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.

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.

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.

A Combination of Essential Fatty Acids, Panax Ginseng Extract, and Green Tea Catechins Modifies Brain fMRI Signals in Healthy Older Adults.

OBJECTIVES: To assess the effects of a combination of omega 3 essential fatty acids, green tea catechins, and ginsenosides on cognition and brain functioning in healthy older adults. DESIGN: Double-blind, placebo-controlled, crossover design randomized controlled trial with 26-day intervention phases and a 30-day washout period. SETTING: The Institute for Dementia Research and Prevention at the Pennington Biomedical Research Center. PARTICIPANTS: Ten independently-living, cognitively-healthy older adults (mean age: 67.3 + 2.01 years). INTERVENTION: Daily consumption of an investigational product (trade name "Cerbella TM") consisting of an emulsified liquid combination of standardized fish oil, panax ginseng extract, and green tea catechins in a flavored base of lecithin phospholipids optimized to maximize bioavailability of the active ingredients. MEASUREMENTS: Before and after supplementation with the investigational product or placebo, participants completed cognitive tests including the Mini Mental State Exam (MMSE), Stroop test, Digit Symbol Substitution Test (DSST), and Immediate and Delayed Recall tests, as well as functional magnetic resonance imaging (fMRI) during a standard cognitive task switching paradigm. RESULTS: Performance on the MMSE, Stroop test, and DSST increased significantly over one month of supplementation with the investigational product (one-sample t tests, p<.05) although differences between these changes and corresponding changes during supplementation with placebo were not significant (two-sample t tests, p>.05). During supplementation with the investigational product, brain activation during task performance increased significantly more than during supplementation with placebo in brain regions known to be activated by this task (anterior and posterior cingulate cortex). Functional connectivity during task execution between task regions (middle frontal gyrus and anterior cingulate cortex) increased significantly during supplementation with the investigational product, relative to placebo. Functional connectivity during rest between task regions (precentral gyrus and middle frontal gyrus) and default mode network regions (medial frontal gyrus and precuneus) decreased during supplementation with the investigational product relative to placebo, suggesting greater segregation of task and rest related brain activity. CONCLUSION: One-month supplementation with a combination of omega 3 essential fatty acids, green tea catechins, and ginsenosides was associated with suggestive changes in cognitive functioning as well as modification of brain activation and brain functional connectivity in cognitively healthy older adults.

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.

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.

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.

How Should Remote Clinical Monitoring Be Used to Treat Alcohol Use Disorders?: Initial Findings From an Expert Round Table Discussion.

Scientific evidence combined with new health insurance coverage now enable a chronic illness management approach to the treatment of alcohol use disorders (AUDs), including regular monitoring of blood alcohol content (BAC), as a useful indicator of disease control. Recent technical advances now permit many different types of remote, real-time monitoring of BAC. However, there is no body of research to empirically guide clinicians in how to maximize the clinical potential of remote BAC monitoring.As an initial step in guiding and supporting such research, the manufacturer of one remote BAC monitoring system sponsored a group of experienced clinicians and clinical researchers to discuss 8 issues that generally affect remote, clinical BAC monitoring of "adults in outpatient AUD treatment."The expert panel unanimously agreed that remote BAC monitoring for at least 12 months during and after the outpatient treatment of AUD was a clinically viable deterrent to relapse. There was also consensus that positive test results (ie, recent alcohol use) should lead to intensified care and monitoring. However, there was no agreement on specific types of clinical intensification after a positive test. The panel agreed that sharing positive and negative test results with members of the patient support group was helpful in reinforcing abstinence, yet they noted many practical issues regarding information sharing that remain concerning. Significant differences within the panel on several important clinical issues underline the need for more clinical and implementation research to produce empirically-supported guidelines for the use of remote BAC monitoring in AUD treatment.

Suppression of the CD8 T cell response by human papillomavirus type 16 E7 occurs in Langerhans cell-depleted mice.

Human papillomavirus (HPV) is an epitheliotropic virus that is the primary causal agent for cervical cancer. Langerhans cells (LC) are skin antigen presenting cells that are reduced in number in HPV-infected skin. The aim of this study was to understand the immune-modulatory effects of HPV16 E7 on LC and on the CD8 T cell response to a skin-expressed antigen. To test this, HPV16 E7 was expressed in mouse skin keratinocytes with the model antigen ovalbumin (Ova). Similar to what is observed in HPV-infected human skin, LC numbers were significantly reduced in E7-expressing mouse skin. This shows that expression of the E7 protein alone is sufficient to mediate LC depletion. Expression of E7 with Ova in keratinocytes strongly suppressed the Ova-specific CD8+ T cell response in the skin draining lymph node. When tested in LC-ablated mice, the CD8 T cell response to skin-expressed Ova in control mice was not affected, nor was the T cell response to Ova restored in E7-expressing skin. These data indicate a role for E7 in regulation of LC homeostasis in the skin and in suppression of antigen specific CD8 T cell expansion, but suggest that these two effects occur independent of each other.

Excess cost associated with primary hip and knee joint arthroplasty surgical site infections: a driver to support investment in quality improvement strategies to reduce infection rates.

AIM: To determine the excess costs attributable to surgical site infections (SSI) following primary hip and knee joint arthroplasty at Auckland City Hospital. METHODS: A retrospective case-control study. Cases were patients who developed a SSI following primary hip (THA) and knee arthroplasty (TKA) surgery within 90 days of the procedure. Cases were matched 1:2 with controls; patients whose primary hip and knee arthroplasty procedures were not complicated by infection. Controls were matched for age, gender, date of surgery, type of surgery, and ASA category. The length of stay (LOS) and hospital costs for the initial admission and subsequent readmission for infection were calculated from the clinical costing system at Auckland District Health Board. RESULTS: Eleven cases were identified; 3 following TKA, 7 following THA, and 1 following hemiarthroplasty of the hip. Infections were classified as superficial, 1, joint space, 1, and deep incisional, 9. Five SSI were identified during the initial admission for joint arthroplasty and 6 patients were readmitted with an SSI. Compared to the control patients, SSIs were associated with an excess mean cost of $40,121 and an excess mean LOS of 42 days. CONCLUSIONS: There is a significant increase in LOS and cost associated with SSI following primary THA and TKA at Auckland City Hospital. In addition to the excess cost associated with SSI, there are also opportunity costs resulting from their impact on elective surgical waiting lists. This reinforces the significant positive economic impact a successful strategy to reduce SSIs associated with primary joint arthroplasty procedures will have.

Converging advances in science, policy and public awareness: A time of great opportunity and change in addiction treatment.

Scientific advances, increased public awareness about addiction as a disease, and significant changes in public policy have led to transformational changes in this field. Preclinical and clinical studies highlighted in this issue have supported the emerging concept of substance use disorders as a novel major concern within the healthcare community. In this Commentary, we discuss the potential impact of recent legislation (Affordable Care Act and the Mental Health Parity and Addiction Equity Act) when fully implemented to end the real and perceived segregation of addiction and substance abuse disorders from mainstream healthcare and insurance reimbursement. These legislative changes, along with the diligence of public interest and scientific advances, have the potential to move prevention and treatment of substance use disorders to mainstream healthcare, and to educate professionals appropriately on the prevention and treatment of substance abuse.

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.

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.