bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence of cilioretinal arteries in 11‐ to 12‐year‐old children and association with maternal smoking during pregnancy: the Copenhagen Child Cohort 2000 Eye Study
Authors: Jønsson Lise Halmø , Larsen Michael , Olsen Else Marie , Skovgaard Anne Mette , Munch Inger Christine
Published: February 2021

Purpose

To estimate the incidence of cilioretinal arteries in a Danish child cohort and associations with birth parameters.

Methods

The population‐based Copenhagen Child Cohort 2000 Eye Study examined 1406 children aged 11–12 years. Colour fundus images of both eyes were graded for cilioretinal arteries in the three categories large temporal (defined as supplying the central macula), small temporal and nasal. Data on maternal smoking during pregnancy, gestational ageand birth weight were obtained from the Danish Medical Birth Registry.

Results

A total of 463/1338 (35%) children were found to have one or more cilioretinal arteries per child. Large temporal cilioretinal arteries were present in 280/1338 (21%) of children and were associated with tobacco smoking during pregnancy, being present in 70/246 (28%) of children with mothers who were smoking during pregnancy, but only in 191/990 (19%) of children whose mothers did not smoke during pregnancy (p = 0.0022). After adjustments for potential confounders, the odds ratio of having one or more large temporal cilioretinal arteries was 1.72 (CI95% 1.19–2.47; p = 0.0035) in the smoking versus none smoking category. No other associations with birth parameters were found.

Conclusion

Cilioretinal arteries were present in more than one third of 11‐ to 12‐year‐old Danish children. Large temporal cilioretinal arteries were found in one fifth of children and were associated with maternal smoking during pregnancy. This finding suggests that the intrauterine environment may have an impact on the development of retinal vessels during foetal life.
Return home and start new businesses: internal migration in China
Authors: Lin Liqiong , Revindo Mohamad D. , Gan Christopher , Nguyen Quang Thi Thieu
Published: February 2021

Internal migration patterns in China are characterised by rapid urbanisation and cross‐regional movement and more recently by the return of migrants to their native counties. This study investigates the drivers of migrants' permanent return and their likelihood of starting new businesses in their counties of origin. The results suggest that migrants are discouraged from permanent resettlement in urban areas because of family ties and the aspiration to start businesses in their villages of origin. The study also provides evidence that the probability of starting a business upon return is affected by the migrants' accumulation of work experience, business experience, the savings earned while away, financial stability, and the social capital they have in their home counties. The results provide important insights for emerging countries in overcoming rapid urbanisation and imbalanced regional economic growth.
A randomized single and multiple ascending dose study in healthy volunteers of LTI‐291, a centrally penetrant glucocerebrosidase activator
Authors: den Heijer Jonas M. , Kruithof Annelieke C. , van Amerongen Guido , de Kam Marieke L. , Thijssen Eva , Grievink Hendrika W. , Moerland Matthijs , Walker Mike , Been Kees , Skerlj Renato , Justman Craig , Dudgeon Lindsay , Lansbury Peter , Cullen Valerie C. , Hilt Dana C. , Groeneveld Geert Jan
Published: February 2021

Aims

A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI‐291 is an allosteric modulator of GCase, enhancing its activity. These first‐in‐human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI‐291 in healthy volunteers.

Methods

In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI‐291 (n = 8 per dose level) or placebo (n = 2 per dose level). Single doses of 3, 10, 30 and 90 mg LTI‐291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle‐aged or elderly volunteers were randomly assigned to LTI‐291 (n = 8 per dose level) or placebo (n = 2 per dose level). Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI‐291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed.

Results

LTI‐291 was generally well tolerated and no deaths or treatment‐related SAEs occurred and no subject withdrew from a study due to AEs. Cmax, AUC0–24 and AUC0‐inf increased in a dose proportional manner. The median half‐life was 28.0 hours after multiple dosing. No dose‐dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected.

Conclusions

These first‐in‐human studies demonstrated that LTI‐291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI‐291 effects in a GBA1‐mutated Parkinson population.
Off‐label use of letrozole in Chinese short pubertal boys: Effectiveness, safety, and exposure–response analysis
Authors: Xu Yuan , Zhang Yan‐Hong , Zhang Qiu‐Ping , Zhao Qian‐Qian , Cao Xiao‐Fu , Zhang Mei , Li Xue , Liu Xi‐Ting , Sun Zhuo‐Xiang , Kan Min , Du Bin , Zhou Yue , Yang Fan , Ban Bo , Zhao Wei
Published: February 2021

Aims

Recently, letrozole has been used off‐label to treat short pubertal boys. The experience on letrozole effectiveness and safety has been obtained primarily from Caucasian children. A simple extrapolation of the data to Chinese paediatric populations is questionable because of the substantial ethnic differences between the two populations. Therefore, the present study aimed to determine the effectiveness and safety of letrozole use in Chinese short pubertal boys as well as to establish an exposure–response relationship.

Methods

Forty‐one Chinese boys were included in the study. Patients were given letrozole tablets (2.5 mg) once daily in combination with growth hormone, and follow‐up visits were made after 1, 3, 6 and 12 months of treatment. Plasma samples were taken from clinical examinations and analysed using high performance liquid chromatography with fluorescence detection.

