Methadone and buprenorphine-related deaths among people prescribed and not prescribed Opioid Agonist Therapy during the COVID-19 pandemic in England.

BACKGROUND: The coronavirus pandemic resulted in many changes which had the potential to impact mortality related to opioid agonist therapy (OAT; methadone, buprenorphine), including changes in the prescribing and dispensing of OAT and patterns of drug availability and use. We aimed to assess the impact of the first lockdown (initiated March 23rd 2020) on methadone- and buprenorphine-related deaths in England in people both prescribed and not prescribed OAT using data from the National Programme on Substance Abuse Deaths. METHODS: This was a retrospective post-mortem toxicology study of OAT-related deaths which occurred in the 3-month period March 23rd to June 22nd in the years 2016-2020. Provisional data regarding numbers accessing treatment for opioid use disorder was provided by the National Drug Treatment Monitoring System. RESULTS: We found a 64% increase in methadone-related deaths in March to June 2020 compared to March to June 2019 (2019 n = 96; 2020 projected n = 157). There were increases in the mortality rate of both in-treatment decedents (22% increase; 2019 n = 45; an exponential smoothing model of the 2016-19 trend [α=0.5] predicted 44 deaths in 2020, 55 were reported) and decedents not prescribed methadone (74% increase; 2019 n = 46; 2016-19 trend predicted 43 deaths in 2020, 80 were reported). There was no increase in buprenorphine-related deaths (2019 n = 9/529; 2020 n = 11/566). There were no changes in the numbers of deaths where other opioids or multiple substances were detected, or in methadone levels detected. Numbers of people accessing treatment for opioid use disorder in 2020 did not decrease relative to previous years (p >0.05). CONCLUSIONS: Methadone-related deaths in non-prescribed individuals, but not prescribed individuals, increased considerably above the annual trend forecast for 2020 during the first COVID-19 lockdown in England. Further studies are thus needed to understand this difference.

Changing demographics and immunity to vaccine preventable diseases in people with HIV in Ireland.

BACKGROUND: HIV infection is associated with an increased risk of morbidity and mortality from vaccine preventable infections. This research describes, in the context of changing patient demographics, the seroprevalence of vaccine preventable viral infections among attendees of the largest centre for HIV positive patients in Ireland. METHODS: Baseline serum IgG results for measles, mumps, rubella, varicella zoster virus (VZV) & hepatitis A, as well as hepatitis B sAg, cAb and sAb results, were retrieved for 2534 clinic attendees attending in 2018. Results were available for between 990 and 2363 attendees (39-93%), depending on the test, and were compared with 2013 clinic data. RESULTS: There was a 35% increase in attendees in 2018 when compared to 2013. The largest increase was in attendees of South American origin. In 2018, males accounted for 73% of the entire cohort and the HIV acquisition risk for 48% of attendees was MSM. 47% of attendees were originally from Ireland. Among those tested, 33% were susceptible to at least one component of the MMR vaccine. 5% were VZV non-immune (significantly associated with younger age and the acquisition risk status of injection drug use). 21% were hepatitis A non-immune (significantly associated with younger age and being of European or South American origin). 32% were hepatitis B cAb seropositive (significantly associated with older age, injection drug use status and being originally from Africa). 3% demonstrated hepatitis B sAg positivity. 64% had hepatitis B sAb ≥ 10mIU. CONCLUSION: In a cohort of attendees to an HIV clinic in a large urban setting, the susceptibility to several common vaccine preventable viral infections, in particular MMR and hepatitis A and B, was high. These results highlight the importance of proactive screening and immunisation to help protect this high risk patient group against vaccine preventable diseases.

Undetected Respiratory Depression in People with Opioid Use Disorder.

