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AbstractDespite evidence that improving financial sector transparency (FST) can help tame clientele (households, businesses and corporate) debts, the empirical literature fails to explore how improving FST can lower/tame the unsustainable soaring government or (regulator) debts, particularly in Africa where alternative government debt management is inevitable. Hence, this study examines the complementarity and nonlinear threshold effects of private and public sector-led financial transparencies on government debts in Africa for the first time. Using a dynamic GMM panel data strategy covering periods between 2004 and 2020, the results show that the joint term of public and private sector-led financial sector transparency has complementary-synergetic effects on long-term debts and interest on debts while having substitutive effects on gross and short-term government debts, implying that private and public sector-led financial transparencies are substitutes to each other or can be used to complement gross and short-term government debts but complementary on long-term debt and interest on debts. Similarly, it is reported that there is a nonlinear inverted U-shaped threshold effect of financial sector transparencies on government debts, implying that financial sector transparencies must reach a minimum threshold/level to induce the desirable reducing effect of financial sector transparencies on government debts in Africa. These results create awareness of how financial regulators can employ FST as a debt-reducing tool and require policymakers to expand and deepen FST information to hasten it and reinforce the reducing effect of financial sector transparencies on government debts.

Abstract In the growing field of peptidomimetics, there is a constant need for new synthetic methods to generate new bioactive compounds. Herein, we present an atom‐economic approach for the branched‐selective allylation of aliphatic amine moieties of α‐amino acids and small oligopeptides. This Rh‐catalyzed hydroamination of allenes with a commercially available ligand forms a new stereocenter, often chemoselectively, in a catalyst‐controlled manner, providing high yields and stereoselectivities without the need for an additive. The method is shown to be effective in gram scale without the need for column chromatography for purification, and ready‐to‐use allylated substrates for solid‐phase peptide synthesis can be synthesized in two steps from the products of the catalysis.

The pulmonary system represents a unique lipidomic environment as it contains cellular membrane-bound lipid species and a specialized reservoir of lipids in the airway epithelial lining fluid. As a major initial point of defense, airway lipids react to inhaled contaminants such as volatile organic compounds, oxides of nitrogen, or ozone (O3), creating lipokine signaling that is crucial for both the initiation and resolution of inflammation within the lung. Dietary modulation of eicosanoids has gained increased attention in recent years for improvements to cardiovascular health. The current study sought to examine how dietary supplementation with eicosanoid precursors (i.e, oils rich in saturated or polyunsaturated fatty acids) might alter the lung lipid composition and subsequently modify the inflammatory response to ozone inhalation. Our study demonstrated that mice fed a diet high in saturated fatty acids resulted in diet-specific changes to lung lipid profiles and increased cellular recruitment to the lung following ozone inhalation. Bioinformatic analysis revealed an ozone-dependent upregulation of several lipid species, including phosphoserine 37:5. Pathway analysis of lipid species revealed the process of lateral diffusion of lipids within membranes to be significantly altered due to ozone exposure. These results show promising data for influencing pulmonary lipidomic profiles via diet, which may provide a pragmatic therapeutic approach to protect against lung inflammation and damage following pulmonary insult.

Abstract Eukaryotic initiation factor 4E (eIF4E) is a pivotal protein involved in the regulatory mechanism for global protein synthesis in both physiological and pathological conditions. MicroRNAs (miRNAs) play a significant role in regulating gene expression by targeting mRNA. However, the ability of miRNAs to regulate eIF4E and its phosphorylation remains relatively unknown. In this study, we predicted and experimentally verified targets for miR-483-5p, including eukaryotic translation initiation factor eIF4E and its binding proteins, 4E-BPs, that regulate protein synthesis. Using the Web of Science database, we identified 28 experimentally verified miR-483-5p targets, and by the TargetScan database, we found 1818 predicted mRNA targets, including EIF4E, EIF4EBP1, and EIF4EBP2. We verified that miR-483-5p significantly reduced ERK1 and MKNK1 mRNA levels in HEK293 cells. Furthermore, we discovered that miR-483-5p suppressed EIF4EBP1 and EIF4EBP2, but not EIF4E. Finally, we found that miR-483-5p reduced the level of phosphorylated eIF4E (pSer209eIF4E) but not total eIF4E. In conclusion, our study suggests that miR-483-5p's multi-targeting effect on the ERK1/ MKNK1 axis modulates the phosphorylation state of eIF4E. Unlike siRNA, miRNA can have multiple targets in the pathway, and thereby exploring the role of miR-483-5p in various cancer models may uncover therapeutic options.

Environmental degradation is attributed to human activities associated with economic development. This study examines renewable energy consumption (REC), financial development (FD), trade openness, and environmental quality nexus in Uganda over the period 1990-2019 using the Autoregressive Distribution Lag (ARDL). Findings show that REC improves environmental quality both in the short and long run. In addition, while trade openness is negatively related to environmental quality in the short and long run, a negative correlation exists between FD and environmental quality only in the long run. Furthermore, economic growth has a positive relationship with environmental quality in the short run while in the long run, GDP2 improves environmental quality. However, the results from the study find no statistical relationship between FDI and environmental quality, and thus neither the pollution haven nor pollution halo hypotheses are confirmed in the Ugandan case. This paper does not only recommend investing more in renewable energy development to improve the quality of the environment but also in financial sector development to support investments that promote a low-carbon and green economy.

