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For the past years, cross-cultural and interlanguage pragmatics have focused on native and non-native speech act descriptions, and only a small number of studies have investigated the preparatory class effect involved in speech act productions. To bridge the gap, this study aims to investigate the degree of directness and amount of lexical / phrasal internal and external modifications of requestive e-mails employed by 25 first grade students of English Language and Literature department with preparatory education and 25 first grade students of English Language and Literature department without preparatory education in their in a state university. It also aims to explore whether there is a difference between two groups according to the degree of imposition while making requests. The participants were given discourse completion tests in e-mail format including two different situations with low and high imposition levels and asked to write two requestive e-mails to their non-native professor. The e-mails were analyzed and classified based on Economidou-Kogetsidis’s (2011) framework which relies on Blum- Kulka et al. (1989) and Biesenbach-Lucas (2006, 2007). Based on the percentages and frequencies, the students with preparatory class education were compared to the students without preparatory class education, with respect to their usage of request strategies, lexical/phrasal internal modification and external modification. The results indicated that these two groups had both similarities and differences with respect to the degree of directness, the amount of internal and external modifications. Turkish ELL learners with and without prep class education employed more direct strategies in both situations. However, the group without prep class education employed more conventionally indirect strategies than the group with prep class education. None of the participants used non-conventionally indirect strategies. The group with prep class education used more internal modification than the group without prep class education. The most common internal modification was the consultative device in both groups. As for external modification, the group with prep class education utilized more supportive moves than the group without prep class education. Grounder was the most preferred supportive move by both groups. Keywords: Turkish ELL learners; requestive e-mails; academic e-mails; directness., Наголошено, що протягом останніх років міжкультурна та міжмовна прагматика зосереджувалась на дослідженні мовних актів рідною та іноземною мовами, і лише невелику кількість досліджень було спрямовано на вивчення впливу передвищої підготовчої освіти на ефективне продукування мовних актів іноземною мовою, зокрема англійською. Щоб подолати цей розрив, дослідження ставило за мету вивчити ступені вільності та кількість лексичних / фразових внутрішніх і зовнішніх модифікацій в англомовних електронних листах-запитах, що використовувалися 25 студентами кафедри англійської мови та літератури, які пройшли курс підготовчого навчання, та 25 студентами тієї ж кафедри без підготовчої освіти в державному університеті Думлупінар у Кютах’ї. Результати показали, що студенти без підготовчого класу використовували більше умовно непрямі стратегії та внутнрішні модифікації у написанні англомовних електронних листів-запитів, ніж студенти з групи з передвищою підготовчою освітою. Ключові слова: навчальні електронні листи; електронні листи-запити; прямі та непрямі стратегії; турецькі студенти, які вивчають англійську мову; передвища підготовча освіта.

A new group of hypoglycemic drugs has been used to treat diabetes type 2. This group is active sodium glucose co-transporter (SGLT2) or SGLT2 inhibitors. It has been shown that besides the treatment of diabetes, this drug class is responsible for the mildness of the cardiovascular events shown in patients with diabetes type 2. However, there is an intriguing question regarding the range of SGLT2 inhibitors and if there is a difference between them or if there is a class effect among their results. EMPA-REG OUTCOME trial and the CVD-study are used to answer this question. Additional information from the DECLARE-TIMI 58 and Dapa-HF trials is studied.

