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Published in final edited form as: J Allergy Clin Immunol Pract. 2024 Nov 2;13(1):155–166.e11. doi: 10.1016/j.jaip.2024.10.031

Effects of Sex and Gender in Immediate Beta-Lactam Antibiotic Allergy: A Systematic Review and Meta-analysis

Nisha B Patel 1, Gabriel Cojuc-Konigsberg 2, Danna Garcia-Guaqueta 3, Divya Shah 4, Darshana Balasubramaniam 5, Avanika Mahajan 6, Fnu Shakuntulla 7, Danielle Gerberi 8, Lyda Cuervo-Pardo 9, Miguel A Park 7, Thanai Pongdee 7, Elina Jerschow 7, Avni Joshi 7, Zhen Wang 10, Alexei Gonzalez-Estrada 11,*, Sergio E Chiarella 7,*
PMCID: PMC11717607  NIHMSID: NIHMS2033455  PMID: 39491589

Abstract

Background:

Beta-lactams are the most common antibiotic class reported to cause allergic drug reactions. Previous literature suggests an increased prevalence of penicillin drug allergy in female patients in both inpatient and outpatient settings. However, the effects of sex and gender have not been well characterized regarding the entire class of beta-lactam antibiotics.

Objective:

This systematic review and meta-analysis aimed to identify sex and gender-based differences in the prevalence of immediate beta-lactam allergy.

Methods:

We performed an electronic search of Ovid MEDLINE/PubMed, Embase, Web of Science, Scopus, and the Cochrane Library between 2013–2023. Patients with a documented beta-lactam allergy who underwent allergy testing with skin testing, oral drug challenge, or serum-specific IgE were included. We quantitatively assessed sex- and gender-based differences in beta-lactam allergy with meta-analysis.

Results:

We included 69 primary studies, assessing 53,989 participants from outpatient and inpatient cohorts. 7,558 patients had a confirmed beta-lactam allergy. There was no difference in the prevalence of positive beta-lactam allergy test between males and females. Sub-group analysis of studies that performed oral challenges did show a higher risk of beta-lactam allergy in females than males (RR 1.40, 95% CI 1.18–1.66, p < 0.001, I2 =77.8%). Finally, there was a higher proportion of females (64.8%) than males enrolled in beta-lactam allergy studies.

Conclusions:

Our findings suggest both sex-based and gender-based differences in the prevalence of immediate beta-lactam allergy. Both biological factors, such as sex hormones, and gender-based behaviors, including increased healthcare utilization, may contribute to higher rates of beta-lactam allergy diagnosis in females.

Keywords: beta-lactam, drug allergy, immediate hypersensitivity, gender, sex, meta-analysis

Introduction

It is well established that there is a female bias for autoimmune diseases and atopic conditions in adults1. Such differences between males and females in immune responses are thought to be influenced by both sex and gender. Sex is a biological variable determined by differential organization of chromosomes and contributes to physiological and anatomical differences in sex hormones and reproductive organs. Unlike sex, gender reflects the behaviors, roles, and identities determined by society and culture, and can lead to differences in exposures and healthcare utilization2.

Past studies have shown an increased prevalence of both IgE-mediated food allergy and vaccine-related anaphylaxis in females3,4. Female sex has also been associated with higher rates of adverse drug reactions (ADRs). Still, the association between female sex and ADRs has not been thoroughly explored in patients regarding specific drug classes5. Adult females are also more likely to have drug-induced anaphylaxis (DIA), although no sex predominance has been reported regarding the severity of DIA6.

Beta-lactams are the most common antibiotic class reported to cause allergic drug reactions, with approximately 10% of the population carrying a beta-lactam allergy label7, 8. Consequences of a beta-lactam allergy label, whether a true allergy or not, include increased mortality, increased length of hospital stay, decreased infection cure rates, and increased risk of adverse events from the use of second-line antibiotics9. Therefore, identifying risk factors is essential in treating patients with potential beta-lactam allergy. Previous literature suggests an increased prevalence of penicillin drug allergy in female patients in both the inpatient and outpatient settings10,11. This difference between males and females may be due to both sex and gender, influenced by biological factors such as sex hormones as well as behavioral factors such as healthcare utilization and exposure to allergens. However, this finding is poorly described regarding the entire class of beta-lactam antibiotics, including other medications such as cephalosporins, monobactams, and carbapenems. We performed a systematic review with meta-analysis with an aim to identify sex and gender differences in the prevalence of immediate beta-lactam antibiotic allergy.

