An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA.

Antibody-mediated rejection (AMR) of solid organ transplants (SOT) is characterized by damage triggered by donor-specific antibodies (DSA) binding donor Class I and II HLA (HLA-I and HLA-II) expressed on endothelial cells. While F(ab')2 portions of DSA cause cellular activation and proliferation, Fc regions activate the classical complement cascade, resulting in complement deposition and leukocyte recruitment, both hallmark features of AMR. We characterized the ability of an anti-C1s monoclonal antibody, TNT003, to inhibit HLA antibody (HLA-Ab)-induced complement activation. Complement deposition induced by HLA-Ab was evaluated using novel cell- and bead-based assays. Human aortic endothelial cells (HAEC) were cultured with HLA-Ab and human complement; production of activated complement proteins was measured by flow cytometry. Additionally, C3d deposition was measured on single antigen beads (SAB) mixed with HLA-Ab and human complement. TNT003 inhibited HLA-Ab mediated complement deposition on HAEC in a concentration-dependent manner; C3a, C4a and C5a anaphylatoxin production was also diminished by TNT003. Finally, TNT003 blocked C3d deposition induced by Class I (HLAI-Ab)- and Class II (HLAII-Ab)-specific antibodies on SAB. These data suggest TNT003 may be useful for modulating the effects of DSA, as TNT003 inhibits complement deposition and split product formation generated by HLA-I/II-Ab in vitro

Codeine misuse and dependence in South Africa – learning from substance abuse treatment admissions

Background. Misuse of prescription and over-the-counter codeine-containing products is a global public health issue. Objectives. To investigate the extent of treatment demand related to the misuse of codeine or codeine dependence in South Africa (SA) and the profile of patients seeking treatment, so as to understand the nature and extent of the problem. Method. Data were collected from centres participating in the South African Community Epidemiology Network on Drug Use in 2014. A total of 17 260 admissions were recorded. Results. There were 435 recorded treatment admissions for codeine misuse or dependence as a primary or secondary substance of abuse (2.5% of all admissions). Of treatment admissions, 137 (0.8%) involved codeine as the primary substance of abuse; 74.9% of patients were males, with an even spread across population groups. Ages ranged from 11 to 70 years, with the highest proportion aged 20 - 29 years; > 40% were referred by self, family and/or friends, and 26.7% by health professionals; and 36.8% had received treatment previously. The majority reported misuse of tablets/capsules, with 17.6% reporting misuse of syrups. Oral use comprised 96.6% and daily use 63.1%. Conclusions. Data from treatment admissions related to codeine misuse and dependence are informative, but provide an incomplete picture of the nature and extent of codeine-related problems in SA. Other data sources must be considered before further regulatory/policy changes regarding codeine are implemented. © 2015, South African Medical Association. All rights reserved

Best Practices and Innovations for Managing Codeine Misuse and Dependence.

PURPOSE: Promoting and ensuring safe use of codeine containing medicines remains a public health issue given the rise in reporting of misuse and dependence particularly in countries where available over-the-counter (OTC). The aim of this unique study was to identify best practices in management of opioid abuse and dependence, particularly codeine, and innovations to meet challenges surrounding safe and compliant use, patient awareness-raising, reducing health harms and enhancing successful treatment of dependence. METHODS: A mixed methods approach using three data points was used that included : (1) analysis of data from existing scoping reviews to identify potential areas for innovation (2) interviews with key national stakeholders from public health, pharmaceutical, regulatory, primary care and addiction practice in three distinct regulatory regimes (Ireland, United Kingdom and South Africa); and (3) a circular email request for information on potential innovations to members of the European Medicine's Agency European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP). Data from these three sources were analysed to identify best practices and opportunities for innovation. RESULTS: Best practices and potential innovations were identified under the nine headings: (1) manufacture; (2) product information and public education; (3) responsible prescribing; (4) monitoring and surveillance; (5) dispensing, screening and brief interventions in community pharmacies; (6) safety in the workplace and on the road; (7) internet supply of codeine and online support; (8) treatment of codeine dependence; and (9) learning resources and training for health professionals. CONCLUSIONS: Challenges ensuring availability of codeine containing medicines for legitimate therapeutic use, while minimising misuse, dependence and related health harms warrant consideration of new innovations. Most promising innovative potential lies across the products' retail lifecycle from manufacture to prescriber and community pharmacy practitioner.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page