We previously have shown that mRNA-based engineering may enhance mesenchymal stem cell (MSC) trafficking. However, optimal conditions for in vitro mRNA engineering of MSCs are unknown. Here, we investigated several independent variables: (1) transfection factor (Lipofectamine 2000 vs. TransIT), (2) mRNA purification method (spin column vs. high-performance liquid chromatography [HPLC] column), and (3) mRNA capping (ARCA vs. β-S-ARCA D1 and β-S-ARCA D2). Dependent variables included protein production based on mRNA template (measured by the bioluminescence of reporter gene luciferase over hours), MSC metabolic activity corresponding with their wellbeing measured by CCK-8 over days, and endogenous expression of genes by RT-qPCR related to innate intracellular immune response and decapping at two time points: days 2 and 5. We have found that Lipofectamine 2000 outperforms TransIT, and used it throughout the study. Then, we showed that mRNA must be purified by HPLC to be relatively neutral to MSCs in terms of metabolic activity and endogenous protein production. Ultimately, we demonstrated that β-S-ARCA D1 enables higher protein production but at the cost of lower MSC metabolic activity, with no impact on RT-qPCR results. Thus Lipofectamine 2000-based in vitro transfection of HPLC-purified and ARCA- or β-S-ARCA D1-capped mRNA is optimal for MSC engineering.

The technology of mRNA-based drugs is currently being intensively developed and implemented. Medical products of this type are already being used as viral vaccines and could potentially find application in a wide range of diseases. The tremendous interest in mRNA is due to the relatively easy production process, which can be quickly adapted to meet societal needs. The properties of this molecule depend on the structure of its individual components, such as the structure of the cap at the 5ʹ end. Modifications of the cap significantly affect the translational potential and lifespan of the whole mRNA. In the current work, we present the synthesis of derivatives of cap analogues modified at the N2 position of 7-methylguanosine. In addition to the substituent at the N2 position, the derivatives had either an extended triphosphate chain, a thiophosphate modification, an added cap1-modified nucleotide or an extended linker between the substituent and 7-methylguanosine. The compounds were tested for use as translation inhibitors and as components for mRNA preparation and appeared of interest for both applications.

Summary: This study examines the effect of proteins on the binding property and microstructure of enzymatic-induced calcium carbonate precipitation (EICP) in cementitious environment. The protein modified precipitates generally demonstrated improved binding to a glass slide surface or cement paste surface compared to the control precipitate. A marked decrease in the amount and binding strength of the precipitates in the cementitious environment was observed due to a reduction in the urease enzyme activity. The protein modified precipitates exhibited noticeable improvement compared to the control precipitate in cementitious environment which could arise from the ability of the proteins to partially shield urease from the negative effect of high pH. The protein gel network formation due to the complexation between the proteins and Ca2+ provides nucleation sites for CaCO3 crystallization. The FTIR, SEM, TGA, and XRD results indicated that vaterite is the dominant polymorph in cementitious environment compared to calcite in deionized water.

Abstract Batrachochytrium salamandrivorans (Bsal) is a fungal pathogen of amphibians that is emerging in Europe and could be introduced to North America through international trade or other pathways. To evaluate the risk of Bsal invasion to amphibian biodiversity, we performed dose-response experiments on 35 North American species from 10 families, including larvae from five species. We discovered that Bsal caused infection in 74% and mortality in 35% of species tested. Both salamanders and frogs became infected and developed Bsal chytridiomycosis. Based on our host susceptibility results, environmental suitability conditions for Bsal, and geographic ranges of salamanders in the United States, predicted biodiversity loss is expected to be greatest in the Appalachian Region and along the West Coast. Indices of infection and disease susceptibility suggest that North American amphibian species span a spectrum of vulnerability to Bsal chytridiomycosis and most amphibian communities will include an assemblage of resistant, carrier, and amplification species. Predicted salamander losses could exceed 80 species in the United States and 140 species in North America.

Summary: Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective—but there has been no superiority evaluation. Methods: This pragmatic, parallel-group, open-label, multi-centre, effectiveness superiority randomised, controlled, phase 3 trial was conducted at five National Health Service community-based treatment clinics in England and Scotland. Participants (adults aged ≥ 18 years; all meeting DSM-5 diagnostic criteria for moderate or severe OUD at admission to their current maintenance treatment episode) were randomly assigned (1:1) to receive continued daily SoC (liquid methadone (usual dose range: 60–120 mg) or sublingual/transmucosal buprenorphine (usual dose range: 8–24 mg) for 24 weeks; or monthly BUP-XR (Sublocade;® two injections of 300 mg, then four maintenance injections of 100 mg or 300 mg, with maintenance dose selected by response and preference) for 24 weeks. In the intent-to-treat population (senior statistician blinded to blinded to treatment group allocation), and with a seven-day grace period after randomisation, the primary endpoint was the count of days abstinent from non-medical opioids between days 8–168 (i.e., weeks 2–24; range: 0–161 days). Safety was reported for the intention-to- treat population. Adopting a broad societal perspective inclusive of criminal justice, NHS and personal social service costs, a trial-based cost-utility analysis estimated the Incremental Cost-effectiveness Ratio (ICER) per quality-adjusted life year (QALY) of BUP-XR versus SoC at the National Institute for Health and Care Excellence threshold. The study was registered EudraCT (2018-004460-63) and ClinicalTrials.gov (NCT05164549), and is completed. Findings: Between Aug 9, 2019 and Nov 2, 2021, 314 participants were randomly allocated to receive SoC (n = 156) or BUP-XR (n = 158). Participants were abstinent from opioids for an adjusted mean of 104.37 days (standard error [SE] 9.89; range: 0–161 days) in the SoC group and an adjusted mean of 123.43 days (SE 4.76; range: 24–161 days) in the BUP-XR group (adjusted incident rate ratio [IRR] 1.18, 95% confidence interval [CI] 1.05–1.33; p-value 0.004). The incidence of any adverse event was higher in the BUP-XR group than the SoC group (128 [81.0%] of 158 participants versus 67 [42.9%] of 156 participants, respectively—most commonly rapidly-resolving (mild–moderate range) pain from drug administration in the BUP-XR group (121 [26.9%] of 450 adverse events). There were 11 serious adverse events (7.0%) in the 158 participants in the BUP-XR group, and 18 serious adverse events (11.5%) in the 156 participants in the SoC group—none judged to be related to study treatment. The BUP-XR treatment group had a mean incremental cost of £1033 (95% central range [CR] −1189 to 3225) and was associated with a mean incremental QALY of 0.02 (95% CR 0.00–0.05), and an ICER of £47,540 (0.37 probability of being cost-effective at the £30,000/QALY gained willingness-to-pay threshold). However, BUP-XR dominated the SoC among participants who were rated more severe at study baseline, and among participants in maintenance treatment for more that 28 days at study enrolment. Interpretation: Evaluated against the daily oral SoC, monthly BUP-XR is clinically superior, delivering greater abstinence from opioids, and with a comparable safety profile. BUP-XR was not cost-effective in a base case cost-utility analysis using the societal perspective, but it was more effective and less costly (dominant) among participants with more severe OUD, or those whose current treatment episode was longer than 28 days. Further trials are needed to evaluate if BUP-XR is associated with better clinical and health economic outcomes over the longer term. Funding: Indivior.

