The Timing and Dose Effect of Acupuncture on Pregnancy Outcomes for Infertile Women Undergoing In Vitro Fertilization and Embryo Transfer: A Systematic Review and Meta-Analysis.

Background: Women undergoing in vitro fertilization and embryo transfer (IVF-ET) often utilize acupuncture to enhance pregnancy outcomes. Yet, the optimal timing for acupuncture sessions and the relationship between dosage and effect remain uncertain. Objectives: To investigate the impact of the timing and dosage of acupuncture on pregnancy outcomes, drawing on existing research. Methods: A comprehensive search of eight databases was conducted from their inception to January 14th, 2023, without restrictions on language. Only randomized controlled trials comparing acupuncture with either sham acupuncture or no adjuvant treatment were selected for inclusion. This meta-analysis assessed the efficacy of acupuncture in IVF-ET, analyzing the influence of varied timing and dosage on pregnancy outcomes. Subgroup analyses were undertaken to address any heterogeneity across the studies. Results: A total of 38 RCTs involving 5,991 participants were analyzed. In infertile women undergoing IVF fresh cycles, acupuncture performed during controlled ovarian hyperstimulation (COH) significantly increased the clinical pregnancy rate (CPR) (relative risk [RR] = 1.33, 95% confidence interval [CI]: 1.07-1.65, p = 0.01), whereas acupuncture administered either before COH or on the day of ET did not demonstrate reproductive benefits. Regarding frozen cycles, acupuncture before freeze-thaw embryo transfer (FET) significantly enhanced the CPR (RR = 1.71, 95% CI: 1.36-2.16, p < 0.00001) and live birth rate (LBR) (RR = 2.40, 95% CI: 1.20-4.79, p = 0.01). Improvements in CPR were observed across all dosage groups, but only the high-dosage group showed a significant increase in LBR (RR = 1.75, 95% CI: 1.05-2.92, p = 0.03). Conclusions: Timing and dosage of acupuncture are crucial factors affecting pregnancy outcomes in IVF-ET. For women undergoing IVF fresh cycles, acupuncture during COH yielded more significant reproductive benefits. In addition, acupuncture before freeze-thaw embryo transfer (FET) was associated with improved pregnancy outcomes in frozen cycles. Furthermore, higher dosages of acupuncture were linked to more favorable outcomes.

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials.

Objective: Several clinical trials have suggested that fenfluramine (FFA) is effective for the treatment of epilepsy in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). However, the exploration of its optimal target dose is ongoing. This study aimed to summarize the best evidence to inform this clinical issue. Materials and methods: We searched PubMed, Embase (via Ovid), and Web of Science for relevant literature published before December 1st, 2023. Randomized, double-blind, placebo-controlled studies that evaluated the efficacy, safety, and tolerability of FFA in DS and LGS were identified and meta-analysis was performed according to doses. The study was registered with PROSPERO (CRD42023392454). Results: Six hundred and twelve patients from four randomized controlled trials were enrolled. The results demonstrated that FFA at 0.2, 0.4, or 0.7 mg/kg/d showed significantly greater efficacy compared to placebo in terms of at least 50% reduction (p < 0.001, p < 0.001, p < 0.001) and at least 75% reduction (p < 0.001, p = 0.007, p < 0.001) in monthly seizure frequency from baseline. Moreover, significantly more patients receiving FFA than placebo were rated as much improved or very much improved in CGI-I by both caregivers/parents and investigators (p < 0.001). The most common treatment-emergent adverse events were decreased appetite, diarrhea, fatigue, and weight loss, with no valvular heart disease or pulmonary hypertension observed in any participant. For dose comparison, 0.7 mg/kg/d group presented higher efficacy on at least 75% reduction in seizure (p = 0.006) but not on at least 50% reduction. Weight loss (p = 0.002), decreased appetite (p = 0.04), and all-cause withdrawal (p = 0.036) were more common in 0.7 mg/kg/d group than 0.2 mg/kg/d. There was no statistical difference in other safety parameters between these two groups. Conclusion: The higher range of the licensed dose achieves the optimal balance between efficacy, safety, and tolerability in patients with DS and LGS. Clinical trial registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023392454.