BACKGROUND: Opioid-related deaths are increasing globally. Respiratory complications of opioid use and underlying respiratory disease in people with Opioid Use Disorder (OUD) are potential contributory factors. Individual variation in susceptibility to overdose is, however, incompletely understood. This study investigated the prevalence of respiratory depression (RD) in OUD treatment and compared this to patients with chronic obstructive pulmonary disease (COPD) of equivalent severity. We also explored the contribution of opioid agonist treatment (OAT) dosage, and type, to the prevalence of RD. METHODS: There were four groups of participants: 1) OUD plus COPD ('OUD-COPD', n = 13); 2) OUD without COPD ('OUD', n = 7); 3) opioid-naïve COPD patients ('COPD'n = 13); 4) healthy controls ('HC'n = 7). Physiological indices, including pulse oximetry (SpO2%), end-tidal CO2 (ETCO2), transcutaneous CO2 (TcCO2), respiratory airflow and second intercostal space parasternal muscle electromyography (EMGpara), were recorded continuously over 40 min whilst awake at rest. Significant RD was defined as: SpO2%< 90% for > 10 s, ETCO2 per breath > 6.6 kPa, TcCO2 overall mean > 6 kPa, respiratory pauses > 10 s RESULTS: At least one indicator was observed in every participant with OUD (n = 20). This compared to RD episode occurrence in only 2/7 HC and 2/13 COPD participants (p < 0.05,Fisher's exact test). The occurrence of RD was similar in OUD participants prescribed methadone (n = 6) compared to those prescribed buprenorphine (n = 12). CONCLUSIONS: Undetected RD is common in OUD cohorts receiving OAT and is significantly more severe than in opioid-naïve controls. RD can be assessed using simple objective measures. Further studies are required to determine the association between RD and overdose risk.

Prediction of genetic merit for live weight and body condition score in dairy cows using routinely available linear type and carcass data.

Accurate estimates of genetic merit for both live weight and body condition score (BCS) could be useful additions to both national- and herd-breeding programs. Although recording live weight and BCS is not technologically arduous, data available for use in routine genetic evaluations are generally lacking. The objective of the present study was to explore the usefulness of routinely recorded data, namely linear type traits (which also included BCS but only assessed visually) and carcass traits in the pursuit of genetic evaluations for both live weight and BCS in dairy cows. The data consisted of on-farm records of live weight and BCS (assessed using both visual and tactile cues) from 33,242 dairy cows in 201 commercial Irish herds. These data were complemented with information on 6 body-related linear type traits (i.e., stature, angularity, chest width, body depth, BCS, and rump width) and 3 cull cow carcass measures (i.e., carcass weight, conformation, and fat cover) on a selection of these animals plus close relatives. (Co)variance components were estimated using animal linear mixed models. The genetic correlation between the type traits stature, angularity, body depth, chest width, rump width, and visually-assessed BCS with live weight was 0.68, -0.28, 0.43, 0.64, 0.61, and 0.44, respectively. The genetic correlation between angularity and BCS measured on farm (based on both visual and tactile appraisal) was -0.79; the genetic and phenotypic correlation between BCS assessed visually as part of the linear assessment with BCS assessed by producers using both tactile and visual cues was 0.90 and 0.27, respectively. The genetic (phenotypic) correlation between cull cow carcass weight and live weight was 0.81 (0.21), and the genetic (phenotypic) correlation between cull cow carcass fat cover and BCS assessed on live cows was 0.44 (0.12). Estimated breeding values (EBV) for live weight and BCS in a validation population of cows were generated using a multitrait evaluation with observations for just the type traits, just the carcass traits, and both the type traits and carcass traits; the EBV were compared with the respective live weight and BCS phenotypic observations. The regression of phenotypic live weight on its EBV from the multitrait evaluations was 1.00 (i.e., the expectation) when the EBV was generated using just linear type trait data, but less than 1 (0.83) when using just carcass data. However, the regression changed across parities and stages of lactation. The partial correlation (after adjusting for contemporary group, parity by stage of lactation, heterosis, and recombination loss) between phenotypic live weight and EBV for live weight estimated using the 3 different scenarios (i.e., type only, carcass only, type plus carcass) ranged from 0.38 to 0.43. Although the prediction of phenotypic BCS from its respective EBV was relatively good when using just the linear type trait data (regression coefficient of 0.83 with a partial correlation of 0.22), the predictive ability of BCS EBV based on just carcass data was poor and should not be used. Overall, linear type trait data are a useful source of information to predict live weight and BCS with minimal additional predictive value from also including carcass data. Nonetheless, in the absence of linear type trait data, information on carcass traits can be useful in predicting genetic merit for mature cow live weight. Prediction of cow BCS from cow carcass data is not recommended.

Short communication: Differences in genetic merit for visually-assessed body condition score materialises as phenotypic differences in tactile-based body condition score in commercial dairy cows.