Results

After 1 year of treatment, 35 (88%) boys showed increased predicted adult heights. However, possible adverse drug reactions were seen in nine boys (22%). Predicted adult heights increased significantly from 168.4 ± 3.7 to 173.0 ± 4.2 cm, while oestrogen levels dropped from 33.2 ± 7.4 to 21.6 ± 7.3 pg/mL. Increments in predicted adult height were significantly correlated with trough letrozole concentrations (r = 0.39, P = .01).

Conclusion

Letrozole treatment in Chinese pubertal populations should be further optimized, and more personalized therapies should be developed.
A cascade of interventions: A classification tree analysis of the determinants of primary cesareans in Australian public hospitals
Authors: Fox Haylee , Topp Stephanie M. , Lindsay Daniel , Callander Emily
Published: February 2021

Background

Both globally and in Australia, there has been a sharp rise in cesarean births (CB). Commonly, this rise has been attributed to the changing epidemiology of women giving birth. A significant body of knowledge exists on the risk factors associated with a greater need for cesarean. Yet, we have little information on the reasons recorded by clinicians as to why cesareans are provided. This study aimed to explore the drivers of primary cesareans in Australian public hospitals.

Methods

Using a linked administrative data set, the frequency and percent of mothers’ characteristics were compared between those who had a cesarean birth and those who had a vaginal birth (n = 98 967) with no history of previous cesareans in Queensland public hospitals between July 1, 2012, and June 30, 2015. The top 10 reasons recorded by clinicians for a primary cesarean were reported. Using a machine‐learning algorithm, two decision trees were built to determine factors driving primary cesarean birth.

Results

“Labour and delivery complicated by fetal heart rate anomaly” (23%) and “primary inadequate contractions” (22.8%) were the top two reasons for a primary cesarean birth. The most common characteristics among mothers who had fetal heart rate anomalies were as follows: artificial rupture of membranes (39%), oxytocin (32%), no obstruction of labor (42%), and epidural (52%). For women who had primary inadequate contractions, the most common characteristics were as follows: epidural (33%), oxytocin (49%), artificial rupture of membranes (45%), and fetal stress (56%).

Conclusions

Efforts should be made by health practitioners during the antenatal period to maximize the use of preventative measures that minimize the need for medical interventions.
Society‐level social axiom moderates the association between growth mindset and achievement across cultures
Authors: Bernardo Allan B. I. , Cai Yuyang , King Ronnel B.
Published: February 2021

Background

Meta‐analytic studies show that the benefits of the growth mindset on academic achievement are heterogenous. Past studies have explored how individual characteristics and proximal environmental factors could explain these variations, but the role of the broader sociocultural environment has seldom been explored.

Aims

We investigated society‐level social axioms to explain variations in growth mindset effects on achievement across cultures. We hypothesized that three society‐level social axioms (social complexity, fate control, and reward for application) imply social norms that would either support or obstruct the growth mindset effect.

Sample and methods

We conducted multilevel SEM with random slopes using data from 273,074 students nested within 39 countries/territories.

Results

We found weaker growth mindset effects in societies with stronger social complexity beliefs; societies believing that there are multiple solutions to problems have social norms that obstruct the growth mindset effects on achievement. No moderating effects were found with other social axioms.

Conclusion

Relevant cultural‐level normative beliefs should be considered to better assess the relevance of the growth mindset construct.
Prognostic value of minimal residual disease measured by fusion‐gene transcript in infants with KMT2A‐rearranged acute lymphoblastic leukaemia treated according to the MLL‐Baby protocol
Authors: Tsaur Grigory , Popov Alexander , Riger Tatiana , Kustanovich Anatoly , Solodovnikov Alexander , Shorikov Egor , Demina Anna , Verzhbitskaya Tatiana , Streneva Olga , Makarova Olga , Lapotentova Elena , Aleinikova Olga , Miakova Natalia , Boichenko Elmira , Kondratchik Konstantin , Ponomareva Natalia , Karachunskiy Alexander , Roumiantsev Alexander , Fechina Larisa
Published: February 2021

The prognostic value of minimal residual disease (MRD) measured by fusion‐gene transcript (FGT) detection was investigated in 76 infants (aged ≤1 year) with acute lymphoblastic leukaemia (ALL) with lysine methyltransferase 2A (KMT2A) rearrangements. Either at the end of induction or at later time‐points, FGT‐MRD‐positivity was associated with poor outcome. FGT‐MRD‐positivity after first consolidation or first high‐risk block detected 46·5% of infants with extremely poor outcome [disease‐free survival (SE) 0·06 (0·06), cumulative incidence of relapse (SE) 0·91 (0·05)], which was also confirmed in multivariable analysis. Thus, FGT‐MRD measurement at a single time‐point clearly identifies infants with ALL who are curable with conventional chemotherapy and those who would benefit only from other treatment approaches.
Experiences and predictors of psychological distress in pregnant women living with HIV
Authors: Ogueji Ifeanyichukwu Anthony
Published: February 2021

Objectives

To explore the experiences and predictors of psychological distress in pregnant women living with HIV.

Design

A mixed‐methods research design.