The dose-effect relationship of acupuncture on limb dysfunction after acute stroke: a systematic review and meta-analysis.

Objective: This study aimed to investigate the relationship between the dose and efficacy of acupuncture in treating limb dysfunction during acute stroke. Methods: Studies were searched from seven databases, including PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Wanfang Data (WF), VIP information database (VIP), and China Biology Medicine Database (CBM). All databases were searched until August 1, 2023 from inception. The risk of bias was assessed using Cochrane Collaboration's risk of bias tool (RoB2). Meta-analyses were performed using RevMan V.5.4 and Stata 12.0 statistical software. We used Fugl-Meyer Assessment (FMA) to measure recovery of limb dysfunction, NIH Stroke Scale (NIHSS) to measure neurological deficits, and Barthel index, Modified Barthel Index (MBI), and Activities of Daily Living (ADL) to measure activities of daily living. The primary outcome measure is FMA. After examining and integrating the raw data, we performed a meta-analysis using a 3-step process. First, we investigated the dose-related effects of acupuncture at varying doses and determined the optimal dosage for maximum therapeutic benefits. Second, we determined the difference between post-intervention and baseline scores on the outcomes of interest to determine minimal clinically important differences (MCID) to provide evidence for clinical treatment. Third, by combining the results of step 1 and step 2, we made the recommendations employing the Grades of Recommendations, Assessment, Development and Evaluations (GRADE) tool. Results: Twenty-six studies containing 1947 participants were included, among which 61.5% of RCTs had a low risk of bias. Through the three-step analysis, the effect in improving limb dysfunction of acute stroke varied across different acupuncture dosages. Regarding the frequency of acupuncture, the results demonstrated a significant improvement in the low (every other day) and moderate-frequency (once a day) groups (low frequency: MD: 9.02, 95%CI: 5.40-12.64, p < 0.00001; moderate frequency: MD: 10.11, 95%CI: 5.05-15.18, p < 0.00001, heterogeneity (p = 0.87), I2 = 0%). For the acupuncture retention time, the results showed no significant difference between the short and medium retention groups (short retention time: MD: 0.05, 95% CI: -0.21-0.31, p = 0.71; medium retention time: MD: -1.16, 95% CI: -2.80-0.48, p = 0.17, heterogeneity (p < 0.00001), I2 = 99%). For the course of acupuncture, the results showed a significant improvement in the short course treatment (less than 2 weeks) group (MD: 14.87, 95% CI: 12.18-17.56, p < 0.00001, heterogeneity (p = 0.45), I2 = 0%). Conclusion: Our study demonstrated the effectiveness of different acupuncture dose in improving limb dysfunction. The pooled data suggested that the optimal intervention dose for acupuncture interval time was low (every other day) and moderate frequency (once a day), the optimal intervention dose for needle course time was short course treatment (less than 2 weeks). But we did not find the optimal intervention dose for needle retention time. Future studies of higher quality are needed to confirm this.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, CRD42023447202.

Low and very low lithium levels: Thyroid effects are small but still require monitoring.

AIM: Low doses of lithium, as might be used for mood or dementia prevention, do not carry the same renal, toxicity, and tolerability problems of doses used for prophylaxis or treatment of mania. However, thyroid effects of low doses have not been investigated. Our goal in this study was to assess the changes in thyroid-stimulating hormone (TSH) associated with a broad range of lithium levels, including those well below the therapeutic range for bipolar disorders. METHODS: This study was conducted in a small healthcare system with 19 associated primary care clinics served by a Collaborative Care program of psychiatric consultation. In this retrospective review of electronic records, we searched for patients who had received a lithium prescription and both pre- and post-lithium thyroid-stimulating hormone (TSH) levels. RESULTS: Patients with low lithium levels (<0.5 mEq/L, N = 197) had a mean thyroid-stimulating hormone (TSH) increase of 0.52 mIU/L. Patients with maintenance lithium levels (0.5-0.8 mEq/L; N = 123) had a mean TSH increase of 1.01 mIU/L; and patients with antimanic lithium levels (>0.8 mEq/L; N = 79) had a mean TSH increase of 2.16 mIU/L. The probability of TSH exceeding the upper limit of normal in our laboratory (>4.2 mIU/L) was positively associated with pre-lithium TSH. CONCLUSION: These results suggest that the risk of lithium-induced hypothyroidism is dose-related, and relatively small with very low doses, but thyroid monitoring, including a pre-lithium TSH, is still warranted.