The cardiorenal benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is) are transforming the care of CKD. An inherent challenge of practice-changing advances on this scale is how to best incorporate them into daily practice. In this vein, although there are four SGLT2is commercially available in the United States, the question remains whether these SGLT2is may be viewed as interchangeable or if specific agents offer unique benefits or harms in specific clinical settings. The more similarities between the agents within a pharmacologic class ( e.g. , chemical structure, pharmacodynamics, and pharmacokinetics), the greater the likelihood of shared class effects. Preclinical data, starting with largely comparable chemical structures, provide a foundation where class effects might be anticipated. Nevertheless, on- and off-target effects may be expected to modify the response to any drug—an area of particular interest when considering the potential for drug, rather than class-specific, effects (1). Although translational, toxicologic, and pharmacologic investigations carried out in model systems may shed light into class- versus drug-specific effects, the ultimate adjudicator of this question is data from sufficiently powered, rigorously controlled, human, randomized clinical trials (RCTs). Before delving into the trial data, it may be helpful to briefly review the preclinical data regarding SGLT2is to explore the a priori bio-plausibility of class- versus drug-specific effects. The origins of SGLT2is can be linked to two earlier tracks of research: familial renal glucosuria (FRG) and phlorizin rodent studies (2). The presence of patients with a familiar tendency to produce elevated levels of glucose in the urine, despite normal blood glucose, had been identified for some time and, as early as the 1920s, work had begun to identify the pattern of inheritance (2,3). The precise molecular mechanism for this clinical finding would take considerably longer to come to light (4). One observation from these patients that …

Objectives Statins have proved to reduce cardiovascular morbidity and mortality in high-risk population and are generally well tolerated, although adverse events can occur. Up to 3% of patients develop aminotransferases elevation, which usually normalizes with continued treatment and hardly is associated with clinical symptoms. Serious statin-related liver injury is exceedingly rare. Furthermore, literature regarding rechallenge with a second statin is extremely poor. Some authors caution that re-exposure to these drugs is associated with a more serious liver injury but safe switching to a second statin after drug-induced liver injury (DILI) is also reported. Case presentation We describe a case of a middle-aged woman who developed hepatocellular liver injury after simvastatin dose escalation; a rechallenge with low dose rosuvastatin caused rapid recurrence of DILI. Conclusions In our opinion, clinicians should be very cautious upon rechallenge and closely follow-up patients who experienced statin-induced liver injury when trying re-exposure to another statin.

Renal protection is likely to be a class effect of SGLT‐2 inhibitors and GLP‐1RA. When used simultaneously, there may be a synergistic effect. Both agents are also safe to use in high renal risk patients (eGFR between 21 and 30 mL/min/1.73m2), Renal protection is likely to be a class effect of SGLT‐2 inhibitors and GLP‐1RA. When used simultaneously, there may be a synergistic effect. Both agents are also safe to use in high renal risk patients (eGFR between 21 and 30 mL/min/1.73 m2)

Bu araştırmada ilkokul 4. sınıf Türkçe dersinde yansıtıcı düşünme destekli yaratıcı yazma çalışmalarının öğrencilerin yaratıcı yazma becerilerine etkisi incelenmiştir. Araştırmanın çalışma grubu, Rize ilinin Pazar ilçesinde bulunan TOKİ İlkokulu 4/A sınıfı (14) öğrencilerinden oluşmaktadır. Araştırma, ön test-son test tek gruplu yarı deneysel bir çalışmadır. Araştırma nitel verilerle desteklenmiştir. Deneysel işlem öncesinde ve sonrasında Yaratıcı Yazma Değerlendirme Rubriği kullanılmıştır. Deneysel çalışmalar altı hafta devam etmiştir. Deneysel çalışma boyunca yazma derslerine yansıtıcı düşünme destekli yaratıcı yazma çalışmaları araştırmacı tarafından yürütülmüştür. Veri toplama araçları çalışma grubunda ön test ve son test olarak uygulanmıştır. Çalışma kapsamında nicel verilerin analizinde SPSS 20.0 istatistik paket programı kullanılmıştır. Araştırma boyunca uygulanan yansıtıcı düşünme günlükleri, içerik analizi yöntemiyle analiz edilmiştir. Araştırma sonuçlarına göre, yansıtıcı düşünme destekli yaratıcı yazma çalışmalarının neticesinde elde edilen son test puanları ön test puanlarına göre yüksek çıkmıştır. Çalışma grubunun ön test ve son test puanları Wilcoxon İşaretli Sıralar Testi uygulanarak karşılaştırılmış ve ön test ve son test puanları arasında manidar bir farklılık olduğu bulunmuştur.