Methods

A representative randomly sampled 840 (age range 22–46 years) HIV‐positive pregnant women in Akwa Ibom, Benue, and Rivers States of Nigeria enrolled for the study. Data were collected using standardized questionnaires and in‐depth interviews for 4 months and 3 weeks in 6 HIV treatment centres. Collected data were analysed using IBM SPSS statistics (v. 22.0) and thematic analysis.

Results

The mean score on psychological distress was 17.07 ± 5.86. Multiple regression analysis found a significant joint prediction of meaning in life, self‐compassion, and acceptance of illness on psychological distress, R = .64, R2 = .41; F (3,828) = 186.18; p = .000, with 41% variance explained. Further, there was a significant independent prediction of each predictor at meaning in life (β = −.19, t = −5.08; p = .000), self‐compassion (β = −.23, t = −5.59; p = .000), and acceptance of illness (β = −.30, t = −7.23; p = .000), with acceptance of illness exerting the greatest independent predictive impact. Socio‐demographic variables (age, length of living with HIV, high‐risk state, highest education attained, marital status, and religious affiliation) had no significant contribution to psychological distress. Qualitative analysis found ‘anxious concerns’, ‘depressive reports, loneliness, and regrets’, ‘self‐blame and guilt feelings’, as the experiences of psychological distress, and these experiences were determined by respondents’ socio‐cultural contexts.

Conclusion

These findings emphasize the importance of psychosocial care for HIV‐positive pregnant women.
Being tolerated: Implications for well‐being among ethnic minorities
Authors: Cvetkovska Sara , Verkuyten Maykel , Adelman Levi , Yogeeswaran Kumar
Published: February 2021

Tolerating or condoning practices that one finds objectionable is typically considered a positive way to negotiate intergroup differences. However, being the target of tolerance might harm well‐being, which we examined in three studies (a survey and two experiments) among a total of 1,054 members of various racial/ethnic minority groups in the United States. In Study 1, we found that perceiving oneself to be tolerated on the basis of one’s ethnic group membership was associated with more negative well‐being. In Study 2, we found that bringing to mind experiences of being tolerated results in less positive and more negative affect than thinking about experiences of acceptance, but more positive and less negative outcomes than thinking about overt discrimination experiences. In Study 3, we replicated the results of Study 2 while demonstrating that threat to social identity needs mediates the tolerance–well‐being link. These results suggest that being tolerated is related to minority targets’ well‐being in ways that are intermediate between being treated with outright discrimination and full acceptance, but that being tolerated follows a pattern closer to discrimination.
An alternative approach for detecting hearing loss in adults with learning disabilities
Authors: McShea Lynzee , Giles Karen , Murphy Ashley , Ling Jonathan
Published: February 2021

Accessible Summary

Annual health checks for people with learning disabilities should include a check of hearing. However, this hearing check only involves asking questions about hearing and does not include an actual hearing test.

We tested the hearing of people with learning disabilities in the community.

We found that some people had hearing problems that had not been picked up at their annual health check.

We think the annual health check should be changed to include a hearing test.

Background

Annual health checks in primary care include hearing assessment, though current guidance recommends subjective assessment only. Previous studies suggest this is inadequate and recommend objective alternatives such as hearing screening. This study aimed to assess the feasibility of hearing screening and examine the last recorded annual health check outcome for hearing, for those diagnosed with hearing loss as a result of the screening process.

Method

Hearing screening took place in four locations and 75 people with learning disabilities participated. Contact was made with each individual's GP to share results and to request onward referral where indicated.

Findings

Wax occlusion prevented screening for 23%. Fifty‐seven people completed the screen, and 25 had suspected hearing loss. Of these, 22 people required referral to Audiology to verify their hearing thresholds. Only 13 were actually referred, and 11 individuals underwent assessment in Audiology, resulting in 10 being diagnosed with hearing loss. The most recent annual health check outcomes for hearing were examined for those diagnosed with hearing loss. Of the records we accessed, hearing loss had not been identified or actioned in every case.

Conclusions

Hearing screening is shown here to be a suitable method for detecting hearing loss. We recommend changing current annual health check practice to incorporate objective screening. Only 12% of those with suspected hearing loss were known to Audiology services, suggesting a substantial proportion of undetected hearing loss in the community. We found evidence of apparent reluctance around referral and hearing aid fitting and make suggestions for improvement.
Securitization of assets and risk transfer in a large emerging market: Evidence from Brazil
Authors: de Mendonça Helder Ferreira , Barcelos Vívian Íris
Published: February 2021

This study analyzes the impact of securitization on the soundness of financial institutions through the two main securitization products in Brazil: Credit Rights Investment Funds (FIDC) and Real Estate Receivables Certificates (CRI). On the basis of a panel data analysis regarding 92 financial institutions from 2003 to 2016, we performed several regressions for different samples and methods. The findings suggest that securitization may increase the insolvency risk. In particular, we observe that the effect on the insolvency risk caused by securitization from CRI operations is higher than from FIDC operations.
Reconstituting neurovascular unit with primary neural stem cells and brain microvascular endothelial cells in three‐dimensional matrix
Authors: Wang Hongjin , Yang Huan , Shi Yuhong , Xiao Yaping , Yin Yue , Jiang Baoxiang , Ren Huijing , Chen Weihai , Xue Qiang , Xu Xiaoyu
Published: February 2021

