Point-of-Care Capillary Blood Ketone Measurements and the Prediction of Future Ketoacidosis Risk in Type 1 Diabetes.

OBJECTIVE: Rather than during illness while diabetic ketoacidosis (DKA) is developing, we aimed to determine if levels of routine point-of-care capillary blood ketones could predict future DKA. RESEARCH DESIGN AND METHODS: We examined previously collected data from placebo-assigned participants in an adjunct-to-insulin medication trial program that included measurement of fasted capillary blood ketone levels twice per week in a 2-month baseline period. The outcome was 6- to 12-month trial-adjudicated DKA. RESULTS: DKA events occurred in 12 of 484 participants at a median of 105 (interquartile range 43, 199) days. Maximum ketone levels were higher in patient cases compared with in control patients (0.8 [0.6, 1.2] vs. 0.3 [0.2, 0.7] mmol/L; P = 0.002), with a nonparametric area under the receiver operating characteristic curve of 0.77 (95% CI 0.66-0.88). Ketone levels ≥0.8 mmol/L had a sensitivity of 64%, a specificity of 78%, and positive and negative likelihood ratios of 2.9 and 0.5, respectively. CONCLUSIONS: This proof of concept that routine capillary ketone surveillance can identify individuals at high risk of future DKA implies a role for future technologies including continuous ketone monitoring.

Drug-induced haemolysis: another reason to be cautious with nitrofurantoin.

We report the case of a previously healthy woman in her 60s who presented to the emergency department with acute confusion, vomiting and fever. She was recently diagnosed with a urinary tract infection as an outpatient and had completed the fifth day of a 7-day course of treatment with nitrofurantoin. We maintained a wide differential diagnosis including infectious, metabolic, autoimmune and medication-related causes. She developed an acute normocytic anaemia in hospital with a haemoglobin drop from 121 g/L to 89 g/L. Further investigation revealed evidence of haemolysis with an elevated bilirubin, lactate dehydrogenase, reticulocyte count and decreased haptoglobin. She was worked up for both inherited and acquired causes of haemolysis and found to have glucose-6-phosphate dehydrogenase deficiency. Her presentation was thought to be secondary to nitrofurantoin-induced haemolysis and she recovered completely with conservative management through intravenous fluids and discontinuation of nitrofurantoin.

Changes in aqueous and vitreous inflammatory cytokine levels in proliferative diabetic retinopathy: a systematic review and meta-analysis.

BACKGROUND: Diabetic retinopathy is a major complication of diabetes mellitus, where in its most advanced form ischemic changes lead to the development of retinal neovascularization, termed proliferative diabetic retinopathy (PDR). While the development of PDR is often associated with angiogenic and inflammatory cytokines, studies differ on which cytokines are implicated in disease pathogenesis and on the strength of these associations. We therefore conducted a systematic review and meta-analysis to quantitatively assess the existing body of data on intraocular cytokines as biomarkers in PDR. METHODS: A comprehensive search of the literature without year limitation was conducted to January 18, 2021, which identified 341 studies assessing vitreous or aqueous cytokine levels in PDR, accounting for 10379 eyes with PDR and 6269 eyes from healthy controls. Effect sizes were calculated as standardized mean differences (SMD) of cytokine concentrations between PDR and control patients. RESULTS: Concentrations (SMD, 95% confidence interval, and p-value) of aqueous IL-1ß, IL-6, IL-8, MCP-1, TNF-α, and VEGF, and vitreous IL-2, IL-4, IL-6, IL-8, angiopoietin-2, eotaxin, erythropoietin, GM-CSF, GRO, HMGB-1, IFN-γ, IGF, IP-10, MCP-1, MIP-1, MMP-9, PDGF-AA, PlGF, sCD40L, SDF-1, sICAM-1, sVEGFR, TIMP, TNF-α, and VEGF were significantly higher in patients with PDR when compared to healthy nondiabetic controls. For all other cytokines no differences, failed sensitivity analyses or insufficient data were found. CONCLUSIONS: This extensive list of cytokines speaks to the complexity of PDR pathogenesis, and informs future investigations into disease pathogenesis, prognosis, and management.

Changes in aqueous and vitreous inflammatory cytokine levels in diabetic macular oedema: a systematic review and meta-analysis.