Codeine misuse and dependence in South Africa – learning from substance abuse treatment admissions

Background. Misuse of prescription and over-the-counter codeine-containing products is a global public health issue.Objectives. To investigate the extent of treatment demand related to the misuse of codeine or codeine dependence in South Africa (SA) and the profile of patients seeking treatment, so as to understand the nature and extent of the problem.Method. Data were collected from centres participating in the South African Community Epidemiology Network on Drug Use in 2014. A total of 17 260 admissions were recorded.Results. There were 435 recorded treatment admissions for codeine misuse or dependence as a primary or secondary substance of abuse (2.5% of all admissions). Of treatment admissions, 137 (0.8%)  involved codeine as the primary substance of abuse; 74.9% of patients were males, with an even spread across population groups. Ages ranged from 11 to 70 years, with the highest proportion aged 20 - 29  years; >40% were referred by self, family and/or friends, and 26.7% by health professionals; and 36.8% had received treatment previously. The majority reported misuse of tablets/capsules, with 17.6% reporting misuse of syrups. Oral use comprised 96.6% and daily use 63.1%.Conclusions. Data from treatment admissions related to codeine misuse and dependence are  informative, but provide an incomplete picture of the nature and extent of codeine-related problems in SA. Other data sources must be considered before further regulatory/policy changes regarding codeine are implemented

A comparative analysis of pharmacists' perspectives on codeine use and misuse - a three country survey

Background: The misuse of codeine is of increasing concern in a number of countries, particularly as this relates to over -the-counter pain and cough relief medication, and is also supplied as a prescription medicine. The study aimed to obtain and analyse the opinions and experience of pharmacy staff with regard to codeine misuse. Methods: A cross-sectional web-based survey of pharmacy staff’s perspectives on this issue was administered through professional or regulatory bodies and completed by samples drawn in South Africa (n = 124), Ireland (n = 464) and the United Kingdom (n = 129). Results: The majority of participants reported combination codeine-containing products as most popular, but significantly more pharmacy staff in South Africa reported codeine-containing cough syrups as most commonly popular (X2 = 122.7(2), p < 0.001). Codeine use was also seen significantly more of a public health problem in South Africa than in the other two countries (X2 = 7.6(2), p = 0.02). There was no difference across countries in the level of codeine misuse reported by pharmacy staff. Further findings indicate that professional training and education is desired, with unequivocal findings for the need for greater codeine control (X2 = 12.0(2), p = 0.002). Conclusion: In conclusion, there were some inter-country differences, but overall the findings seem to suggest that pharmacists across all three countries view codeine misuse as a problem among their customers. Recommendations centre on risk management, surveillance and staff training

Medical Professionals' Perspectives on Prescribed and Over-The-Counter Medicines Containing Codeine: A Cross-Sectional Study

Objectives: To explore prescribing practitioners' perspectives on prescribed codeine use, their ability to identify dependence and their options for treatment in the UK. Design: Cross-sectional design using a questionnaire containing closed-ended and open-ended items. Setting: A nationally representative sample of prescribing professionals working in the UK. Participants: 300 prescribing professionals working in primary care and pain settings. Results: Participants stated that they regularly reviewed patients prescribed codeine, understood the risks of dependence and recognised the potential for codeine to be used recreationally. Over half the participants felt patients were unaware of the adverse health consequences of high doses of combination codeine medicines. One-quarter of participants experienced patient resentment when asking about medicines containing codeine. Just under 40% of participants agreed that it was difficult to identify problematic use of codeine without being informed by the patient and did not feel confident in identification of codeine dependence. Less than 45% of all participants agreed that codeine dependence could be managed effectively in general practice. Slow or gradual withdrawal was the most popular suggested treatment in managing dependence. Education and counselling was also emphasised in managing codeine-dependent patients in primary care. Conclusions: Communication with patients should involve assessment of patient understanding of their medication, including the risk of dependence. There is a need to develop extra supports for professionals including patient screening tools for identifying codeine dependence. The support structure for managing codeine-dependent patients in primary care requires further examination

Incarceration, Menstruation and COVID-19: Exacerbated inequalities and health disparities in South African Correctional Facilities.

