In South Africa (SA), increasing illicit opioid use and associated health challenges can be managed with opioid substitution therapy (OST), such as methadone, if the recommended dose and duration of ...use are prescribed. The Community Oriented Substance Use Programme (COSUP) provides free methadone to patients with opioid use disorder in Tshwane, SA, on need-based criteria.
To determine selected sociodemographic and substance use treatment factors associated with retention for at least 6 months among participants receiving methadone as part of OST in COSUP.
This was a retrospective cohort study using secondary data of patients treated with methadone at 8 COSUP sites. The factors associated with at least 6 months' retention for 575 participants from December 2016 to September 2018 were analysed.
There were 91.3% males, 86.4% South Africans and 85.9% black Africans, with a median age of 30 years. At baseline, the majority were injecting heroin (55.5%) and were provided with free methadone (59.3%). The median dose of methadone at 6 months or on leaving the programme was 20 mg; 38.4% of participants were retained for at least 6 months. Of those not retained, the median duration on methadone was 56 days, whereas for those retained for at least 6 months, the median number of days on methadone were 254. After adjusting for sex and age, participants receiving methadone doses <50 mg had lower odds of being retained (0 - 20 mg: adjusted odds ratio (aOR) 0.25; p=0.002; 95% confidence interval (CI) 0.10 - 0.61; >20 - 40 mg: aOR 0.20; p<0.001; 95% CI 0.08 - 0.49) than those administered ≥50 mg. Participants who received free methadone had 3.75 the odds of being retained than those buying it themselves (p<0.001; 95% CI 2.47 - 5.70). Participants treated in the inner city had 5.19 the odds of being retained than those in a suburban setting (p<0.001; 95% CI 2.99 - 9.03). Compared with black African participants, white participants had 3.39 the odds of being retained (p=0.001; 95% CI 1.64 - 7.00). Injecting heroin users had 0.63 the odds of being retained (p=0.032; 95% CI 0.41 - 0.96).
To maximise retention on OST, methadone should be free, with maintenance doses >50 mg. Reasons for lower retention among participants from periurban settings, those who inject and those from previously disadvantaged racial groups need to be explored, and findings used to inform programming.
Paracrine release of ovine interferon tau (oIFNT) from the conceptus alters release of endometrial prostaglandin F2 alpha (PGF) and prevents luteolysis. Endocrine release of oIFNT into the uterine ...vein occurs by Day 15 of pregnancy and may impart resistance of the corpus luteum (CL) to PGF. It was hypothesized that infusion of recombinant oIFNT (roIFNT) into the uterine or jugular veins on Day 10 of the estrous cycle would protect the CL against exogenous PGF-induced luteolysis. Osmotic pumps were surgically installed in 24 ewes to deliver bovine serum albumin (BSA; n = 12) or roIFNT (200 μg/day; n = 12) for 24 h into the uterine vein. Six ewes in each treatment group received a single injection of PGF (4 mg/58 kg body weight) 12 h after pump installation. In a second experiment, BSA or roIFNT was delivered at 20 or 200 μg/day into the uterine vein or 200 μg/day into the jugular vein for 72 h in 30 ewes. One half of these ewes received an injection of PGF 24 h after pump installation. Concentrations of progesterone in serum declined in BSA-treated ewes injected with PGF, but were sustained in all ewes infused with 20 μg/day of roIFNT into the uterine vein and 200 μg of roIFNT into the jugular vein followed 24 h later with injection of PGF. All concentrations of roIFNT and modes of delivery (uterine or jugular vein) increased luteal concentrations of IFN-stimulated gene (i.e., ISG15) mRNA. Infusion of 200 μg of IFNT over 24 h induced greater mRNA concentrations for cell survival genes, such as BCL2-like 1 (BCL2L1 or Bcl-xL), serine/threonine kinase (AKT), and X-linked inhibitor of apoptosis (XIAP) and decreased prostaglandin F receptor (PTGFR) mRNA concentrations, when compared to controls. It is concluded that endocrine delivery of roIFNT, regardless of route (uterine or jugular vein), effectively protects CL from the luteolytic actions of PGF by mechanisms that involve ISGs and stabilization of cell survival genes.
