Mobile telephone delivered contingency management for encouraging adherence to supervised methadone consumption: feasibility study for an RCT of clinical and cost-effectiveness (TIES).

BACKGROUND: Prescription methadone or buprenorphine enables people with opioid use disorder to stop heroin use safely while avoiding withdrawal. To ensure methadone is taken as prescribed and to prevent diversion onto the illicit market, people starting methadone take their daily dose under a pharmacist's supervision. Many patients miss their daily methadone dose risking withdrawal, craving for heroin and overdose due to loss of heroin tolerance. Contingency management (CM) can improve medication adherence, but remote delivery using technology may be resource-light and cost-effective. We developed an innovative way to deliver CM by mobile telephone. Software monitors patients' attendance and supervised methadone consumption through an internet self-login at the pharmacy and sends reinforcing text messages to patients' mobile telephones. A linked system sends medication adherence reports to prescribers and provides early warning alerts of missed doses. A pre-paid debit card system provides financial incentives. METHODS: A cluster randomised controlled trial design was used to test the feasibility of conducting a future trial of mobile telephone CM to encourage adherence to supervised methadone in community pharmacies. Each cluster (drug service/3 allied pharmacies) was randomly allocated to provide patient's presenting for a new episode of opiate agonist treatment (OAT) with either (a) mobile telephone text message CM, (b) mobile telephone text message reminders, or (c) no text messages. We assessed acceptability of the interventions, recruitment, and follow-up procedures. RESULTS: Four drug clinics were approached and three recruited. Thirty-three pharmacists were approached and 9 recruited. Over 3 months, 173 individuals were screened and 10 enrolled. Few patients presented for OAT and high numbers were excluded due to receiving buprenorphine or not attending participating pharmacies. There was 96% consistency in recording medication adherence by self-login vs. pharmacy records. In focus groups, CM participants were positive about using self-login, the text messages, and debit card. Prescribers found weekly reporting, time saving, and allowed closer monitoring of patients. Pharmacists reported that the tablet device was easy to host. CONCLUSION: Mobile telephone CM worked well, but a planned future trial will use modified eligibility criteria (existing OAT patients who regularly miss their methadone/buprenorphine doses) and increase the number of participating pharmacies. TRIAL REGISTRATION: The trial is retrospectively registered, ISRCTN 58958179 .

The Relationship Between Cerebral Reperfusion And Regional Expression Of Matrix Metalloproteinase-9 In Rat Brain Following Focal Cerebral Ischemia.

We investigated the effect of full and partial mechanical reperfusion on MMP-9 expression in rat brain following middle cerebral artery occlusion, mimicking mechanical thrombectomy. Using percentage hemispheric lesion volume and oedema as measures, partial reperfusion reduced extent of brain damage caused by MCA occlusion, but the protective effect was less pronounced than with complete reperfusion. Using ELISA quantification in fresh frozen tissue, confirmed by immunofluorescence in perfusion fixed tissue, increased MMP-9 expression was observed in infarcted tissue. MMP-9 was increased in lesioned tissue of the anterior and posterior temporal cortex and underlying striatal tissue, but also the normal appearing frontal cortex. No significant increase in MMP-9 in the hippocampus was observed, nor in the unlesioned contralateral hemisphere. Both partial reperfusion and full reperfusion reduced the regional MMP expression significantly. The highest levels of MMP-9 were observed in lesioned brain regions in the non-reperfused group. MMP-9 expression was evident in microvessels and in neuronal cell bodies of affected tissue. This study shows that MMP-9 brain levels are reduced relative to the extent of reperfusion. These observations suggest targeting early increases in MMP-9 expression as a possible neuroprotective therapeutic strategy and highlight the rat MCA occlusion model as an ideal model in which to study candidate therapeutics.

An observational study to compare the utilisation of computed tomography colonography with optical colonoscopy as the first diagnostic imaging tool in patients with suspected colorectal cancer.

