26.0%) were exceptions not meeting requirements. However, 94.2% of the 31,101 tested samples were successfully reported, including 80.5% of exception samples. Positive predictive value of PCR-CGP for ERBB2 amplification in exceptions and/or sequencing QC-failure breast cancer samples was 96.7%. Importantly, 84.0% of tested prostate carcinomas and 87.9% of lung adenocarcinomas yielded results informing treatment selection. CONCLUSION: Most real-world tissue samples from patients with advanced cancer desiring CGP are limited, requiring optimized CGP approaches to produce meaningful results. An optimized PCR-CGP test, coupled with an inclusive exception testing policy, delivered reportable results for > 94% of samples, potentially expanding the proportion of CGP-testable patients and impact of biomarker-guided therapies.

All-Arthroscopic Biceps Tenodesis Using the Anterolateral Anchor During Concomitant Double-Row Rotator Cuff Repair.

Arthroscopic biceps tenodesis is a commonly performed procedure; however, there is a paucity of literature regarding concomitant biceps tenodesis and double-row rotator cuff repair. In this Technical Note, we describe an all-arthroscopic biceps tenodesis using the stay sutures from the anterolateral anchor in the setting of a double-row rotator cuff repair. The anterolateral anchor is placed adjacent to the bicipital groove to accommodate the tenodesis. Two sutures loaded into the anterolateral anchor are passed through the long head of the biceps tendon in a cinch configuration without the need to externalize the tendon. The sutures are tied arthroscopically, thereby securing the tendon to the anterolateral row anchor and completing the tenodesis.

Four-dimensional surface motions of the Slumgullion landslide and quantification of hydrometeorological forcing.

Landslides modify the natural landscape and cause fatalities and property damage worldwide. Quantifying landslide dynamics is challenging due to the stochastic nature of the environment. With its large area of ~1 km2 and perennial motions at ~10-20 mm per day, the Slumgullion landslide in Colorado, USA, represents an ideal natural laboratory to better understand landslide behavior. Here, we use hybrid remote sensing data and methods to recover the four-dimensional surface motions during 2011-2018. We refine the boundaries of an area of ~0.35 km2 below the crest of the prehistoric landslide. We construct a mechanical framework to quantify the rheology, subsurface channel geometry, mass flow rate, and spatiotemporally dependent pore-water pressure feedback through a joint analysis of displacement and hydrometeorological measurements from ground, air and space. Our study demonstrates the importance of remotely characterizing often inaccessible, dangerous slopes to better understand landslides and other quasi-static mass fluxes in natural and industrial environments, which will ultimately help reduce associated hazards.

Clinical Outcomes of an All-Arthroscopic Biceps Tenodesis Using the Anterolateral Anchor During Concomitant Double-Row Rotator Cuff Repair.

BACKGROUND: Pathology of the long head of the biceps tendon frequently occurs concomitantly with rotator cuff tears, necessitating a surgical treatment, often in the form of a tenodesis procedure. Many techniques for a tenodesis exist; however, they often require additional implants or a separate incision. PURPOSE: To report an average of 2-year outcomes of an all-arthroscopic biceps tenodesis employing the stay sutures from the anterolateral anchor during concomitant double-row rotator cuff repair (RCR). STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Data were prospectively collected and retrospectively reviewed for all patients who underwent an all-arthroscopic biceps tenodesis during concomitant double-row RCR by the senior author between January 2014 and May 2018. Patients were included if they underwent this procedure and had baseline preoperative patient-reported outcomes (PROs) with a minimum of 1 year of postoperative PROs for the American Shoulder and Elbow Surgeons (ASES) score and visual analog scale (VAS) for pain score. Additionally, patient data, surgical history, postoperative complications, and satisfaction were reported. RESULTS: Fifteen patients were eligible for the study. There were 12 (80%) men and 3 (20%) women with a mean age of 50.0 years (range, 35-64 years). The mean follow-up time was 25.2 months (range, 13-63 months). Six of 15 (40%) patients also had an arthroscopic subscapularis repair performed. ASES shoulder scores improved from 37.1 preoperatively to 94.1 postoperatively (P < .001), and VAS scores improved from 6.4 preoperatively to 0.5 postoperatively (P < .001). One patient who underwent concomitant subscapularis repair reported continued anterior groove pain. No patients experienced biceps cramping, developed a deformity, or required a repeat operation at the final follow-up. Overall, 93.3% of the patients reported being highly satisfied with their surgery. CONCLUSION: This study presents the clinical results of an all-arthroscopic technique for concomitant double-row RCR and biceps tenodesis, which resulted in high rates of patient satisfaction and significant improvement in reported shoulder outcome and pain scores. Additionally, this technique offers the potential benefits of avoiding a secondary incision, which may decrease surgical morbidity while also decreasing cost by eliminating the need for an extra, tenodesis-specific implant.