[Drug-drug interactions-How can we protect ourselves from the flood of information?] / Arzneimittelwechselwirkungen ­ wie kann man sich vor der Informationsflut schützen?

Physicians look at drug-drug interactions (DDI), or more correctly xenobiotic interactions, in an emotional mixture of fear and interest, due to the apparently countless number of adverse drug effects (ADE) that can occur. The interactions as such are seen as errors; however, interactions cannot be avoided and are an inevitable part of the normal work of physicians. The problem is how to recognize interactions and how to handle them. A xenobiotic interaction can often even improve the effectiveness of a pharmacotherapy and minimize the risks. If all examples of what can possibly happen are not necessarily counted, the flood of information becomes relatively manageable. There are only seven different classes of interactions, four pharmacodynamic and three pharmacokinetic interactions. Currently, there are hotlines and both analogue as well as digital databanks to answer questions and address uncertainties, unfortunately of markedly different quality! Aids, such as therapeutic drug monitoring (TDM) supplement these offers. Every pharmacokinetic interaction can be recognized by determination of the concentration of the active agent. The comprehensive clinical pharmacological TDM report explain the information contained in the concentration of the active agent about the individual patient from whom the blood was drawn. All physicians can learn how to compile the clinical pharmacological TDM report by themselves or they can request it in interdisciplinary cooperation via a council. Medical expertise in handling xenobiotic interactions not only opens the door to adaptation of the pharmacotherapy to the needs of the individual patient but also saves huge budget resources for the healthcare system.

The Dose-Related Efficacy of Acupuncture on Endometrial Receptivity in Infertile Women: A Systematic Review and Meta-Analysis.

Background: Progress has been achieved by using acupuncture widely for poor endometrial receptivity (PER). However, different acupuncture dosages may lead to controversy over efficacy. Objective: To evaluate the evidence-based conclusions of dose-related acupuncture on infertile women with PER. Method: References were retrieved from nine databases from inception to 26 February 2022. This meta-analysis included randomized controlled trials (RCTs) that investigated the dose-related efficacy of acupuncture for PER with outcomes of endometrium receptivity (ER) parameters by transvaginal sonography (TVS) and the subsequent pregnancy outcomes in three acupuncture-dose groups: the high-dosage group (three menstrual cycles), the moderate-dosage group (one menstrual cycle), and the low-dosage group (two or four days). Since there remained sufficient heterogeneity among the three subsets, we prespecified seven subgroup variables (four clinical and three methodological) to investigate the heterogeneities. Results: A total of 14 RCTs (1,564 women) of moderate or low overall quality were included. The results were different when the dosage of acupuncture was restricted. For the moderate or high-dosage group, CPR and part of ER parameters were improved in the acupuncture group (i.e., CPR: OR = 2.00, 95% CI [1.24, 3.22], p = 0.004, I2 = 0% in one menstrual cycle; OR = 2.49, 95%CI [1.67, 3.72], p < 0.05, I2 = 0% in three menstrual cycles). However, for the low-dosage group, no statistical difference was observed in CPR (OR = 0.07, 95% CI [-0.10, 0.23], p = 0.44, I2 = 82%) and a part of the ER parameters. In subgroup analysis, four subgroup variables (the routine treatment, risk of performance bias, duration of acupuncture treatment, and the age of participants) could explain some of the heterogeneities across all trials. Conclusion: The finding indicated that the trend of relatively more acupuncture dosage showed better effects for poor endometrial receptivity among PER women. It remains a potential heterogeneity in our studies. Further high-quality trials with a homogeneity trial design need to be conducted.

Excess dose-related parameters (Vex, Rex, and iRex): novel predictors and late toxicity correlations in cervical cancer image-guided adaptive brachytherapy.