Neurovascular dysfunction is a primary or secondary cause in the pathogenesis of several cerebrovascular and neurodegenerative disorders, including stroke. Therefore, the overall protection of the neurovascular unit (NVU) is a promising therapeutic strategy for various neurovascular diseases. However, the complexity of the NVU limits the study of the pathological mechanisms of neurovascular dysfunction. Reconstituting the in vitro NVU is important for the pathological study and drug screening of neurovascular diseases. In this study, we generated a spontaneously assembled three‐dimensional NVU (3D NVU) by employing the primary neural stem cells and brain microvascular endothelial cells in a Matrigel extracellular matrix platform. This novel model exhibits the fundamental structures and features of the NVU, including neurons, astrocytes, oligodendrocytes, vascular‐like structures, and blood–brain barrier‐like characteristics. Additionally, under oxygen‐glucose deprivation, the 3D NVU exhibits the neurovascular‐ or oxidative stress‐related pathological characteristics of cerebral ischemia and the injuries can be mitigated, respectively, by supplementing with the vascular endothelial growth factor or edaravone, which demonstrated that the availability of 3D NVU in ischemic stroke modeling. Finally, the 3D NVU promoted the angiogenesis and neurogenesis in the brain of cerebral ischemia rats. We expect that the proposed in vitro 3D NVU model will be widely used to investigate the relationships between angiogenesis and neurogenesis and to study the pathology and pharmacology of neurovascular diseases.
Health‐related quality of life in adults with osteogenesis imperfecta
Authors: Murali Chaya N. , Slater Brady , Musaad Salma , Cuthbertson David , Nguyen Dianne , Turner Alicia , Azamian Mahshid , Tosi Laura , Rauch Frank , Sutton V. Reid , Lee Brendan ,   Members of the BBD Consortium, Nagamani Sandesh C. S.
Published: February 2021

Patient‐reported outcome measures (PROMs) are increasingly utilized as endpoints in clinical trials. The Short Form Health Survey‐12 (SF‐12v2) is a generic PROM for adults. We sought to evaluate the validity of SF‐12v2 in adults with osteogenesis imperfecta (OI). Physical and mental health‐related quality of life (HRQoL) were assessed in a large cohort of adults in a multicenter, observational, natural history study. Physical HRQoL scores were correlated with the Gillette Functional Assessment Questionnaire (GFAQ). We calculated sample sizes required in clinical trials with crossover and parallel‐group designs to detect clinically meaningful changes in physical HRQoL. Three hundred and two adults with OI types I, III, and IV were enrolled. Physical HRQoL scores in the study population were lower than population norms. Physical HRQoL scores moderately correlated with GFAQ for OI types I and IV. We found no correlations between mental and physical HRQoL. From a clinical trial readiness perspective, we show that SF‐12v2 reliably measures physical function in adults with OI and can be utilized in crossover trials to detect meaningful physical HRQoL changes with small sample sizes. This study shows that SF‐12v2 can be used to measure changes in physical HRQoL in response to interventions in OI.
Novel pathogenic variants in NLRP7, NLRP5, and PADI6 in patients with recurrent hydatidiform moles and reproductive failure
Authors: Rezaei Maryam , Suresh Beena , Bereke Eric , Hadipour Zahra , Aguinaga Monica , Qian Jianhua , Bagga Rashmi , Fardaei Majid , Hemida Reda , Jagadeesh Sujatha , Majewski Jacek , Slim Rima
Published: February 2021

Recurrent hydatidiform moles (RHMs) are human pregnancies with abnormal embryonic development and hyperproliferating trophoblast. Biallelic mutations in NLRP7 and KHDC3L, members of the subcortical maternal complex (SCMC), explain the etiology of RHMs in only 60% of patients. Here we report the identification of seven functional variants in a recessive state in three SCMC members, five in NLRP7, one in NLRP5, and one in PADI6. In NLRP5, we report the first patient with RHMs and biallelic mutations. In PADI6, the patient had four molar pregnancies, two of which had fetuses with various abnormalities including placental mesenchymal dysplasia and intra‐uterine growth restriction, which are features of Beckwith‐Wiedemann syndrome and Silver Russell syndrome, respectively. Our findings corroborate recent studies and highlight the common oocyte origin of all these conditions and the continuous spectrum of abnormalities associated with deficiencies in the SCMC genes.
Instructed Hand Movements Affect Students’ Learning of an Abstract Concept From Video
Authors: Zhang Icy (Yunyi) , Givvin Karen B. , Sipple Jeffrey M. , Son Ji Y. , Stigler James W.
Published: February 2021