AIM: To evaluate the clinical and cost implications of using computed tomography colonography (CTC) compared to optical colonoscopy (OC) as the initial colonic investigation in patients with low-to-intermediate risk of colorectal cancer (CRC). MATERIALS AND METHODS: A non-randomised, prospective single-centre study recruited 180 participants to compare the cost implications of two clinical pathways used in the diagnosis of low-to-intermediate risk of CRC that differ in the initial diagnostic test, either CTC or OC. Costs were compared using generalised linear models (GLM) and combined with quality-adjusted life years (QALYs, based on the EQ-5D-5L) to estimate cost-effectiveness at 6 months post-recruitment. Secondary outcomes assessed access to care and patient satisfaction. RESULTS: Mean (SD, n) cost at 6 months post-recruitment per participant was £991 (£316, n=105) for the OC group and £645 (£607, n=68) for the CTC group, leading to an estimated cost difference of -£370 (95% CI: -£554, -£185, p<0.001). Assuming a £20,000 willingness-to-pay per QALY threshold, there was a 91.4% probability of CTC being cost-effective at month 6. The utilisation of CTC led to improved access to care, with a shorter mean time from referral from primary care to results (6.3 days difference, p=0.005). No differences in patient satisfaction were detected between both groups. CONCLUSION: The utilisation of CTC as the first-line investigation for patients with low-to-intermediate risk of CRC has the potential to release OC capacity, of pivotal importance for patients more likely to benefit from an invasive diagnostic approach.

Efficacy of non-antibiotic treatment options for digital dermatitis on an organic dairy farm.

The objective of this study was to evaluate the efficacy of two non-antibiotic treatment options for digital dermatitis (DD) on an organic certified dairy farm. A randomized clinical trial was conducted using 70 multiparous Holstein cows with an early DD lesion at a USDA certified organic dairy farm in Northern Colorado, USA. Cows were enrolled in the study based on the presence of early DD lesions (scores M1 and M2) and randomly assigned to one of three treatments: (1) topical application of copper sulfate and iodine (CUI); (2) topical application of honey and iodine (HOI); and (3) control subject to no treatment (CON). Cows were evaluated at enrolment and on days 3, 12, 28, and 120 post treatment for pain and lesion size and received a locomotion and a lesion score. Cure was defined as the transition from active to non-active stages (M1/M2 to M0 or M4). The formulations had variable effects on the treatment of DD. The cure rate was numerically higher for CUI on all follow up days. The proportion of cows experiencing pain on d3 after treatment was greater in CON, followed by HOI and CUI. However, this proportion increased in HOI during the follow up period. The CUI group had a greater reduction in lesion size and larger lesions persisted in HOI. Non-antibiotic treatment formulations were partially effective in the treatment of DD in organic dairy cows: The two non-antibiotic formulations resulted in an earlier transition to mature lesions compared with the control group. The CUI combination was the most effective treatment in reducing lesion size, pain, and lameness in affected cows. However, this combination had short-term efficacy, which did not persist throughout the duration of the study. The HOI combination produced only transient reduction in lesion size.

Clinical and cost implications of using immediate MRI in the management of patients with a suspected scaphoid fracture and negative radiographs results from the SMaRT trial.