Diabetic macular oedema (DME) is considered a chronic inflammatory disease associated with aberrations in many intraocular cytokines. Studies assessing the role of these cytokines as biomarkers in the diagnosis and management of DME have demonstrated inconsistent findings. We quantitatively summarized data related to 116 candidate aqueous and vitreous inflammatory cytokines as biomarkers in DME. A systematic search without year limitation was performed up to 19 October 2020. Studies were included if they provided data on aqueous or vitreous cytokine concentrations in patients with DME. Effect sizes were generated as standardized mean differences (SMDs) of cytokine concentrations between patients with DME and controls. Data were extracted from 128 studies that included 4163 study eyes with DME and 1281 control eyes. Concentrations (standard mean difference, 95% confidence interval and p-value) of aqueous IL-6 (1.28, 0.57-2.00, p = 0.004), IL-8 (1.06, 0.74-1.39, p < 0.00001), MCP-1 (1.36, 0.57-2.16, p = 0.0008) and VEGF (1.31, 1.01-1.62, p < 0.00001) and vitreous VEGF (2.27, 1.55-2.99, p < 0.00001) were significantly higher in patients with DME (n = 4163) compared to healthy controls (n = 1281). No differences, failed sensitivity analyses or insufficient data were found between patients with DME and healthy controls for the concentrations of the remaining cytokines. This analysis implicates multiple cytokine biomarker candidates other than VEGF in DME and clarifies previously reported inconsistent associations. As the therapeutic options for DME expand to include multiple agents with multiple targets, it will be critical to manage the treatment burden with tailored therapy that optimizes outcomes and minimizes treatment burden. Intraocular cytokines have the promise of providing a robust individualized assessment of disease status and response to therapy. We have identified key candidate cytokines that may serve as biomarkers in individualized treatment algorithms.

Chiral Transplacental Pharmacokinetics of Fexofenadine: Impact of P-Glycoprotein Inhibitor Fluoxetine Using the Human Placental Perfusion Model.

PURPOSE: Fexofenadine is a well-identified in vivo probe substrate of P-glycoprotein (P-gp) and/or organic anion transporting polypeptide (OATP). This work aimed to investigate the transplacental pharmacokinetics of fexofenadine enantiomers with and without the selective P-gp inhibitor fluoxetine. METHODS: The chiral transplacental pharmacokinetics of fexofenadine-fluoxetine interaction was determined using the ex vivo human placenta perfusion model (n = 4). In the Control period, racemic fexofenadine (75 ng of each enantiomer/ml) was added in the maternal circuit. In the Interaction period, racemic fluoxetine (50 ng of each enantiomer/mL) and racemic fexofenadine (75 ng of each enantiomer/mL) were added to the maternal circulation. In both periods, maternal and fetal perfusate samples were taken over 90 min. RESULTS: The (S)-(-)- and (R)-(+)-fexofenadine fetal-to-maternal ratio values in Control and Interaction periods were similar (~0.18). The placental transfer rates were similar between (S)-(-)- and (R)-(+)-fexofenadine in both Control (0.0024 vs 0.0019 min-1) and Interaction (0.0019 vs 0.0021 min-1) periods. In both Control and Interaction periods, the enantiomeric fexofenadine ratios [R-(+)/S-(-)] were approximately 1. CONCLUSIONS: Our study showed a low extent, slow rate of non-enantioselective placental transfer of fexofenadine enantiomers, indicating a limited fetal fexofenadine exposure mediated by placental P-gp and/or OATP2B1. The fluoxetine interaction did not affect the non-enantioselective transplacental transfer of fexofenadine. The ex vivo placental perfusion model accurately predicts in vivo placental transfer of fexofenadine enantiomers with remarkably similar values (~0.17), and thus estimates the limited fetal exposure.

Changes in aqueous and vitreous inflammatory cytokine levels in neovascular age-related macular degeneration: a systematic review and meta-analysis.