Background Acamprosate is an effective and cost-effective medication for alcohol relapse prevention but poor adherence can limit its full benefit. Effective interventions to support adherence to acamprosate are therefore needed. Objectives To determine the effectiveness of Medication Management, with and without Contingency Management, compared to Standard Support alone in enhancing adherence to acamprosate and the impact of adherence to acamprosate on abstinence and reduced alcohol consumption. Design Multicentre, three-arm, parallel-group, randomised controlled clinical trial. Setting Specialist alcohol treatment services in five regions of England (South East London, Central and North West London, Wessex, Yorkshire and Humber and West Midlands). Participants Adults (aged 18 years or more), an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of alcohol dependence, abstinent from alcohol at baseline assessment, in receipt of a prescription for acamprosate. Interventions (1) Standard Support, (2) Standard Support with adjunctive Medication Management provided by pharmacists via a clinical contact centre (12 sessions over 6 months), (3) Standard Support with adjunctive Medication Management plus Contingency Management that consisted of vouchers (up to £120) to reinforce participation in Medication Management. Consenting participants were randomised in a 2 : 1 : 1 ratio to one of the three groups using a stratified random permuted block method using a remote system. Participants and researchers were not blind to treatment allocation. Main outcome measures Primary outcome: self-reported percentage of medication taken in the previous 28 days at 6 months post randomisation. Economic outcome: EuroQol-5 Dimensions, a five-level version, used to calculate quality-adjusted life-years, with costs estimated using the Adult Service Use Schedule. Results Of the 1459 potential participants approached, 1019 (70%) were assessed and 739 (73 consented to participate in the study, 372 (50%) were allocated to Standard Support, 182 (25%) to Standard Support with Medication Management and 185 (25%) to Standard Support and Medication Management with Contingency Management. Data were available for 518 (70%) of participants at 6-month follow-up, 255 (68.5%) allocated to Standard Support, 122 (67.0%) to Standard Support and Medication Management and 141 (76.2%) to Standard Support and Medication Management with Contingency Management. The mean difference of per cent adherence to acamprosate was higher for those who received Standard Support and Medication Management with Contingency Management (10.6%, 95% confidence interval 19.6% to 1.6%) compared to Standard Support alone, at the primary end point (6-month follow-up). There was no significant difference in per cent days adherent when comparing Standard Support and Medication Management with Standard Support alone 3.1% (95% confidence interval 12.8% to −6.5%) or comparing Standard Support and Medication Management with Standard Support and Medication Management with Contingency Management 7.9% (95% confidence interval 18.7% to −2.8%). The primary economic analysis at 6 months found that Standard Support and Medication Management with Contingency Management was cost-effective compared to Standard Support alone, achieving small gains in quality-adjusted life-years at a lower cost per participant. Cost-effectiveness was not observed for adjunctive Medication Management compared to Standard Support alone. There were no serious adverse events related to the trial interventions reported. Limitations The trial’s primary outcome measure changed substantially due to data collection difficulties and therefore relied on a measure of self-reported adherence. A lower than anticipated follow-up rate at 12 months may have lowered the statistical power to detect differences in the secondary analyses, although the primary analysis was not impacted. Conclusions Medication Management enhanced with Contingency Management is beneficial to patients for supporting them to take acamprosate. Future work Given our findings in relation to Contingency Management enhancing Medication Management adherence, future trials should be developed to explore its effectiveness and cost-effectiveness with other alcohol interventions where there is evidence of poor adherence. Trial registration This trial is registered as ISRCTN17083622 https://doi.org/10.1186/ISRCTN17083622. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 22. See the NIHR Journals Library website for further project information. Plain language summary What is the problem? Many people who are trying to stop drinking alcohol can find it difficult to remain alcohol free. There is a medication called acamprosate (Campral) that can reduce cravings thereby increasing the likelihood of abstinence. However, some people have trouble taking the right amount of acamprosate tablets needed every day at the right time, preferably at mealtimes. This means the medication is not as effective. We have tested some new ways to help support people taking acamprosate. What did we do? We tested three different strategies to find the best way to support people taking acamprosate. We recruited 739 people aged 18 and over who were receiving alcohol treatment to stop drinking and were taking acamprosate. We randomly allocated these people to three groups. The first was Standard Support, the usual support people receive when taking acamprosate. The second group received Standard Support plus Medication Management. This consisted of 12 telephone calls over 6 months with a trained pharmacist to discuss the importance of taking the right amount of the medication, how the medication works and strategies to help people take the medication correctly. The third group received Standard Support, Medication Management and Contingency Management. This involved giving people shopping vouchers for participating with Medication Management calls. The maximum value of vouchers per person was £120. What did we find out? People who were in the group receiving Medication Management and Contingency Management took a greater number of acamprosate tablets. We also found that Medication Management plus Contingency Management was more cost-effective; there were greater gains in health with a smaller cost per person compared to Standard Support alone. This shows that there is likely to be a benefit to patients of Medication Management plus Contingency Management for supporting people taking acamprosate. Scientific summary Background Alcohol is a significant risk factor for morbidity and mortality. In the UK there has been an increase in harm related to alcohol while also a reduction in funding to public health budgets, including alcohol services. While some individuals do successfully complete alcohol treatment, the majority will undergo frequent episodes of relapse. Providing effective treatment can reduce relapse rates and associated harms thus having a positive impact on cost-effectiveness. The National Institute for Health and Care Excellence (NICE) recommends acamprosate in combination with psychological intervention as a first-line treatment for relapse prevention in alcohol dependence, however, acamprosate adherence poses a problem for its effectiveness in clinical practice. The reasons for non-adherence are complex and often due to multiple influences. Currently there is insufficient evidence as to which forms of intervention are effective in increasing adherence. Psychosocial interventions to support medication adherence have the potential to promote positive beliefs about medication and any concerns. Medication Management (MM) is a psychosocial intervention which aims to improve medication and treatment adherence by providing education, support, and practical advice about drinking behaviour and medication. There has also been an increasing focus on extending the role of the community pharmacist and the delivery of MM to improve medication adherence compliments this expanding role. Engagement in psychological interventions and retention in treatment is often poor in alcohol dependence but there is evidence that Contingency Management (CM) improves engagement and retention in substance use disorder treatment. There is currently limited evidence of its effectiveness within alcohol treatment but if shown to be effective it has the potential to also be adopted within the NHS and community pharmacies. Objectives Our aim was to evaluate the effectiveness and cost-effectiveness of adjunctive MM with and without CM in improving adherence to acamprosate for relapse prevention in alcohol dependence. To conduct a definitive three-arm, randomised controlled trial (RCT) of the effectiveness of MM with and without CM compared to Standard Support (SS) alone in enhancing adherence to acamprosate in alcohol dependence relapse prevention. To estimate the cost-effectiveness of MM with and without CM compared to SS alone in enhancing adherence to acamprosate in alcohol dependence relapse prevention. To assess the impact of adherence to acamprosate for alcohol dependence relapse prevention on abstinence and reduced alcohol consumption. Methods Trial design This was a three-arm, parallel-group, pragmatic RCT, which began with an internal pilot phase to demonstrate recruitment, randomisation and interventions could be implemented as planned. Eligibility and recruitment Participants presenting to alcohol services in one of the trial sites (London, Southampton, Birmingham, Yorkshire and Humber) who met the trial inclusion criteria were recruited via service staff. Participants Inclusion criteria were: (1) adults, aged 18 years and over; (2) an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of alcohol dependence; (3) abstinent from alcohol at baseline assessment; (4) in receipt of a prescription of acamprosate; and (5) willing and able to provide informed consent. Exclusion criteria were: (1) a diagnosis of a severe physical/mental illness likely to preclude active participation in treatment or follow-up, (2) unable to understand verbal English at a level necessary to engage in the intervention and follow-up and (3) concurrent dependence on an illicit substance (other than cannabis). Randomisation and interventions Participants were randomised in a 2 : 1 : 1 ratio to SS, SS + MM or SS + MM + CM using a stratified random permuted block method using a remote system. Participants and researchers were not blind to treatment allocation. SS typically comprised of monthly dispensing of prescribed acamprosate, monthly monitoring of the service user for 3 months by the specialist alcohol service, and then returned to the care of their GP for monthly monitoring in accordance with NICE guidelines and current clinical NHS clinical practice. SS + MM participants followed the same care pathway as those in SS, with the addition of MM delivered by a central telephone support service by trained pharmacists. MM was delivered once a week for the first 6 weeks, reducing to once a fortnight for the following 6 weeks, and then monthly for 3 months. SS + MM + CM participants followed the same care pathway as those in the SS + MM arm but with the addition of CM. Incentives in the form of vouchers were provided to reinforce attendance at MM sessions, up to a total of £120. Outcomes The primary outcome measure was the self-reported per cent of medication taken as prescribed during the 6-month target phase of prescribing, post