AIMS: The aim of the Scaphoid Magnetic Resonance Imaging in Trauma (SMaRT) trial was to evaluate the clinical and cost implications of using immediate MRI in the acute management of patients with a suspected fracture of the scaphoid with negative radiographs. PATIENTS AND METHODS: Patients who presented to the emergency department (ED) with a suspected fracture of the scaphoid and negative radiographs were randomized to a control group, who did not undergo further imaging in the ED, or an intervention group, who had an MRI of the wrist as an additional test during the initial ED attendance. Most participants were male (52% control, 61% intervention), with a mean age of 36.2 years (18 to 73) in the control group and 38.2 years (20 to 71) in the intervention group. The primary outcome was total cost impact at three months post-recruitment. Secondary outcomes included total costs at six months, the assessment of clinical findings, diagnostic accuracy, and the participants' self-reported level of satisfaction. Differences in cost were estimated using generalized linear models with gamma errors. RESULTS: The mean cost up to three months post-recruitment per participant was £542.40 (sd £855.20, n = 65) for the control group and £368.40 (sd £338.60, n = 67) for the intervention group, leading to an estimated cost difference of £174 (95% confidence interval (CI) -£30 to £378; p = 0.094). The cost difference per participant increased to £266 (95% CI £3.30 to £528; p = 0.047) at six months. Overall, 6.2% of participants (4/65, control group) and 10.4% of participants (7/67, intervention group) had sustained a fracture of the scaphoid (p = 0.37). In addition, 7.7% of participants (5/65, control group) and 22.4% of participants (15/67, intervention group) had other fractures diagnosed (p = 0.019). The use of MRI was associated with higher diagnostic accuracy both in the diagnosis of a fracture of the scaphoid (100.0% vs 93.8%) and of any other fracture (98.5% vs 84.6%). CONCLUSION: The use of immediate MRI in the management of participants with a suspected fracture of the scaphoid and negative radiographs led to cost savings while improving the pathway's diagnostic accuracy and patient satisfaction. Cite this article: Bone Joint J 2019;101-B:984-994.

Positive reinforcement targeting abstinence in substance misuse (PRAISe): Study protocol for a Cluster RCT & process evaluation of contingency management.

There are approximately 256,000 heroin and other opiate users in England of whom 155,000 are in treatment for heroin (or opiate) addiction. The majority of people in treatment receive opiate substitution treatment (OST) (methadone and buprenorphine). However, OST suffers from high attrition and persistent heroin use even whilst in treatment. Contingency management (CM) is a psychological intervention based on the principles of operant conditioning. It is delivered as an adjunct to existing evidence based treatments to amplify patient benefit and involves the systematic application of positive reinforcement (financial or material incentives) to promote behaviours consistent with treatment goals. With an international evidence base for CM, NICE recommended that CM be implemented in UK drug treatment settings alongside OST to target attendance and the reduction of illicit drug use. While there was a growing evidence base for CM, there had been no examination of its delivery in UK NHS addiction services. The PRAISe trial evaluates the feasibility, acceptability, clinical and cost effectiveness of CM in UK addiction services. It is a cluster randomised controlled effectiveness trial of CM (praise and financial incentives) targeted at either abstinence from opiates or attendance at treatment sessions versus no CM among individuals receiving OST. The trial includes an economic evaluation which explores the relative costs and cost effectiveness of the two CM intervention strategies compared to TAU and an embedded process evaluation to identify contextual factors and causal mechanisms associated with variations in outcome. This study will inform UK drug treatment policy and practice. Trial registration ISRCTN 01591254.

Animal Models of Focal Cerebral Ischaemia and Haemorrhagic Transformation: Considerations in Experimental Stroke Study Design.

BACKGROUND: Ischaemic stroke is often complicated with haemorrhage within the infarct zone or in a remote location especially when treated with intravenous thrombolysis and/or thrombectomy. While these early recanalisation treatments are highly effective, some of the benefit is lost because of haemorrhagic complications and consequential neurological deterioration of the patients. A number of mechanisms have been described that mediate the haemorrhagic changes and several agents have been tested in experimental models for inhibiting post-stroke haemorrhage. METHODS: Here, we review and discuss the small animal models of focal cerebral ischaemia and postischaemic stroke haemorrhagic transformation and how these models can best be utilised for developing further insights as well as potential treatment approaches for this serious clinical complication. RESULTS: The need to use appropriate animal models with relevant stroke risk factors to improve the clinical relevance and applicability of findings is becoming ever more apparent. Current focal ischaemia models can be adapted for the study of haemorrhagic transformation post-stroke. CONCLUSION: A number of factors can be added to the animal model design to increase the incidence and/or severity of haemorrhagic transformation post-ischaemic stroke, which can improve clinical relevance, aid the study of the pathophysiology and the future development of novel interventions.

Missing pieces of the puzzle to effectively control digital dermatitis.

