Conversion of anti-tissue factor antibody sequences to chimeric antigen receptor and bi-specific T-cell engager format.

BACKGROUND: The efficacy of antibody-targeted therapy of solid cancers is limited by the lack of consistent tumour-associated antigen expression. However, tumour-associated antigens shared with non-malignant cells may still be targeted using conditionally activated-antibodies, or by chimeric antigen receptor (CAR) T cells or CAR NK cells activated either by the tumour microenvironment or following 'unlocking' via multiple antigen-recognition. In this study, we have focused on tissue factor (TF; CD142), a type I membrane protein present on a range of solid tumours as a basis for future development of conditionally-activated BiTE or CAR T cells. TF is frequently upregulated on multiple solid tumours providing a selective advantage for growth, immune evasion and metastasis, as well as contributing to the pathology of thrombosis via the extrinsic coagulation pathway. METHODS: Two well-characterised anti-TF monoclonal antibodies (mAb) were cloned into expression or transposon vectors to produce single chain (scFv) BiTE for assessment as CAR and CD28-CD3-based CAR or CD3-based BiTE. The affinities of both scFv formats for TF were determined by surface plasmon resonance. Jurkat cell line-based assays were used to confirm the activity of the BiTE or CAR constructs. RESULTS: The anti-TF mAb hATR-5 and TF8-5G9 mAb were shown to maintain their nanomolar affinities following conversion into a single chain (scFv) format and could be utilised as CD28-CD3-based CAR or CD3-based BiTE format. CONCLUSION: Because of the broad expression of TF on a range of solid cancers, anti-TF antibody formats provide a useful addition for the development of conditionally activated biologics for antibody and cellular-based therapy.

Use and Misuse of Opioids in Chronic Pain.

The prescribing of opioid analgesics for pain management-particularly for management of chronic noncancer pain (CNCP)-has increased more than fourfold in the United States since the mid-1990s. Yet there is mounting evidence that opioids have only limited effectiveness in the management of CNCP, and the increased availability of prescribed opioids has contributed to upsurges in opioid-related addiction cases and overdose deaths. These concerns have led to critical revisiting and modification of prior pain management practices (e.g., guidelines from the Centers for Disease Control and Prevention), but the much-needed changes in clinical practice will be facilitated by a better understanding of the pharmacology and behavioral effects of opioids that underlie both their therapeutic effects (analgesia) and their adverse effects (addiction and overdose). With these goals in mind, this review first presents an overview of the contemporary problems associated with opioid management of CNCP and the related public health issues of opioid diversion, overdose, and addiction. It then discusses the pharmacology underlying the therapeutic and main adverse effects of opioids and its implications for clinical management of CNCP within the framework of recent clinical guidelines for prescribing opioids in the management of CNCP.

Can older adults improve the identification of moderate intensity using walking cadence?

BACKGROUND: The majority of older adults do not reach the physical activity guidelines. One possible explanation for this may be that older adults overestimate their physical activity levels, because they are unable to identify exercise intensity. METHODS: Forty-four older adults were recruited and randomly assigned into two walking groups lasting 6 weeks. The intervention group was asked to walk a minimum of 150 min per week at moderate intensity using walking cadence indicated with a pedometer. The control group did not get any feedback on walking intensity. RESULTS: The ability to identify moderate intensity while walking did not significantly improve in neither groups (p = 0.530). However, participants in the intervention group increased significantly the time spent at moderate intensity, in 10 min bouts (p < 0.01). DISCUSSION: A pedometer providing walking cadence to reach moderate intensity is a good tool for increasing time walked at the recommended intensity, but not because participants know more what is considered moderate intensity.

Substance Misuse and Substance use Disorders: Why do they Matter in Healthcare?

This paper first introduces important conceptual and practical distinctions among three key terms: substance "use," "misuse," and "disorders" (including addiction), and goes on to describe and quantify the important health and social problems associated with these terms. National survey data are presented to summarize the prevalence and varied costs associated with misuse of alcohol, illegal drugs, and prescribed medications in the United States. With this as background, the paper then describes historical views, perspectives, and efforts to deal with substance misuse problems in the United States and discusses how basic, clinical, and health service research, combined with recent changes in healthcare legislation and financing, have set the stage for a more effective, comprehensive public health approach.

Use of the Internet to Obtain Drugs without a Prescription Among Treatment-involved Adolescents and Young Adults.

Nonmedical use of prescription drugs is common and poses risks such as injury, overdose, and development of abuse and dependence. Internet pharmacies offer prescription drugs without a prescription, creating a source of illicit drugs accessible to anyone with an Internet connection. We examined this issue in a convenience sample of 1,860 adolescents and young adults from 24 residential and outpatient treatment programs. Few individuals obtained drugs from the Internet (n = 26, 2.3%). Pain relievers were the most frequently purchased type of drug. The majority of adolescents and young adult online purchasers made the purchases from their own or a friend's house.