PURPOSE: In this paper, excess dose is originally proposed to represent the dose outside the target volume that encompass only organs at risk (OARs), not the whole dose volume of isodose surface volume (ISV). By means of spatial consideration, excess dose-related parameters would also compensate inconsistent applicator positions and OARs motion, which may deviate the identical dose small-volume assumption of D2cc. Late toxicity correlations of these parameters were investigated. MATERIAL AND METHODS: A retrospective review was performed on cervical cancer high-dose-rate image-guided adaptive brachytherapy (HDR-IGABT). From ISVs of 60 to 100 Gy EQD2 (a/ß = 3), excess dose-related parameters were derived as following: toxicity negligible volume (Vneg = V60 of toxicity negligible organs; high-risk clinical target volume - HR-CTV, uterus, and vagina), excess dose volume (Vex = ISV - Vneg), Vneg normalized parameters of excess dose volume ratio (Rex = Vex/Vneg), and indirect excess dose volume ratio (iRex = ISV/Vneg). Relationships between toxicity and these parameters were analyzed using a mean difference and a probit analysis method. Net reclassification indices (NRIs) were used to compare iRex60 and D2cc gastrointestinal (GI) toxicity prediction. RESULTS: From 143 cases with an incidence of 34.9% and 10.5% of 3-year grade 2-4 GI and genitourinary (GU) toxicity, respectively, comparisons of means showed significant difference between grade 0-1 and 2-4 toxicities for late GI toxicity for all parameters, except ISV. There was a dose-response relationship with toxicity for each parameter across the range of 60-100 Gy EQD2. ED10 of iRex60 and iRex70 were 2.1 and 1.2, respectively. By comparing iRex60 and D2cc, additive and absolute NRIs were +6.45 and +7.69%, respectively. The reclassification significantly occurred in range of 65-75 Gy of rectum D2cc. CONCLUSIONS: Excess dose-related parameters, including Vex, Rex, and iRex, showed significant mean differences and parameter-toxicity relationships for late GI but not for GU toxicities. Positive NRIs suggest iRex60 utilization for spatial control of dose expansion, in addition to high-dose control with OAR small volumes. Further investigations are needed to define the optimum use of these predictors.

Is there a safe and effective way to wean patients off long-term glucocorticoids?

Glucocorticoids are highly effective medicines in the treatment of inflammatory disorders. However they cause severe adverse reactions, particularly where taken at high doses systemically for prolonged periods. Systemic glucocorticoids are therefore given at dosage sufficient to control the disease, then withdrawn as fast as is possible to minimise dose- and time-related adverse drug reactions without losing disease control. Adverse withdrawal reactions present a major challenge in the withdrawal of long term glucocorticoids. Suppression of the hypothalamic-pituitary-adrenal (HPA) axis causes adrenal insufficiency, which is potentially life threatening and can become symptomatic as treatment is withdrawn. Adrenal insufficiency can be extremely difficult to differentiate from 'glucocorticoid withdrawal syndrome', where patients experience symptoms despite adequate adrenal function, and from psychological dependence. Long term systemic glucocorticoids should therefore be withdrawn slowly. The rate at which the dose is tapered should initially be determined by treatment requirements of the underlying disease. Once 'physiological' doses are reached, the rate of reduction is determined by rate of HPA recovery and need for exogenous glucocorticoid cover while endogenous secretion recovers. If symptoms prevent treatment withdrawal, HPA testing should be used to look for adrenal insufficiency. Patients with adrenal insufficiency require 'physiological' doses of glucocorticoids for adrenal replacement, which may be lifelong if the HPA axis fails to recover.

Presence of allele CYP3A4*16 does not have any bearing on carbamazepine-induced adverse drug reactions in North Indian people with epilepsy.

OBJECTIVES: The objectives of this study were to determine the relationship between genetic polymorphisms in gene encodings for CYP3A4 and carbamazepine (CBZ)-induced dose-related side effects in North Indian people with epilepsy. PATIENTS AND METHODS: The current prospective study included 37 patients with CBZ-induced dose-related side effects and 102 patients who did not experience side effects while on CBZ. The genotyping for CYP3A4 allele (CYP3A4*16) was done using real-time polymerase chain reaction (RT-PCR) in Applied Biosystems 7500 RT-PCR System (USA). CBZ was administered in all patients at a dose varying from 15 to 20 mg/kg daily. RESULTS: Various demographic variables were comparable between the groups except that control of seizures was far better in controls. After testing, it was found that none of our patients had the presence of CYP3A4*16 allele. CONCLUSION: CYP3A4*16 allele is not represented significantly in North Indian people with CBZ-induced dose-related side effects.