randomisation. Data collection Data were collected at baseline, 2, 4, 6 and 12 months. Following an amendment, the 12-month follow-up was removed to maximise participant recruitment, and the recruitment period was extended without extending the trial end date. Data that had been collected at the 12-month follow-up were still included in the trial analysis plan. The primary outcome was collected at the 6-month follow-up. Sample size The sample size aimed to detect a clinically important effect size difference of 0.3, about 13% difference in per cent adherence. In order to make the study cost-efficient, we proposed to allocate twice as many to the SS group than to the SS + MM and SS + MM + CM groups. With power at 80%, alpha of 0.05 and a two-sided test, this required 524 to be followed up at the primary end point, 262 in the SS group and 131 in each of the other groups. We anticipated a loss to follow-up at month 6 of 30% and inflated the required sample at baseline to 748 to account for this. Sample sizes were calculated using Stata 12 (StataCorp LP, College Station, TX, USA). Statistical methods The primary analysis was an analysis by treatment allocated (ATA) and was based on all available data for participants who were randomised, irrespective of whether they complied with their allocation or not. The primary analysis was based on the ATA. Secondary analyses examined treatment effects under different scenarios for compliance with allocation/treatment: complier average causal effects (CACE). Two scenarios of compliance were defined in this trial. The first compliance for those in the SS + MM and SS + MM + CM group was defined as adhering to at least 50% of the MM calls. In the second, the threshold was increased to 100%. Both scenarios are modelled in the analysis. We considered missing data as being missing at random (MAR) or missing not at random (MNAR). We conducted a multiple imputation to address MAR and a sensitivity analysis to address MNAR. Fractional regression was conducted to model the relationship between pre-randomisation factors and per cent adherence to acamprosate and per cent days abstinent from alcohol at month 6. Interaction terms with treatment allocation were included in the model and a significance level of 0.1 was used as a threshold to determine which variables were maintained in the final model reported. Baseline variables included initially in the model include age, gender, marital status, ethnicity, employment status, number of children, age of first drink, weekly and daily drinking, frequency and quantity of alcohol consumption, severity of alcohol dependence, alcohol urges and alcohol-related problems. This analysis was augmented with an additional analysis for the SS + MM and SS + MM + CM groups where the same dependent variable was assessed with the same independent variables with the addition of therapeutic alliance. Method of economic evaluation The primary economic analysis was a cost-utility analysis where outcomes were expressed as quality-adjusted life-years (QALYs), as recommended by NICE. A secondary analysis explored cost-effectiveness in terms of the primary clinical outcome which was adherence to relapse prevention medication. The primary economic perspective was the NHS and personal social services (NHS/PSS) perspective preferred by NICE. The primary time horizon of the economic analyses using both QALYs and relapse medication adherence was the 6-month follow-up, consistent with the primary clinical analysis. A secondary analysis was carried out at the 12-month follow-up using QALYs. The primary economic outcome was QALYs calculated using the EuroQol-5 Dimensions, a five-level version measure of health-related quality-of-life scores at baseline, 6- and 12-month follow-ups. The primary economic analysis was composed of two separate comparisons: (1) SS + MM + CM versus SS alone; and (2) SS + MM versus SS alone, both at 6 months post randomisation, and assessed cost-effectiveness in terms of cost per QALY using the EuroQol-5 Dimensions measure of quality of life. Two secondary economic evaluations were carried out, a cost-utility analysis at 12 months post randomisation and a cost-effectiveness analysis using adherence to relapse medication which was the primary clinical outcome. Cost-effectiveness was explored using incremental cost-effectiveness ratios (difference in mean cost divided by difference in mean effect) and cost-effectiveness acceptability curves (CEACs), which show the probability that SS + MM + CM or SS + MM are cost-effective compared to SS alone for different levels of willingness to pay for improvements in outcome. Sensitivity analyses were carried out to test the impact of varying methods and assumptions on the relative cost-effectiveness of the interventions being compared. We planned three sensitivity analyses: (1) a broader analytical perspective to include the cost of crime (which was not completed as no crimes were reported), (2) a complete case analysis for comparison with the results that used multiple imputation for missing data and (3) a cost-utility analysis using QALYs calculated from EuroQol-5 Dimensions, three-level version tariffs. Results A total of 1459 potential participants were approached of whom 1019 (70%) were assessed. Of these 739 (73%) were eligible and consented to participate in the study. Allocation was in the ratio of 2 : 1 : 1, 372 (50%) were allocated to SS, 182 (25%) to SS + MM and 185 (25%) to SS + MM + CM. At the primary end point, 6 months post randomisation, 518 (70%) were successfully followed up with 255 (68.5%) allocated to SS, 122 (67.0%) to SS + MM and 141 (76.2%) to SS + MM + CM. There were no serious adverse events related to the trial interventions reported. The mean difference in per cent adherence to acamprosate at month 6 between those allocated to SS and SS + MM + CM versus SS was 10.6% [95% confidence interval (CI) 19.6% to 1.6%]; this difference was statistically significant. When the SS + MM group was compared to SS alone, the SS + MM group had a lower per cent days adherent than the SS group, mean difference 3.1% (95% CI 12.8% to −6.5%); this was not significant. A similar non-significant finding was seen when we compared the SS + MM and SS + MM + CM groups, mean difference 7.9% (95% CI 18.7% to −2.8%). Our secondary analysis included per cent days abstinent from alcohol at month 6. The ATA found differences favouring both intervention groups over SS alone but neither of these was significant. When a CACE analysis was conducted using scenario 2, both intervention groups had a significantly greater per cent days abstinent than SS alone. This analysis also highlighted the relationship between adherence to acamprosate and better outcomes, something additionally highlighted by a significant correlation between adherence to acamprosate and increased per cent days abstinent at month 6. CACE analysis: Under scenario 1, 50% adherence, the mean difference in per cent adherence increases from 10.6% (95% CI 19.6 to 1.62) to 12.4% (95% CI 17.8% to 7.1%) in the SS + MM + CM versus SS comparison, indicating that at 50% compliance those allocated to SS + MM + CM have a mean of 12.44% more adherence to acamprosate at month 6 than those allocated to SS alone. When comparing the SS + MM versus the SS group, a previous non-significant difference 3.14% (95% CI 12.8% to −6.5%) becomes a significant difference of 13.2% (25.4–1.15%). Under scenario 2, the differences are larger in magnitude, the SS + MM + CM group having 22.2% (95% CI 29.7% to 14.7%) more adherent days than the SS group alone. At the same time, the magnitude of difference is larger for the SS + MM versus SS comparison 31.8% (95–60.5% vs. 3.10%), although this comparison is based on a small number of participants, 20, and should be interpreted with caution. For SS + MM + CM versus SS, the primary economic analysis at 6-month follow-up using QALYs, the secondary economic analysis at 6-month follow-up using medication adherence and the economic modelling over a 20-year time horizon using QALYs all found SS + MM + CM to dominate SS (better outcomes at lower cost). At 12-month follow-up, although SS + MM + CM was not dominant, it generated more QALYs at an additional cost that was below the NICE cost per QALY threshold. CEACs also showed there was a higher probability of SS + MM + CM being cost-effective compared to SS alone in all analyses and at all time points. For SS + MM versus SS, at 6- and 12-month follow-up and when modelled over 20 years, SS + MM achieved better outcomes at higher cost compared to SS. In terms of cost-effectiveness, SS + MM was not found to be cost-effective at 6-month follow-up but had a higher probability of being cost-effective compared to SS at both the 12-month follow-up (using the higher £30,000 per QALY NICE threshold) and when modelled over 20 years (over the full £20,000–30,0000 cost per QALY threshold). Conclusions When comparing SS + MM + CM versus SS alone, we observed a significantly higher per cent adherence to acamprosate in the SS + MM + CM group, and the differences were of the magnitude that would indicate a clinically important difference. Differences were also observed when comparing SS + MM versus SS and SS + MM + CM versus SS + MM, but these were not significant. We explored how robust these findings were to assumptions about the nature of any missing data and we explored a missing data imputation model to explore the impact of data that may be MAR and a sensitivity analysis to explore data that may not be MAR. Neither of these analyses found any significant deviation from the analysis based on observed values, we can be confident that our findings from the ATA analysis are robust. To explore the effect of compliance to MM we conducted a CACE analysis using two scenarios of compliance, 50% and 100%. In both scenarios, we found greater benefits associated with SS + MM + CM and SS + MM versus SS alone and these benefits were significant and clinically important. There were several limitations to the current trial that should be taken into consideration. The trial’s primary outcome measure changed substantially due to data collection difficulties and therefore relied on a measure of self-reported adherence. A lower than anticipated follow-up rate at 12 months may have lowered the statistical power to detect differences in the secondary analyses, although the primary analysis was not impacted. The results of the primary economic analysis at the 6-month follow-up point suggest that MM was only cost-effective when supported by incentives to encourage support session uptake. This finding was heavily influenced by lower total costs in the SS + MM + CM group as a result of lower use of residential rehabilitation facilities compared to both SS + MM and SS alone, which may be related to the significantly higher medication adherence seen in the CM group. Over the medium (12 months) and longer term (20 years), SS + MM + CM remained cost-effective compared to SS and there was a higher probability of SS + MM being cost-effective compared to SS. These results support the addition of MM to SS for alcohol dependence, with or without CM. However, the economic benefit was stronger when CM was included. Trial registration This trial is registered as ISRCTN17083622 https://doi.org/10.1186/ISRCTN17083622. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 22. See the NIHR Journals Library website for further project information.