Purpose: To determine if fluorescein angiographic (FA) findings after intravitreal ranibizumab (IVR) for retinopathy of prematurity (ROP) conform to a class effect previously described with bevacizumab. Methods: Single-center retrospective case series of all infants treated with 0.2 mg (0.02 mL) IVR for Type 1 ROP from July 2016 to November 2018. FA were obtained at 40, 52, 62, and 72 weeks of postmenstrual age (PMA) using wide-angle photography. FA images were analyzed and the peripheral avascular areas measured with ImageJ using a reference disc diameter (DD). Based on the extent of the avascular area and tortuosity of the retinal vessels all eyes were classified into four categories: complete vascular maturity (vascularization within 2 DD of the ora serrata), VAA (avascular area >2 DD of the ora serrata), VAT (avascular area >2 DD of the ora serrata and posterior tortuosity), and reactivation (recurrence of stage disease). Results: About 13 infants were enrolled and 24 eyes were available in this study. None of the eyes reached complete vascular maturity at an average PMA of 60 weeks, 7 (29%) eyes presented with VAA, 8 (33%) with VAT, and 9 (37.5%) reactivated. The reactivated eyes presented with the largest area of peripheral ischemia, followed by the VAT and then the VAA groups ( p = 0.02). Conclusion: IVR conforms to the previously described regression patterns following intravitreal bevacizumab for ROP indicative of a class effect. Follow-up using FA might help to optimize the management of these infants after injection of the drug.

Background Network meta-analysis synthesises data from a number of clinical trials in order to assess the comparative efficacy of multiple healthcare interventions in similar patient populations. In situations where clinical trial data are heterogeneously reported i.e. data are missing for one or more outcomes of interest, synthesising such data can lead to disconnected networks of evidence, increased uncertainty, and potentially biased estimates which can have severe implications for decision-making. To overcome this issue, strength can be borrowed between outcomes of interest in multivariate network meta-analyses. Furthermore, in situations where there are relatively few trials informing each treatment comparison, there is a potential issue with the sparsity of data in the treatment networks, which can lead to substantial parameter uncertainty. A multivariate network meta-analysis approach can be further extended to borrow strength between interventions of the same class using hierarchical models. Methods We extend the trivariate network meta-analysis model to incorporate the exchangeability between treatment effects belonging to the same class of intervention to increase precision in treatment effect estimates. We further incorporate a missing data framework to estimate uncertainty in trials that did not report measures of variability in order to maximise the use of all available information for healthcare decision-making. The methods are applied to a motivating dataset in overactive bladder syndrome. The outcomes of interest were mean change from baseline in incontinence, voiding and urgency episodes. All models were fitted using Bayesian Markov Chain Monte Carlo (MCMC) methods in WinBUGS. Results All models (univariate, multivariate, and multivariate models incorporating class effects) produced similar point estimates for all treatment effects. Incorporating class effects in multivariate models often increased precision in treatment effect estimates. Conclusions Multivariate network meta-analysis incorporating class effects allowed for the comparison of all interventions across all outcome measures to ameliorate the potential impact of outcome reporting bias, and further borrowed strength between interventions belonging to the same class of treatment to increase the precision in treatment effect estimates for healthcare policy and decision-making.

Bradykinin-mediated angioedema is a rare but potentially fatal adverse event. Angioedema induced by angiotensin-converting enzyme (ACE) inhibitors is generally attributed to an inhibition of bradykinin degradation following ACE inhibition. Clinical studies on ACE inhibitors mainly focus on their efficacy. Few examine their potential to generate undesirable adverse effects, particularly with regard to angioedema.We report here a case of angioedema occurring after ramipril initiation in a patient chronically treated with quinapril. Angioedema subsided spontaneously after ramipril discontinuation and quinapril reintroduction.Our clinical case suggests that despite similar pharmacodynamic properties, quinapril and ramipril do not have the same potential to generate angioedema. To explain this difference, we suggest a potentiation of the effect of bradykinin at the B2 receptor level by ramipril, which does not occur with quinapril. Consequently, angioedema may not always be a class effect of ACE inhibitors.

