Importance of measuring pharmacologically active metabolites of edoxaban: development and validation of an ultra-high-performance liquid chromatography coupled with a tandem mass spectrometry method

Journal of Thrombosis and Thrombolysis - Although DOACs do not require regular measurements of their blood concentrations, clinical situations may require an assessment of their concentration....     

Hypercalcemia is associated with a poor prognosis in lymphoma a retrospective monocentric matched-control study and extensive review of published reported cases

Annals of Hematology - The prognostic significance of hypercalcemia in lymphoma has only been studied on small series to date. We conducted a retrospective, monocentric, matched-control study that...     

Risk factors associated with anaphylaxis and other allergic-like events following receipt of 2009 monovalent AS03-adjuvanted pandemic influenza vaccine in Quebec,Canada

Introduction

In Quebec, Canada, receipt of the 2009 AS03-adjuvanted pandemic H1N1 vaccine was associated with increased risk of anaphylaxis and other allergic-like events (ALE), especially among women of childbearing age. In response to this safety signal, a case–control study was conducted to identify potential risk factors.

Methods

A total of 435 ALE (50 anaphylaxis) occurring <24 h following pandemic vaccination were compared to 849 age-gender matched controls randomly selected from the provincial Pandemic Influenza Vaccination Registry. More than 60 potential risk factors were evaluated through phone interviews and included demographic information, medical history, medication use or acute respiratory illnesses (ARI) concurrent with vaccination and other risk factors associated with general allergy. Odds ratios (ORs) with 95% confidence intervals were estimated with unconditional logistic regression.

Results

Factors associated with increased risk of anaphylaxis included concurrent ARI (18% cases vs. 4% controls, ORadj 7.67, 95%CI: 3.04–13.37), food allergy (26% cases vs. 4% controls, ORadj 3.84, 95%CI: 1.51–9.74) and vaccination during the first four weeks of the campaign (66% cases vs. 50% controls, ORadj 2.16, 95%CI: 1.10–4.25) whereas alcohol exposure (≥1 drink/week) was associated with reduced risk (29% cases vs. 42% controls, ORadj 0.26, 95%CI: 0.13–0.57). These factors were also significantly associated with any ALE but the strength of association was weaker. Allergy to components found in the vaccine (e.g., egg, thimerosal) was infrequent and did not significantly differ between cases and controls.

Conclusion

Increased anaphylaxis and other allergic-like events observed in association with AS03-adjuvanted pandemic H1N1 vaccine remain mostly unexplained despite extensive risk factor review. However, prior to mass vaccination with similar formulations this safety signal warrants further consideration and better understanding. In particular, the predominance among women of childbearing age may be a clue to underlying biological or hormonal influences on adverse immunological responses to vaccine.     

The benefits of redesigning Benin's vaccine supply chain

Introduction

New vaccine introductions have put strains on vaccine supply chains around the world. While increasing storage and transportation may be the most straightforward options, it is also important to consider what financial and operational benefits can be incurred. In 2012, suboptimal vaccine coverage and impending vaccine introductions prompted the Republic of Benin's Ministry of Health (MOH) to explore ways to improve their vaccine supply chain.

Methods

Working alongside the Beninese MOH, we utilized our computational model, HERMES, to explore the impact on cost and vaccine availability of three possible options: (1) consolidating the Commune level to a Health Zone level, (2) removing the Commune level completely, and (3) removing the Commune level and expanding to 12 Department Stores. We also analyzed the impact of adding shipping loops during delivery.

Results

At baseline, new vaccine introductions without any changes to the current system increased the logistics cost per dose ($0.23 to $0.26) and dropped the vaccine availability to 71%. While implementing the Commune level removal scenario had the same capital costs as implementing the Health Zone scenario, the Health Zone scenario had lower operating costs. This increased to an overall cost savings of $504,255 when implementing shipping loops.

Discussion

The best redesign option proved to be the synergistic approach of converting to the Health Zone design and using shipping loops (serving ten Health Posts/loop). While a transition to either redesign or only adding shipping loops was beneficial, implementing a redesign option and shipping loops can yield both lower capital expenditures and operating costs.     

Implication of the ERK/MAPK Pathway in Antipsychotics-induced Dopamine D2 Receptor Upregulation and in the Preventive Effects of (±)-α-lipoic acid in SH-SY5Y Neuroblastoma Cells

Chronic administration of antipsychotics (APs) has been associated with dopamine D2 receptor (D2R) upregulation and tardive dyskinesia. We previously showed that haloperidol, a first-generation AP, exerted a more robust increase in D2R expression than amisulpride, a second-generation AP and that (±)-α-lipoic acid pre-treatment reversed the AP-induced D2R upregulation. We also demonstrated that the Akt/GSK-3β/β-catenin pathway is involved in the control of D2R expression levels, but is unlikely implicated in the preventive effects of (±)-α-lipoic acid since co-treatment with haloperidol and (±)-α-lipoic acid exerts synergistic effects on Akt/GSK-3β activation. These findings led us to examine whether the ERK/MAPK signaling pathway may be involved in D2R upregulation elicited by APs, and in its reversal by (±)-α-lipoic acid, in SH-SY5Y human neuroblastoma cells. Our results revealed that haloperidol, in parallel with an elevation in D2R mRNA levels, induced a larger increase of ERK (p42/p44) phosphorylation than amisulpride. Pre-treatment with the selective ERK inhibitor U0126 attenuated haloperidol-induced increase in D2R upregulation. Furthermore, (±)-α-lipoic acid prevented AP-induced ERK activation. These results show that (1) the ERK/MAPK pathway is involved in haloperidol-induced D2R upregulation; (2) the preventive effect of (±)-α-lipoic acid on haloperidol-induced D2R upregulation is in part mediated by an ERK/MAPK-dependent signaling cascade. Taken together, our data suggest that (±)-α-lipoic acid exerts synergistic effects with haloperidol on the Akt/GSK-3β pathway, potentially involved in the therapeutic effects of APs, and antagonism of ERK activation and D2R upregulation, potentially involved in tardive dyskinesia and treatment resistance.     