Abstract Background Despite the commendable progress made globally in tobacco control, the world is falling short of achieving a 30% relative reduction in current tobacco use by 2025. The African region remains the least in the efforts in fighting the tobacco epidemic and is most exploited by the tobacco industry. Schools have been continuously used for over three decades as a setting for delivering youth smoking prevention programmes; however, the evidence of the effectiveness of those school-based interventions provides varying outcomes. Also, interventions that proved to be effective, in high-income countries (HICs), may not necessarily be effective in the African region as a result of cultural differences and other contrasting factors. An existing systematic review that explored school-based tobacco prevention programmes among the youth in African countries from 2000 to 2016 showed partial effectiveness. This review will address the gap by updating the 2016 review to examine studies in LMICs to generate findings to help target resources which have the potential to save lives by preventing smoking initiation among young people. Methods The JBI methodology for systematic reviews of effectiveness will guide the conduct of this review. A comprehensive strategic search will be developed to retrieve both published and unpublished studies that evaluate school-based interventions to prevent tobacco smoking initiation among in-school young people in LMICs compared to non-intervention programmes. Published studies would be from databases such as MEDLINE via Ovid, CINAHL via EBSCO, Embase, PsycINFO, PsycEXTRA, and the Cochrane Central Register of Controlled Trials. Sources of grey literature would be ProQuest Dissertations and Theses, MedNar, EBSCO Open Dissertations, Open Access Theses and Dissertations, and Trove. The databases will be searched for published studies in the English language. The processes of study selection, critical appraisal, data extraction, and data synthesis will be in accordance with the JBI approach for reviews of effectiveness with a minimum of two reviewers at each stage. The primary outcome of the review will be the non-initiation of tobacco smoking by the youth. Discussion The review will provide synthesized evidence on the effectiveness of school-based smoking initiation prevention among young people in LMICs. The findings of the review would support policymakers and programme implementers to develop targeted interventions for effective tobacco control initiatives. Systematic review registration PROSPERO CRD42021246206

