bluuebunny/crossref_metadata_2025 huggingface dataset:
Allergen‐specific immunotherapy induces the suppressive secretoglobin 1A1 in cells of the lower airways
Authors: Zissler Ulrich M. , Jakwerth Constanze A. , Guerth Ferdinand , Lewitan Larissa , Rothkirch Sandra , Davidovic Miodrag , Ulrich Moritz , Oelsner Madlen , Garn Holger , Schmidt‐Weber Carsten B. , Chaker Adam M.
Published: February 2021

Background

While several systemic immunomodulatory effects of allergen‐specific immunotherapy (AIT) have been discovered, local anti‐inflammatory mechanisms in the respiratory tract are largely unknown. We sought to elucidate local and epithelial mechanisms underlying allergen‐specific immunotherapy in a genome‐wide approach.

Methods

We induced sputum in hay fever patients and healthy controls during the pollen peak season and stratified patients by effective allergen immunotherapy or as untreated. Sputum was directly processed after induction and subjected to whole transcriptome RNA microarray analysis. Nasal secretions were analyzed for Secretoglobin1A1 (SCGB1A1) and IL‐24 protein levels in an additional validation cohort at three defined time points during the 3‐year course of AIT. Subsequently, RNA was extracted and subjected to an array‐based whole transcriptome analysis.

Results

Allergen‐specific immunotherapy inhibited pro‐inflammatory CXCL8, IL24, and CCL26mRNA expression, while SCGB1A1, IL7, CCL5, CCL23, and WNT5BmRNAs were induced independently of the asthma status and allergen season. In our validation cohort, local increase of SCGB1A1 occurred concomitantly with the reduction of local IL‐24 in upper airways during the course of AIT. Additionally, SCGB1A1 was identified as a suppressor of epithelial gene expression.

Conclusions

Allergen‐specific immunotherapy induces a yet unknown local gene expression footprint in the lower airways that on one hand appears to be a result of multiple regulatory pathways and on the other hand reveals SCGB1A1 as novel anti‐inflammatory mediator of long‐term allergen‐specific therapeutic intervention in the local environment.
Guideline on the peri‐operative management of patients with sickle cell disease
Authors: Walker I. , Trompeter S. , Howard J. , Williams A. , Bell R. , Bingham R. , Bankes M. , Vercueil A. , Dalay S. , Whitaker D. , Elton C.
Published: February 2021

Sickle cell disease is a multisystem disease characterised by chronic haemolytic anaemia, painful vaso‐occlusive crises and acute and chronic end‐organ damage. It is one of the most common serious inherited single gene conditions worldwide and has a major impact on the health of affected individuals. Peri‐operative complications are higher in patients with sickle cell disease compared with the general population and may be sickle or non‐sickle‐related. Complications may be reduced by meticulous peri‐operative care and transfusion, but unnecessary transfusion should be avoided, particularly to reduce the risk of allo‐immunisation. Planned surgery and anaesthesia for patients with sickle cell disease should ideally be undertaken in centres with experience in caring for these patients. In an emergency, advice should be sought from specialists with experience in sickle cell disease through the haemoglobinopathy network arrangements. Emerging data suggest that patients with sickle cell disease are at increased risk of COVID‐19 infection but may have a relatively mild clinical course. Outcomes are determined by pre‐existing comorbidities, as for the general population.
Development and evaluation of a novel pre‐operative surgery school and behavioural change intervention for patients undergoing elective major surgery: Fit‐4‐Surgery School
Authors: Fecher‐Jones I. , Grimmett C. , Edwards M. R. , Knight J. S. , Smith J. , Leach H. , Moyses H. , Jack S. , Grocott M. P. W. , Levett D. Z. H.
Published: February 2021

Group pre‐operative education has usually been limited to conditioning expectations and providing education. Prehabilitation has highlighted modifiable lifestyle factors that are amenable to change and may improve clinical outcomes. We instituted a pre‐operative ‘Fit‐4‐Surgery School’ for patients scheduled for major surgery, to educate and promote healthy behaviour. We evaluated patients’ views having attended the school, and after surgery we asked how it had changed their behaviour with a lifestyle questionnaire. The school was launched in May 2016 and was attended by 586/1017 (58%) of invited patients. Patients who did not attend: lived further away, median (IQR [range]) 8 (4–19 [0–123]) miles vs. 5 (3–14 [0–172]) miles, p < 0.001; and were more deprived, Index of Multiple Deprivation Rank decile median (IQR [range]), 6 (4–8 [1–10]) vs. 7 (4–9 [1–10]), p = 0.04. Of the 492/586 (84%) participants who completed an evaluation questionnaire, 462 (94%) would recommend the school to a friend having surgery and 296 (60%) planned lifestyle changes. After surgery, 232/586 (40%) completed a behavioural change questionnaire, 106 (46%) of whom reported changing at least one lifestyle factor, most commonly by increasing exercise. The pre‐operative school was acceptable to patients.
Low BMI, but not high BMI, influences the timing of puberty in boys
Authors: Oehme Ninnie Helen Bakken , Roelants Mathieu , Bruserud Ingvild Særvold , Madsen Andre , Bjerknes Robert , Rosendahl Karen , Juliusson Petur B.
Published: February 2021

Background

Previous studies investigating the association between weight status and onset of puberty in boys have been equivocal. It is currently unclear to what extent weight class influences puberty onset and progression.