Clinical Adverse Events of High-Dose vs Low-Dose Sodium-Glucose Cotransporter 2 Inhibitors in Type 2 Diabetes: A Meta-Analysis of 51 Randomized Clinical Trials.

AIMS: The aims of this work are to assess the clinical adverse events (AEs) of high-dose vs low-dose sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) in patients with type 2 diabetes mellitus (T2DM). METHODS: We searched MEDLINE, EMBASE, and Cochrane Library from January 1, 2006 to March 10, 2020, for identifying eligible randomized clinical trials (RCTs) that reported AEs by high-dose and low-dose SGLT2 inhibitors in T2DM patients. Random-effects models was used to obtain summary relative risks (RRs) with associated 95% CIs. Prespecified subgroup analyses according to individual SGLT2 inhibitors and follow-up duration, and leave-one-out sensitivity analysis were conducted. RESULTS: A total of 51 RCTs involving 24 371 patients (12 208 received high-dose and 12 163 received low-dose SGLT2 inhibitors) were included. Overall, the heterogeneity among included studies was relatively low (I2 < 50% for each outcome). No significant differences between high-dose and low-dose SGLT2 inhibitors were observed for overall safety (including any AEs, serious AEs, AEs leading to discontinuation, and death) and specified safety (including infections and infestations, musculoskeletal disorders, gastrointestinal disorders, osmotic diuresis-related AEs, volume-related AEs, renal-related AEs, and metabolism and nutrition), except for a mild increase in risk for AEs related to study drugs (RR: 1.08; 95% CI, 1.01-1.16) that mainly derived from canagliflozin (RR: 1.17; 95% CI, 1.05-1.30). Subgroup analyses were consistent with the primary outcomes. CONCLUSIONS: This study provided substantial evidence that AEs of SGLT2 inhibitors were not dose related.

10-Year Paclitaxel Dose-Related Outcomes of Drug-Eluting Stents Treated Below the Knee in Patients with Chronic Limb-Threatening Ischemia (The PADI Trial).

PURPOSE: Recently, two meta-analyses concluded that there appears to be an increased risk of long-term mortality of paclitaxel-coated balloons and stents in the superficial femoral and popliteal artery, and paclitaxel-coated balloons below the knee. In this post hoc study of the PADI Trial, we investigated the long-term safety of first-generation paclitaxel-coated drug-eluting stents (DES) below the knee and the dose-mortality relationships of paclitaxel in patients with chronic limb-threatening ischemia (CLI). MATERIALS AND METHODS: The PADI Trial compared paclitaxel-coated DES with percutaneous transluminal angioplasty with bail-out bare-metal stents (PTA ± BMS) in patients with CLI treated below the knee. Follow-up was extended to 10 years after the first inclusion, and survival analyses were performed. In addition, dose-related mortality and dose per patient weight-related mortality relations were examined. RESULTS: A total of 140 limbs in 137 patients were included in the PADI Trial. Ten years after the first inclusion, 109/137 (79.6%) patients had died. There was no significant difference between mortality in the DES group compared with the PTA ± BMS group (Log-rank p value = 0.12). No specific dose-related mortality (HR 1.00, 95% CI 0.99-1.00, p = 0.99) or dose per weight mortality (HR 1.05, 95% CI 0.93-1.18, p = 0.46) relationships were identified in the Cox-proportional Hazard models or by Kaplan-Meier survival analyses. CONCLUSIONS: There is a poor 10-year survival in both paclitaxel-coated DES and PTA ± BMS in patients with CLI treated below the knee. No dose-related adverse effects of paclitaxel-coated DES were observed in our study of patients with CLI treated below the knee. LEVEL OF EVIDENCE: The PADI Trial: level 1, randomized clinical trial.

Chloroquine dosage regimens in patients with COVID-19: Safety risks and optimization using simulations.