Abstract
Historical trends in the direction and magnitude of ocean surface wave height, period, or direction are debated due to diverse data, time-periods, or methodologies. Using a consistent ...community-driven ensemble of global wave products, we quantify and establish regions with robust trends in global multivariate wave fields between 1980 and 2014. We find that about 30–40% of the global ocean experienced robust seasonal trends in mean and extreme wave height, period, and direction. Most of the Southern Hemisphere exhibited strong upward-trending wave heights (1–2 cm per year) and periods during winter and summer. Ocean basins with robust positive trends are far larger than those with negative trends. Historical trends calculated over shorter periods generally agree with satellite records but vary from product to product, with some showing a consistently negative bias. Variability in trends across products and time-periods highlights the importance of considering multiple sources when seeking robust change analyses.
Abstract Here, we review work over the past two decades that has indicated drug reward is modulated by the circadian system that generates daily (i.e., 24 h) rhythms in physiology and behavior. ...Specifically, drug-self administration, psychomotor stimulant-induced conditioned place preference, and locomotor sensitization vary widely across the day in various species. These drug-related behavioral rhythms are associated with rhythmic neural activity and dopaminergic signaling in the mesocorticolimbic pathways, with a tendency toward increased activity during the species typical wake period. While the mechanisms responsible for such cellular rhythmicity remain to be fully identified, circadian clock genes are expressed in these brain areas and can function locally to modulate both dopaminergic neurotransmission and drug-associated behavior. In addition, neural and endocrine inputs to these brain areas contribute to cellular and reward-related behavioral rhythms, with the medial prefrontal cortex playing a pivotal role. Acute or chronic administration of drugs of abuse can also alter clock gene expression in reward-related brain regions. Emerging evidence suggests that drug craving in humans is under a diurnal regulation and that drug reward may be influenced by clock gene polymorphisms. These latter findings, in particular, indicate that the development of therapeutic strategies to modulate the circadian influence on drug reward may prove beneficial in the treatment of substance abuse disorders.
Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with ...small vessel disease.
We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated.
Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years SD 9·9) and 26 with CADASIL (53·1 years 7·0) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10–4%/mm Hg SE 20·1; 95% CI –37·6 to 41·2 for amlodipine; 16·7 × 10–4%/mm Hg 20·0; –22·3 to 55·8 for losartan; –7·1 × 10–4%/mm Hg 19·6; –45·5 to 31·1 for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10–4%/mm Hg SE 27·5; 95% CI –38·3 to 69·7 for amlodipine; 19·4 × 10–4%/mm Hg 27·9; –35·3 to 74·2 for losartan; –23·9 × 10–4%/mm Hg 27·5; –77·7 to 30·0 for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (–39·6 × 10–4%/mm Hg 95% CI –72·5 to –6·6; p=0·019) and with losartan compared with atenolol (–43·3 × 10–4%/mm Hg –74·3 to –12·3; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake.
4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research.
EU Horizon 2020 programme.
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors ...because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
Studies in the USA and Canada have reported increasing or stable rates of hospital admissions for hypoglycaemia. Some data from small studies are available for other countries. We aimed to gather ...information about long-term trends in hospital admission for hypoglycaemia and subsequent outcomes in England to help widen understanding for the global burden of hospitalisation for hypoglycaemia.
We collected data for all hospital admissions listing hypoglycaemia as primary reason of admission between Jan 1, 2005, and Dec 31, 2014, using the Hospital Episode Statistics database, which contains details of all admissions to English National Health Service (NHS) hospital trusts. We calculated trends in crude and adjusted (for age, sex, ethnic group, social deprivation, and Charlson comorbidity score) admissions for hypoglycaemia; in admissions for hypoglycaemia per total hospital admissions and per diabetes prevalence in England; and in length of stay, in-hospital mortality, and 1 month readmissions for hypoglycaemia.
79 172 people had 101 475 admissions for hypoglycaemia between 2005 and 2014, of which 72 568 (72%) occurred in people aged 60 years or older. 13 924 (18%) people had more than one admission for hypoglycaemia during the study period. The number of admissions increased steadily from 7868 in 2005, to 11 756 in 2010 (49% increase) and then remained more stable until 2014 (10 977; 39% increase from baseline, range across English regions 11-89%); the trend was similar after adjustment for risk factors, with a rate ratio of 1·53 (95% CI 1·29-1·81) for 2014 versus 2005. Admissions for hypoglycaemia per 100 000 total hospital admissions increased from 63·6 to 78·9 between 2005-06 and 2010-11 (24% increase), and then fell to 72·3 per 100 000 in 2013-14 (14% overall increase). Accounting for diabetes prevalence data, rates declined from 4·64 to 3·86 admissions per 1000 person-years with diabetes between 2010-11 and 2013-14. We were unable to compare prevalence rates with data prior to 2010, as the populations were not comparable; data were available for all individuals prior to 2010 but only for those aged 17 years or older after 2010. With some differences across regions, from 2005 to 2014, the adjusted proportion of admissions to receive same-day discharge increased by 43·8% (from 18·9 to 27·1 same-day discharges per 100 admissions); in-hospital mortality decreased by 46·3% (from 4·2 to 2·3 deaths per 100 admissions); and 1 month readmissions decreased by 63·0% (from 48·1 to 17·8 per 100 readmissions).