Objectives

To explore the relationship between degree of sexual maturation and anthropometric measures in Norwegian boys.

Methods

The following endpoints were collected in a Norwegian cross‐sectional study of 324 healthy boys aged 9–16: ultrasound‐determined testicular volume (USTV), total serum testosterone, Tanner pubic hair stage, height, weight, waist circumference (WC), subscapular skinfolds (SSF), and body fat percentage (%BF). Testicular volume‐for‐age z‐scores were used to classify “early,” “average,” or “late” maturing boys. Ordinal logistic regression analyses with a proportional odds model were applied to analyze the association between anthropometric variables and age‐adjusted degree of pubertal development, with results expressed as age‐adjusted odds ratios (AOR). Cumulative incidence curves for reaching pubertal milestones were stratified by BMI.

Results

Boys with a low BMI for age (BMIz < −1) were less likely to have reached a pubertal testicular volume (USTV ≥ 2.7 mL) or a pubertal serum level of testosterone (≥0.5 nmol/L) compared to normal weight boys (AOR 0.3, p = 0.038, AOR 0.3, p = 0.026, respectively), and entered puberty on average with a delay of approximately eight months. Boys with high BMI for age (BMIz > 1) exhibited a comparable timing as normal weight boys. The same was found for WC. Pubertal markers were not associated with SSF or %BF.

Conclusion

By examining the association between puberty and weight status classified as low, average, or high, we found that a low BMI or WC for age were associated with a less advanced pubertal development and delayed timing of puberty in boys. No significant association was observed for a high BMI or WC. Moreover, no significant effects of SSF or %BF were observed. A low weight status should also be considered when assessing pubertal development in boys.
Intraoperative fluoroscopy alone versus routine post‐operative X‐rays in identifying return to theatre after fracture fixation
Authors: Nair Sachin , Nambiar Mithun , Pope Alun , Parkes Muhajir , De Jong Kenneth , Hau Raphael
Published: February 2021

Background

Post‐operative imaging aims to assess fracture reduction and fixation with better resolution than intraoperative fluoroscopy (IF). However, this routine practice may increase costs and delay the discharge of patients. The aim of this study is to assess the role of post‐operative imaging in identifying patients that require a return to theatre following the use of IF.

Methods

A retrospective cohort study was conducted in a single health network comprising of two hospitals over 1 year. All fracture fixations that required IF were included. Patients who had post‐operative imaging were identified and complications requiring a return to theatre were obtained. Non‐trauma patients and those who did not have IF were excluded.

Results

A total of 1319 patients had IF. Of these patients, 1131 patients had post‐operative radiographs within 7 days of their operation. In total, 12 patients (1.1%) returned to theatre as a result of a finding identified in their post‐operative imaging. The calculated number of X‐rays required to be taken to identify a complication was 94. The main reasons identified for these cases to require a return to theatre despite having had IF included: (i) insufficient quality/views of IF, (ii) loss of position/new injury occurring in post‐operative period and (iii) poor reduction/fixation demonstrated intraoperatively that was missed/accepted.

Conclusion

The use of post‐operative radiographs can identify significant complications despite the use of IF in trauma patients. However, further consideration needs to be made regarding the benefits and costs of this practice in evaluating its clinical effectiveness.
Effects of COVID‐19 lockdown measures on emergency plastic and reconstructive surgery presentations
Authors: Cordova Leonardo Z. , Savage Nicholas , Ram Rachna , Ellis Lisa , Tobin Vicky , Rozen Warren M. , Seifman Marc A.
Published: February 2021

Background

In Australia, the COVID‐19 pandemic has caused severe social disruptions, including restrictions to the movement of people. Healthcare centres around the world have seen changes in the nature of injuries acquired during the COVID‐19 pandemic; we therefore hypothesize that social isolation measures have changed the pattern of plastic and reconstructive surgery presentations.

Methods

A prospective cohort study was designed comparing patient presentations during the enforced COVID‐19 lockdown to two previous periods. All emergency referrals requiring operative intervention by the plastic and reconstructive surgery unit of our institution were included. Patient demographics, place and mechanism of injury, drug and alcohol involvement, delays to presentation, length of admission and complication rates were collected.

Results

Demographics and complication rates were similar across all groups. A 31.8% reduction in total number of emergency cases was seen during the lockdown period. Increase in do‐it‐yourself injuries (P = 0.001), bicycle injuries (P = 0.001) and injuries acquired via substance abuse (P = 0.041) was observed. Head and neck injuries, mostly due to animal bites and falls, were also more prevalent compared to the same period the previous year (P = 0.007). As expected, over 80% of plastic surgery operations during the COVID‐19 period were due to injuries acquired at home, a significant increase compared to previous periods.

Conclusion

Despite changes in the pattern of presentations requiring plastic and reconstructive emergency surgery, traumatic injuries continued to occur during the pandemic. Thus, planning will be essential to ensure resource allocation for emergency procedures is sustained as second and third waves of COVID‐19 cases emerge worldwide.
Psychological impact and social support in pregnant women during lockdown due to SARS‐CoV2 pandemic: A cohort study
Authors: Brik Maia , Sandonis Miguel Angel , Fernández Sara , Suy Anna , Parramon‐Puig Gemma , Maiz Nerea , Dip Maria Emilia , Ramos‐Quiroga Josep Antoni , Carreras Elena
Published: February 2021

Introduction

Anxiety and depression during pregnancy can lead to adverse maternal and neonatal outcomes. The SARS CoV‐2 pandemic, and the complete lockdown required during the first wave in most countries are stressors for pregnant women and can lead to anxiety and depression during pregnancy. The aim of this study was to explore depression and anxiety symptoms, and social support in pregnant women during the SARS CoV‐2 lockdown, as well as to explore demographic risk factors.