Currently no specific medicinal treatment exists against the new SARS-CoV2 and chloroquine is widely used, since it can decrease the length of hospital stay and improve the evolution of the associated COVID-19 pneumonia. However, several safety concerns have been raised from chloroquine use due to the lack of essential information regarding its dosing. The aim of this study is to provide a critical appraisal of the safety information regarding chloroquine treatment and to apply simulation techniques to unveil relationships between the observed serious adverse events and overdosing, as well as to propose optimized dosage regimens. The dose related adverse events of chloroquine are unveiled and maximum tolerated doses and concentration levels are quoted. Among others, treatment with chloroquine can lead to severe adverse effects like prolongation of the QT interval and cardiomyopathy. In case of chloroquine overdosing, conditions similar to those produced by SARS-CoV2, such as pulmonary oedema with respiratory insufficiency and circulatory collapse, can be observed. Co-administration of chloroquine with other drugs for the treatment of COVID-19 patients, like azithromycin, can further increase the risk of QT prolongation and cardiomyopathy. For elder patients there is a high risk for toxicity and dose reduction should be made. This study unveils the risks of some widely used dosing regimens and binds the observed serious adverse events with dosing. Based on simulations, safer alternative dosage regimens are proposed and recommendations regarding chloroquine dosing are made.

Assessment of adherence to diuretics and ß-blockers by serum drug monitoring in comparison to urine analysis.

Purpose: Toxicological screenings for identifying antihypertensive drugs proved to be a useful tool for assessing adherence. However, misinterpretation may occur in case of highly metabolised drugs with low renal excretion, as well as for drugs with a prolonged detectability. The aim of the present study was to compare a recently developed therapeutic drug monitoring (TDM) method based on serum concentrations to an urine drug detection method for assessing adherence in outpatients.Materials and methods: Corresponding urine and blood samples were obtained at the same time from 26 outpatients without supervised medication. Urine and serum analyses were performed using established high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies. Adherence was assumed if drugs were detectable in urine or if serum concentrations were above individually calculated lower dose-related concentrations (DRC) or literature-based therapeutic reference ranges (TRR) used as cut-off, respectively.Results: The identification of analytes in urine as well as the quantitative serum assay were performed for atenolol (n = 6 patients), bisoprolol (n = 8), nebivolol (n = 6), canrenone (n = 6, metabolite of spironolactone), hydrochlorothiazide (n = 12) and furosemide (n = 2). On the basis of drug detectability in urine, adherence was assumed in 88% of prescriptions. In 81% (DRC) and 50% (TRR) of the serum analyses the cut-off value was exceeded, which confirms patients' adherence in a lower number. Differences in adherence rates were found in five patients, mainly for ß-blockers.Conclusion: This study suggests that assessment of adherence can be performed more precisely on the basis of serum drug concentrations with individually calculated lower DRC than by using the TRR or qualitative urinalysis.

Intoxicated aggression: Do alcohol and stimulants cause dose-related aggression? A review.

RATIONALE: Violence and drug use are significant public health challenges that are strongly linked. It is known that alcohol plays a major role in the causation of unnatural deaths and that stimulants like cocaine and amphetamine are often implicated in aggressive acts or violence. However, a clear causal relationship between these substances and aggression, and more specifically a blood concentration threshold at which intoxicated aggression emerges is lacking. In case of a crime and subsequent law enforcement, knowledge about dose-response relationships could be of pivotal importance when evaluating the role of alcohol and drugs in aggressive offences. AIMS: The present review aimed to determine whether there is a causal relation between intoxication with these psychoactive substances and aggression, and to define blood concentration thresholds above which these substances elicit aggression. METHODS: Empirical articles published between 2013 and 2017 and review papers containing the predefined search strings were identified through searches in the PubMed and Embase databases and additional reference list searches. The complete search query yielded 1578 publications. Initially all articles were manually screened by title and abstract. Articles with irrelevant titles, given the selected search terms and review aims were discarded. Remaining articles were carefully studied and those that did not comply with the main objectives of this review were discarded. At the end of this process, 167 titles were found eligible for review. FINDINGS AND CONCLUSION: While placebo-controlled experimental studies clearly showed a causal link between alcohol and aggression, it is evident that such a link has not yet been established for cocaine and amphetamines. In case of alcohol, it is clear that there are various individual and contextual factors that may contribute to the occurrence of an aggressive act during intoxication. A clear threshold blood alcohol concentration has not been defined yet for alcohol, but a statistically significant increase of aggression has been demonstrated at a dose of 0.75 g/kg and higher. Future studies into intoxicated aggression should include multiple doses of alcohol and stimulants and take into account individual and contextual factors.