Since the first report of bovine digital dermatitis (DD) in 1974, there is a large body of the literature published; however, effective prevention and control of the disease remain elusive. Although many aspects of the pathogenesis of DD have been investigated, even some of the most basic questions such as the aetiology of this disease remain under debate. Treponema spp. have been strongly associated with DD lesions and occur in abundance in advanced lesions; however, efforts to induce disease with pure cultures of these organisms have been largely underwhelming and inconsistent. Furthermore, although the disease has been presented for several decades, there is limited scientific evidence regarding effective treatment of DD. Apparent discrepancies between effectiveness in vitro and in vivo have challenged the scientific community to identify new potential treatment options. With no treatment resulting in a 100% cure rate, the current expectation is manageable control, but prospects for the eradication of the disease are unlikely using current approaches. In order to develop more effective approaches to control DD on-farm, there is a critical need for a deeper understanding regarding the causation, ecology, transmission and treatment of this disease. In this article, we attempt to provide insights into specific research needs related to DD in order to assist the industry, researchers, pharmaceutical companies and research sponsors with decision-making and identified research gaps.

Traumatic Lesions of the Sole.

Traumatic lesions of the sole are a common cause of lameness in beef and dairy cattle. This article provides a brief description of traumatically induced conditions with specific attention to underlying causes, treatment, and prevention. Lameness, traumatic lesions of the sole, sole punctures, thin soles, thin sole toe ulcers, toe tip necrosis syndrome, and toe abscesses are discussed.

An Update on the Assessment and Management of Pain Associated with Lameness in Cattle.

Lameness affects the cattle industry via both economic losses and welfare considerations. In addition to production deficits, the pain and distress associated with lameness have been documented. Evaluation and prevalence of lame cattle are among the primary factors in third-party welfare audit programs. Mean lameness prevalence in herds has been reported to be as high as 36.8%, although a less than 10% prevalence of lame cattle was reported by some producers. Note that lameness is usually underreported by producers compared with independent observers, potentially because of a decreased sensitivity in detecting lame cattle.

Pathogenesis and Treatment of Sole Ulcers and White Line Disease.

Sole ulcers and white line disease are 2 of the most common claw horn lesions in confined dairy cattle. Predisposing causes include unbalanced weight bearing, and metabolic, enzymatic, and hormonal changes. The white line serves as the junction between the sole and axial and abaxial wall. It is vulnerable to trauma and separation, permitting organic matter to become entrapped. Colonization contributes to retrograde movement of the infection to the solar and perioplic corium, where an abscess forms resulting in pain and lameness. Successful treatment requires an orthopedic foot block to the healthy claw and corrective trimming of the lesion.

The Impact of Lameness on Welfare of the Dairy Cow.

The five freedoms offer a framework for discussion of lameness and its impact on the welfare of cows. Altered feeding behavior is a cause of reduced body condition, smaller digital cushion, and lameness. Providing a comfortable environment is critical to recovery and welfare. Pain associated with injury or disease of feet or legs is manifested by lameness. Pain management is an important part of therapy. In cases of severe lameness, euthanasia may be preferred. Lameness interferes with an animal's ability to exhibit natural behaviors by altering lying time, social interaction, ovarian activity and estrus intensity, and rumination behavior.

Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity.

BACKGROUND AND PURPOSE: Neutrophil serine proteases (NSPs) are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. The effects of neutrophil turnover rate on NSP activity following DPP1 inhibition was studied in a rat pharmacokinetic/pharmacodynamic model. EXPERIMENTAL APPROACH: Rats were treated with a DPP1 inhibitor twice daily for up to 14 days; NSP activity was measured in onset or recovery studies, and an indirect response model was fitted to the data to estimate the turnover rate of the response. KEY RESULTS: Maximum NSP inhibition was achieved after 8 days of treatment and a reduction of around 75% NSP activity was achieved at 75% in vitro DPP1 inhibition. Both the rate of inhibition and recovery of NSP activity were consistent with a neutrophil turnover rate of between 4-6 days. Using human neutrophil turnover rate, it is predicted that maximum NSP inhibition following DPP1 inhibition takes around 20 days in human. CONCLUSIONS AND IMPLICATIONS: Following inhibition of DPP1 in the rat, the NSP activity was determined by the amount of DPP1 inhibition and the turnover of neutrophils and is thus supportive of the role of neutrophil maturation in the activation of NSPs. Clinical trials to monitor the effect of a DPP1 inhibitor on NSPs should take into account the delay in maximal response on the one hand as well as the potential delay in a return to baseline NSP levels following cessation of treatment.