Abstract Background Sublingual tablet buprenorphine (BUP-SL) and oral liquid methadone (MET) are the daily, standard-of-care (SOC) opioid agonist treatment medications for opioid use disorder (OUD). A sizable proportion of the OUD treatment population is not exposed to sufficient treatment to attain the desired clinical benefit. Two promising therapeutic technologies address this deficit: long-acting injectable buprenorphine and personalised psychosocial interventions (PSI). This study will determine (A) the effectiveness and cost-effectiveness — monthly injectable, extended-release (BUP-XR) in a head-to-head comparison with BUP-SL and MET, and (B) the effectiveness of BUP-XR with adjunctive PSI versus BUP-SL and MET with PSI. Safety, retention, craving, substance use, quality-adjusted life years, social functioning, and subjective recovery from OUD will be also evaluated. Methods This is a pragmatic, multi-centre, open-label, parallel-group, superiority RCT, with a qualitative (mixed-methods) evaluation. The study population is adults. The setting is five National Health Service community treatment centres in England and Scotland. At each centre, participants will be randomly allocated (1:1) to BUP-XR or SOC. At the London study co-ordinating centre, there will also be allocation of participants to BUP-XR with PSI or SOC with PSI. With 24 weeks of study treatment, the primary outcome is days of abstinence from non-medical opioids during study weeks 2–24 combined with up to 12 urine drug screen tests for opioids. For 90% power (alpha, 5%; 15% inflation for attrition), 304 participants are needed for the BUP-XR versus SOC comparison. With the same planning parameters, 300 participants are needed for the BUP-XR and PSI versus SOC and PSI comparison. Statistical and health economic analysis plans will be published before data-lock on the Open Science Framework. Findings will be reported in accordance with the Consolidated Standards of Reporting Trials and Consolidated Health Economic Evaluation Reporting Standards. Discussion This pragmatic randomised controlled trial is the first evaluation of injectable BUP-XR versus the SOC medications BUP-SL and MET, with personalised PSI. If there is evidence for the superiority of BUP-XR over SOC medication, study findings will have substantial implications for OUD clinical practice and treatment policy in the UK and elsewhere. Trial registration EU Clinical Trials register 2018-004460-63.