Producing content‐related gestures has been found to impact students’ learning, whether such gestures are spontaneously generated by the learner in the course of problem‐solving, or participants are instructed to pose based on experimenter instructions during problem‐solving and word learning. Few studies, however, have investigated the effect of (a) performing instructed gestures while learning concepts or (b) producing gestures without there being an implied connection between the gestures and the concepts being learned. The two studies reported here investigate the impact of instructed hand movements on students’ subsequent understanding of a concept. Students were asked to watch an instructional video—focused on the concept of statistical model—three times. Two experimental groups were given a secondary task to perform while watching the video, which involved moving their hands to mimic the placement and orientation of red rectangular bars overlaid on the video. Students were told that the focus of the study was multitasking, and that the instructed hand movements were unrelated to the material being learned. In the content‐match group the placement of the hands reinforced the concept being explained, and in the content‐mismatch group it did not. A control group was not asked to perform a secondary task. In both studies, findings indicate that students in the content‐match group performed better on the posttest, and showed less variation in performance, than did students in the content‐mismatch group, with control students falling in between. Instructed hand movement—even when presented as an unrelated, secondary task—can affect students’ learning of a complex concept.
An international 3‐center training and reading study to assess basal cell carcinoma surgical margins with ex vivo fluorescence confocal microscopy
Authors: Kose Kivanc , Fox Christi Alessi , Rossi Anthony , Jain Manu , Cordova Miguel , Dusza Stephen W. , Ragazzi Moira , Gardini Stefano , Moscarella Elvira , Diaz Alba , Pigem Ramon , Gonzalez Salvador , Bennassar Antoni , Carrera Cristina , Longo Caterina , Rajadhyaksha Milind , Nehal Kishwer S.
Published: February 2021

Background

Novel solutions are needed for expediting margin assessment to guide basal cell carcinoma (BCC) surgeries. Ex vivo fluorescence confocal microscopy (FCM) is starting to be used in freshly excised surgical specimens to examine BCC margins in real time. Training and educational process are needed for this novel technology to be implemented into clinic.

Objective

To test a training and reading process, and measure diagnostic accuracy of clinicians with varying expertise level in reading ex vivo FCM images.

Methods

An international three‐center study was designed for training and reading to assess BCC surgical margins and residual subtypes. Each center included a lead dermatologic/Mohs surgeon (clinical developer of FCM) and three additional readers (dermatologist, dermatopathologist, dermatologic/Mohs surgeon), who use confocal in clinical practice. Testing was conducted on 30 samples.

Results

Overall, the readers achieved 90% average sensitivity, 78% average specificity in detecting residual BCC margins, showing high and consistent diagnostic reading accuracy. Those with expertise in dermatologic surgery and dermatopathology showed the strongest potential for learning to assess FCM images.

Limitations

Small dataset, variability in mosaic quality between centers.

Conclusion

Suggested process is feasible and effective. This process is proposed for wider implementation to facilitate wider adoption of FCM to potentially expedite BCC margin assessment to guide surgery in real time.
Risk factors for early‐onset basal cell carcinomas and the trend towards their female predominance
Authors: Matas‐Nadal Clara , Sagristà Marc , Gómez‐Arbonés Xavier , Sobrino Bermejo Carmen , Fernández‐Armenteros Josep Manel , Àngel Baldó Joan , Casanova Seuma Josep Manel , Aguayo Ortiz Rafael
Published: February 2021

Background

A dramatic rise in the incidence rates of basal cell carcinoma (BCC) in young women has been reported.

Objectives

We investigate potential risk factors (RF) for sporadic BCC in young patients and the current distribution of such RF in the general population of Catalonia, comparing the differences among men and women.

Patients and Methods

A case‐control study was performed, 69 BCCs diagnosed in patients ≤ 45 years of age vs. 69 healthy controls. Afterward, 1,078 participants from the general population completed an RF questionnaire.

Results

Repeated sunburns were more frequent in instances of early‐onset BCC in covered skin than in sun‐exposed skin (P  =  0.029). In the general population, 39.1 % of participants reported sunbed use (50.1 % in women, 10.9 % in men). Sunbed use was the only relevant RF more predominant in women than men, favoring the trend to female predominance of BCCs above other RF. Additionally, we found a significant trend in young participants for reduced sunbed use (P < 0.001), although they had the same percentage of repeated sunburns. Repeated sunburns are the most relevant RF for early‐onset BCCs that can be targeted in prevention campaigns.

Conclusions

We should be aware of the more relevant RF for early‐onset BCCs and their distribution among the general population to address preventive campaigns.
Sex hormones and acne: State of the art
Authors: Hu Tingting , Wei Ziyu , Ju Qiang , Chen WenChieh
Published: February 2021

Acne is an androgen‐dependent inflammatory disease of sebaceous follicles. Herein, we reviewed and discussed the underlying pathways of androgen biosynthesis and metabolism, non‐genomic regulation of androgen receptor expression and function, posttranslational regulation of androgen excess in acne and acne‐associated syndromes, such as polycystic ovary syndrome, and congenital adrenal hyperplasia. We provide insights into the involvement of sex hormones, particularly androgens, in skin homeostasis and acne pathogenesis, including comedogenesis, lipogenesis, microbiota, and inflammation. Advanced understanding of the action mechanisms of classical acne treatment and new development of antiandrogens, both topical and systemic, are also highlighted.
MR‐proADM as marker of endotheliitis predicts COVID‐19 severity
Authors: García de Guadiana‐Romualdo Luis , Calvo Nieves María Dolores , Rodríguez Mulero María Dolores , Calcerrada Alises Ismael , Hernández Olivo Marta , Trapiello Fernández Wysali , González Morales Mercedes , Bolado Jiménez Cristina , Albaladejo‐Otón María Dolores , Fernández Ovalle Hilda , Conesa Hernández Andrés , Azpeleta Manrique Eugenio , Consuegra‐Sánchez Luciano , Nogales Martín Leonor , Conesa Zamora Pablo , Andaluz‐Ojeda David
Published: February 2021

Background

Early identification of patients at high risk of progression to severe COVID‐19 constituted an unsolved challenge. Although growing evidence demonstrates a direct association between endotheliitis and severe COVID‐19, the role of endothelial damage biomarkers has been scarcely studied. We investigated the relationship between circulating mid‐regional proadrenomedullin (MR‐proADM) levels, a biomarker of endothelial dysfunction, and prognosis of SARS‐CoV‐2‐infected patients.