A novel rat model of contrast-induced nephropathy based on dehydration.

BACKGROUND: Contrast-induced nephropathy (CIN) is a frequent cause of hospital-acquired acute kidney injury. Previous animal models developed to explore the pathogenesis of CIN were based primarily on surgery or indomethacin treatment. Thus, we sought to explore a novel CIN rat model comparable to the human CIN. METHODS AND RESULTS: Both serum creatinine and tubular injury score were used to assess the successful establishment of the present model. In our study, dehydration duration and the iohexol dosage were found to be the two most important factors to develop a rat CIN model. And, dehydration for 3 days plus furosemide (10 mL/kg) injection before iohexol (15 mL/kg) administration was demonstrated the optimal strategy. Renal injury induced by 15 mL/kg iohexol was almost twice more severe than 10 mL/kg. Moreover, significant renal function decrease, morphological damage and mitochondrial dysfunction occurred as early as 6 h after iohexol injection, not 24 h as previous studies reported. Unexpectedly, we firstly discovered that dehydration after iohexol administration did not increase the extent of renal damage, indicating that hydration after contrast media exposure may be ineffective. CONCLUSIONS: A novel CIN rat model based on dehydration and iohexol exposure was established and validated to assist in understanding and preventing CIN.

Dependence of neutrons generated by 7Li(p,n) reaction on Li thickness under free-air condition in accelerator-based boron neutron capture therapy system employing solid-state Li target.

PURPOSE: An accelerator-based boron neutron capture therapy (BNCT) system with a solid-state Li target is reported to have degradation of the Li target. The degradation reduces the Li thickness, which may change spectra of the generated neutrons corresponding to the Li thickness. This study aims to examine the relationship between the Li thickness and the generated neutrons and to investigate the effects of the Li thickness on the absorbed dose in BNCT. METHOD: The neutron energy spectra were calculated via Monte Carlo simulation for Li thicknesses ranging from 20 to 150 µm. Using the system, the saturated radioactivity of gold induced by reactions between 197Au and the generated neutrons was evaluated with the simulation and the measurement, and those were compared. Additionally, for each Li thickness, the saturated radioactivity was compared with the number of generated neutrons. The absorbed doses delivered by 10B(n,α)7Li, 14N(n,p)14C, 1H(n, g)2H, and (n,n') reactions in water were also calculated for each Li thickness. RESULTS: The measurement and simulation indicated a reduction in the number of neutrons due to the degradation of the Li target. However, the absorbed doses were comparable for each Li thickness when the requisite number of neutrons for BNCT was delivered. Additionally, the saturated radioactivity of 198Au could be a surrogate for the number of neutrons even if the Li thickness was varied. CONCLUSIONS: No notable effect to the absorbed dose was observed when required neutron fluence was delivered in the BNCT even if the degradation of the Li was observed.

[Therapeutic drug monitoring in neuropsychopharmacology : Summary of the consensus guidelines 2017 of the TDM task force of the AGNP]. / Therapeutisches Drug-Monitoring in der Neuropsychopharmakologie : Zusammenfassung der Konsensusleitlinien 2017 der TDM-Arbeitsgruppe der AGNP.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood serum or plasma to optimize pharmacological therapy. TDM is an instrument with which the high interindividual variability of pharmacokinetics of patients can be identified and therefore enables a personalized pharmacotherapy. In September 2017 the TDM task force of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update of the consensus guidelines on TDM published in 2011. This article summarizes the essential statements for the clinical practice in psychiatry and neurology.

Concept Animation - a potential instructional scaffolding.