Purpose - The menstrual health and menstrual hygiene management (MHM) of incarcerated women remains relatively low on the agenda of public health interventions globally, widening the inequitable access of incarcerated women to safe and readily available menstrual health products (MHP). The COVID-19 pandemic has adversely impacted on the MHM gains made in various development sectors in the global North and South, through its amplification of vulnerability for already at-risk populations. This is especially significant to developing countries such as South Africa where the incarcerated female population are an often-forgotten minority. Design/methodology/approach - This Viewpoint highlights the ignominious silence of research and policy attention within the South African carceral context in addressing MHM. The ethical and political implications of such silences are unpacked by reviewing international and local literature that confront issues of inequality and equitable access to MHP and MHM resources within incarcerated contexts. Findings - Structural inequalities in various contexts around the world have exacerbated COVID�19 and MHM. Within the prison context in South Africa, women face multiple layers of discrimination and punishment that draw attention to the historical discourses of correctional facilities as a site of surveillance and discipline. Originality - It is hoped that the gaps in literature and nodes for social and human rights activism highlighted within this Viewpoint establish the need for further participatory research, human rights advocacy, and informed civic engagement to ensure the voices of these women, and their basic human rights are upheld

Maturation-related adaptations in running speed in response to sprint training in youth soccer players

Objectives This study investigated the effects of a previously recommended dose of sprint training (ST) in young male soccer players of differing maturity status. Design Quasi-experimental design. Methods Male soccer players from two professional academies were divided into Pre-PHV (Training: n = 12; Control: n = 13) and Mid-PHV (Training: n = 7; Control = 10) groups. The training groups completed 16 sprints of 20 m with 90 seconds recovery, once per week. Results Between-group effect sizes (ES) were substantially larger in Pre-PHV (10 m [1.54, CI: 0.74 to 2.23]; 20 m [1.49, CI: 0.75 to 2.23]; 5-10-5 [0.92, CI: 0.23 to 1.61]) than in Mid-PHV (10 m [-0.00, CI: −0.81 to 0.81]; 20 m [-0.12, CI: −0.93 to 0.69]; 5-10-5 [-0.41, CI: −1.22 to 0.41]). Within-group effects demonstrated a similar, though less accentuated, trend which revealed ST to be effective in both Pre-PHV (10 m [0.44, CI: −0.24 to 1.12]; 20 m [0.45, CI: −0.23 to 1.13]; 5-10-5 [0.69, CI: 0.00 to 1.38]) and Mid-PHV (10 m [0.51, CI: −0.38 to 1.40]; 20 m [0.33, CI: −0.56 to 1.21]; 5-10-5 [0.43, CI: −0.46 to 1.32]). Conclusions ST, in the amount of 16 sprints over 20 m with a 90 s rest, may be more effective in Pre-PHV youths than in Mid-PHV youths

Information acquisition differences between experienced and novice time trial cyclists

Purpose: To use eye-tracking technology to directly compare information acquisition behavior of experienced and novice cyclists during a self-paced 10 mile (16.1 km) time-trial. Method: Two groups of novice (N=10) and experienced cyclists (N=10) performed a 10-mile self-paced time-trial (TT) on two separate occasions during which a number of feedback variables (speed, distance, power output, cadence, heart rate, and time) were projected within their view. A large RPE scale was also presented next to the projected information and participants. Participants were fitted with a head-mounted eye32 tracker and heart rate monitor. Results: Experienced cyclists performed both time-trials quicker than novices (F1,18=6.8, P=.018) during which they primarily looked at speed (9 of 10 participants) whereas novices primarily looked at distance (6 of 10 participants). Experienced cyclists looked at primary information for longer than novices across the whole time-trial (24.5±4.2% vs. 34.2±6.1%, t18=4.2, P<0.001) and less frequently than novices during the last quarter of the time-trial (49±19 vs. 80±32, t18=-2.6, P=0.009). The most common combination of primary and secondary information looked at by experienced cyclists was speed and distance respectively. Looking at ten different primary-secondary feedback permutations, the novices were less consistent than the experienced cyclists in their information acquisition behavior. Conclusion: This study challenges the importance placed on knowledge of the endpoint to pacing in previous models, especially for experienced cyclists for whom distance feedback was looked at secondary to, but in conjunction with, information about speed. Novice cyclists have a greater dependence upon distance feedback, which they look at for shorter and more frequent periods of time than the experienced cyclists. Experienced cyclists are more selective and consistent in attention to feedback during time-trial cycling