Material and methods

A prospective cohort study was performed at Hospital Universitari Vall d’Hebron, Barcelona, including pregnant women attending the antenatal clinic during the SARS‐CoV2 lockdown period. Three questionnaires were administered to study depression (EPDS), anxiety (STAI) and Social Support (MOS‐SSS). STAI state (STAIs) described the actual state of anxiety and the STAI trait (STAIt) described the trait of anxiety. A cut‐off of 10 for EPDS and 40 for STAI was considered to be clinically relevant. The main outcome measures were depression and anxiety symptoms.

Results

A total of 217 women were invited to participate, and 204 accepted (94%). From these, 164 filled in the EPDS, 109 STAI and 159 MOS‐SSS questionnaires: 37.8% (95% confidence interval [CI] 30.5%‐45.7%) (62/164) of women showed an EPDS result ≥10, 59.6% (95% CI 49.8%‐68.8%) (65/109) a STAI state (STAIs) ≥40, and 58.7% (95% CI 48.9%‐67.9%) (64/109) a STAI trait (STAIt) ≥40. Regression analysis showed that mental health disorder, Latin American origin and lack of social support were independent risk factors for anxiety symptoms in the STAIs (P = .032, P = .040 and P = .029, respectively). Regarding depressive symptoms, maternal body mass index, mental health disorders and social support were independent factors (P = .013, P = .015 and P = .000, respectively).

Conclusions

A lockdown scenario during the first wave of the SARS‐CoV 2 pandemic increased the symptoms of anxiety and depression among pregnant women, particularly affecting those with less social support.
Frozen section diagnosis of borderline ovarian tumors with suspicious features of invasive cancer is a devil’s dilemma for the surgeon: A systematic review and meta‐analysis
Authors: De Decker Koen , Jaroch Karina H. , Edens Mireille A. , Bart Joost , Kooreman Loes F. S. , Kruitwagen Roy F. P. M. , Nijman Hans W. , Kruse Arnold‐Jan
Published: February 2021

Introduction

Frozen section diagnoses of borderline ovarian tumors are not always straightforward and a borderline frozen section diagnosis with suspicious features of invasive carcinoma (reported as “at least borderline” or synonymous descriptions) presents us with the dilemma of whether or not to perform a full surgical staging procedure. By performing a systematic review and meta‐analysis, the prevalence of straightforward borderline and “at least borderline” frozen section diagnoses, as well as proportion of patients with a final diagnosis of invasive carcinoma in these cases, were assessed and compared, as quantification of this dilemma may help us with the issue of this clinical decision.

Material and methods

PubMed, EMBASE and Cochrane library databases were searched and studies discussing “at least borderline” frozen section diagnoses were included in the review. Numbers of specific frozen section diagnoses and subsequent final histological diagnoses were extracted and pooled analysis was performed to compare the proportion of patients diagnosed with invasive carcinoma following borderline and “at least borderline” frozen section diagnoses, presented as risk ratio and risk difference with 95% confidence intervals (95% CI).

Results

Of 4940 screened records, eight studies were considered eligible for quantitative analysis. A total of 921 women was identified and 230 (25.0%) of these women were diagnosed with “at least borderline” ovarian tumor at the time of frozen section. Final histological diagnoses were reported in five studies, including 61 women with an “at least borderline” diagnosis and 290 women with a straightforward borderline frozen section diagnosis. Twenty‐five of 61 women (41.0%) of the “at least borderline” group had invasive cancer at final diagnosis, compared with 28 of 290 women (9.7%) of the straightforward borderline frozen section group (risk difference −0.34, 95% CI −0.53 to −0.15; relative risk 0.25, 95% CI 0.13–0.50).

Conclusions

Women diagnosed with “at least borderline” frozen section diagnoses were found to have a higher chance of carcinoma upon final diagnosis when compared with women with a straightforward borderline frozen section diagnosis (41.0% vs 9.7%). Especially in the serous subtype, and after preoperative consent, full staging during initial surgery might be considered in these cases to prevent a second surgical procedure.
Long‐term effectiveness of an online decision aid for female cancer patients regarding fertility preservation: Knowledge, attitude, and decisional regret
Authors: Ehrbar Verena , Germeyer Ariane , Nawroth Frank , Dangel Astrid , Findeklee Sebastian , Urech Corinne , Rochlitz Christoph , Stiller Ruth , Tschudin Sibil
Published: February 2021

Introduction

The decision, whether to undergo fertility preservation or not is highly demanding for cancer patients. Decision aids may act as an additional source of support. So far, only a limited number of decision aids regarding fertility preservation for female cancer patients exist and have been evaluated systematically. This paper presents the results of secondary analyses of the first randomized controlled trial evaluating an online decision aid for female cancer patients affected by different types of cancer. It focuses on fertility‐related knowledge, attitude toward fertility preservation, and long‐term effectiveness regarding decisional regret.