Refractory depression: mechanisms and evaluation of radically open dialectical behaviour therapy (RO-DBT) [REFRAMED]: protocol for randomised trial.

INTRODUCTION: Only 30-40% of depressed patients treated with medication achieve full remission. Studies that change medication or augment it by psychotherapy achieve only limited benefits, in part because current treatments are not designed for chronic and complex patients. Previous trials have excluded high-risk patients and those with comorbid personality disorder. Radically Open Dialectical Behaviour Therapy (RO-DBT) is a novel, transdiagnostic treatment for disorders of emotional over-control. The REFRAMED trial aims to evaluate the effectiveness and cost-effectiveness of RO-DBT for patients with treatment-resistant depression. METHODS AND ANALYSIS: REFRAMED is a multicentre randomised controlled trial, comparing 7 months of individual and group RO-DBT treatment with treatment as usual (TAU). Our primary outcome measure is depressive symptoms 12 months after randomisation. We shall estimate the cost-effectiveness of RO-DBT by cost per quality-adjusted life year. Causal analyses will explore the mechanisms by which RO-DBT is effective. ETHICS AND DISSEMINATION: The National Research Ethics Service (NRES) Committee South Central - Southampton A first granted ethical approval on 20 June 2011, reference number 11/SC/0146. TRIAL REGISTRATION NUMBER: ISRCTN85784627.

Family quality of life of Australian families with a member with an intellectual/developmental disability.

BACKGROUND: Family quality of life (FQOL) is a recent concept in intellectual/developmental disability research. Outcomes for the family are important to the provision of services because families, rather than institutions, are increasingly considered the primary support unit. This article presents Australian findings using the international Family Quality of Life Survey: Main Caregivers of People with Intellectual or Developmental Disabilities (FQOLS-2006). METHOD: Forty-two South Australian main caregivers of people with an intellectual/developmental disability were interviewed using the FQOLS-2006. The FQOL domains assessed were Health of the Family, Financial Well-being, Family Relationships, Support from Other People, Support from Disability-Related Services, Influence of Values, Careers, Leisure and Recreation, and Community Interaction. Domains were measured in terms of Importance, Opportunities, Attainment, Initiative, Stability and Satisfaction. The FQOLS-2006 asked about the family's practical and emotional Support from Other People together, whereas the current study separated the constructs of practical and emotional support. Questions pertaining to FQOL in the past were also added, in order to gain a broader picture of present FQOL. RESULTS: Results indicated that families considered all the FQOL domains to be important. However, Health, Family Relationships and Financial Well-being were regarded as slightly more important than Practical and Emotional Support from Others. The attainment of Family Relationships, Health, Values, and Leisure and Recreation were rated as quite a bit, but Practical Support from Other People was only rated as a little. Families were generally satisfied with all FQOL domains, but they were satisfied with their Family Relationships and they were neither satisfied or dissatisfied with their Financial Well-being. Results also indicated that there was a need to distinguish between the provision of practical and emotional support from others, because the attainment of emotional support was rated at a slightly higher level than practical support. CONCLUSIONS: The FQOLS-2006 provided a comprehensive measure of FQOL, which, with some additional modifications, could be used to better inform service provisions and ultimately enhance the quality of life of people with intellectual/developmental disabilities and their families.

Differentiating short- and long-term effects of diet in the obese mouse using (1) H-nuclear magnetic resonance metabolomics.