Effective secondary fracture prevention: implementation of a global benchmarking of clinical quality using the IOF Capture the Fracture® Best Practice Framework tool.

UNLABELLED: Fracture Liaison Services are the best model to prevent secondary fractures. The International Osteoporosis Foundation developed a Best Practice Framework to provide a quality benchmark. After a year of implementation, we confirmed that a single framework with set criteria is able to benchmark services across healthcare systems worldwide. INTRODUCTION: Despite evidence for the clinical effectiveness of secondary fracture prevention, translation in the real-world setting remains disappointing. Where implemented, a wide variety of service models are used to deliver effective secondary fracture prevention. To support use of effective models of care across the globe, the International Osteoporosis Foundation's Capture the Fracture® programme developed a Best Practice Framework (BPF) tool of criteria and standards to provide a quality benchmark. We now report findings after the first 12 months of implementation. METHODS: A questionnaire for the BPF was created and made available to institutions on the Capture the Fracture website. Responses from institutions were used to assign gold, silver, bronze or black (insufficient) level of achievements mapped across five domains. Through an interactive process with the institution, a final score was determined and published on the Capture the Fracture website Fracture Liaison Service (FLS) map. RESULTS: Sixty hospitals across six continents submitted their questionnaires. The hospitals served populations from 20,000 to 15 million and were a mix of private and publicly funded. Each FLS managed 146 to 6200 fragility fracture patients per year with a total of 55,160 patients across all sites. Overall, 27 hospitals scored gold, 23 silver and 10 bronze. The pathway for the hip fracture patients had the highest proportion of gold grading while vertebral fracture the lowest. CONCLUSION: In the first 12 months, we have successfully tested the BPF tool in a range of health settings across the globe. Initial findings confirm a significant heterogeneity in service provision and highlight the importance of a global approach to ensure high quality secondary fracture prevention services.

A qualitative study of the reactions of young adults with epilepsy to SUDEP disclosure, perceptions of risks, views on the timing of disclosure, and behavioural change.

OBJECTIVE: We examined young adults' responses to information about sudden unexpected death in epilepsy (SUDEP). METHOD: Consecutive patients attending a specialist epilepsy clinic, aged 16-30years, with a Hospital Anxiety and Depression Scale (HADS) score of <11, and who had been told about SUDEP at least 2weeks previously, were invited to the study. Semistructured in-depth interviews were conducted by an experienced qualitative interviewer until data saturation was achieved. An inductive thematic analysis of the data was conducted, facilitated by the use of the qualitative data analysis software (NVivo). The study was approved by the South East Scotland Research Ethics Committee. RESULTS: Twenty-seven patients (15 females) aged 18-29years were interviewed. All said that they were satisfied with the information that they had received about SUDEP. However, at the interview, their understanding of SUDEP was often limited and incorrect. Many were not aware of their own SUDEP risk status. Twenty-two (81%) said that everyone should be told about SUDEP. Most thought that disclosure should happen at the time of the diagnosis or soon after, preferably in a face-to-face consultation; clinician judgment on timing was highlighted. Few reported seeking further information on SUDEP for themselves beyond the initial consultation. Most were either untroubled by the initial disclosure of SUDEP or reported initial anxiety that was not long-lasting. A minority reported changing their behavior, for example, improving medication adherence, but most reported no change. The majority expressed a fatalistic view of SUDEP as something outside of their control. SIGNIFICANCE: Our results suggest that clinicians can be more confident that most of their young adult patients want to know about SUDEP, want to be told early, and do not have long-lasting anxiety due to its disclosure. Getting information on SUDEP will not, on its own, increase medication adherence in most patients. Methods to increase patient understanding of SUDEP are needed.

Assessing Adolescent Substance Abuse Programs with Updated Quality Indicators: The Development of a Consumer Guide for Adolescent Treatment.

When adolescent substance abuse requires treatment, few parents know which treatment features are important and which treatment programs are effective. There are few resources to help them select appropriate care. We describe early work on an evaluation method and comparative treatment guide for parents based upon the premise that the quality of a program and its potential effectiveness is a function of the number and frequency of evidence-based treatment practices (EBPs) delivered. Thus, we describe the development of and measurement approach for a set of EBPs toward the goal of developing a Consumer Guide to Adolescent Substance Abuse Treatment.

Recent outbreaks of infectious syphilis, United Kingdom, January 2012 to April 2014.