Body condition score (BCS) is a known risk factor for cow health and well-being. Many different BCS scales and systems for assessment exist;while the scales used for assessing BCS vary, differences in how BCS is assessed (i.e., visual versus visual plus tactile) and the extent of training and experience of the assessor (i.e., professional linear classifiers versus producers) also contributes to the underlying variability. Registered dairy cows globally are routinely assessed for linear type traits which describe biological extremes in the morphological attributes; BCS and a correlated trait angularity are within this suite of traits assessed. These linear-type data are used to generate estimates of genetic merit (predicted transmitting ability), but how these estimates manifest themselves as phenotypic differences when assessed by producers on commercial multiparous cows has never been quantified. To evaluate this, 58440 phenotypic BCS records from 48823 lactations in 38608 cows were used. Associations were undertaken using linear mixed models relating phenotypic BCS to genetic merit after accounting for nuisance factors. Differences in genetic merit for either BCS or angularity (assessed visually by professionals on a 1 to 9 scale just once during lactation in primiparous registered cows) translated to phenotypic difference in BCS (assessed by producers using both tactile and visual assessment on a 1 to 5 scale across lactation in commercial dairy cows). The partial correlation between test phenotypic BCS and genetic merit for either BCS or angularity was 0.13 and 0.10, respectively. Based on the model coefficients estimated in the present study, the mean expected difference in phenotypic BCS on a 1 to 5 scale between the top and bottom 10% on genetic merit for BCS or angularity was 0.28 and 0.31 units, respectively. Results from the present study clearly provide confidence that genetic merit for BCS or angularity based on a single visual assessment in primiparous cows is useful to breed for cows of better body condition, irrespective of stage of lactation or parity.

Formulation of a decision support tool incorporating both genetic and non-genetic effects to rank young growing cattle on expected market value.

While breeding indexes exist globally to identify candidate parents of the next generation, fewer tools exist that provide guidance on the expected monetary value of young animals. The objective of the present study was therefore to develop the framework for a cattle decision-support tool which incorporates both the genetic and non-genetic information of an animal and, in doing so, better predict the potential market value of an animal, whatever the age. Two novel monetary indexes were constructed and their predictive ability of carcass value was compared to that of the Irish national Terminal breeding index, typical of other terminal indexes used globally. A constructed Harvest index was composed of three carcass-related traits [i.e., 1) carcass weight, 2) carcass conformation and 3) carcass fat, each weighted by their respective economic value] and aimed at purchasers of animals close to harvest; the second index, termed the Calf index, also included docility and feed intake (weighted by their respective economic value), thus targeting purchasers of younger calves for growing (and eventually harvesting). Genetic and non-genetic fixed and random effect model solutions from the Irish national genetic evaluations underpinned all indexes. The two novel indexes were formulated using three alternative estimates of an animal's total merit for comparative purposes: 1) an index based solely on the animal's breed solutions, 2) an index which also included within-breed animal differences, and 3) an index which, as well as considering additive and non-additive genetic effects, also included non-genetic effects (referred to as production values [PVs]). As more information (i.e., within breed effects and subsequently non-genetic effects) was included in the total merit estimate, the correlations strengthened between the two proposed indexes and the animal's calculated carcass market value; the correlation coefficients almost doubled in strength when total merit was based on PV-based estimates as compared to the breed solutions alone. Including phenotypic live-weight data, collected during the animal's life, strengthened the predictive ability of the indexes further. Based on the results presented, the proposed indexes may fill the void in decision support when purchasing or selling cattle. In addition, given the dynamic nature of indexes, they have the potential to be updated in real-time as information becomes available.

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 .

Predicting male dairy calf live weight for use in calf management decision support.