Material and methods

Young female cancer patients between 18 and 40 years of age were recruited after fertility counseling with a reproductive specialist. They were assigned to either the control group (counseling only) or the intervention group (counseling followed by the additional use of the decision aid). Both groups had to complete a questionnaire after counseling as well as 1 and 12 months later, covering topics such as fertility‐related knowledge, attitude towards fertility preservation, decisional conflict and regret. Recruitment was ongoing during 18 months in eight fertility centers located in Switzerland and Germany.

Results

Mean age of participating women was 29.31 years (SD 4.57). Of the entire sample (n = 51) 53% were affected with breast cancer, 27.4% with lymphoma, and 19.6% with various other types of cancer. Knowledge regarding the most common fertility preservation methods was high and comparable in both groups. Positive attitude significantly exceeded negative attitude among all participants (p = 0.001). Although the altogether low scores for decisional regret were on a higher level in the control group (T2: mean = 19.00, SD = 13.24; T3: mean = 22.0, SD = 20.67) than in the intervention group (T2: mean = 14.12, SD = 11.07; T3: mean = 12.94, SD = 13.24), there were no statistically significant differences between and within both groups. There was a positive association between decisional conflict and decisional regret at T3 (p = 0.001, r = 0.510).

Conclusions

This decision aid was suitable as an additional source of knowledge and may positively impact decisional regret in the long term. Results suggest that the provision of an online decision aid as a complement to fertility counseling may facilitate decision‐making.
Extracorporeal membrane oxygenation survival: External validation of current predictive scoring systems focusing on influenza A etiology
Authors: Maca Jan , Matousek Vojtech , Bursa Filip , Klementova Olga , Hanak Roman , Burda Michal , Sevcik Pavel , Rulisek Jan
Published: February 2021

Despite increasing clinical experience with extracorporeal membrane oxygenation (ECMO), its optimal indications remain unclear. Here, we externally evaluated all currently available ECMO survival‐predicting scoring systems and the APACHE II score in subjects undergoing veno‐venous ECMO (VV ECMO) support due to acute respiratory distress syndrome (ARDS) with influenza (IVA) and non‐influenza (n‐IVA) etiologies. Our aim was to find the best scoring system for influenza A ARDS ECMO success prediction. Retrospective data were analyzed to assess the abilities of the PRESERVE, RESP, PRESET, ECMOnet, Roch, and APACHE II scores to predict patient outcome. Patients treated with veno‐venous ECMO support for ARDS were divided into two groups: IVA and n‐IVA etiologies. Parameters collected within 24 hours before ECMO initiation were used to calculate PRESERVE, RESP, PRESET, ECMOnet, Roch, and APACHE II scores. Compared to the IVA group, the n‐IVA group exhibited significantly higher ICU, 28‐day, and 6‐month mortality (P = .043, .034, and .047, respectively). Regarding ECMO support success predictions, the area under the receiver operating characteristic curve (AUC) was 0.62 for PRESERVE, 0.44 for RESP, 0.57 for PRESET, and 0.67 for ECMOnet, and 0.62 for Roch calculated for all subjects according to the original papers. In the IVA group, APACHE II had the best predictive value for ICU, hospital, 28‐day, and 6‐month mortality (AUC values of 0.73, 0.73, 0.70, and 0.73, respectively). In the n‐IVA group, APACHE II was the best predictor of survival in the ICU and hospital (AUC 0.54 and 0.57, respectively). From all possible ECMO survival scoring systems, the APACHE II score had the best predictive value for VV ECMO subjects with ARDS caused by influenza A‐related pneumonia with a cut‐off value of about 32 points.
The COVID‐19 pandemic dramatically reduced admissions of children with and without chronic conditions to general paediatric wards
Authors: Gavish Rachel , Levinsky Yoel , Dizitzer Yotam , Bilavsky Efraim , Livni Gilat , Pirogovsky Avinoam , Scheuerman Oded , Krause Irit
Published: February 2021

Aim

We examined the impact of the COVID‐19 pandemic on how many children were admitted to Israel's largest tertiary paediatric hospital and why they were admitted.

Methods

Israel declared COVID‐19 a national emergency on 19 March 2020. This study examined daily hospital admissions to our three general paediatric wards during the COVID‐19 lockdown period from 20 March to 18 April 2020. These 258 admissions were compared with the 4217 admissions from the period immediately before this, 1 February to 19 March 2020, plus 1 February to 18 April in 2018 and 2019. We also compared why patients were admitted during the study period, and any pre‐existing conditions, with 638 children hospitalised during the same period in 2019.

Results

The mean number of daily hospitalisations during the COVID‐19 lockdown period was 8.6, which was 59% lower than the 20.9 recorded during the other three periods before COVID‐19. There was a significant decrease in the number of patients admitted with infectious (74%) and non‐infectious (44%) aetiologies from 2019 to 2020, and these occurred among patients with (58%), and without (55%), pre‐existing medical conditions.