English teaching includes several parts such as self-study instruction, cooperative inquiry, intensive lecture and after class practice. In this paper, the role of extracurricular application on the effectiveness of college English teaching is explored through questionnaires, teaching experiments and interviews. The experimental design and study of college English teaching in the first year of Nanning University, using R language to analyze the experimental data. The conclusion is that extracurricular application has positive effect on college English teaching. Moreover, it is found that although students have different attitudes and opinions, some of them also affirm the positive effect of after class application. At the same time, in the process of teaching implementation, we should pay attention to the difficulty of practice content and the variety of practice methods, but we should not excessively occupy after class time of students. The most importance is to provide students with feedback and summary of after class practice in time. The research shows that after class application can improve the effectiveness of classroom teaching when it is well integrated with classroom teaching.

Purpose: To provide a comprehensive review to determine whether there is a class effect among angiotensin receptor blockers (ARBs) in relation to serum uric acid. Summary: A literature search was conducted and 8 articles were identified for inclusion in this review. In the studies reviewed, candesartan and valsartan were shown to have either a neutral or negative effect on serum uric acid. Azilsartan was shown to have a negative impact on serum uric acid while eprosartan appeared to have no impact on serum uric acid levels. Irbesartan demonstrated either a neutral or positive effect on serum uric acid while losartan exhibited a positive effect. Conclusion: The available data indicate that the reduction of serum uric acid is not a class effect of ARBs. Of the available agents, only losartan has clear evidence of its ability to lower serum uric acid. For patients with high blood pressure and elevated serum uric acid, losartan should be considered as a first-line agent with irbesartan as an alternative when appropriate.

The Absorb bioresorbable scaffold (BRS), the most studied device among all BRS, suffered a major setback following the negative results of the ABSORB trials. However, approximately 34 BRSs from 22 companies are currently under development. The potential device-specific factors related to the increased event rate in Absorb were: 1) weak mechanical properties, 2) larger strut thickness (less embedment and larger protrusion) and width (larger footprint) predisposing to underexpansion/protrusion of struts, eventually resulting in increased thrombogenicity, and 3) longer bioresorption time combined with failure of encapsulation of struts before the dismantling process ensues. Given the diversity of bioresorbable materials (even amongst PLLA), and the different mechanical properties and bioresorption profiles of each new BRS, one could expect considerable difference in early and late clinical outcomes. As a matter of fact, data from first-in-man (FIM) and pivotal trials have demonstrated variable clinical results. Indeed, early clinical evidence from FIM trials does not support a class effect. However, the absence of a comparator precludes us from drawing definitive conclusions. Further clinical evidence should confirm the absence (or presence) of a class effect.

As an important environmental factor in family education in China, the class effect of father presence on middle school students' academic performance is unclear. The impacts on students' academic performance are based on the 2014–2015 tracking data of the China Education Panel Survey (CEPS), and a hierarchical linear model was used to explore the school effects of father presence on middle school students' academic performance in terms of the type of father presence. The study found that: students' self-efficacy had a significant effect on individual academic performance, and self-efficacy was a positive predictor of achievement; father involvement in parenting was classified as physical presence, disciplinary presence, and emotional presence; and father involvement had a significant positive effect on middle school students' academic performance. Specifically, the improvement of spatial presence and emotional presence had a positive impact on middle school students' academic performance, while disciplinary father presence had a negative impact. Based on previous research on influencing factors of individuals, campus, and peer groups, the finding of school effects of father involvement is an important basis for family education improvement.