The growing awareness and scrutiny of the management of young dairy calves, especially male calves, necessitates a support tool to aid in the planning of resource allocation on dairy farms. There is a desire among some vendors for a minimum calf weight when purchasing young dairy bull calves. Hence, the objective of the present study was to investigate whether live weight of young calves (approximately 10-50 d old) can be predicted using readily accessible animal-level features, especially features that may be available in advance of birth. A multiple linear regression mixed model was developed with the live weight of 602 dairy bull calves aged between 10 and 42 d as the dependent variable; the age at which an animal is predicted to reach a predefined live weight was then estimated based on the model regression coefficients. Fixed effects included in the multiple regression model were dam parity, gestation length, and parental average genetic merit for relevant traits available in Ireland; namely, birth weight, birth size, and carcass weight. Herd of origin was included as a random effect, with all calves having been sold directly from the farm of birth. Live weight data were recorded at the point of sale when calves were, on average, 26 d old with a mean live weight of 56.6 kg. Animals were randomly assigned to 10 separate (i.e., folds) cross-validation data sets without replacement (i.e., each fold consisted of a different 10% of the data to test the model, with the remaining 90% of data being used to train the model) to quantify the accuracy of prediction. Across all data, the correlation between actual and predicted live weight was 0.76; the regression coefficient of actual live weight on predicted live weight across all data was 0.99. The root mean squared error of prediction varied from 4.40 to 6.66 kg per fold. Across all data, the root mean squared error was 5.61 kg, implying that 68% of live weight predictions were within 5.61 kg of the actual live weight. Given the potential availability of all model features in advance of birth (gestation length can be predicted from ultrasound examination of the pregnant uterus, although substituting parental average genetic merit for gestation length had minimal effect on model performance), predictions can be integrated into a dairy farm decision support tool to aid in the management of labor and infrastructure resources to achieve minimum live weight specifications before sale.

COPD and asthma in patients with opioid dependency: a cross-sectional study in primary care.

Patients treated for drug addiction have high asthma and COPD prevalence rates. The relative contributions of cigarette smoking, smoking intensity and possible smoking of other substances has not been described. We aimed to describe the prevalence and determinants of asthma and COPD in patients prescribed methadone as opioid substitution therapy (OST). In a cross-sectional study of an anonymised patient-level primary care dataset of UK inner-city general practices (n = 46), 321,395 patients aged ≥18 years were identified. A total of 676 (0.21%) had a record of a methadone ever issued in primary care. The association between respiratory disease and methadone prescribing was examined using logistic regression. Models were adjusted for potential effects of clustering by practice. A total of 97.3% of patients prescribed methadone were cigarette smokers, either current (81.2%) or ex-smokers (16.1%). The prevalences of asthma and COPD were higher in methadone patients (14.2% and 12.4%, respectively) compared to non-methadone patients (4.4% and 1.1%, respectively). Methadone was an independent determinant of asthma, adjusting for smoking status (OR 3.21; 95% CI: 2.52, 4.10) or for smoking intensity (3.08; 2.27, 4.19), and of COPD, adjusting for smoking status (6.00; 4.61, 7.80) or for smoking intensity (5.80; 4.12, 8.17). COPD and asthma prevalence were substantially higher in those prescribed methadone compared to those never prescribed methadone. Prescription of methadone was an independent predictor for both COPD and asthma, even after adjustment for smoking status and smoking intensity. Possible explanations include confounding by association with smoking of heroin or crack cocaine, both of which may have a causal association with COPD and asthma.

Incidence and risk factors for invasive pneumococcal disease in HIV-positive individuals in the era of highly active antiretroviral therapy.

Invasive pneumococcal diseases (IPDs) remain a significant cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals despite the widespread use of highly active antiretroviral therapy (HAART) and availability of pneumococcal vaccines. The aim of this study was to measure temporal trends in incidence and risk factors for IPD (defined as culture of Streptococcus pneumoniae from blood, cerebrospinal fluid or both) in a cohort of HIV-positive patients attending an ambulatory HIV care centre in Dublin, Ireland over a 10-year period 2006-2015. Incidence of IPD was determined as events per 100,000 person-years' follow-up. Poisson regression was used to assess linear trend in incidence over time. A nested case-control study (four controls per case) was undertaken to assess risk factors for IPD. Forty-seven episodes of IPD were identified in 42 HIV-positive individuals (median [IQR] age 38 years [33-43], 69% male, 86% injecting drug users (IDUs), median CD4 T-cell count 213 cells/mm3) over 16,008 person-years' follow-up (overall incidence rate 293/100,000 person-years). Three patients had two episodes and one patient had three episodes of IPD during the study period. The overall case fatality rate was 15% (95% confidence interval [CI] 4-24%). The incidence of IPD per 100,000 person-years decreased from 728 (95% CI, 455-1002), to 242 (95% CI, 120-365) to 82 (95% CI, 40-154) in calendar periods 2006-2008, 2009-2012 and 2013-2015, respectively (p < 0.01 for linear trend). Older age (p = 0.02), male gender (p = 0.05), detectable HIV viral load (p < 0.01) and non-receipt of pneumococcal vaccine (p = 0.03) were associated with IPD while IDU as risk of acquisition of HIV was of borderline significance (p = 0.06). HIV-positive individuals remain at greater risk of IPD compared to the general population. Pneumococcal vaccine should be seen as a priority to ensure optimal protection for HIV-positive patients.