Methods

Study Criteria Required for Systematic Review

We included original studies published in English or Spanish in which the primary outcome of immediate allergy to a beta-lactam antibiotic (penicillin, cephalosporin, carbapenem, monobactam) could be assessed. Included studies consisted of those which assessed patients with confirmed beta-lactam allergy and reported results by sex. Studies with fewer than ten patients with confirmed beta-lactam allergy, solely pediatric populations (age <18 years), or a focus on solely delayed reactions were excluded. Included studies had received informed consent from all study participants. This study is a systematic review with meta-analysis and follows the Preferred Reporting Items for a Systematic Review and Meta-analysis (PRISMA) reporting guideline12.

Search Methods

The literature was searched by an experienced medical librarian for the concepts of beta-lactam antibiotic allergies and sex or gender. Search strategies were created using a combination of keywords and standardized index terms. Searches were run on January 5, 2023, in Ovid Cochrane Central Register of Controlled Trials (1991+), Ovid Embase (1974+), Ovid Medline (1946+ including epub ahead of print, in-process & other non-indexed citations), Scopus (1788+), and Web of Science Core Collection (Science Citation Index Expanded 1975+ & Emerging Sources Citation Index 2015+). Limitations to the search strategies included publication date range of the last 10 years with the removal of conference abstracts, case reports and case series. Conference abstracts were excluded due to a lack of adequate information to appraise study design and validity of allergy testing, as well as lack of results reported by sex/gender13. A total of 4,167 citations were retrieved. Deduplication was initially performed manually in EndNote (Clarivate Analytics, Philadelphia, PA) following the Bramer method, leaving 3,433 citations after 734 duplicates were removed14. Covidence Software (Veritas Health Innovation, Australia) further removed 400 duplicates, with another 477 duplicates removed manually for a total of 2,556 citations to screen. The full search strategies are available in Table E1 in the Online Repository.

Study Selection and Data Collection and Analysis

After deduplication, two researchers independently screened each study by abstracts and titles. Any disagreements were resolved by consulting a third review author. The remaining studies were evaluated as full-text publications using pre-determined inclusion and exclusion criteria. The reason for the exclusion of each study was documented at this stage. Data was extracted from each study regarding publication characteristics (year of publication, country, study design), population characteristics and demographics (sampling method, study setting, sample size, participant sex, and age distributions), and characteristics of index reactions (culprit drug, diagnostic allergy test, clinical manifestations, and timing and severity of allergic reaction). Diagnostic allergy tests included skin prick test, intradermal test, serum-specific immunoglobulin E (IgE) quantification, and/or oral challenge. Severe allergic reaction was defined as systemic reactions including anaphylaxis involving skin, cardiovascular, gastrointestinal, or respiratory symptoms15. Immediate reactions were defined as initial reactions occurring within the first hour after administration of the culprit drug, whereas nonimmediate reactions were defined as those occurring after the first hour. For primary studies assessing patients with both immediate and delayed reactions, but presenting discriminate results by reaction type, we retrieved data concerning only immediate reactions. Study quality was independently assessed by two researchers using the Joanna Briggs Institute Checklist for Prevalence Studies (Table E2 in the Online Repository). For all data selection and extraction, discrepancies between reviewers were resolved with a third reviewer consulted if necessary.