Methods

Prospective observational study enrolling adult patients with confirmed COVID‐19. On admission to emergency department, a blood sample was drawn for laboratory test analysis. Primary and secondary endpoints were 28‐day all‐cause mortality and severe COVID‐19 progression. Area under the curve (AUC) and multivariate regression analysis were employed to assess the association of the biomarker with the established endpoints.

Results

A total of 99 patients were enrolled. During hospitalization, 25 (25.3%) cases progressed to severe disease and the 28‐day mortality rate was of 14.1%. MR‐proADM showed the highest AUC to predict 28‐day mortality (0.905; [CI] 95%: 0.829‐0.955; P < .001) and progression to severe disease (0.829; [CI] 95%: 0.740‐0.897; P < .001), respectively. MR‐proADM plasma levels above optimal cut‐off (1.01 nmol/L) showed the strongest independent association with 28‐day mortality risk (hazard ratio [HR]: 10.470, 95% CI: 2.066‐53.049; P < .005) and with progression to severe disease (HR: 6.803, 95% CI: 1.458‐31.750; P = .015).

Conclusion

Mid‐regional proadrenomedullin was the biomarker with highest performance for prognosis of death and progression to severe disease in COVID‐19 patients and represents a promising predictor for both outcomes, which might constitute a potential tool in the assessment of prognosis in early stages of this disease.
Nonalcoholic fatty liver disease or metabolic dysfunction‐associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches
Authors: Dongiovanni Paola , Paolini Erika , Corsini Alberto , Sirtori Cesare R. , Ruscica Massimiliano
Published: February 2021

Background

A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction‐associated fatty liver disease (MAFLD), to describe more appropriately the liver disease related to metabolic derangements. MAFLD is closely intertwined with type 2 diabetes, obesity, dyslipidaemia, all linked to a rise in the risk of cardiovascular disease (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises the odds of CVD, the present review aims to evaluate the impact of NAFLD/MAFLD aetiologies on CV health and the potential correction by dietary and drug approaches.

Results

Epidemiological studies indicate that NAFLD raises risk of fatal or non‐fatal CVD events. NAFLD patients have a higher prevalence of arterial plaques and stiffness, coronary calcification, and endothelial dysfunction. Although genetic and environmental factors strongly contribute to NAFLD pathogenesis, a Mendelian randomization analysis indicated that the PNPLA3 genetic variant leading to NAFLD may not be causally associated with CVD risk. Among other genetic variants related to NAFLD, TM6SF2 appears to be protective, whereas MBOAT7 may favour venous thromboembolism.

Conclusions

NAFLD is correlated to a higher CVD risk which may be ameliorated by dietary interventions. This is not surprising, since new criteria defining MAFLD include other metabolic risk abnormalities fuelling development of serious adverse extrahepatic outcomes, for example CVD. The present lack of a targeted pharmacological approach makes the identification of patients with liver disease at higher CVD risk (eg diabetes, hypertension, obesity or high levels of C‐reactive protein) of major clinical interest.
SARS‐CoV‐2 re‐infection risk in Austria
Authors: Pilz Stefan , Chakeri Ali , Ioannidis John PA , Richter Lukas , Theiler‐Schwetz Verena , Trummer Christian , Krause Robert , Allerberger Franz
Published: February 2021

Background

A key question concerning coronavirus disease 2019 (COVID‐19) is how effective and long lasting immunity against this disease is in individuals who were previously infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). We aimed to evaluate the risk of SARS‐CoV‐2 re‐infections in the general population in Austria.

Methods

This is a retrospective observational study using national SARS‐CoV‐2 infection data from the Austrian epidemiological reporting system. As the primary outcome, we aim to compare the odds of SARS‐CoV‐2 re‐infections of COVID‐19 survivors of the first wave (February to April 30, 2020) versus the odds of first infections in the remainder general population by tracking polymerase chain reaction (PCR)‐confirmed infections of both groups during the second wave from September 1 to November 30, 2020. Re‐infection counts are tentative, since it cannot be excluded that the positive PCR in the first and/or second wave might have been a false positive.

Results

We recorded 40 tentative re‐infections in 14 840 COVID‐19 survivors of the first wave (0.27%) and 253 581 infections in 8 885 640 individuals of the remaining general population (2.85%) translating into an odds ratio (95% confidence interval) of 0.09 (0.07 to 0.13).

