Illicit drug use and cerebral microbleeds in stroke and transient ischemic attack patients

Background: Cerebral microbleeds (CMB) signal cerebral small vessel disease and are associated with ischemic stroke (IS) incidence, recurrence, and complications. While illicit drug use (IDU) is associated with cerebral small vessel disease, the association between CMB and IDU is understudied. We sought to delineate differences in vascular risk factors between IDU and CMB and determine the effect of this relationship on outcomes in IS/transient ischemic attack (TIA) patients. Methods: We included 2001 consecutive IS and TIA patients (years 2009-2018) with a readable T2*gradient-echo MRI sequence. CMB rating followed standardized guidelines and CMB were grouped topographically into lobar, deep or infratentorial. IDU data (history and/or urine toxicology) was available for 1746 patients. The adverse composite outcome included pneumonia, urinary tract infection, deep venous thrombosis or death during hospitalization. Good functional outcome was defined as modified Rankin scale score < 3 and ambulatory on discharge. Univariate analysis was used to assess vascular risk factors and multivariable logistic regression was used to characterize the IDU/CMB relationship on outcomes. Results: We observed IDU in 13.8 % (n=241), and CMB in 32.9% (n=575, 53.8% lobar, 27.3% deep and 18.8% infratentorial). Patients with IDU and at least one CMB were older (53.6±10.5 vs. 56.9±11.5, p=0.04), had a lower BMI (28.1±5.9 vs. 26.6±4.4, p=0.04), and were more likely to have had a previous IS/TIA (25.1% vs. 41.9%, p=0.01). IDU trended higher for those with severe CMB (10+) compared with those without CMB and 1-9 CMB (25% [n=9] vs 14.3% [n=1171] and 12.1% [n=65] respectively; p=0.07) without individual drug deviations from this pattern. Adverse and good functional outcomes were observed in 177 and 905 total patients, respectively. No significant interaction was observed between IDU and CMB with either adverse or functional composite outcomes. Conclusion: IDU prevalence was high in our urban study population, and showed a borderline association with increasing CMB burden. Patients with CMB and IDU history were older and more likely to have had a previous IS/TIA. Further studies are required to clarify the clinical consequences related to the relationship between IDU and CMB.Author Disclosures: B. Petrie: None. H. Lau: None. F. Cajiga-Pena: None. S. Abbas: None. B. Finn: None. K. Dam: None. A. Cervantes-Arslanian: None. T.N. Nguyen: None. H. Aparicio: None. D. Greer: None. J.R. Romero: Speakers' Bureau; Modest; Received speaker honoraria from Ferrer Group

Biotic phase micropollutant distribution in horizontal sub-surface flow constructed wetlands.

The distribution of micropollutants in biotic phases of horizontal sub-surface flow (HSSF) constructed wetlands was investigated. 88 diverse micropollutants (personal care products, pharmaceuticals and illicit drugs) were monitored for in full-scale HSSF steel slag and gravel beds to assess their fate and behaviour during tertiary wastewater treatment. Of the studied micropollutants 54 were found in receiving and treated wastewaters. Treatment reduced concentrations of several micropollutants by >50% (removal range −112% to 98%) and resulted in changes to the stereo-isomeric composition of chiral species. For example, stereo-selective changes were observed for 3,4-methylenedioxymethamphetamine (MDMA) and atenolol during HSSF constructed wetland treatment for the first time. Analysis of sludge present within the HSSF beds found 37 micropollutants to be present. However, concentrations for the majority of these micropollutants were not considered high enough to suggest partitioning into sludge was a contributing mechanism of removal. Nevertheless the preservative methylparaben was found at 2772 mg bed−1. Its daily removal from wastewater of 3.4 mg d−1 indicates partitioning and accumulation in sludge contributes to its removal. Other micropollutants found at high levels in sludge (relative to their overall removals) were the antidepressants sertraline and fluoxetine, and the metabolite desmethylcitalopram. Furthermore, process balances indicated uptake and metabolism by Phragmites australis (Cav.) Trin. ex Steud did not contribute significantly to micropollutant removal. However analysis of plant tissues evidenced uptake, metabolism and accumulation of recalcitrant micropollutants such as ketamine and carbamazepine. It is considered that the rate of uptake was too slow to have a notable impact on removal at the 14 h hydraulic retention time. Despite evidence of other removal mechanisms at play (e.g., partitioning into sludge and plant uptake), findings indicate biodegradation is the dominant mechanism of micropollutant removal in HSSF constructed wetlands