Aims In 2008, the US Food and Drug Administration (FDA) issued a guidance requiring that cardiovascular outcome trials (CVOTs) be conducted for newer hypoglycaemic drugs for type 2 diabetes (T2D). We aimed to examine the decisions by 3 regulatory authorities in response to identical CVOT data. Methods We surveyed ClinicalTrials.gov to identify CVOTs and examined the revision histories of drug labels in databases from the FDA, the European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan. Results We selected 14 drugs and corresponding CVOTs, 12 of which were conducted as postmarketing trials. In the USA and the EU, the pre-CVOT indication on all 14 labels was "improvement in glycaemic control". Six drugs showed significant cardiovascular risk reduction, which led to an additional indication regarding reduction of cardiovascular adverse events in the USA, and a change to the EU indication to specify treatment of adults with T2D. The initial indication in Japan, T2D, remained unchanged. Regarding safety, significant increases in heart failure were observed only in the saxagliptin trial. A warning was added to the saxagliptin labels in the EU and Japan, whereas the FDA required a class effect warning to be added to the labels of all 4 dipeptidyl peptidase-4 inhibitors. Conclusions Regulatory authorities using identical trial data made substantially different decisions regarding both safety and efficacy of hypoglycaemic drugs. The differences in initial indication wording between Japan and the other authorities suggest that trial data and T2D are interpreted differently in these regions.

Hospitalization for major diabetes complications, including myocardial infarction, stroke, lower-extremity amputation, and end-stage kidney disease, is on the rise and represents a great health burden for patients with type 2 diabetes (T2D), in particular for older people. Newer glucose-lowering medications have generated some optimism on the possibility to influence the natural history of cardiorenal complications of T2D. This review summarizes work in the area of sodium–glucose cotransporter 2 inhibitors (SGLT-2i) treatment and prevention of cardiorenal complications in patients with T2D (major adverse cardiovascular events, hospitalization for heart failure, kidney outcomes), with a particular emphasis on the effect of age, the role of primary versus secondary prevention and the possible extension of their cardiorenal benefits to the entire class of SGLT-2i.

Em Portugal, o domínio da investigação sobre as relações entre imigração, etnicidade e educação centrouse, durante um longo período de tempo, nos desempenhos e trajetórias escolares individuais dos alunos. Este centramento contrastava com o destaque dado à investigação e ao debate sobre o efeito-escola e o efeito-turma naquela relação, muito por efeito do Relatório Coleman. Estes tópicos de investigação e debate só mais recentemente teriam maior desenvolvimento em Portugal. É sobretudo a partir da segunda década do século XXI que se multiplicam estudos que procuram relacionar a vertente organizacional da escola, a formação de turmas e as características culturais e sociais da turma e da escola com o desempenho escolar de uma população escolar que, factualmente, está em desvantagem nos sistemas educativos: os alunos com background imigrante de meios sociais desfavorecidos. Neste quadro, a presente investigação pretende contribuir para a discussão, em Portugal, sobre o efeitoescola e o efeito-turma no desempenho escolar dos alunos da escola pública com background imigrante. Complementarmente, procura também evidenciar as diferenças nesse desempenho devidas à heterogeneidade migrante. Para o efeito usa microdados disponibilizados pela Direção-Geral de Estatísticas da Educação e Ciência (DGEEC) sobre os alunos da Área Metropolitana de Lisboa matriculados nos segundo e terceiro ciclos do ensino básico entre 2012/13 e 2016/17. São quatro os objetivos principais prosseguidos: (i) comparar o perfil sociocultural dos alunos por origem nacional e background migratório; (ii) relacionar resultados escolares e condições sociais e culturais dos alunos; (iii) analisar as características socioétnicas das turmas e das escolas; e, por último, (iv) comparar o desempenho de alunos com diferentes características socioculturais e diferentes inserções em escolas e turmas com graus variáveis de segregação socioétnica. Para este último objectivo recorreu-se a uma análise estatística de regressões linear múltiplas. In Portugal, the domain of the investigation regarding the relations between immigration, ethnicity and education has centred, for a long period in the performance and individual school trajectories of students. This centring contrasted with the highlight given to the investigation and debate of the school-effect and the class-effect in that relation, much due to the influence of the Coleman Report. These topics of investigation and debate only recently have gained more development in Portugal. It was mainly starting from the second decade of the XXI century that studies have multiplied seeking to relate the organizational aspect of the school, the formation of classes and the cultural and social characteristics of the class and school with the school performance of a school population that, factually, is in disadvantage in the educational systems: students with an immigrant background and socially disadvantaged. Within this picture, the present investigation seeks to contribute for the discussion, in Portugal, regarding the school-effect and the class-effect on the school performance of public school students with an immigrant background. Complementarily, it also looks to demonstrate the differences in that performance due to migrant heterogeneity. For this matter, it uses microdata provided by the General-Directorate of Statistics of Education and Science (DGEEC), concerning the students of the Metropolitan Area of Lisbon, registered in the second and third cycles of the basic education between 2012/13 and 2016/17. There are four main objectives pursued: (i) compare the sociocultural profile of students by national origin and migrant background; (ii) relate school results and social and cultural conditions of the students; (iii) analyse the socio-ethnical characteristics of the classes and schools; and, finally, (iv) compare the performance of students with different sociocultural characteristics and different insertions in schools and classes with variable degrees of socio ethnical segregation. For the latter objective, it was used a statistical analyses of multiple linear regressions.