Six outbreaks of infectious syphilis in the United Kingdom, ongoing since 2012, have been investigated among men who have sex with men (MSM) and heterosexual men and women aged under 25 years. Interventions included case finding and raising awareness among healthcare professionals and the public. Targeting at-risk populations was complicated as many sexual encounters involved anonymous partners. Outbreaks among MSM were influenced by the use of geospatial real-time networking applications that allow users to locate other MSM within close proximity.

Capture the Fracture: a Best Practice Framework and global campaign to break the fragility fracture cycle.

UNLABELLED: The International Osteoporosis Foundation (IOF) Capture the Fracture Campaign aims to support implementation of Fracture Liaison Services (FLS) throughout the world. INTRODUCTION: FLS have been shown to close the ubiquitous secondary fracture prevention care gap, ensuring that fragility fracture sufferers receive appropriate assessment and intervention to reduce future fracture risk. METHODS: Capture the Fracture has developed internationally endorsed standards for best practice, will facilitate change at the national level to drive adoption of FLS and increase awareness of the challenges and opportunities presented by secondary fracture prevention to key stakeholders. The Best Practice Framework (BPF) sets an international benchmark for FLS, which defines essential and aspirational elements of service delivery. RESULTS: The BPF has been reviewed by leading experts from many countries and subject to beta-testing to ensure that it is internationally relevant and fit-for-purpose. The BPF will also serve as a measurement tool for IOF to award 'Capture the Fracture Best Practice Recognition' to celebrate successful FLS worldwide and drive service development in areas of unmet need. The Capture the Fracture website will provide a suite of resources related to FLS and secondary fracture prevention, which will be updated as new materials become available. A mentoring programme will enable those in the early stages of development of FLS to learn from colleagues elsewhere that have achieved Best Practice Recognition. A grant programme is in development to aid clinical systems which require financial assistance to establish FLS in their localities. CONCLUSION: Nearly half a billion people will reach retirement age during the next 20 years. IOF has developed Capture the Fracture because this is the single most important thing that can be done to directly improve patient care, of both women and men, and reduce the spiralling fracture-related care costs worldwide.

Demonstration of an app-delivered digital therapeutic program for methamphetamine use disorder.

This study assessed the feasibility and utility of a digital, all-virtual program designed for treatment of methamphetamine use disorder (MUD). Forty-nine adults with moderate- to severe-level MUD (per DSM-5 criteria) commenced the 8-week intervention. All aspects of the program were delivered via smartphone-based app. Intervention components included counseling (cognitive behavioral therapy in group and individual sessions), app-based therapeutic tasks, remote biological drug testing, medical oversight by psychiatrists/nurse practitioners, and contingency management procedures (including rewards for methamphetamine-free saliva drug tests, accomplishing tasks, and engaging in assigned activities). Of the 49 participants who commenced treatment, 27 participants (55%) completed the program. Repeated-measures mixed-model analyses show that participants were more likely to test negative for meth use from week 1 to week 8 (OR = 1.57, 95% CI [1.28, 1.97]; p = 0.034). Well-being and social functioning improved among the majority of participants. These results demonstrate the utility of the all-virtual, digital therapeutic program and its ability to help individuals with MUD to reduce or cease methamphetamine use. The program was efficiently implemented and was well received by participants and clinical personnel, indicating its ability to deliver comprehensive, effective care and to retain the difficult-to-engage population of persons with MUD. Of the 27 completers, 16 responded to a 1-month follow-up survey and reported no meth use in the month since completing the program.

Integrating addiction medicine into graduate medical education in primary care: the time has come.

Substance use disorders create an enormous burden of medical, behavioral, and social problems and pose a major and costly public health challenge. Despite the high prevalence of substance use and its consequences, physicians often do not recognize these conditions and, as a result, provide inadequate patient care. At the center of this failure is insufficient training for physicians about substance use disorders. To address this deficit, the Betty Ford Institute convened a meeting of experts who developed the following 5 recommendations focused on improving training in substance abuse in primary care residency programs in internal medicine and family medicine: 1) integrating substance abuse competencies into training, 2) assigning substance abuse teaching the same priority as teaching about other chronic diseases, 3) enhancing faculty development, 4) creating addiction medicine divisions or programs in academic medical centers, and 5) making substance abuse screening and management routine care in new models of primary care practice. This enhanced primary care residency training should represent a major step forward in improving patient care.

Evolution of concept, but not action, in addiction treatment.