Conclusions

We observed a relatively low re‐infection rate of SARS‐CoV‐2 in Austria. Protection against SARS‐CoV‐2 after natural infection is comparable with the highest available estimates on vaccine efficacies. Further well‐designed research on this issue is urgently needed for improving evidence‐based decisions on public health measures and vaccination strategies.
When is variable importance estimation in species distribution modelling affected by spatial correlation?
Authors: Harisena Nivedita Varma , Groen Thomas A. , Toxopeus A. G. , Naimi Babak
Published: February 2021

Species distribution models are generic empirical techniques that have a number of applications. One of these applications is to determine which environmental conditions are most important for a species. The calculation of this variable importance depends on a number of assumptions, including that the observations that are used to estimate the models are independent of each other. Spatial autocorrelation, which is a common feature most environmental factors confounds this assumption. Besides, many species distribution models are trained using a number of explanatory variables that have different levels of spatial autocorrelation. In this study we quantified the effects of differences in spatial autocorrelation in explanatory variables and the type of species responses to environmental gradients on variable importance estimations in species distribution models. We simulated data for both environmental predictors and species, so that we were in control of the true contribution of every variable in the model and the importance that could be estimated after fitting the models. We found that spatial autocorrelation in the predictors inflated the variable importance estimates, but only when the response of species to the environmental gradients is linear. This inflation effect was larger when the environmental preferences of species coincided with the dominant environmental conditions in a study site. Additionally we find that unimodal responses to the predictors yield systematically a higher variable importance compared to linear responses. We conclude that the type of response to environmental conditions and the relative levels of spatial autocorrelation in the environmental variables cause most bias in relative variable importance estimations. In this way, this study helps to clarify in a systematic and controlled approach how to make proper inferences about variable importance in species distribution models.
Reference values for the EORTC QLQ‐C30 in patients with advanced stage Hodgkin lymphoma and in Hodgkin lymphoma survivors
Authors: Vachon Hugo , Mierzynska Justyna , Taye Mekdes , Pe Madeline , Coens Corneel , Martinelli Francesca , Fortpied Catherine , Flechtner Hans‐Henning , Vestmoe Maraldo Maja , Hutchings Martin , Meijnders Paul , Aleman Berthe , Lugtenburg Pieternella , Spina Michele , André Marc , Hertzberg Mark , Briones Javier , Bottomley Andrew ,   the EORTC Quality of Life Group, Lymphoma Group
Published: February 2021

Objectives

To provide reference values for the European Organisation for Treatment and Research of Cancer (EORTC) Quality of Life Questionnaire (QLQ‐C30) in advanced‐stage Hodgkin lymphoma (HL) patients and 5‐year HL survivors. The QLQ‐C30 is the most widely used cancer‐specific questionnaire to assess Health‐Related Quality of Life (HRQoL).

Methods

The EORTC database was searched to identify HL RCTs in which patients’ and survivors’ HRQoL was assessed by the QLQ‐C30. HRQoL mean scores were calculated and stratified by age and gender. Minimal important differences were used to assess the clinical relevance of the findings. Data from one RCT with HRQoL scores available at baseline (n = 343) and four RCTs with HRQoL scores available at follow‐up (n = 1665) were analyzed.

Results

Patients reported worse HRQoL scores than survivors across most functioning scales and symptoms’ scales. These scores varied as a function of gender but not age. Survivors’ HRQoL reports were comparable to the ones of the general population.

Conclusions

These values provide an assessment framework for the comparison and interpretation of QLQ‐C30 scores in advanced‐stage HL. Our findings suggest that although HL patients’ HRQoL scores are worse than the general population, HRQoL scores may normalize over long‐term survival.
Prognostic impact of early‐versus‐late responses to different induction regimens in patients with myeloma undergoing autologous hematopoietic cell transplantation: Results from the CALM study by the CMWP of the EBMT
Authors: Garderet Laurent , Sbianchi Giulia , Iacobelli Simona , Blaise Didier , Byrne Jenny L. , Remenyi Peter , Apperley Jane F. , Touzeau Cyrille , Isaksson Cecilia , Browne Paul , Mayer Jiri , Lenhoff Stig , Gonzalez Muniz Soledad , Parody Porras Rocio , Basak Grzegorz , Poire Xavier , Trneny Marek , Nagler Arnon , Michieli Mariagrazia , Tanase Alina , Koster Linda , Hayden Patrick J. , Beksac Meral , Schönland Stefan , Yakoub‐Agha Ibrahim
Published: February 2021

Background

In autologous stem cell transplant (ASCT)‐eligible myeloma patients, prolonged induction does not necessarily improve the depth of response.

Method

We analyzed 1222 ASCT patients who were classified based on (a) the interval between induction and stem cell collection, (b) the type of induction regimen: BID (Bortezomib, IMiDs, and Dexamethasone), Bortezomib‐based, or CTD (Cyclophosphamide, Thalidomide, and Dexamethasone), and (c) the time to best response (Early ie, best response within 4 or 5 months, depending on the regimen vs Late; Good ie, VGPR or better vs Poor).

Results

The length of induction treatment required to achieve a Good response did not affect PFS (P = .65) or OS (P = .61) post‐ASCT. The three types of regimen resulted in similar outcomes: median PFS 31, 27.7 and 30.8 months (P = .31), and median OS 81.7, 92.7, and 77.4 months, respectively (P = .83). On multivariate analysis, neither the type nor the duration of the induction regimen affected OS and PFS, except for Early Good Responders who had a better PFS compared to Early Poor Responders (HR = 1.21, P‐value = .02). However, achieving a Good response at induction was associated with a better response (≥VGPR) post‐transplant.