Influenza and pertussis vaccination in pregnancy: Portrayal in online media articles and perceptions of pregnant women and healthcare professionals.

INTRODUCTION: Online media may influence women's decision to undergo vaccination during pregnancy. The aims of this mixed-methods study were to: (1) examine the portrayal of maternal vaccination in online media and (2) establish the perceived target of vaccine protection as viewed by pregnant women and maternity healthcare professionals (HCPs). METHODS: Online media articles on maternal vaccination (published July-December 2012 or November 2015-April 2016) were identified through the London School of Hygiene & Tropical Medicine's Vaccine Confidence Database and thematically analysed. Questionnaires for pregnant women and HCPs were distributed within four English hospitals (July 2017-January 2018). RESULTS: Of 203 articles identified, 60% related to pertussis vaccination, 33% to influenza and 6% both. The majority positively portrayed vaccination in pregnancy (97%), but inaccurate, negative articles persist which criticize pertussis vaccination's safety and efficacy. Positively-worded articles about pertussis tended to focus on infant protection and highlight examples of recent cases, whereas positively-worded articles about influenza focused on maternal protection. These themes were reflected in questionnaire responses from 314 pregnant women and 204 HCPs, who perceived pertussis vaccination as protecting the baby, and influenza vaccination as protecting the mother, or mother and baby equally. A minority of the pregnant women surveyed intended to decline influenza (22%) or pertussis (8%) vaccination. CONCLUSIONS: The majority of online articles support pertussis and influenza vaccination during pregnancy. The portrayal of pertussis vaccination as primarily benefiting the child, using real-examples, may influence its higher uptake compared with influenza. This approach should be considered by HCPs when recommending vaccination. HCPs should be prepared to provide advice to women hesitant about vaccination, including addressing any negative media, and consider educational strategies to counteract inaccurate information. Future studies should directly assess the influence of media on vaccine decision-making and establish which media platforms are typically used by pregnant women to gather information.

Risk perception and the influence on uptake and use of biomedical prevention interventions for HIV in sub-Saharan Africa: A systematic literature review.

BACKGROUND: Risk perception has been found to be a crucial factor explaining inconsistent or non-use of HIV prevention interventions. Considerations of risk need to expand beyond risk of infection to also include the personal, social, emotional, and economic risks associated with prevention intervention use. OBJECTIVES: This systematic review of qualitative peer-reviewed literature from sub-Saharan Africa examines perceptions of risk associated with HIV infection and HIV prevention intervention use. DATA SOURCES: We searched Medline, Embase, PsychInfo, Africa Wide Info, CINAHL, and Global Health for publications and screened them for relevance. STUDY ELIGIBILITY CRITERIA: Peer-reviewed qualitative studies published since 2003 were eligible for inclusion if they examined risk perception or uncertainty in the context of a medically regulated intervention. Only studies focusing on adults were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Included publications were quality assessed using the Hawker method and coded thematically. RESULTS: 10318 unique papers were identified, of which 29 are included. Among the themes identified, a particularly salient one was the potential of HIV prevention interventions to threaten the stability of a relationship and impact on how and when people may-or may not-choose to use prevention interventions. LIMITATIONS: This literature review excludes grey-literature, which may have distinct valuable insights. We also excluded quantitative studies that may have challenged or triangulated our findings. CONCLUSIONS AND IMPLICATIONS: When considering the risk of HIV acquisition, it is insufficient to examine biological risk in isolation from the personal, relational and economic costs associated with intervention use. This loss of emotional, physical, or material support may be perceived as more consequential than the prevention of a potential infection.

The State of Vaccine Confidence 2016: Global Insights Through a 67-Country Survey.