Dihydrocodeine for detoxification and maintenance treatment in individuals with opiate use disorders

BACKGROUND: Medical treatment and detoxification from opiate disorders includes oral administration of opioid agonists. Dihydrocodeine (DHC) substitution treatment is typically low threshold and therefore has the capacity to reach wider groups of opiate users. Decisions to prescribe DHC to patients with less severe opiate disorders centre on its perceived safety, reduced toxicity, shorter half-life and more rapid onset of action, and potential retention of patients. This review set out to investigate the effects of DHC in comparison to other pharmaceutical opioids and placebos in the detoxification and substitution of individuals with opiate use disorders. OBJECTIVES: To investigate the effectiveness of DHC in reducing illicit opiate use and other health-related outcomes among adults compared to other drugs or placebos used for detoxification or substitution therapy. SEARCH METHODS: In February 2019 we searched Cochrane Drugs and Alcohol's Specialised Register, CENTRAL, PubMed, Embase and Web of Science. We also searched for ongoing and unpublished studies via ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and Trialsjournal.com. All searches included non-English language literature. We handsearched references of topic-related systematic reviews and the included studies. SELECTION CRITERIA: We included randomised controlled trials that evaluated the effect of DHC for detoxification and maintenance substitution therapy for adolescent (aged 15 years and older) and adult illicit opiate users. The primary outcomes were abstinence from illicit opiate use following detoxification or maintenance therapy measured by self-report or urinalysis. The secondary outcomes were treatment retention and other health and behaviour outcomes. DATA COLLECTION AND ANALYSIS: We followed the standard methodological procedures that are outlined by Cochrane. This includes the GRADE approach to appraise the quality of evidence. MAIN RESULTS: We included three trials (in five articles) with 385 opiate-using participants that measured outcomes at different follow-up periods in this review. Two studies with 150 individuals compared DHC with buprenorphine for detoxification, and one study with 235 participants compared DHC to methadone for maintenance substitution therapy. We downgraded the quality of evidence mainly due to risk of bias and imprecision. For the two studies that compared DHC to buprenorphine, we found low-quality evidence of no significant difference between DHC and buprenorphine for detoxification at six-month follow-up (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.25 to 1.39; P = 0.23) in the meta-analysis for the primary outcome of abstinence from illicit opiates. Similarly, low-quality evidence indicated no difference for treatment retention (RR 1.29, 95% CI 0.99 to 1.68; P = 0.06). In the single trial that compared DHC to methadone for maintenance substitution therapy, the evidence was also of low quality, and there may be no difference in effects between DHC and methadone for reported abstinence from illicit opiates (mean difference (MD) -0.01, 95% CI -0.31 to 0.29). For treatment retention at six months' follow-up in this single trial, the RR calculated with an intention-to-treat analysis also indicated that there may be no difference between DHC and methadone (RR 1.04, 95% CI 0.94 to 1.16). The studies that compared DHC to buprenorphine reported no serious adverse events, while the DHC versus methadone study reported one death due to methadone overdose. AUTHORS' CONCLUSIONS: We found low-quality evidence that DHC may be no more effective than other commonly used pharmacological interventions in reducing illicit opiate use. It is therefore premature to make any conclusive statements about the effectiveness of DHC, and it is suggested that further high-quality studies are conducted, especially in low- to middle-income countries