Pharmacological target-mediated drug disposition (TMDD) represents a special source of nonlinear pharmacokinetics, and its occurrence in large-molecule compounds has been well recognized because numerous protein drugs have been reported to have TMDD due to specific binding to their pharmacological targets. Although TMDD can also happen in small-molecule compounds, it has been largely overlooked. In this mini-review we summarize the occurrence of TMDD that we discovered recently in a series of small-molecule soluble epoxide hydrolase (sEH) inhibitors. Our journey started with an accidental discovery of target-mediated kinetics of 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), a potent sEH inhibitor, in a pilot clinical study. To confirm what we observed in human, we conducted a series of mechanism experiments in animals, including pharmacokinetic experiments using sEH-knockout mice as well as in vivo displacement experiments with co-administration of another potent sEH inhibitor. Our mechanism studies confirmed that the TMDD of TPPU is due to its pharmacological target sEH. We further expanded our evaluation to various other sEH inhibitors and found that TMDD is a class effect of this group of small-molecule sEH inhibitors. In addition to summarizing the occurrence of TMDD in sEH inhibitors, in this mini-review we also highlighted the importance of recognizing TMDD of small-molecule compounds and its impact in clinical development as well as utilizing pharmacometric modeling in facilitating quantitative understanding of TMDD.

Objective The aim of this study was to assess the causality of anti-TNFα agents-associated pleuropericarditis in VigiBase with a focus on its diverse types. Methods All variables contained in the pleuropericarditis reports were reviewed. Well-documented reports, vigiGrade completeness score ≥ 0.80 or with an informative narrative, were analyzed and with a focus on the clinical features of the cases. Bradford-Hill criteria were used in the case series assessment of causality. Results From 1968 up to 18 December 2019, there were 94 unique cases from 18 countries reporting pleuropericarditis with anti-TNFα agents as a suspected or interacting medicine. Among the 94 reports, 42 were identified as well-documented and further assessed for clinical features. Of the 42 cases, 39 were serious, including three fatal and seven life-threatening. In 35 cases, an anti-TNFα agent was the only suspected drug. Positive de- and re-challenge were reported in 95% and 17% of the 42 cases, respectively. The times to onset (TTO) varied greatly among individual cases, ranging from one month to 75 months (mean = 24 months). The most commonly involved anti-TNFα agents were adalimumab, infliximab and etanercept; and the mostly reported pleuropericarditis types were classified as autoimmune-related with (n = 17) or without (n = 15) co-reported drug-induced lupus (DIL), or infection-related (n = 8). While adalimumab was the most reported in the infection-related cases (7/8), infliximab was the most frequent in the autoimmune-related cases, in particular co-reported with DIL (9/17). There were four cases where the reaction occurred one to two months after the anti-TNFα agents (infliximab and adalimumab) were stopped. Based on the review of the case series using Bradford-Hill criteria the anti-TNFα agents associated pleuropericarditis are considered as a class effect. Conclusions To clinically recognize and manage these potentially life-threatening serious cardiopulmonary complications, health care professionals should be aware of this possible risk. Meanwhile, attention should be paid to the clinical features of pleuropericarditis cases, since they may cause diagnostic and therapeutic difficulties. Considering the long elimination time, clinicians need to be reminded to remain vigilant for the adverse reactions even after discontinuing anti-TNFα therapy.