BACKGROUND: Public trust in immunization is an increasingly important global health issue. Losses in confidence in vaccines and immunization programmes can lead to vaccine reluctance and refusal, risking disease outbreaks and challenging immunization goals in high- and low-income settings. National and international immunization stakeholders have called for better monitoring of vaccine confidence to identify emerging concerns before they evolve into vaccine confidence crises. METHODS: We perform a large-scale, data-driven study on worldwide attitudes to immunizations. This survey - which we believe represents the largest survey on confidence in immunization to date - examines perceptions of vaccine importance, safety, effectiveness, and religious compatibility among 65,819 individuals across 67 countries. Hierarchical models are employed to probe relationships between individual- and country-level socio-economic factors and vaccine attitudes obtained through the four-question, Likert-scale survey. FINDINGS: Overall sentiment towards vaccinations is positive across all 67 countries, however there is wide variability between countries and across world regions. Vaccine-safety related sentiment is particularly negative in the European region, which has seven of the ten least confident countries, with 41% of respondents in France and 36% of respondents in Bosnia & Herzegovina reporting that they disagree that vaccines are safe (compared to a global average of 13%). The oldest age group (65+) and Roman Catholics (amongst all faiths surveyed) are associated with positive views on vaccine sentiment, while the Western Pacific region reported the highest level of religious incompatibility with vaccines. Countries with high levels of schooling and good access to health services are associated with lower rates of positive sentiment, pointing to an emerging inverse relationship between vaccine sentiments and socio-economic status. CONCLUSIONS: Regular monitoring of vaccine attitudes - coupled with monitoring of local immunization rates - at the national and sub-national levels can identify populations with declining confidence and acceptance. These populations should be prioritized to further investigate the drivers of negative sentiment and to inform appropriate interventions to prevent adverse public health outcomes.

Ethics and the Responsible Conduct of Research in the Chemical Community: The Unique Role and Challenges of the News Media.

Journalists who cover scientific research, including chemistry research, have an obligation to report on alleged cases of research misconduct when knowledge of these surface. New Government definitions of research misconduct, beginning in the late 1990s with the Clinton Administration, have helped scientists, policymakers, as well as journalists sort out and make sense of alleged research misconduct. Journalistic reporting on research misconduct includes many challenges: gathering information from sources who are intimidated or afraid to speak, strict adherence to journalist ethics that take on a new dimension when careers, reputations, and research funding are at stake; efforts by government and institutional bureaucrats to dampen or thwart legitimate news coverage. The Internet, blogging, and social media have added still more complexity and ethical quandaries to this blend. The author, News Editor of Chemical & Engineering News published by the American Chemical Society, provides examples from his own career and that of colleagues. He suggests that an enhanced spirit of understanding and cooperation between journalists and members of the scientific community can lead to avenues of open discussion of research misconduct--discussions that might prevent and mitigate the very real damage caused by bad actors in science who betray themselves, their peers, and the body of modern day scientific knowledge when they make the decision to march into the darkness of dishonesty, plagiarism, or falsification.

Measuring vaccine confidence: introducing a global vaccine confidence index.

BACKGROUND: Public confidence in vaccination is vital to the success of immunisation programmes worldwide. Understanding the dynamics of vaccine confidence is therefore of great importance for global public health. Few published studies permit global comparisons of vaccination sentiments and behaviours against a common metric. This article presents the findings of a multi-country survey of confidence in vaccines and immunisation programmes in Georgia, India, Nigeria, Pakistan, and the United Kingdom (UK) - these being the first results of a larger project to map vaccine confidence globally. METHODS: Data were collected from a sample of the general population and from those with children under 5 years old against a core set of confidence questions. All surveys were conducted in the relevant local-language in Georgia, India, Nigeria, Pakistan, and the UK. We examine confidence in immunisation programmes as compared to confidence in other government health services, the relationships between confidence in the system and levels of vaccine hesitancy, reasons for vaccine hesitancy, ultimate vaccination decisions, and their variation based on country contexts and demographic factors. RESULTS: The numbers of respondents by country were: Georgia (n=1000); India (n=1259); Pakistan (n=2609); UK (n=2055); Nigerian households (n=12554); and Nigerian health providers (n=1272). The UK respondents with children under five years of age were more likely to hesitate to vaccinate, compared to other countries. Confidence in immunisation programmes was more closely associated with confidence in the broader health system in the UK (Spearman's ρ=0.5990), compared to Nigeria (ρ=0.5477), Pakistan (ρ=0.4491), and India (ρ=0.4240), all of which ranked confidence in immunisation programmes higher than confidence in the broader health system. Georgia had the highest rate of vaccine refusals (6 %) among those who reported initial hesitation. In all other countries surveyed most respondents who reported hesitating to vaccinate went on to receive the vaccine except in Kano state, Nigeria, where the percentage of those who ultimately refused vaccination after initially hesitating was as high as 76%) Reported reasons for hesitancy in all countries were classified under the domains of "confidence," "convenience," or "complacency," and confidence issues were found to be the primary driver of hesitancy in all countries surveyed.

Vaccine hesitancy: clarifying a theoretical framework for an ambiguous notion.