Conclusion

The Israeli COVID‐19 lockdown had a dramatic effect on admissions to the paediatric wards of a tertiary hospital.
Formulation of a recombinant HIV‐1 polytope candidate vaccine with naloxone/alum mixture: induction of multi‐cytokine responses with a higher regulatory mechanism
Authors: Fathi Meimanat , Nezamzadeh Reza , Abdollahpour‐Alitappeh Meghdad , Yazdi Mohammad Hossein , Khoramabadi Nima , Mahdavi Mehdi
Published: February 2021

The potency of a vaccine highly depends upon the nature of the adjuvant used. There are a variety of ineffective vaccines, such as HIV‐1 vaccine candidates, that need to be optimized with new adjuvant formulations to improve vaccine potency and efficacy. Studies show the potency of naloxone (NLX)/alum mixture in the induction of Th1/Th2 response for vaccine. However, other immunologic patterns inducing by this adjuvant and its immunoregulatory effect is unclear. In this regard, the aim of the present study was to investigate the effect of the NLX/alum mixture, as an adjuvant, on cytokine networks and immunoregulatory activity for an HIV‐1 polytope vaccine. BALB/c mice were divided into six groups (n = 6) and immunized subcutaneously with 10 μg of the vaccine formulated with NLX/alum, NLX, alum, and Freund's adjuvants. At the same time, the mice in the control groups received an equal volume of PBS or NLX. The lymphocyte proliferation assay was carried out using the BrdU method. ELISA was used to measure the levels of IFN‐γ, IL‐2, IL‐4, IL‐10, IL‐12, and IL‐17 cytokines, total IgG, as well as IgG1 and IgG2a subtypes in serum samples. Our findings showed that mice receiving the NLX/alum‐adjuvanted vaccine exhibited increased antibody levels compared with other groups. In addition, there was a considerable difference in the levels of IgG1, IgG2a, IFN‐γ, IL‐2, IL‐10, IL‐12, and IL‐17 in mice receiving the NLX/alum‐adjuvanted vaccine as compared with other groups. The NLX/alum mixture, as an adjuvant, may have a positive effect on the induction of multi‐cytokine responses, as well as the increased level of IL‐10, showing its higher immunogenicity with a higher immunoregulatory mechanism.
Phase I evaluation of pharmacokinetics and tolerability of the HIV‐1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults
Authors: Pene Dumitrescu Teodora , Joshi Samit R. , Xu Jianfeng , Greene Thomas J. , Johnson Mark , Butcher Laurie , Zimmerman Eric , Webster Lindsey , Pham Theresa T. , Lataillade Max , Min Sherene
Published: February 2021

Aims

GSK3640254, a novel, next‐generation maturation inhibitor effective against a range of HIV polymorphisms with no cross‐resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2‐drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed.

Methods

Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1–5 in period 1, GSK3640254 200 mg QD on Days 1–7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1–7 in period 3. All treatments were administered with a moderate‐fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored.

Results

Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration–time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118–1.233), 1.09 (1.044–1.138) and 1.24 (1.160–1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04 (0.992–1.094), 0.99 (0.923–1.065) and 0.10 (0.939–1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady‐state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed.

Conclusion

Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated.
A pharmacovigilance study of pharmacokinetic drug interactions using a translational informatics discovery approach
Authors: Wang Lei , Shendre Aditi , Chiang Chien‐Wei , Cao Weidan , Ning Xia , Zhang Ping , Zhang Pengyue , Li Lang
Published: February 2021

Background

While the pharmacokinetic (PK) mechanisms for many drug interactions (DDIs) have been established, pharmacovigilance studies related to these PK DDIs are limited. Using a large surveillance database, a translational informatics approach can systematically screen adverse drug events (ADEs) for many DDIs with known PK mechanisms.

Methods

We collected a set of substrates and inhibitors related to the cytochrome P450 (CYP) isoforms, as recommended by the United States Food and Drug Administration (FDA) and Drug Interactions Flockhart table™. The FDA's Adverse Events Reporting System (FAERS) was used to obtain ADE reports from 2004 to 2018. The substrate and inhibitor information were used to form PK DDI pairs for each of the CYP isoforms and Medical Dictionary for Regulatory Activities (MedDRA) preferred terms used for ADEs in FAERS. A shrinkage observed‐to‐expected ratio (Ω) analysis was performed to screen for potential PK DDI and ADE associations.

Results

We identified 149 CYP substrates and 62 CYP inhibitors from the FDA and Flockhart tables. Using FAERS data, only those DDI‐ADE associations were considered that met the disproportionality threshold of Ω > 0 for a CYP substrate when paired with at least two inhibitors. In total, 590 ADEs were associated with 2085 PK DDI pairs and 38 individual substrates, with ADEs overlapping across different CYP substrates. More importantly, we were able to find clinical and experimental evidence for the paclitaxel‐clopidogrel interaction associated with peripheral neuropathy in our study.

Conclusion

In this study, we utilized a translational informatics approach to discover potentially novel CYP‐related substrate‐inhibitor and ADE associations using FAERS. Future clinical, population‐based and experimental studies are needed to confirm our findings.
MCRT, a multifunctional ligand of opioid and neuropeptide FF receptors, attenuates neuropathic pain in spared nerve injury model
Authors: He Chunbo , Wang Xiaoli , Zhang Jing , Wang Hao , Zhao Yaofeng , Shah Jagat Narayan , Ma Chan , Li Hailan , Su Wenting , Zhang Zhe , Chen Shasha , Zhou Lanxia , Dong Shouliang
Published: February 2021