In recent years, successive reports have been made on large-scale cardiovascular outcome trials using novel hypoglycemic drugs. Their results have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors are hypoglycemic drugs that could potentially greatly improve the heart failure-related outcomes in type 2 diabetes patients with a high cardiovascular risk. Further analyses have subsequently been performed from various perspectives, and SGLT2 inhibitors with their class effect have been indicated to be potentially useful for heart failure in type 2 diabetes patients with extensive clinical background. As a result, a clear concept has globally emerged with SGLT2 inhibitors as drugs of choice in clinical practice to prevent heart failure in type 2 diabetes patients. Further studies are needed to examine the next research topics on heart failure prevention using SGLT2 inhibitors, including their detailed pharmacological mechanism of action and their effectiveness and safety against heart failure in patients regardless of diabetes status. This paper outlines (1) the current evidence of heart failure prevention by SGLT2 inhibitors based on the results of recent large-scale cardiovascular outcome trials and (2) future research topics on their further applications in clinical practice.

Mammalian target of rapamycin inhibitors (mTORi) are used to treat a variety of malignancies and have an established role in organ transplantation. Interstitial lung disease (ILD) is one of the complications of mTORi and is believed to be a class effect. More cases of ILD have been reported with sirolimus than with everolimus in the literature, possibly due to earlier introduction and wider use of sirolimus. We report the case of a kidney transplant recipient who developed ILD secondary to sirolimus and improved rapidly after switching to everolimus.

Objectives There are increasing concerns regarding proton pump inhibitor (PPI) use and the risk of fractures in adults. Few studies have evaluated this risk among pediatric patients. This study examined fractures and fracture location among pediatric patients exposed to PPI compared with those without documented exposure. Study design Encounters for patients 6 months to 15.5 years were identified between July 1, 2011 to December 31, 2015 in the Pediatric Hospital Information System database. Exclusion criteria was applied for chronic illnesses, conditions or medications predisposing to fracture. Encounters were classified as PPI encounters if a charge for PPI was documented. PPI encounters were propensity matched to non-PPI encounters. Following initial encounter, patients were evaluated over a 2-year period for hospitalizations resulting from fracture. Results There was a statistically significant higher rate of fractures among the PPI-exposed group (1.4% vs 1.2%, P = 0.019). Adjusting for remaining differences in sex, race, encounter type, payer, and resource intensity after matching, the difference remained statistically significant (P = 0.017) with an adjusted odds ratio (95% CI) of 1.2 (1.0--1.4). Upper extremity was the most common location for fracture; however, the PPI cohort was more likely to suffer from lower extremity, rib, and spinal fractures (P = 0.01). Conclusions This study suggests an increased risk of fracture among pediatric patients taking PPI. Among patients hospitalized with a fracture, those with PPI exposure had a higher rate of lower extremity, rib, and spine fractures compared with controls. This appeared to be a class effect not related to individual PPI agent.