Reproductive outcomes from ten years of elective oocyte cryopreservation

Research question: To assess the relationship between the number of oocytes retrieved during elective oocyte cryopreservation (EOC) cycles with various clinical, biochemical, and radiological markers, including age, body mass index (BMI), baseline anti-Müllerian hormone (AMH), antral follicle count (AFC), Oestradiol level (E2) and total number of follicles ≥ 12 mm on the day of trigger. To also report the reproductive outcomes from women who underwent EOC. Methods: A retrospective cohort of 373 women embarking on EOC and autologous oocyte thaw cycles between 2008 and 2018 from a single London clinic in the United Kingdom. Results: 483 stimulation cycles were undertaken amongst 373 women. The median (range) age at cryopreservation was 38 (26–47) years old. The median numbers of oocytes retrieved per cycle was 8 (0–37) and the median total oocytes cryopreserved per woman was 8 (0–45). BMI, E2 level and number of follicles ≥ 12 mm at trigger were all significant predictors of oocyte yield. Multivariate analysis confirmed there was no significant relationship between AFC or AMH, whilst on univariate analysis statistical significance was proven. Thirty six women returned to use their cryopreserved oocytes, of which there were 41 autologous oocyte thaw cycles undertaken. There were 12 successful livebirths achieved by 11 women. The overall livebirth rate was 26.8% per cycle. No livebirths were achieved in women who underwent EOC ≥ 40 years old, and 82% of all livebirths were achieved in women who had done so between 36 and 39 years old. Conclusion: Clinical, biochemical and radiological markers can predict oocyte yield in EOC cycles. Reproductive outcomes are more favourable when cryopreservation is performed before the age of 36, with lower success rates of livebirth observed in women aged 40 years and above

Multi-residue determination of micropollutants in Phragmites australis from constructed wetlands using microwave assisted extraction and ultra-high-performance liquid chromatography tandem mass spectrometry.

In constructed wetlands, micropollutants can be removed from water by phytoremediation. However, micropollutant uptake and metabolism by plants here is poorly understood due to the lack of good analytical approaches. Reported herein is the first methodology developed and validated for the multi-residue determination of 81 micropollutants (pharmaceuticals, personal care products and illicit drugs) in the emergent macrophyte Phragmites australis. The method involved extraction by microwave-accelerated extraction (MAE), clean-up using off-line solid phase extraction and analysis by ultra-high-performance liquid chromatography tandem mass spectrometry. Development of the MAE method found the influence of studied variables on micropollutant recovery to be: extraction temperature > sample mass > solvent composition. Validation of the developed extraction protocol revealed that method recoveries were in the range 80-120% for the majority of micropollutants. Method quantitation limits (MQLs) were generally < 5 ng g-1 dry weight, demonstrating the sensitivity of the methodology. Application of the method to P. australis from a constructed wetland used to treat trickling filter effluent found 17 micropollutants above their MQL, up to concentrations of 200 ng g-1. Other than uptake, the presence of several metabolites (carbamazepine 10,11 epoxide, desvenlafaxine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, N-desmethyltramadol and norketamine) indicated that metabolism within the plant may also occur. This new analytical methodology will enable a process mass balance of the constructed wetland to be attained for the first time, and thus help understand the role of phytoremediation in micropollutant removal by such systems

Reduced endothelin-1– and nitric oxide–mediated arteriolar tone in hypertensive renal transplant recipients

Reduced endothelin-1– and nitric oxide–mediated arteriolar tone in hypertensive renal transplant recipients.BackgroundThe prevalence of hypertension is high in renal transplant recipients. It has been suggested that calcineurin inhibitors (CI) contribute to the development of post-transplant hypertension by stimulating endothelin (ET-1)-mediated and/or reducing nitric oxide (NO)-mediated vascular tone.MethodsWe tested this hypothesis using 2 groups of renal transplant recipients [normotensive patients without a need for antihypertensive medication (Normo-Tx), and hypertensive patients requiring antihypertensives (Hyper-Tx)] in the presence of CI-based immunosuppression. In addition, we studied matched control subjects (C). BQ 123 (ET-A receptor antagonist), BQ123 + BQ788 (ET-A/B-receptor antagonist), ET-1, L-NMMA (NO-synthase inhibitor), acetylcholine (ACH; endothelium-dependent vasodilator), glyceroltrinitrate (GTN, NO donor), and norepinephrine (NE, endothelium-independent vasoconstrictor) were infused into the brachial artery. Forearm blood flow (FBF) was measured by venous occlusion plethysmography.ResultsEndothelium-independent vasomotion in response to GTN and NE was similar in all groups. Vascular responses to selective and combined blockade of ET receptors in both Normo-Tx and Hyper-Tx did not exceed those of C. In fact, we observed a significantly lower increase in FBF after BQ 123 (P = 0.03), as well as after BQ 123/788 (P = 0.03) in Hyper-Tx compared with Normo-Tx. This was associated with an increased vascular sensitivity to exogenous ET-1 in Hyper-Tx compared with Normo-Tx (P = 0.04). Vasoconstriction after L-NMMA was reduced in Hyper-Tx compared with Normo-Tx (P = 0.015), while the response to ACH was reduced in both groups of Tx patients to a similar degree (P = 0.005 vs. C).ConclusionOur results do not support a major role for the vascular endothelin system in the hypertension of renal transplant recipients, whereas deficient baseline NO production may be a contributing factor