Chimeric peptide MCRT (YPFPFRTic‐NH2) was a multifunctional ligand of opioid and neuropeptide FF (NPFF) receptors and reported to be potentially antalgic in acute tail‐flick test. Here, we developed spared nerve injury (SNI) model to explore its efficacy in chronic neuropathic pain. Analgesic tolerance, opioid‐induced hyperalgesia and gastrointestinal transit were measured for safety evaluation. Intracerebroventricular (i.c.v.) and intraplantar (i.pl.) injections were conducted as central and peripheral routes, respectively. Results demonstrated that MCRT alleviated neuropathic pain effectively and efficiently, with the ED50 values of 4.93 nmol/kg at the central level and 3.11 nmol/kg at the peripheral level. The antagonist blocking study verified the involvement of mu‐, delta‐opioid and NPFF receptors in MCRT produced anti‐allodynia. Moreover, the separation of analgesia from unwanted effects was preliminarily achieved and that MCRT caused neither analgesic tolerance nor hyperalgesia after chronic i.c.v. administration, nor constipation after i.pl. administration. Notably, the local efficacy of MCRT in SNI mice was about one thousandfold higher than morphine and ten thousandfold higher than pregabalin, indicating a great promise in the future treatment of neuropathic pain.
Proarrhythmic potential of metoclopramide in a sensitive whole‐heart model
Authors: Wolfes Julian , Ellermann Christian , Burde Sophie , Fehr Michael , Eckardt Lars , Frommeyer Gerrit
Published: February 2021

Background

Metoclopramide (MCP) is a dopamine D2‐receptor antagonist, mainly used to treat post‐operative or chemotherapy‐induced nausea. While it is very effective in the cure of gastric symptoms, MCP can cause severe neurologic side effects. Furthermore, there is growing evidence for severe arrhythmic side effects resulting from inhibitory effects on cardiac sodium and potassium channels.

Methods and Results

Thirteen hearts of New Zealand white rabbits were retrogradely perfused, and electrophysiology studies were performed to obtain action potential duration (APD90) and effective refractory period (ERP). After generating baseline data, the hearts were perfused with increasing concentrations of metoclopramide (MCP 10 µM, MCP 50 µM, MCP 100 µM) and the standardized protocol was repeated for each concentration. Perfusion with MCP resulted in a significant prolongation of APD90 and QT interval. In parallel, the incidence of ventricular tachycardias was significantly increased by high doses of MCP.

Conclusion

This is the first experimental study that investigated the effect of increasing doses of metoclopramide on a sensitive whole‐heart model of proarrhythmia. MCP led to a significant increase in action potential duration and QT interval; meanwhile, the number of ventricular tachycardias was significantly increased.
Nomograms for predicting adverse obstetric outcome in IVF pregnancy: A preliminary study
Authors: Portal Alice , Sunyach Claire , Loundou Anderson , Lacroix‐Paulmye Odile , Perrin Jeanne , Courbiere Blandline
Published: February 2021

Background

In a previous study, we showed that the obstetric complication rate after in vitro fertilization (IVF) pregnancy was 40%. The main objective of our study was to determine maternal prognosis factors that influence the IVF pregnancy outcome.

Methods

We conducted an observational retrospective monocentric study between January 2014 and January 2018. Pregnancy over 22 gestational weeks (GW) obtained after IVF in our infertility clinic was included. Maternal characteristics and pregnancy outcome were collected.

Results

Data from 498 IVF pregnancies were analyzed. The most significant maternal prognosis factors for obstetric complications were maternal age above 40 years (OR 3,0 [95% IC 1,30‐7,09], P = 0,010), twin pregnancies (3.8 [95% IC 1.49‐9.99], P = .005), daily maternal smoking above 10 cigarettes (7.1 [95% IC 1.22‐41.74], P = .029), maternal obesity (2.2 [95% IC 1.19‐4.07], P = .012), endometriosis stages III and IV (6.4 [95% IC 1.52‐27.04], P = .011), and history of ovarian hyperstimulation syndrome (OHSS) in early pregnancy (5.7 [95% IC 1.29‐24.74], P = .021). Risk increase was independent of pregnancy type (singleton or twin) and allowed the elaboration of 2 nomograms.

Conclusions

Our study showed a link between some maternal factors and increase in obstetric complications after IVF. Screening of these factors during preconceptional visit is essential to identify at high‐risk pregnancies and adapt their monitoring.
Women’s childbirth experiences: A content analysis from the Listening to Mothers in California survey
Authors: Edmonds Joyce K. , Declercq Eugene , Sakala Carol
Published: February 2021

Background

The World Health Organization's recent recommendations on intrapartum care regard women's experience of care as an essential aspect of high‐quality maternity care. A better understanding of women's perspectives on their childbirth experiences in the United States is needed to place women in the center of care and optimize their experience of childbirth.

Methods

This study analyzed data from the Listening to Mothers in California survey completed by a representative sample of women who gave birth in 2016 in California hospitals. Responses to one or both open‐ended questions about the best and worst part of respondent's hospital stay for childbirth were subject to a content analysis.

Results

Findings from 2539 participants included 2336 best and 1410 worst part responses. References to the attitudes and behaviors of health care practitioners were the most commonly reported (47% best and 29.1% worst part). Nurses were the most frequently mentioned practitioner type. Additional best part categories in rank order included the quality of physical care of the mom and feelings about the care experience. Additional worst part categories in rank order included the quality of the facility and food, delays in care, infant feeding, the quality of physical care of the mom, and lack of privacy.