Over 10 years, hospital admissions in England for hypoglycaemia increased by 39% in absolute terms and by 14% considering the general increase in hospitalisation; however, accounting for diabetes prevalence, there was a reduction of admission rates. Hospital length of stay, mortality, and 1 month readmissions decreased progressively and consistently during the study period. Given the continuous rise of diabetes prevalence, ageing population, and costs associated with hypoglycaemia, individual and national initiatives should be implemented to reduce the burden of hospital admissions for hypoglycaemia.
None.
Aims/hypothesis
In the context of increasing prevalence of diabetes in elderly people with multimorbidity, intensive glucose control may increase the risk of severe hypoglycaemia, potentially leading ...to death. While rising trends of severe hypoglycaemia rates have been reported in some European, North American and Asian countries, the global burden of hypoglycaemia-related mortality is unknown. We aimed to investigate global differences and trends of hypoglycaemia-related mortality.
Methods
We used the WHO mortality database to extract information on death certificates reporting hypoglycaemia or diabetes as the underlying cause of death, and the United Nations demographic database to obtain data on mid-year population estimates from 2000 to 2014. We calculated crude and age-standardised proportions (defined as number of hypoglycaemia-related deaths divided by total number of deaths from diabetes i.e. the sum of hypoglycaemia- and diabetes-related deaths) and rates (hypoglycaemia-related deaths divided by mid-year population) of hypoglycaemia-related mortality and compared estimates across countries and over time.
Results
Data for proportions were extracted from 109 countries (31 had data from all years analysed 2000–2014 available). Combining all countries, the age-standardised proportion of hypoglycaemia-related deaths was 4.49 (95% CI 4.44, 4.55) per 1000 total diabetes deaths. Compared with the overall mean, most Central American, South American and (mainly) Caribbean countries reported higher proportions (five more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths in Chile, six in Uruguay, 11 in Belize and 22 in Aruba), as well as Japan (11 more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths). In comparison, lower proportions were noted in most European countries, the USA, Canada, New Zealand and Australia. For countries with data available for all years analysed, trend analysis showed a 60% increase in hypoglycaemia-related deaths until 2010 and stable trends onwards. Rising trends were most evident for Argentina, Brazil, Chile, the USA and Japan. Data for rates were available for 105 countries (30 had data for all years analysed 2000–2014 available). Combining all countries, the age-standardised hypoglycaemia-related death rate was 0.79 (95% CI 0.77, 0.80) per 1 million person-years. Most Central American, South American and Caribbean countries similarly reported higher rates of hypoglycaemia-related death, whilst virtually all European countries, the USA, Canada, Japan, New Zealand and Australia reported lower rates compared with the overall mean. Age-standardised rates were very low for most countries (lower than five per 1 million person-years in 89.5% of countries), resulting in small absolute differences among countries. As noted with the proportions analysis, trend analysis showed an overall 60% increase in hypoglycaemia-related deaths until 2010 and stable rate trends onwards; rising rates were particularly evident for Brazil, Chile and the USA.
Conclusions/interpretation
Most countries in South America, Central America and the Caribbean showed the highest proportions of diabetes-related deaths attributable to hypoglycaemia and the highest rates of hypoglycaemia-related deaths. Between 2000 and 2014, rising trends were observed in Brazil, Chile and the USA for both rates and proportions of hypoglycaemia-related death, and in Argentina and Japan for proportions only. Further studies are required to unravel the contribution of clinical and socioeconomic factors, difference in diabetes prevalence and heterogeneity of death certification in determining lower rates and proportions of hypoglycaemia-related deaths in high-income countries in Europe, North America and Asia.
Data availability
Data used for these analyses are available at
https://doi.org/10.17632/ndp52fbz8r.1
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