Inflammatory cytokines are involved in the pathogenesis of neovascular age-related macular degeneration (nAMD) and have been shown to be useful as diagnostic and predictive biomarkers. Given the heterogeneity of data within the literature, we aimed to quantitatively summarize data related to inflammatory cytokines in nAMD. A systematic search without year limitation was performed up to 13 April 2020. Studies were included if they provided data on aqueous or vitreous cytokine concentrations in patients with nAMD. Data were extracted from 95 studies that encompassed 3105 study eyes with nAMD and 1209 control eyes. Effect sizes were generated as standardized mean differences (SMDs) of cytokine concentrations between patients with nAMD and controls. Among the 4314 eyes in 95 studies, aqueous concentrations (standard mean difference, 95% confidence interval and p-value) of MCP-1 (0.43, 0.09 to 0.77 and p = 0.01), MIG (0.63, 0.31 to 0.94 and p = 0.0001), TGF-ß (0.45, 0.07 to 0.82 and p = 0.02) and VEGF (0.64, 0.31 to 0.98 and p = 0.0001) were significantly higher in patients with nAMD compared to healthy controls. No differences, failed sensitivity analyses or insufficient data were found between patients with nAMD and healthy controls for the concentrations of the remaining cytokines and with all vitreous samples. Previous studies had shown conflicting associations with nAMD for all 27 cytokines assessed. Our analysis indicates multiple candidate cytokines other than VEGF that are implicated in nAMD and adds clarity to the previous literature. This will help focus translational research in nAMD investigating biomarkers and therapeutic targets.

The value proposition of the Global Health Security Index.

Infectious disease outbreaks pose major threats to human health and security. Countries with robust capacities for preventing, detecting and responding to outbreaks can avert many of the social, political, economic and health system costs of such crises. The Global Health Security Index (GHS Index)-the first comprehensive assessment and benchmarking of health security and related capabilities across 195 countries-recently found that no country is sufficiently prepared for epidemics or pandemics. The GHS Index can help health security stakeholders identify areas of weakness, as well as opportunities to collaborate across sectors, collectively strengthen health systems and achieve shared public health goals. Some scholars have recently offered constructive critiques of the GHS Index's approach to scoring and ranking countries; its weighting of select indicators; its emphasis on transparency; its focus on biosecurity and biosafety capacities; and divergence between select country scores and corresponding COVID-19-associated caseloads, morbidity, and mortality. Here, we (1) describe the practical value of the GHS Index; (2) present potential use cases to help policymakers and practitioners maximise the utility of the tool; (3) discuss the importance of scoring and ranking; (4) describe the robust methodology underpinning country scores and ranks; (5) highlight the GHS Index's emphasis on transparency and (6) articulate caveats for users wishing to use GHS Index data in health security research, policymaking and practice.

The pharmacogenetics of opioid therapy in the management of postpartum pain: a systematic review.

AIMS: Opioids are commonly prescribed for postpartum pain. Yet, providing adequate pain relief, while ensuring that the mother and her breastfeeding infant are protected from adverse events can be challenging. The objective of this systematic review was to identify the role of opioid pharmacogenetics in analgesia and adverse events among patients being treated for postpartum pain, along with their breastfeeding infants. METHODS: A comprehensive search of the literature was conducted in seven databases on June 3-4, 2015. Two reviewers independently screened studies for eligibility, extracted data and evaluated study quality using the Newcastle-Ottawa Scale. RESULTS: Among the 2082 papers retrieved from the search, 17 were included in the review. These 17 papers consisted of various study designs, opioids, polymorphisms and patient outcomes. This systematic review reveals that CYP2D6, OPRM1 A118G, UGT2B7 C802T and ABCB1 G2677AT may contribute to postpartum analgesia or adverse events. CONCLUSION: These findings may assist in personalizing care for patients receiving opioids during the postpartum period.

The Effectiveness of Folate-Fortified Oral Contraceptives in Maintaining Optimal Folate Levels to Protect Against Neural Tube Defects: A Systematic Review.

OBJECTIVE: To conduct a systematic review evaluating the effectiveness of a folate-fortified oral contraceptive preparation in increasing blood folate concentrations to levels providing optimal protection against neural tube defects (> 906 nmol/L). METHODS: We searched Medline, EMBASE, Web of Science, and the Cochrane Library for human studies published from inception to June 2013 that evaluated oral contraceptive use and folate status. Case-control studies, cohort studies, and clinical trials were included. Efficacy and bioequivalence data were evaluated from included studies. RESULTS: Overall, efficacy and bioequivalence data for the folate-fortified oral contraceptive show that it is at least as effective as folic acid alone in raising blood folate concentrations, and that the concomitant administration of folate with the oral contraceptive component does not affect its absorption or kinetics. CONCLUSION: A folate-fortified oral contraceptive preparation provides an option for women to maintain blood folate levels, especially those who may be planning a family after the cessation of oral contraceptive therapy.