Discussion

Women's hospital experiences during childbirth, while multidimensional in nature, are primarily shaped by their relationships with health care practitioners, the care provided, and the facility in which childbirth occurs. Women's feedback provides actionable information to promote a positive birth experience.
Patients with haemophilia A with inhibitors in China: a national real‐world analysis and follow‐up
Authors: Dou Xueqing , Liu Wei , Poon Man‐Chiu , Zhang Xinsheng , Wu Jingsheng , Zeng Xiaojing , Wu Runhui , Hu Qun , Li Chengping , Wang Xiaomin , Song Xuewen , Chen Lingling , Zhang Lei , Xue Feng , Yang Renchi
Published: February 2021

The development of alloantibodies (inhibitors) against coagulation factor VIII (FVIII) is the most serious complication of FVIII replacement therapy in patients with haemophilia A (HA). We carried out a nationwide study focussing on patients with HA with inhibitors in China to evaluate the condition and management of this population. The study retrospectively analysed patient characteristics, clinical history, manifestation, treatment strategy as well as individual haemophilia care of 493 patients with inhibitors (466 with severe HA and 27 with non‐severe HA) registered all over China. The median (interquartile range) age at diagnosis of FVIII inhibitors was 13 (5–28) years in patients with severe HA and 24 (10·5–39·5) years in patients with non‐severe HA. Most patients (85%) had high‐titre inhibitors. Prothrombin complex concentrate and recombinant activated coagulation factor VII were used respectively in 76·2% and 29·2% of patients for acute bleeding. Only 22·3% of patients underwent immune tolerance induction (ITI) treatment, of whom 64·9% achieved negative inhibitor titre. In patients who did not undergo ITI, the inhibitors turned negative in 17·7%, and patients with low peak inhibitor titre were more likely to acquire negative titre spontaneously (odds ratio 11·524, 95% confidence interval 5·222–25·432; P = 0·000). We recorded that 3·2% of the patients died from haemophilia‐related life‐threatening bleeding.
Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series
Authors: Brivio Erica , Chantrain Christophe F. , Gruber Tanja A. , Thano Adriana , Rialland Fanny , Contet Audrey , Elitzur Sarah , Dalla‐Pozza Luciano , Kállay Krisztián Miklós , Li Chi‐kong , Kato Motohiro , Markova Inna , Schmiegelow Kjeld , Bodmer Nicole , Breese Erin H. , Hoogendijk Raoull , Pieters Rob , Zwaan Christian Michel
Published: February 2021

No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22+ blasts was 72% (range 40–100%, n = 9). The median dose in the first course was 1.74 mg/m2 (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)‐positive patient became MRD‐negative. Six‐month overall survival was 47% (95% confidence interval [CI] 27–80%). Two patients developed veno‐occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.
Characteristics and outcome of patients with acute myeloid leukaemia and t(8;16)(p11;p13): results from an International Collaborative Study*
Authors: Kayser Sabine , Hills Robert K. , Langova Ralitsa , Kramer Michael , Guijarro Francesca , Sustkova Zuzana , Estey Elihu H. , Shaw Carole M. , Ráčil Zdeněk , Mayer Jiri , Zak Pavel , Baer Maria R. , Brunner Andrew M. , Szotkowski Tomas , Cetkovsky Petr , Grimwade David , Walter Roland B. , Burnett Alan K. , Ho Anthony D. , Ehninger Gerhard , Müller‐Tidow Carsten , Platzbecker Uwe , Thiede Christian , Röllig Christoph , Schulz Angela , Warsow Gregor , Brors Benedikt , Esteve Jordi , Russell Nigel H. , Schlenk Richard F. , Levis Mark J.
Published: February 2021

In acute myeloid leukaemia (AML) t(8;16)(p11;p13)/MYST3–CREBBP is a very rare abnormality. Previous small series suggested poor outcome. We report on 59 patients with t(8;16) within an international, collaborative study. Median age was 52 (range: 16–75) years. AML was de novo in 58%, therapy‐related (t‐AML) in 37% and secondary after myelodysplastic syndrome (s‐AML) in 5%. Cytogenetics revealed a complex karyotype in 43%. Besides MYST3–CREBBP, whole‐genome sequencing on a subset of 10 patients revealed recurrent mutations in ASXL1, BRD3, FLT3, MLH1, POLG, TP53, SAMD4B (n = 3, each), EYS, KRTAP9‐1 SPTBN5 (n = 4, each), RUNX1 and TET2 (n = 2, each). Complete remission after intensive chemotherapy was achieved in 84%. Median follow‐up was 5·48 years; five‐year survival rate was 17%. Patients with s‐/t‐AML (P = 0·01) and those with complex karyotype (P = 0·04) had an inferior prognosis. Allogeneic haematopoietic cell transplantation (allo‐HCT) was performed in 21 (36%) patients, including 15 in first complete remission (CR1). Allo‐HCT in CR1 significantly improved survival (P = 0·04); multivariable analysis revealed that allo‐HCT in CR1 was effective in de novo AML but not in patients with s‐AML/t‐AML and less in patients exhibiting a complex karyotype. In summary, outcomes of patients with t(8;16) are dismal with chemotherapy, and may be substantially improved with allo‐HCT performed in CR1.
Shared and unique features of mammalian sleep spindles – insights from new and old animal models
Authors: Iotchev Ivaylo Borislavov , Kubinyi Eniko
Published: February 2021