Today, according to many public health experts, public confidence in vaccines is waning. The term "vaccine hesitancy" (VH) is increasingly used to describe the spread of such vaccine reluctance. But VH is an ambiguous notion and its theoretical background appears uncertain. To clarify this concept, we first review the current definitions of VH in the public health literature and examine its most prominent characteristics. VH has been defined as a set of beliefs, attitudes, or behaviours, or some combination of them, shared by a large and heterogeneous portion of the population and including people who exhibit reluctant conformism (they may either decline a vaccine, delay it or accept it despite their doubts) and vaccine-specific behaviours. Secondly, we underline some of the ambiguities of this notion and argue that it is more a catchall category than a real concept. We also call into question the usefulness of understanding VH as an intermediate position along a continuum ranging from anti-vaccine to pro-vaccine attitudes, and we discuss its qualification as a belief, attitude or behaviour. Thirdly, we propose a theoretical framework, based on previous literature and taking into account some major structural features of contemporary societies, that considers VH as a kind of decision-making process that depends on people's level of commitment to healthism/risk culture and on their level of confidence in the health authorities and mainstream medicine.

Measuring vaccine hesitancy: The development of a survey tool.

In March 2012, the SAGE Working Group on Vaccine Hesitancy was convened to define the term "vaccine hesitancy", as well as to map the determinants of vaccine hesitancy and develop tools to measure and address the nature and scale of hesitancy in settings where it is becoming more evident. The definition of vaccine hesitancy and a matrix of determinants guided the development of a survey tool to assess the nature and scale of hesitancy issues. Additionally, vaccine hesitancy questions were piloted in the annual WHO-UNICEF joint reporting form, completed by National Immunization Managers globally. The objective of characterizing the nature and scale of vaccine hesitancy issues is to better inform the development of appropriate strategies and policies to address the concerns expressed, and to sustain confidence in vaccination. The Working Group developed a matrix of the determinants of vaccine hesitancy informed by a systematic review of peer reviewed and grey literature, and by the expertise of the working group. The matrix mapped the key factors influencing the decision to accept, delay or reject some or all vaccines under three categories: contextual, individual and group, and vaccine-specific. These categories framed the menu of survey questions presented in this paper to help diagnose and address vaccine hesitancy.

Human U251MG glioma cells expressing the membrane form of macrophage colony-stimulating factor (mM-CSF) are killed by human monocytes in vitro and are rejected within immunodeficient mice via paraptosis that is associated with increased expression of three different heat shock proteins.

Human U251MG glioma cells retrovirally transduced with the human gene for the membrane form of macrophage colony-stimulating factor (mM-CSF) were investigated. The clones, MG-2F11 and MG-2C4, that expressed the most mM-CSF, but not the viral vector or the parental U251MG cells, were killed by both murine and human monocyte/macrophages in cytotoxicity assays. MG-2F11 cells failed to form subcutaneous tumors in either nude or NIH-bg-nu-xidBR mice, while mice inoculated with the U251MG viral vector (MG-VV) cells developed tumors. Electron microscopy studies showed that 4 hours after subcutaneous injection, the mM-CSF-transduced cells began dying of a process that resembled paraptosis. The dying tumor cells were swollen and had extensive vacuolization of their mitochondria and endoplasm reticulum. This killing process was complete within 24 hours. Macrophage-like cells were immediately adjacent to the killed MG-2F11 cells. Immunohistological staining for the heat shock proteins HSP60, HSP70 and GRP94 (gp96) showed that 18 hours after inoculation into nude mice, the MG-2F11 injection site was two to four times more intensely stained than the MG-VV cells. This study shows that human gliomas transduced with mM-CSF have the potential to be used as a safe live tumor cell vaccine.

Discovery of phosphonic diamide prodrugs and their use for the oral delivery of a series of fructose 1,6-bisphosphatase inhibitors.

Like most phosphonic acids, the recently discovered potent and selective thiazole phosphonic acid inhibitors of fructose 1,6-bisphosphatase (FBPase) exhibited low oral bioavailability (OBAV) and therefore required a prodrug to achieve oral efficacy. Syntheses of known phosphonate prodrugs did not afford the desired OBAV; hence, a new class of prodrugs was sought. Phosphonic diamides derived from amino acid esters were discovered as viable prodrugs, which met our preset goals: excellent aqueous stability over a wide pH range, benign byproducts (amino acids and low molecular weight alcohols), and most importantly good OBAV leading to robust oral glucose lowering effects. These desirable properties of phosphonic diamides represent significant improvements over existing prodrug classes. Optimization of the diamide prodrugs of phosphonic acid 2a (MB05032) led to the identification of diamide 8 (MB06322), the first reported orally efficacious FBPase inhibitor.

Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs.

Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TRbeta(1), K(i) < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T(3), PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED(50) 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.