Conclusion

The kinetics of response did not affect outcomes.
Shape of species climate response curves affects community response to climate change
Authors: Bonachela Juan A. , Burrows Michael T. , Pinsky Malin L.
Published: February 2021

Understanding how community composition is reshaped by changing climate is important for interpreting and predicting patterns of community assembly through time or across space. Community composition often does not perfectly correspond to expectations from current environmental conditions, leading to community‐climate mismatches. Here, we combine data analysis and theory development to explore how species climate response curves affect the community response to climate change. We show that strong mismatches between community and climate can appear in the absence of demographic delays or limited species pools. Communities simulated using species response curves showed temporal changes of similar magnitude to those observed in natural communities of fishes and plankton, suggesting no overall delays in community change despite substantial unexplained variation from community assembly and other processes. Our approach can be considered as a null model that will be important to use when interpreting observed community responses to climate change and variability.
Acute‐onset delirium in intensive care COVID patients: association of imperfect brain repair with foodborne micro‐pollutants
Authors: Schneider Francis , Agin Arnaud , Baldacini Mathieu , Maurer Loïc , Schenck Maleka , Alemann Mathieu , Solis Morgane , Helms Julie , Villette Claire , Artzner Thierry , Kremer Stéphane , Heintz Dimitri
Published: February 2021

Background and purpose

COVID‐19 affects the brain in various ways, amongst which delirium is worrying. An assessment was made of whether a specific, long‐lasting, COVID‐19‐related brain injury develops in acute respiratory distress syndrome patients after life‐saving re‐oxygenation.

Methods

Ten COVID+ patients (COVID+) with unusual delirium associated with neuroimaging suggestive of diffuse brain injury and seven controls with non‐COVID encephalopathy were studied. The assessment took place when the intractable delirium started at weaning off ventilation support. Brain magnetic resonance imaging (MRI) was performed followed by standard cerebrospinal fluid (CSF) analyses and assessment of CSF erythropoietin concentrations (as a marker for the assessment of tissue repair), and of non‐targeted CSF metabolomics using liquid chromatography high resolution mass spectrometry.

Results

Patients were similar as regards severity scores, but COVID+ were hospitalized longer (25 [11.75; 25] vs. 9 [4.5; 12.5] days, p = 0.03). On admission, but not at MRI and lumbar puncture performance, COVID+ were more hypoxic (p = 0.002). On MRI, there were leptomeningeal enhancement and diffuse white matter haemorrhages only in COVID+. In the latter, CSF erythropoietin concentration was lower (1.73 [1.6; 2.06] vs. 3.04 [2.9; 3.91] mIU/ml, p = 0.01), and CSF metabolomics indicated (a) increased compounds such as foodborne molecules (sesquiterpenes), molecules from industrialized beverages and micro‐pollutants (diethanolamine); and (b) decreased molecules such as incomplete breakdown products of protein catabolism and foodborne molecules (glabridin). At 3‐month discharge, fatigue, anxiety and depression as well as MRI lesions persisted in COVID+.

Conclusions

Some COVID+ are at risk of a specific delirium. Imperfect brain repair after re‐oxygenation and lifestyle factors might influence long‐lasting brain injuries in a context of foodborne micro‐pollutants.
Symptomatology of carbamazepine‐ and oxcarbazepine‐induced hyponatremia in people with epilepsy
Authors: Berghuis Bianca , Hulst Janic , Sonsma Anja , McCormack Mark , de Haan Gerrit‐Jan , Sander Josemir W. , Lindhout Dick , Koeleman Bobby P. C.
Published: February 2021

Objective

To ascertain whether adverse effects experienced by people taking carbamazepine or oxcarbazepine could be attributed to carbamazepine‐ or oxcarbazepine‐induced hyponatremia (COIH).

Methods

We performed an observational study, collecting data between 2017 and 2019 on serum sodium levels and adverse effects retrospectively in people with epilepsy while receiving treatment with either carbamazepine (CBZ) or oxcarbazepine (OXC). We defined hyponatremia as sodium level ≤134 mEq/L and severe hyponatremia as sodium level ≤128 mEq/L. Adverse effects experienced were compared between groups of individuals with and without hyponatremia.

Results

A total of 1370 people using CBZ or OXC were identified, of whom 410 had at least one episode of hyponatremia. We checked for symptoms related to the use of CBZ and OXC in 710 people (410 with and 300 without hyponatremia) and found relevant information in 688. Adverse effects occurred in 65% of people with hyponatremia compared to 21% with normal sodium levels (odds ratio [OR] 7.5, P ≤ .001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (P ≤ .001). Significant predictors of adverse effects were the drug (OXC vs CBZ), and the number of concomitant anti‐seizure medications. Dizziness (28% vs 6%), tiredness (22% vs 7%), instability (19% vs 3%), and diplopia (16% vs 4%) were reported more often in the hyponatremia group than in patients with normal levels.

Significance

People with COIH had a 7‐fold increased risk of developing adverse effects during treatment. Clinicians should consider ascertainment of sodium levels in patients taking CBZ and OXC and act upon findings.