Sleep spindles are phasic events observed in mammalian non‐rapid eye movement sleep. They are relevant today in the study of memory consolidation, sleep quality, mental health and ageing. We argue that our advanced understanding of their mechanisms has not exhausted the utility and need for animal model work. This is both because some topics, like cognitive ageing, have not yet been addressed sufficiently in comparative efforts and because the evolutionary history of this oscillation is still poorly understood. Comparisons across species often are either limited to referencing the classical cat and rodent models, or are over‐inclusive, uncritically including reports of sleep spindles in rarely studied animals. In this review, we discuss the emergence of new (dog and sheep) models for sleep spindles and compare the strengths and shortcomings of new and old models based on the three validation criteria for animal models – face, predictive, and construct validity. We conclude that an emphasis on cognitive ageing might dictate the future of comparative sleep spindle studies, a development that is already becoming visible in studies on dogs. Moreover, reconstructing the evolutionary history of sleep spindles will require more stringent criteria for their identification, across more species. In particular, a stronger emphasis on construct and predictive validity can help verify if spindle‐like events in other species are actual sleep spindles. Work in accordance with such stricter validation suggests that sleep spindles display more universally shared features, like defining frequency, than previously thought.
Rhizophora zonation, salinity, and nutrients in the western atlantic
Authors: Cerón‐Souza Ivania , Barreto María Beatriz , Barreto‐Pittol Eduardo , Silva Angie , Feliner Gonzalo N. , Medina Ernesto
Published: February 2021

Rhizophora is the dominant genus of mangrove forests on the Atlantic coast of northern South America. What determines the zonation frequently observed in sympatric populations of the two neotropical species, R. mangle and R. racemosa, and their hybrids, R. × harrisonii, is an open question. The most widely held hypothesis is that differences in salinity tolerance among the taxonomic groups explain the observed zonation. To address this question, we analyzed the elemental composition of soils and canopy leaves from 60 Rhizophora spp. trees distributed in different intertidal zones of an estuarine site of the Paria Gulf, Venezuela. The low intertidal zone showed lower salinity, organic matter, C, N, S, and Na, and higher bulk density, Al, Fe, and Mn concentrations compared with the higher intertidal zones. Using morphological characters and microsatellite molecular markers, we identified 39 pure R. mangle, 19 hybrids, and only two pure R. racemosa. We found that both intertidal position and taxonomic groups explained most of the differences in leaf variables measured across trees. The ratio Mg/Ca, however, was higher in R. mangle than in R. racemosa and hybrids regardless of intertidal position. Moreover, at some specific intertidal position, R. mangle differed from R. racemosa and hybrids in the values of C, N, K, Mg, Fe, Mn, C/N, K/Ca, S/Ca, and δ13C. We conclude that despite the scarcity of R. racemosa and the absence of a clear species zonation, our results suggest that R. mangle copes with salinity differently than R. racemosa and R. × harrisonii.
LPAR5 promotes thyroid carcinoma cell proliferation and migration by activating class IA PI3K catalytic subunit p110β
Authors: Zhao Wei‐Jun , Zhu Liu‐Lian , Yang Wei‐Qiang , Xu Shuai‐Jun , Chen Jie , Ding Xiao‐Fei , Liang Yong , Chen Guang
Published: February 2021

Lysophosphatidic acid receptor 5 (LPAR5) is involved in mediating thyroid cancer progression, but the underlying mechanism needs to be further revealed. In this study, we confirmed that LPAR5 is upregulated in papillary thyroid carcinoma (PTC), especially in BRAF‐like PTC, by analyzing The Cancer Genome Atlas (TCGA) database and performing immunohistochemistry assay in human thyroid cancer tissues. LPAR5‐specific antagonist TC LPA5 4 treatment inhibited CGTH‐W3, TPC‐1, B‐CPAP, and BHT‐101 cell proliferation, CGTH‐W3 and TPC‐1 cell migration significantly. In vivo, TC LPA5 4 treatment could delay CGTH‐W3 xenograft growth in nude mice. We also found that LPAR5‐specific antagonist TC LPA5 4, PI3K inhibitor wortmannin, or mTOR inhibitor rapamycin pretreatment abrogated phosphorylation of Akt and p70S6K1 stimulated by LPA in CGTH‐W3 and TPC‐1 cells. Stimulating CGTH‐W3 cells transfected with pEGFPC1‐Grp1‐PH fusion protein with LPA resulted in the generation of phosphatidylinositol (3,4,5)‐triphosphate, which indicates that PI3K was activated by LPA directly. The p110β‐siRNA instead of p110α‐siRNA transfection abrogated the increase of levels of phosphorylated Akt and S6K1 stimulated by LPA. Furthermore, immunoprecipitation assay confirmed an interaction between LPAR5 and p110β. Overall, we provide new insights that the downregulation of LPAR5 decreased the proliferation and migration phenotype via the PI3K/Akt pathway. Inhibition of LPAR5 or the PI3K/Akt signal may be a novel therapeutic strategy for treating thyroid cancer.
The noncanonical role of EZH2 in cancer
Authors: Huang Jinhua , Gou Hongwei , Yao Jia , Yi Kaining , Jin Zhigang , Matsuoka Masao , Zhao Tiejun
Published: February 2021

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2). Dysregulation of EZH2 causes alteration of gene expression and functions, thereby promoting cancer development. The regulatory function of EZH2 varies across different tumor types. The canonical role of EZH2 is gene silencing through catalyzing the trimethylation of lysine 27 of histone H3 (H3K27me3) in a PRC2‐dependent manner. Accumulating evidence indicates that EZH2 has an H3K27me3‐independent function as a transcriptional coactivator and plays a critical role in cancer initiation, development, and progression. In this review, we summarize the regulation and function of EZH2 and focus on the current understanding of the noncanonical role of EZH2 in cancer.