Quality and methods of developing practice guidelines

BACKGROUND: It is not known whether there are differences in the quality and recommendations between evidence-based (EB) and consensus-based (CB) guidelines. We used breast cancer guidelines as a case study to assess for these differences. METHODS: Five different instruments to evaluate the quality of guidelines were identified by a literature search. We also searched MEDLINE and the Internet to locate 8 breast cancer guidelines. These guidelines were classified in three categories: evidence based, consensus based and consensus based with no explicit consideration of evidence (CB-EB). Each guideline was evaluated by three of the authors using each of the instruments. For each guideline we assessed the agreement among 14 decision points which were selected from the NCCN (National Cancer Comprehensive Network) guidelines algorithm. For each decision point we recorded the level of the quality of the information used to support it. A regression analysis was performed to assess if the percentage of high quality evidence used in the guidelines development was related to the overall quality of the guidelines. RESULTS: Three guidelines were classified as EB, three as CB-EB and two as CB. The EB guidelines scored better than CB, with the CB-EB scoring in the middle among all instruments for guidelines quality assessment. No major disagreement in recommendations was detected among the guidelines regardless of the method used for development, but the EB guidelines had a better agreement with the benchmark guideline for any decision point. When the source of evidence used to support decision were of high quality, we found a higher level of full agreement among the guidelines' recommendations. Up to 94% of variation in the quality score among guidelines could be explained by the quality of evidence used for guidelines development. CONCLUSION: EB guidelines have a better quality than CB guidelines and CB-EB guidelines. Explicit use of high quality evidence can lead to a better agreement among recommendations. However, no major disagreement among guidelines was noted regardless of the method for their development

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

20,000 years of societal vulnerability and adaptation to climate change in southwest Asia.

The Fertile Crescent, its hilly flanks and surrounding drylands has been a critical region for studying how climate has influenced societal change, and this review focuses on the region over the last 20,000 years. The complex social, economic, and environmental landscapes in the region today are not new phenomena and understanding their interactions requires a nuanced, multidisciplinary understanding of the past. This review builds on a history of collaboration between the social and natural palaeoscience disciplines. We provide a multidisciplinary, multiscalar perspective on the relevance of past climate, environmental, and archaeological research in assessing present day vulnerabilities and risks for the populations of southwest Asia. We discuss the complexity of palaeoclimatic data interpretation, particularly in relation to hydrology, and provide an overview of key time periods of palaeoclimatic interest. We discuss the critical role that vegetation plays in the human-climate-environment nexus and discuss the implications of the available palaeoclimate and archaeological data, and their interpretation, for palaeonarratives of the region, both climatically and socially. We also provide an overview of how modelling can improve our understanding of past climate impacts and associated change in risk to societies. We conclude by looking to future work, and identify themes of "scale" and "seasonality" as still requiring further focus. We suggest that by appreciating a given locale's place in the regional hydroscape, be it an archaeological site or palaeoenvironmental archive, more robust links to climate can be made where appropriate and interpretations drawn will demand the resolution of factors acting across multiple scales. This article is categorized under:Human Water > Water as Imagined and RepresentedScience of Water > Water and Environmental ChangeWater and Life > Nature of Freshwater Ecosystems

Research about eye health and eye health services in Pacific Island Countries and Territories: a scoping review

Background: We aimed to summarise the extent and nature of published research about eye health and eye health services in Pacific Island Countries and Territories since 1980. Methods: We searched Medline, EMBASE, Global Health and Cochrane Library to identify publications about eye health and eye health services in 22 Pacific Island Countries and Territories from 1 January 1980 to 26 January 2024. Study selection and data extraction were conducted by two reviewers independently. Findings: Of the 1610 publications identified, 180 were included. This research was most commonly conducted in Papua New Guinea (n = 52) or Fiji (n = 33) and focused on diabetic retinopathy (n = 29) or trachoma (n = 18), with few focused on cataract or refractive error. While eye health services research was common in the past, recent research focused on trachoma. The included research was largely undertaken and funded by people and organisations from Australia, Aotearoa New Zealand and the USA, though authors with Pacific affiliations is increasing. Interpretation: Few countries have up-to-date estimates of the prevalence of vision impairment or service coverage to enable evidence-informed planning. Increased effort is required to strengthen research capability to ensure research priorities in eye health are set by Pacific Peoples. Funding: The Fred Hollows Foundation New Zealand