Abstract Background and Aims Female head‐porters are a cohort of women who have migrated from their rural communities into commercial cities in search of better economic opportunities. These young women are vulnerable to untoward reproductive experiences. The study assesses the reproductive experiences of women and the factors influencing contraceptive use among them. Methods A cross‐sectional study was conducted from January to May 2021 in the Kumasi Metropolis (n = 280). The study included 280 female head‐porters within the reproductive age of 15–49 years. Convenience sampling and consecutive recruitment were used to obtain the needed sample size. All statistical significance was declared at a p‐value of

Udang vaname merupakan udang introduksi bernilai ekonomis tinggi. Banyaknya limbah organik dari sisa pakan dan hasil metabolisme udang yang dibudidayakan dengan pola intensif, menyebabkan penurunan kualitas air. Tujuan dari penelitian ini adalah mengetahui perbedaan hasil dari penambahan probiotik Lactobacillus plantarum dengan dosis berbeda terhadap pertumbuhan berat, panjang cephalothorax, FCR, dan sintasan udang vaname (Litopenaeus vannamei). Desain penelitian yang digunakan adalah RAL (Rancangan Acak Lengkap) satu faktor dengan 5 perlakuan dan 3 kali ulangan. Pertumbuhan berat rata-rata berkisar antara 17,19 g – 24,02 g. Pertumbuhan panjang cephalothorax rata-rata berkisar antara 42,66 mm – 50,33 mm. FCR rata-rata berkisar antara 1,23 – 1,37. Sintasan rata-rata berkisar antara 65% – 95%. Kesimpulan yang diperoleh dari penelitian ini adalah penambahan probiotik Lactobacillus plantarum pada pakan memberikan pengaruh yang berbeda nyata terhadap pertumbuhan berat, FCR dan pendapatan hasil budidaya. Hasil terbaik terdapat pada perlakuan 3 (10 ml/kg pakan) yaitu 24,02 g; 12 723 590 g; 1,23; Rp954.225.000. Penambahan probiotik Lactobacillus plantarum pada pakan memberikan pengaruh yang tidak berbeda nyata terhadap pertumbuhan panjang cephalothorax, LPHS dan sintasan.

We tested 294 domestic pet dogs in Mexico for neutralizing antibodies for mosquito-borne flaviviruses. We found high (42.6%) exposure to West Nile virus in Reynosa (northern Mexico) and low (1.2%) exposure in Tuxtla Gutierrez (southern Mexico) but very limited exposure to Aedes-borne flaviviruses. Domestic dogs may be useful sentinels for West Nile virus.

Understanding young inmates’ experiences are essential since their lives have been shaped by the impact of social exclusion. This study aimed to explore the meaning of the lived experiences of young adults inside the prison system. The phenomenological inquiry was utilized, which is grounded in Martin Heidegger’s philosophy. Semi-structured interviews were conducted with 18 to 29-year-old inmates incarcerated for at least one year. Through interpretative phenomenological analysis, four themes emerged: An Unfamiliar Melody (with two subthemes: Humming with Frustrations and Tunes of Solitude); The Eyes Outside the Cage; Turning Over a New Feather; and If My Wings Unclipped. The “songs” of the caged bird tell about the “meanings” of restricted freedom--from being able to dip its wings in the orange sun rays down to being tied in chains. Being held inside a prison limits a person from experiencing life as they should. Opportunities to soar high were taken away. The consequences caused them the fragility of emotions: frustration, loneliness, and humiliation; yet, they still have a speck of hope. Abstrak Nyanyian Burung dalam Sangkar: Sebuah Pandangan terhadap Kehidupan Remaja dalam Sistem Penjara. Memahami pengalaman narapidana berusia muda sangat penting karena kehidupan mereka yang terdampak oleh pengucilan sosial. Tujuan penelitian ini untuk mengeksplorasi makna dari pengalaman hidup orang berusia dewasa muda di dalam sistem penjara. Penelitian menggunakan pendekatan fenomenologis yang didasarkan pada filosofi Martin Heidegger. Pengumpulan data menggunakan metode wawancara semi-berstruktur dengan narapidana berusia 18 hingga 29 tahun yang sudah dipenjara setidaknya selama satu tahun. Berdasarkan analisis fenomenologi interpretatif, muncul empat tema, yaitu: An Unfamiliar Melody (dengan dua subtema: Humming with Frustrations dan Tunes of Solitude); The Eyes Outside the Cage; Turning Over a New Feather; dan If My Wings Unclipped. “Nyanyian” burung dalam sangkar yang menceritakan tentang “makna” kebebasan yang terbatas—mulai dari mencelupkan sayapnya di bawah sinar matahari jingga hingga diikat dengan rantai. Kondisi dipenjara membatasi seseorang untuk menjalankan kehidupan sebagaimana mestinya. Peluang mereka untuk terbang melambung tinggi dirampas. Hal ini menyebabkan emosi mereka rapuh: frustrasi, kesepian, dan penghinaan; tetapi, mereka masih memiliki setitik harapan. Kata Kunci: fenomenologi, frustasi, narapidana dewasa muda, sistem penjara

We report two cases of ectopic bone formation in the head and neck following treatment with recombinant human bone morphogenetic protein-2 (rhBMP-2). Surgical pathologic data, laryngoscopy imaging, CT imaging, and patient medical history were obtained. First, we report osseous metaplasia in the vocal fold in a 67-year-old male following mandibular dental implants with rhBMP-2; second, a case of severe bony overgrowth of the larynx and fusion to the anterior cervical spine (ACS) in a 73-year-old male following multiple anterior cervical discectomies and fusions with rhBMP-2. Ectopic bone formation following rhBMP-2 has been previously reported. Adverse events like local swelling and edema leading to dysphagia and even airway obstruction after cervical spine application of rhBMP-2 have also been widely reported. Due to the uncommon nature of abnormal bony growth in soft tissue areas of the head and neck and the previously documented adverse effects of rhBMP-2 use, especially in the cervical spine, we consider the two unusual case presentations of ectopic bony formation highly likely to be linked with rhBMP-2. We urge awareness of the adverse effects caused by rhBMP-2, and urge caution in dosing.