Objectif : Mener une analyse systématique de l'efficacité d'un contraceptif oral enrichi en folate pour ce qui est d'accroître les concentrations sanguines en folate jusqu'aux niveaux offrant une protection optimale contre les anomalies du tube neural (> 906 nmol/l). Méthodes : Nous avons mené des recherches dans Medline, EMBASE, Web of Science, et la Cochrane library en vue d'en tirer les études menées chez l'homme, publiées entre le début de nos travaux et juin 2013, qui ont évalué l'utilisation de contraceptifs oraux et les taux de folate. Les études cas-témoins, les études de cohorte et les essais cliniques ont été admis aux fins de notre analyse. Les issues ont été soumises à une méta-analyse faisant appel à un modèle à effets aléatoires. Résultats : De façon globale, les données sur l'efficacité et la bioéquivalence en ce qui concerne les contraceptifs oraux enrichis en folate indiquent que ceux-ci sont au moins aussi efficaces que l'acide folique administré seul pour ce qui est d'augmenter les concentrations sanguines en folate; elles indiquent également que l'administration concomitante de folate et d'un composé contraceptif oral n'en affecte ni l'absorption ni la cinétique. Conclusion : Les contraceptifs oraux enrichis en folate offrent une option aux femmes pour le maintien de leurs taux sanguins de folate; cette option s'avère particulièrement adaptée aux femmes qui pourraient souhaiter devenir enceintes à la suite de l'abandon de la contraception orale.

Association Between Use of Oral Contraceptives and Folate Status: A Systematic Review and Meta-Analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of the effect of oral contraceptive use on plasma and red blood cell (RBC) folate concentrations. METHODS: We searched Medline, EMBASE, Web of Science, and the Cochrane library for human studies published from inception to June 2013 evaluating oral contraceptive use and folate status. Case-control studies, cohort studies, and clinical trials were included. A random-effects model of outcomes was used for the meta-analysis. RESULTS: A total of 2831 women in 17 studies were included in the analysis. In those whose plasma folate concentrations were available, there was a significant folate-lowering effect of oral contraceptives observed (mean reduction 1.27 µg/L; 95% CI 1.85 to 0.69, P < 0.001). Similarly, after analyzing data from 1389 women in 12 studies whose RBC folate concentrations were available, significantly lower folate status was observed among oral contraceptive users (mean reduction 59.32 µg/L; 95% CI 58.03 to 23.04, P < 0.001). CONCLUSION: Because of the reduction in blood folate concentrations associated with the use of oral contraceptives, it is critical for women of childbearing age to continue folate supplementation during oral contraceptive use.

Objectif : Mener une analyse systématique et une méta-analyse quant à l'effet du recours à la contraception orale sur les concentrations plasmatiques et érythrocytaires en folate. Méthodes : Nous avons mené des recherches dans Medline, EMBASE, Web of Science et la Cochrane library en vue d'en tirer les études menées chez l'homme, publiées entre le début de nos travaux et juin 2013, qui ont évalué l'utilisation de contraceptifs oraux et les taux de folate. Les études cas-témoins, les études de cohorte et les essais cliniques ont été admis aux fins de notre analyse. Un modèle à effets aléatoires quant aux issues a été utilisé dans le cadre de la méta-analyse. Résultats : Au total, 2 831 femmes issues de 17 études ont été admises à l'analyse. Chez les femmes pour lesquelles les concentrations plasmatiques en folate étaient disponibles, nous avons constaté que les contraceptifs oraux exerçaient un effet considérable d'atténuation de ces concentrations (baisse moyenne, 1,27 µg/l; IC à 95 %, 1,85 - 0,69, P < 0,001). De façon semblable, après avoir analysé les données traitant de 1 389 femmes issues de 12 études pour lesquelles les concentrations érythrocytaires en folate étaient disponibles, nous avons constaté une baisse considérable de ces concentrations chez les utilisatrices de contraceptifs oraux (baisse moyenne, 59,32 µg/l; IC à 95 %, 58,03 - 23,04, P < 0,001). Conclusion : En raison de la baisse des concentrations sanguines en folate qui sont associées à l'utilisation de contraceptifs oraux, il est crucial que les femmes en âge de procréer qui ont recours à une telle contraception continuent à prendre une supplémentation en folate.