This study determined whether targeted metabolomic profiling of serum, using 1H nuclear magnetic resonance, could be employed to distinguish the effects of obesity from those of diet in mice. Following weaning, littermates were randomly divided into two diet groups: chow and high fat. After 12 weeks of dietary manipulation, fat-fed animals were obese and hyperglycaemic. Mice from each treatment either maintained their current diet or switched to the opposite diet for a final week. Differences in metabolite levels were determined using orthogonal projection to latent structures and cross-validated discriminant analysis. The short- and long-term effects of each diet could be clearly distinguished. Short-term diet effects are the major contributor to the metabolic profile, underscoring the need for controls beyond the standard fast before serum collection. This work shows the importance of dietary controls when attempting to isolate obesity-related changes and highlights the ability of metabolomics to identify subtle changes when experiments are properly structured.

Core neuropsychological characteristics of children and adolescents with 22q11.2 deletion.

BACKGROUND: The 22q11.2 deletion syndrome (22qDS) confers high risk for intellectual disability and neuropsychological/academic impairment, although a minority of patients show average intelligence. Intellectual heterogeneity and the high prevalence of psychiatric diagnoses in earlier studies may have obscured the prototypical neuropsychological profile in 22qDS. METHODS: We examined intelligence, memory, reading and mathematical processes in 31 children/adolescents with 22qDS, selected for educational underachievement and an absence of psychiatric diagnoses, using standardised, psychometrically matched instruments that specify how typical a score is for a given intelligence quotient (IQ). RESULTS: Corroborating earlier findings, verbal IQ was significantly superior to performance IQ; verbal memory and basic reading were relative strengths; and visual/spatial memory was a relative weakness. All four findings transcended performance characteristics that are typical of low-IQ individuals. Rote learning yielded the highest score; reading comprehension, numerical operations and mathematical reasoning were among the lowest-performed academic domains. Albeit in the expected direction, performance in the respective components could not be clearly differentiated from what is IQ-appropriate. CONCLUSIONS: A superiority of verbal intelligence over non-verbal intelligence, relative strengths in verbal memory and basic reading, and a relative weakness in visual/spatial memory are likely to be core characteristics of children/adolescents with 22qDS, transcending performance features that are typical of individuals with low IQ.

Seasonal incidence of lameness and risk factors associated with thin soles, white line disease, ulcers, and sole punctures in dairy cattle.

Lameness is a multifactorial condition with many causes. In this study, cow lifetime records were used to quantify the incidence of specific lameness-causing lesions and investigate factors associated with those lesions. Of primary interest were the effects of seasonality and the effects of thin soles (TS). Thin sole-induced toe ulcers (TSTU) occurring adjacent to the white line in the apical portion of the weight-bearing surface were distinguished from white line disease (WLD) occurring in the region of the abaxial heel sole junction. Sole (SU), heel (HU), and toe (TU) ulcers; TS; sole punctures (SP); leg injuries (INJ); and other (OTH) lesions (e.g., infectious diseases, laminitis, unclassified hemorrhage) were also considered. Data were collected from May 2004 through October 2007 and included records for 4,915 cows of which 1,861 had at least one recorded lameness event. Of these, 20% were TSTU, 20% OTH, 16% SU, 13% TS, 10% WLD, 8% HU, 6% INJ, 4% SP, and 2% TU. Annual incidence risk for lameness was 49.1%. Overall incidence rate for lameness was 1.41/1,000 cow-days, and rates for all lesions were highest in the summer. As parity increased, so did incidence rates for TS, SU, WLD, HU, and INJ. For TS, TSTU, and WLD, incidence rates were lowest in early lactation (16 to 60 DIM), whereas for SU, HU, TU, incidence rates were highest in mid lactation (61 to 150 DIM). Cox proportional hazard models for TS, TSTU, WLD, SU, HU, TU, and SP included age and year of first calving and milk production capacity. Prior/concurrent lameness events, season, parity, and stage of lactation were included as time-dependent effects. Prior/concurrent TS increased the hazard for all other lesions, particularly TSTU, and HU. Having any other prior claw lesion also increased the hazard for all lesions. Hazard was highest in summer for all lesions except TU. Stage of lactation was a significant effect in hazard of TSTU, which was lowest in mid lactation (61 to 150 DIM).