Objective: This exploratory analysis of a large, randomized, double-blind study (NCT02106351) describes the effect of treatment with abobotulinumtoxinA followed by a tailored home exercises therapy programme in enabling children with upper limb spasticity due to cerebral palsy to achieve their functional goals using goal attainment scaling (GAS). Methods: Children with cerebral palsy and spasticity in ≥ 1 upper limb received up to 4 injection cycles of abobotulinumtoxinA (2 U/kg (cycle 1 only), 8U/kg and 16U/kg) into the elbow and wrist flexors and other upper limb muscles selected to support individual treatment goals. Children followed a home exercises therapy programme, which included stretches and exercises specifically chosen to facilitate goal achievement and engagement in activities. Results: For cycle 1, most children had active function goals set as their primary goal (69.7% vs 19.2% passive function goals). GAS T- scores and goal responder rates at week 16 indicated that most types of primary goal were achieved at least as expected during cycle 1 (all groups). Primary goal GAS T-scores were generally maintained for the first 3 abobotulinumtoxinA treatment cycles. Conclusion: Most children with upper limb spasticity treated with repeat cycles of abobotulinumtoxinA supported by an individualized home exercises therapy programme achieved their functional goals. LAY ABSTRACT Treatment with botulinum toxins (such as abobotulinumtoxinA; aboBoNT-A) is often recommended to treat spasticity of the upper limb to help children with cerebral palsy improve their hand skills. In this large study, children with cerebral palsy were treated with up to 4 aboBoNT-A injection cycles followed by a home exercises programme that was specifically made for each child to help them meet their treatment goals. This study aimed to explore the types of goals the children wanted to achieve with this treatment and the factors that influence goal attainment. Most children in this study had “active function” goals set, including “involving the affected arm more in daily activities” and improving “reaching”, “use of limb as a helping hand” and “grasp and release”. Combined treatment with aboBoNT-A and the exercise programme helped most children achieve their goals, but it was difficult to discern any differences in efficacy between the aboBoNT-A doses used in the study. The authors suggest that the high rates of goal achievement in this study indicate that botulinum toxin should not usually be given without a physiotherapy programme.

In vitro transcribed (IVT) synthetic mRNAs are in high demand due to their attractive bench to clinic translational processes. Mainly, the procedure to make IVT mRNA using bacteriophage RNA polymerases (RNAP) is relatively uncomplicated and scalable to produce large quantities in a short time period. However, IVT mRNA preparations are accompanied by contaminants such as double-stranded RNA (dsRNA) as by-products that elicit undesired cellular immune responses upon transfections. Therefore, removing dsRNA contaminants is critical in IVT mRNA preparations for therapeutic applications. One such method to minimize dsRNA contaminants is to use genetically modified thermostable bacteriophage polymerase, HiT7 RNAP that performs IVT reaction at a higher temperature than typically used. However, the cellular RNA sensor response for IVT mRNA preparations by HiT7 RNAP is not characterized. Here, we compared the cellular RNA sensor response for mRNAs prepared by HiT7 RNAP (at 50°C) and SP6 RNAP (at 37°C) in HeLa cells. We show that IVT mRNA preparations by HiT7 RNAP reduced the dsRNA levels and dsRNA specific RNA sensor response (retinoic acid-inducible gene I, RIG-I and melanoma differentiation-associated 5, MDA5) compared to the IVT mRNA preparations by SP6 RNAP. Similarly, the incorporation of pseudouridine nucleotides instead of uridine nucleotides reduced dsRNA sensor response and increased the mRNA translation. Overall, the least dsRNA mediated RNA sensor response is observed when mRNA is synthesized by HiT7 RNAP and incorporated with pseudouridine nucleotides.

Introduction Opioid use disorder (OUD) is a debilitating and persistent disorder. The standard-of-care treatment is daily maintenance dosing of sublingual buprenorphine (BUP-SL) or oral methadone (MET). Monthly, extended-release, subcutaneous injectable buprenorphine (BUP-XR) has been developed to enhance treatment effectiveness. This study aims to investigate the experiences of participants who have been offered BUP-XR (evaluation 1), health-related quality-of-life among participants who have opted to receive BUP-XR longer term (evaluation 2) and the experiences of participants allocated to receive BUP-XR or BUP-SL or MET with the offer of adjunctive personalised psychosocial intervention (evaluation 3).Methods and analysis Three qualitative–quantitative (mixed-methods) evaluations embedded in a five-centre, head-to-head, randomised controlled trial of BUP-XR versus BUP-SL and MET in the UK. Evaluation 1 is a four-centre interview anchored on an OUD-related topic guide and conducted after the 24-week trial endpoint. Evaluation 2 is a two-centre interview anchored on medications for opioid use disorder-specific quality-of-life topic guide conducted among participants after 12–24 months. Evaluation 3: single-centre interview after the 24-week trial endpoint. All evaluations include selected trial clinical measures, with evaluation 2 incorporating additional questionnaires. Target participant recruitment for evaluations 1 and 2 is 15 participants per centre (n=60 and n=30, respectively). Recruitment for evaluation 3 is 15 participants per treatment arm (n=30). Each evaluation will be underpinned by theory, drawing on constructs from the behavioural model for health service use or the health-related quality-of-life model. Qualitative data analysis will be by iterative categorisation.Ethics and dissemination Study protocol, consent materials and questionnaires were approved by the London-Brighton and Sussex research ethics committee (reference: 19/LO/0483) and the Health Research Authority (IRAS project number 255522). Participants will be provided with information sheets and informed written consent will be obtained for each evaluation. Study findings will be disseminated through peer-reviewed scientific journals.Trial registration number 2018-004460-63.

The aim of this paper is to present Parthian-Armenian relations from the end of the 2nd century BCE to the so-called Treaty of Rhandeia (63 CE). This covers the period from the first contact of both states to the final conclusion of long-drawn-out military conflicts over Armenia between the Arsacids ruling the Parthian Empire and Rome. The author discusses reasons for the Parthian involvement in Armenia during the rule of Mithradates II and various efforts of the Arsacids to win control over this area. He also identifies three phases of their politics towards Armenia in the discussed period.