Rivaroxaban transfer across the dually perfused isolated human placental cotyledon.

OBJECTIVE: The purpose of this study was to determine the rate and extent of rivaroxaban transfer across the term human placenta and determine whether passive diffusion was the primary mechanism involved in this transfer. STUDY DESIGN: The transplacental pharmacokinetics of rivaroxaban was determined with the ex-vivo placenta perfusion model. Rivaroxaban was added to the maternal or fetal circulation only (250 ng/mL). Additional experiments were conducted under equilibrative conditions with the addition of rivaroxaban to both the maternal and fetal circulations (250 ng/mL). Rivaroxaban concentrations were measured with the use of liquid chromatography-tandem mass spectrometry. RESULTS: There was rapid transfer of rivaroxaban across the human placenta in both the maternal-to-fetal and fetal-to-maternal directions, as evidenced by transfer ratios of 0.69 (interquartile range, 0.58-0.73; n = 5) and 0.69 (interquartile range, 0.67-0.71; n = 2), respectively, after 3 hours. Under equilibrative conditions (n = 2), rivaroxaban concentrations remained relatively constant, which suggests that rivaroxaban crosses the placenta down a concentration gradient. CONCLUSION: This is the first direct evidence of rivaroxaban transfer across the term human placenta from both the mother-to-fetus and fetus-to-mother directions. Our results document that unbound rivaroxaban rapidly crosses the placental barrier via passive diffusion. However, because rivaroxaban is highly bound to plasma proteins (up to 95%), this suggests that the amount of unbound drug that may reach the fetus is likely much lower. Additional studies will need to explore its safety before administering rivaroxaban to a pregnant woman.

Dynamic decomposition of motion in essential and parkinsonian tremor.

BACKGROUND: Treatment options for essential (ET) and Parkinson disease (PD) tremor are suboptimal, with significant side effects. Botulinum toxin type A (BoNT A) is successfully used in management of various focal movement disorders but is not widely used for tremor. METHOD: This study examines complexity of wrist tremor in terms of involvement of its three anatomical degrees of freedom (DOF) in two common situations of rest and posture. The study examines tremor in 11 ET and 17 PD participants by kinematic decomposition of motion in 3-DOF. RESULTS: Tremor decomposition showed the motion involved more than one DOF (<70% contribution in one DOF) in most ET (rest: 100%, posture: 64%) and PD (rest: 77%, posture: 77%) patients. Task variation resulted in change in both amplitude and composition in ET, but not in PD. Amplitude significantly increased from rest to posture in ET. Directional bias was observed at the wrist for ET (pronation), and PD (extension, ulnar deviation, pronation). Average agreement between clinical visual and kinematic selection of muscles was 55% across all subjects. CONCLUSION: This study shows the complexity of tremor and the difficulty in visual judgment of tremor, which may be key to the success of targeted focal treatments such as BoNT A.

Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta.