The Western approach to addiction treatment involves a medical or disease orientation to understanding the onset, course, and management of addiction, and a clinical goal of abstinence or very significant reductions in drug use, usually with a combination of behavioral and pharmacological interventions. Even within this Western approach, and despite several consensually accepted features of addiction, a significant mismatch remains between what this culture has come to accept as the nature of the disease and how that same culture continues to treat the disease. This paper discusses the evolution of these Western concepts over the past decade without a corresponding evolution in the nature, duration, or evaluation standards for addiction treatment. (1) Here, we take the position that continuing care and adaptive treatment protocols, combining behavioral therapies, family and social supports, and, where needed, medications show much promise to address the typically chronic, relapsing, and heterogeneous nature of most cases of serious addiction. By extension, methods to evaluate effectiveness of addiction treatment should focus upon the functional status of patients during the course of their treatment instead of post-treatment, as is the evaluation practice used with most other chronic illnesses.

Quantitative detection of seizures with minimal-density EEG montage using phase synchrony and cross-channel coherence amplitude in critical care.

Seizures frequently occur in paediatric emergency and critical care, with up to 74% being sub-clinical seizures making detection difficult. Delays in seizure detection and treatment worsen the neurological outcome of critically-ill patients. Gold-standard seizure detections using multi-channels electroencephalograms (EEG) require trained clinical physiologists to apply scalp electrodes and highly specialised neurologists to interpret and identify seizures. In this study, we extracted phase synchrony and cross-channel coherence amplitude across 4 and 8 pre-selected scalp EEG signals. Binary classification is used to determine whether the signal segment is seizure or non-seizure, and the predictions were compared against the gold-standard seizure onset markings. The application of the algorithm on a cohort of forty routinely collected EEGs from paediatric patients showed an average accuracy of 77.2 % and 76.5% using 4 and 8 channels, respectively. Clinical Relevance- This work demonstrates the feasibility of seizure detection with pre-defined 4 and 8 EEG electrodes with an average accuracy of 77%. This means for the first time seizure detection is possible using an EEG montage that can be applied readily at the bedside independent of expert input.

Fracture liaison services for the evaluation and management of patients with osteoporotic fracture: a cost-effectiveness evaluation based on data collected over 8 years of service provision.

SUMMARY: The cost-effectiveness of Fracture Liaison Services (FLSs) for prevention of secondary fracture in osteoporosis patients in the United Kingdom (UK), and the cost associated with their widespread adoption, were evaluated. An estimated 18 fractures were prevented and £21,000 saved per 1,000 patients. Setup across the UK would cost an estimated £9.7 million. INTRODUCTION: Only 11% to 28% of patients with a fragility fracture receive osteoporosis treatment in the UK. FLSs provide an efficient means to identify patients and are endorsed by the Department of Health but have not been widely adopted. The objective of this study was to evaluate the cost-effectiveness of FLSs in the UK and the cost associated with their widespread adoption. METHODS: A cost-effectiveness and budget-impact model was developed, utilising detailed audit data collected by the West Glasgow FLS. RESULTS: For a hypothetical cohort of 1,000 fragility-fracture patients (740 requiring treatment), 686 received treatment in the FLS compared with 193 in usual care. Assessments and osteoporosis treatments cost an additional £83,598 and £206,544, respectively, in the FLS; 18 fractures (including 11 hip fractures) were prevented, giving an overall saving of £21,000. Setup costs for widespread adoption of FLSs across the UK were estimated at £9.7 million. CONCLUSIONS: FLSs are cost-effective for the prevention of further fractures in fragility-fracture patients. The cost of widespread adoption of FLS across the UK is small in comparison with other service provision and would be expected to result in important benefits in fractures avoided and reduced hospital bed occupancy.

Coordinator-based systems for secondary prevention in fragility fracture patients.

The underlying causes of incident fractures--bone fragility and the tendency to fall--remain under-diagnosed and under-treated. This care gap in secondary prevention must be addressed to minimise both the debilitating consequences of subsequent fractures for patients and the associated economic burden to healthcare systems. Clinical systems aimed at ensuring appropriate management of patients following fracture have been developed around the world. A systematic review of the literature showed that 65% of systems reported include a dedicated coordinator who acts as the link between the orthopaedic team, the osteoporosis and falls services, the patient and the primary care physician. Coordinator-based systems facilitate bone mineral density testing, osteoporosis education and care in patients following a fragility fracture and have been shown to be cost-saving. Other success factors included a fracture registry and a database to monitor the care provided to the fracture patient. Implementation of such a system requires an audit of existing arrangements, creation of a network of healthcare professionals with clearly defined roles and the identification of a 'medical champion' to lead the project. A business case is needed to acquire the necessary funding. Incremental, achievable targets should be identified. Clinical pathways should be supported by evidence-based recommendations from national or regional guidelines. Endorsement of the proposed model within national healthcare policies and advocacy programmes can achieve alignment of the objectives of policy makers, professionals and patients. Successful transformation of care relies upon consensus amongst all participants in the multi-disciplinary team that cares for fragility fracture patients.