Maternal immunization with reduced antigen content tetanus-diphtheria-acellular pertussis (Tdap)-containing vaccines has been recommended to prevent infant pertussis. However, maternal antibodies may interfere with infant responses to routine immunization with diphtheria-tetanus-acellular pertussis (DTaP)-containing vaccines, raising concerns of suboptimal protection after infant vaccination. We performed a narrative literature review to assess whether blunting occurs regardless of the manufacturer of maternal and infant vaccines. Because internationally agreed correlates of protection are lacking, the clinical significance of blunting is not yet fully understood. We have reviewed the evidence available to date.Thirteen studies that evaluated blunting after maternal immunization and infant primary/booster series were identified. Blunting was observed with various combinations of Tdap- and DTaP-containing vaccines for maternal and pediatric immunization. Studies assessing the effectiveness of maternal Tdap immunization beyond the primary infant immunization series in England and in the United States suggested no evidence of a clinically relevant blunting effect so far.This review indicates that the phenomenon of blunting does not depend on the manufacturer/brand of the pertussis-containing vaccines used for immunizing mothers or children. Currently, there is no epidemiological evidence that children whose mothers received Tdap are at increased risk of pertussis after pediatric vaccinations, although longer follow-up is required.

International audience; We thank Brož et al. for their interest in our study aiming to determine if drug-induced hypoglycemia could be a class effect for opioids [1] and for their useful comments.The French PharmacoVigilance Database (FPVD) contains a narrative description of cases provided by the declarant, which we examined for this study. The description of the report’s narrative in pharmacovigilance study is a complement to disproportionality analysis that may identify potential mechanisms underlying the associations found between drugs and adverse drug reactions. We are glad that they shared our interest in finding such mechanisms to further investigate the link between hypoglycemia and opioids. As they accurately mentioned, 45 of the 93 tramadol-associated hypoglycemia cases included in our descriptive study in the FPVD were related to diabetic patients. Indeed, hypoglycemia in these patients could have been favored by the antihyperglycemic treatment they received. We agree with them that sleepiness, one of the common side effect of opioids, combined to the use of those antihyperglycemic treatments could have been one of the factors leading to the onset of hypoglycemia in those patients. However, not all the reports mentioned sleepiness and the prescription of opioids appeared to be the trigger factor causing the hypoglycemia even in diabetic patients, regardless of the underlying mechanism.

Drug-induced liver injury is a common cause of acute liver failure. β-blockers are a widely prescribed class of medications; however, hepatotoxicity is a rare adverse effect of this medication of which clinicians must be aware. This case suggests that hepatotoxicity may be a class effect of β-blockers.

The paper discusses the effects of drugs from different pharmacological groups on cognitive functions. It details the impact of drugs used to treat nervous system, cardiovascular, gastrointestinal, respiratory, and endocrine diseases on cognitive functions. It is emphasized that many drugs exert both negative and (less frequently) positive effect on cognitive functions, but it is especially pronounced in drugs used to treat nervous system diseases. There is evidence suggesting that different representatives of a number of pharmacological groups have no class effect on cognitive functions.

Background:The atypical antipsychotics (AAPs) are associated with a recognized class effect of glucose and lipid dysregulation. The use of these medications is rapidly increasing in elderly patients with, and without, dementia. However, the metabolic risks specific to elderly remain poorly studied.Methods:Design: A case-control study.Setting: Psychogeriatric service in Auckland, New Zealand.Participants: Elderly patients either receiving AAP treatment (cases) or not (controls) between 1 Jan 2008 and 1 Jan 2014.Main outcome measures: metabolic data of glucose, HbA1c, lipids, and cardiovascular events and death. The data were analyzed usingt-tests and linear regression models for each metabolic outcome.Results:There were 330 eligible cases and 301 controls from a total study population of 5,307. There was a statistically significant change in the HbA1c over time, within the cases group of −1.14 mmol/mol (p = 0.018, 95% CI −0.19 to −2.09). Also statistically significant was the reduction in total cholesterol of −0.13 mmol/L (p = 0.036, 95% CI −0.008 to −0.245). The only significant difference found between cases and controls was in the change in cholesterol ratio of 0.16 mmol/L between groups (95%CI 0.01–0.31, p = 0.036).Conclusions:AAP use was not associated with any clinically significant change in metabolic outcomes in this study population.