OBJECTIVE: To assess the transplacental pharmacokinetics at term of the oral thrombin inhibitor, dabigatran, and its prodrug, dabigatran etexilate mesylate, to estimate fetal drug exposure. METHODS: Placentae were obtained with informed consent after cesarean delivery of healthy term pregnancies in Toronto, Ontario, Canada. The transplacental transfer of dabigatran and dabigatran etexilate mesylate was separately assessed using the ex vivo dual perfusion of an isolated human placental cotyledon. Dabigatran, at a concentration of 35 ng/mL, was added to the maternal circulation at the start of the experimental phase. Maternal and fetal samples were taken throughout the preexperimental (1 hour) and experimental (3 hours) phases for measurement of dabigatran and markers of placental viability. Separate placenta perfusions with dabigatran etexilate mesylate were conducted at an initial maternal concentration of 3.5 ng/mL. Dabigatran and dabigatran etexilate mesylate were measured using liquid chromatography-tandem mass spectrometry. RESULTS: There was slower transfer of dabigatran compared with antipyrine from the maternal-to-fetal circulation, because the median fetal-to-maternal concentration ratio was 0.33 (interquartile range 0.29-0.38) after 3 hours (n=3). The prodrug, dabigatran etexilate mesylate, had limited placental transfer as characterized by a fetal-to-maternal ratio of 0.17 (interquartile range 0.15-0.17) after 3 hours (n=3). Placental viability markers for all perfusions were within normal ranges. CONCLUSION: This report provides direct evidence of the transfer of dabigatran and its prodrug across the term human placenta from the mother to the fetus. From a clinical perspective, these data suggest that, pending further study, dabigatran should not be used for anticoagulation of pregnant women, because the drug may have an adverse effect on fetal blood coagulation.

The role of VariZIG in pregnancy.

Varicella infection during pregnancy is associated with serious maternal and fetal complications such as congenital varicella syndrome, maternal pneumonia and neonatal varicella. Pregnant women are ineligible to receive the varicella vaccination, thus women who lack evidence of immunity to varicella are at an increased risk for developing a varicella infection if exposed to a contagious individual. Presently, post-exposure prophylaxis involves the administration of a varicella zoster immunoglobulin (VariZIG™) to prevent or reduce the severity of an infection. The US FDA recently approved VariZIG for licensure and recommend that it be administered as soon as possible following VZV exposure, ideally within 96 h for greatest effectiveness. The following review critically examines the role of VariZIG in post-exposure prophylaxis of varicella during pregnancy.

Effectiveness of BoNT A in Parkinson's disease upper limb tremor management.

OBJECTIVE: One the greatest challenges of BoNT A therapy for tremor lies in the complexity and variation of components involved in tremor movement, and the lack of objective measures to determine these components. This 3 month open-label single injection study aims to couple clinician best judgment with kinematics to improve effect of BoNT A (incobotulinumtoxinA) injection in 7 patients with upper limb Parkinson's disease (PD) tremor. METHODS: Injection was guided with clinical and kinematic assessment of tremor using angular wrist position in 3 degrees of freedom: flexion/extension, pronation/supination, and radial/ulnar deviation. Overall tremor severity and change were measured by linear finger acceleration. RESULTS: Kinematic data from static and functional tasks demonstrate no improvement at one month post-injection, but significant improvement at two and three months. Clinical scales across UPDRS Items 20 (1, 2, 3 months post) and 21 (2 months), and spiral drawings (3 months) showed significant improvement from baseline, while line drawings did not. CONCLUSIONS: This study suggests injection of BoNT A as a viable focal management option for upper limb PD tremor. In addition to clinical judgment, objective quantification of tremor dynamics by kinematics may be a feasible assessment and guidance tool which can be used to optimize injection conditions for focal tremor therapy. Kinematic analysis of tremor across a variety of joints in all degrees of movement may provide important insight into tremor dynamics, allowing optimized, targeted focal therapy.

Enhanced imaging and accelerated photothermalysis of A549 human lung cancer cells by gold nanospheres.

BACKGROUND & AIMS: Gold nanoparticles are excellent photon-thermal energy converters. The purpose of this work was to investigate the influence of gold nanoparticles on the photothermalysis of A549 lung tumor cells. MATERIALS & METHODS: A549 lung tumor cells were exposed to goat antihuman immunoglobulin (Ig)G-conjugated gold nanospheres (40 nm) and were then imaged under a dark-field microscope. The live cells were then subjected to photoirradiation using a 633-nm laser at different power levels. The viability of tumor cells under laser irradiation was monitored by confocal microscopy using a viability-assay kit. RESULTS & DISCUSSION: The death rates of A549 lung tumor cells after gold nanoparticle exposure increased significantly under laser irradiation. The maximum initial cell death rate was observed at a laser power level of 3.75 mW, with the initial deactivation rate accelerated by a factor of 6.6 and a total loss of 92% of cell viability. CONCLUSION: This work demonstrated potential applications of gold nanospheres as both imaging probes and enhancing agents for photothermal therapy of cancer.