This article was migrated. The article was marked as recommended. Concept animation - the graphical array of pictures accompanied by text as speech balloons, can help to improve learner's comprehension from basic to advanced levels concepts. When the process of concept comprehension is not facilitated, the learner may come in a transitional state of misperception and understanding, that can restrain their learning to a surface approach. The basic science concepts learned at the inception of a Health Sciences program play a vital role towards the development of higher-order thinking and problem-solving aptitude in the subsequent years. Hence, it is important to facilitate meaningful learning of core concepts and principles in difficult basic science disciplines, like Pharmacology. This work reports our experiences of employing concept animations as a 'visual aid' instructional strategy to simplify pharmacology concepts to undergraduate Optometry students. The fundamental ideas of drug pharmacokinetics, pharmacodynamics and side effects were transformed into concept animations. The effects of these concept animations are explained by using Vygotsky's 'zone of proximal development, Mayer's cognitive theory of multimedia learning and cognitive load theory.

Transcriptome and Zymogram Analyses Reveal a Cellobiose-Dose Related Reciprocal Regulatory Effect on Cellulase Synthesis in Cellulosilyticum ruminicola H1.

The rumen bacterium Cellulosilyticum ruminicola H1 efficiently hydrolyzes cellulose. To gain insights into the regulatory mechanisms of cellulase synthesis, comparative transcriptome analysis was conducted for cultures grown on 2% filter paper, 0.5 and 0.05% cellobiose, and 0.5% birchwood xylan. It was found that cellulose induced a majority of (hemi)cellulases, including 33 cellulases and a cellulosomal scaffoldin (1.3- to 22.7-fold); seven endoxylanases, two mannanases, and two pectatelyases (2- to 16-fold); and pyruvate formate-lyase (PFL, 1.5- to 7-fold). Noticeably, 3- and 2.5-fold increased transcription of a cellobiohydrolase and the cellulosomal scaffoldin precursor were detected in 0.05% than in 0.5% cellobiose. Consistently, 9- and 4-fold higher specific cellobiohydrolase activities were detected in the filter paper and 0.05% cellobiose culture. SDS- and native-PAGE zymograms of cellulose-enriched proteins from the filter paper culture displayed cellulase activities, and cellulolytic "complexes" were enriched from the filter paper- and 0.05% cellobiose-cultures, but not from the 0.5% cellobiose culture. LC-MS/MS identified the cellulosomal scaffoldin precursor in the "complexes" in addition to cellulase, hemicellulase, and PFL proteins. The addition of 0.5% cellobiose, but not 0.05% cellobiose remarkably inhibited strain H1 to degrade filter paper. Therefore, this work reveals a cellobiose-dose related regulatory mechanism of cellulase synthesis by lower for induction and higher for repression, which has extended our understanding of the regulation of microbial cellulase synthesis.

A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy.

BACKGROUND: Although studies of oral immunotherapy (OIT) for food allergy have shown promise, treatment is frequently complicated by adverse reactions and, even when successful, has limited long-term efficacy because benefits usually diminish when treatment is discontinued. OBJECTIVE: We sought to examine whether the addition of omalizumab to milk OIT reduces treatment-related reactions, improves outcomes, or both. METHODS: This was a double-blind, placebo-controlled trial with subjects randomized to omalizumab or placebo. Open-label milk OIT was initiated after 4 months of omalizumab/placebo with escalation to maintenance over 22 to 40 weeks, followed by daily maintenance dosing through month 28. At month 28, omalizumab was discontinued, and subjects passing an oral food challenge (OFC) continued OIT for 8 weeks, after which OIT was discontinued with rechallenge at month 32 to assess sustained unresponsiveness (SU). RESULTS: Fifty-seven subjects (7-32 years) were randomized, with no significant baseline differences in age, milk-specific IgE levels, skin test results, or OFC results. At month 28, 24 (88.9%) omalizumab-treated subjects and 20 (71.4%) placebo-treated subjects passed the 10-g "desensitization" OFC (P = .18). At month 32, SU was demonstrated in 48.1% in the omalizumab group and 35.7% in the placebo group (P = .42). Adverse reactions were markedly reduced during OIT escalation in omalizumab-treated subjects for percentages of doses per subject provoking symptoms (2.1% vs 16.1%, P = .0005), dose-related reactions requiring treatment (0.0% vs 3.8%, P = .0008), and doses required to achieve maintenance (198 vs 225, P = .008). CONCLUSIONS: In this first randomized, double-blind, placebo-controlled trial of omalizumab in combination with food OIT, we found significant improvements in measurements of safety but not in outcomes of efficacy (desensitization and SU).