Mechanism of the medium‐duration afterhyperpolarization in rat serotonergic neurons

Most serotonergic neurons display a prominent medium‐duration afterhyperpolarization (mAHP), which is mediated by small‐conductance Ca²⁺‐activated K⁺ (SK) channels. Recent ex vivo and in vivo experiments have suggested that SK channel blockade increases the firing rate and/or bursting in these neurons. The purpose of this study was therefore to characterize the source of Ca²⁺ which activates the mAHP channels in serotonergic neurons. In voltage‐clamp experiments, an outward current was recorded at ?60 mV after a depolarizing pulse to +100 mV. A supramaximal concentration of the SK channel blockers apamin or (‐)‐bicuculline methiodide blocked this outward current. This current was also sensitive to the broad Ca²⁺ channel blocker Co²⁺ and was partially blocked by both ω‐conotoxin and mibefradil, which are blockers of N‐type and T‐type Ca²⁺ channels, respectively. Neither blockers of other voltage‐gated Ca²⁺ channels nor DBHQ, an inhibitor of Ca²⁺‐induced Ca²⁺ release, had any effect on the SK current. In current‐clamp experiments, mAHPs following action potentials were only blocked by ω‐conotoxin and were unaffected by mibefradil. This was observed in slices from both juvenile and adult rats. Finally, when these neurons were induced to fire in an in vivo‐like pacemaker rate, only ω‐conotoxin was able to increase their firing rate (by ~30%), an effect identical to the one previously reported for apamin. Our results demonstrate that N‐type Ca²⁺ channels are the only source of Ca²⁺ which activates the SK channels underlying the mAHP. T‐type Ca²⁺ channels may also activate SK channels under different circumstances.     

Disentangling the influence of neighborhood and individual characteristics on early residential mobility among newly diagnosed patients with schizophrenia: a multilevel analysis

Purpose

Early residential mobility of schizophrenic patients may relate to discontinuity of treatment and adverse outcome. However, factors influencing early residential mobility of these patients are still poorly examined. The aim of this study was to disentangle the influence of individual and neighborhood characteristics on early residential mobility of schizophrenic patients.

Methods

The study used administrative data of 13, 400 individuals newly diagnosed with schizophrenia in Quebec between 2001 and 2002. These individuals were nested in 163 different health territories. Multilevel analyses were used to assess the contribution of individual and neighborhood characteristics on early residential mobility.

Results

The final model indicates that at the individual level, being men, wonder patients and physical comorbidity increased the likelihood of early residential mobility whereas older patients were less likely to migrate earlier. The health territory level explains about 7 % of the variation of early residential mobility and variables influencing residential mobility at this level are the fourth and the third quartiles of the population density.

Conclusions

Factors influencing early residential mobility of schizophrenic patients are located at both individual and neighborhood levels. This suggests that policies targeting only one-level factors are unlikely to significantly delays early residential mobility.     

Smoking behavior characteristics of non-selected smokers with childhood attention-deficit/hyperactivity disorder (AD/HD) history: a systematic review and meta-analysis

It is unclear whether adult smokers with childhood attention-deficit/hyperactivity disorder history (CH) have more severe smoking behavior than non-CH smokers, while it is clearly suggested that CH adolescents have more severe smoking behavior than CH adolescents. The aim of the present comprehensive meta-analysis is to determine whether CH smokers have more severe smoking behavior characteristics than those without and the effect of age on the association between CH and smoking behavior. We included all case–control studies and first round data collection of observational studies addressing the difference in smoking behavior characteristics of CH smokers versus non-CH smokers, with validated scales or structured interviews, without any language or date restriction. Nine studies (including 365 smokers with CH and 1,708 smokers without) were included. Compared to non-CH smokers, CH smokers smoked significantly more cigarettes [standardized mean differences (SMD) = 0.15, 95 % CI 0.01–0.28, p = 0.04] and began to regularly smoke earlier (SMD = ?0.28, 95 % CI ?0.49; ?0.07, p = 0.01) but were not significantly more nicotine dependent (SMD = 0.23, 95 % CI ?0.04 to 0.48, p = 0.08). After removing the single adolescent study, the significant association between CH and number of daily smoked cigarettes disappeared, and subgroups analyses confirmed that the significant association between CH and number of daily smoked cigarettes disappeared as age increased. Our meta-analysis illustrates a clinically important link between CH and tobacco smoking in adolescence but not later in life. Further high-quality studies are needed to confirm this finding, as only two studies included participants with a mean age below 20 years.