How herd best linear unbiased estimates affect the progress achievable from gains in additive and nonadditive genetic merit.

Sustainable dairy cow performance relies on coevolution in the development of breeding and management strategies. Tailoring breeding programs to herd performance metrics facilitates improved responses to breeding decisions. Although herd-level raw metrics on performance are useful, implicitly included within such statistics is the mean herd genetic merit. The objective of the present study was to quantify the expected response from selection decisions on additive and nonadditive merit by herd performance metrics independent of herd mean genetic merit. Performance traits considered in the present study were age at first calving, milk yield, calving to first service, number of services, calving interval, and survival. Herd-level best linear unbiased estimates (BLUE) for each performance trait were available on a maximum of 1,059 herds, stratified as best, average, and worst for each performance trait separately. The analyses performed included (1) the estimation of (co)variance for each trait in the 3 BLUE environments and (2) the regression of cow-level phenotypic performance on either the respective estimated breeding value (EBV) or the heterosis coefficient of the cow. A fundamental assumption of genetic evaluations is that 1 unit change in EBV equates to a 1 unit change in the respective phenotype; results from the present study, however, suggest that the realization of the change in phenotypic performance is largely dependent on the herd BLUE for that trait. Herds achieving more yield, on average, than expected from their mean genetic merit, had a 20% greater response to changes in EBV as well as 43% greater genetic standard deviation relative to herds within the worst BLUE for milk yield. Conversely, phenotypic performance in fertility traits (with the exception of calving to first service) tended to have a greater response to selection as well as a greater additive genetic standard deviation within the respective worst herd BLUE environments; this is suggested to be due to animals performing under more challenging environments leading to larger achievable gains. The attempts to exploit nonadditive genetic effects such as heterosis are often the basis of promoting cross-breeding, yet the results from the present study suggest that improvements in phenotypic performance is largely dependent on the environment. The largest gains due to heterotic effects tended to be within the most stressful (i.e., worst) BLUE environment for all traits, thus suggesting the heterosis effects can be beneficial in mitigating against poorer environments.

Genetic selection for hoof health traits and cow mobility scores can accelerate the rate of genetic gain in producer-scored lameness in dairy cows.

Cattle breeding programs that strive to reduce the animal-level incidence of lameness are often hindered by the availability of informative phenotypes. As a result, indicator traits of lameness (i.e., hoof health and morphological conformation scores) can be used to improve the accuracy of selection and subsequent genetic gain. Therefore, the objectives of the present study were to estimate the variance components for hoof health traits using various phenotypes collected from a representative sample of Irish dairy cows. Also of interest to the present study was the genetic relationship between both hoof health traits and conformation traits with producer-scored lameness. Producer-recorded lameness events and linear conformation scores from 307,657 and 117,859 Irish dairy cows, respectively, were used. Data on hoof health (i.e., overgrown sole, white line disease, and sole hemorrhage), mobility scores, and body condition scores were also available from a research study on up to 11,282 Irish commercial dairy cows. Linear mixed models were used to quantify variance components for each trait and to estimate genetic correlations among traits. The estimated genetic parameters for hoof health traits in the present study were greater (i.e., heritability range: 0.005 to 0.27) than previously reported in dairy cows. With the exception of analyses that considered hoof health traits in repeatability models, little difference in estimated variance components existed among the various hoof-health phenotypes. Results also suggest that producer-recorded lameness is correlated with both hoof health (i.e., genetic correlation up to 0.48) and cow mobility (i.e., genetic correlation = 0.64). Moreover, cows that genetically tend to have rear feet that appear more parallel when viewed from the rear are also genetically more predisposed to lameness (genetic correlation = 0.39); genetic correlations between lameness and other feet and leg type traits, as well as between lameness and frame type traits, were not different from zero. Results suggest that if the population breeding goal was to reduce lameness incidence, improve hoof health, or improve cow mobility, genetic selection for either of these traits should indirectly benefit the other traits. Results were used to quantify the genetic gains achievable for lameness when alternative phenotypes are available.