Statistical Analysis

We narratively synthesized studies to summarize beta-lactam allergy and clinical outcomes. The studies were divided into two groups based on study design. Group 1 included 46 studies that performed allergy testing during the study and were, therefore, able to report a subset of the study population with a confirmed beta-lactam allergy. In these studies, inclusion criteria required high suspicion of beta-lactam allergy, which had not yet been confirmed. For Group 1, we conducted separate analyses to assess for sex versus gender-based factors contributing to differences in beta-lactam allergy. To assess sex-based factors, we calculated the proportion of females with beta-lactam allergy from the total number of females in the study population (Figure 2A). This analysis evaluated the outcome of positive beta-lactam allergy test, including skin tests and oral challenges. To assess gender-based factors, we calculated the proportion of females in the total study population (Figure 2B) and the proportion of allergic females in the total allergic population (Figure 2C). This analysis evaluated the outcome of reporting a beta-lactam allergy and presenting for testing.

Figure 2.

Figure 2.

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Forest plots of Group 1 assessing the prevalence of beta-lactam allergy by A) Proportion of females with beta-lactam allergy out of the total study females, B) Proportion of females in the total study population, and C) Proportion of females with beta-lactam allergy out of the total population with beta-lactam allergy. CI, Confidence interval; DL, DerSimonian-Laird; HKSJ, Hartung-Knapp-Sidik-Jonkman; I2, I-squared statistic

Group 2 included 23 studies that required confirmatory testing for beta-lactam allergy prior to study enrollment as inclusion criteria for all participants. As all study participants already had a confirmed beta-lactam allergy, we assessed gender-based factors in this group by calculating the proportion of allergic females in the total allergic population (Figure 3).

Figure 3.

Figure 3.

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Forest plot of Group 2 assessing the prevalence of beta-lactam allergy by the proportion of females with beta-lactam allergy out of the total population with beta-lactam allergy. CI, Confidence interval; DL, DerSimonian-Laird; HKSJ, Hartung-Knapp-Sidik-Jonkman; I2, I-squared statistic

We extracted or calculated relative risk (RR) and related 95% confidence interval (CI) between sex/gender difference. The DerSimonian-Laird random-effects model with the Hartung-Knapp-Sidik-Jonkman variance correction was used to pool RR across the included studies. Subgroup analyses were conducted for studies within Group 1 based on participant age group, oral challenges, allergic reaction severity, and drug type within the beta-lactam class (penicillins, aminopenicillins, cephalosporins). Heterogeneity between studies was assessed by the I-squared statistic (I2) indicator. If I2 > 50%, the heterogeneity was considered as substantial. All statistical analyses were conducted using Stata version 17.0 (StataCorp LLP, College Station, TX, USA).

Results

Our search strategy identified 2,556 unique citations, of which 139 were selected for full-text evaluation. Another 70 studies were excluded based on the application of eligibility criteria (Figure 1). A total of 69 primary studies were included in this systematic review16–84. These studies were performed primarily outpatient (n=49) and were conducted mostly in Europe (n=42), followed by Asia (n=12), North America (n=6), Australia (n=4), and Africa (n=1). There were four multicenter studies that spanned multiple geographic areas. There were 20 studies assessing adults only, 30 studies assessing adults and children, and 19 studies with no specific age range included.

Figure 1.

Figure 1.

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Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram

The meta-analysis assessing the prevalence of beta-lactam allergy between males and females included all 69 studies. The studies were divided into groups based on study design, with 46 studies in Group 116–18, 22–24, 28–30, 32–35, 37, 39–41, 43, 46, 47, 49–56, 58, 59, 64, 65, 67–70, 73–75, 78–84 and 23 studies in Group 219–21, 25–27, 31, 36, 38, 42, 44, 45, 48, 57, 60–63, 66, 71, 72, 76, 77 (Tables E3 & E4 in the Online Repository). The studies assessed a total of 53,989 participants, of which 35,009 were female (65%). There were 7,558 participants with a confirmed beta-lactam allergy (14%), of which 4,791 were female (63%). Meta-analysis of Group 1 assessing 46 studies with 50,437 participants showed no statistically significant difference between males and females in the risk of positive beta-lactam allergy test (RR 1.0, 95% CI 0.99–1.02, p =1.000, I2 = 0.0%) (Figure 2A). Females made up a significantly higher proportion of 65% (n=32,769) of the Group 1 total study population (95% CI 0.61–0.65, p < 0.001, I2 = 94.0%) and 64% (n=2,591) of the total allergic population (95% CI 0.61–0.69, p < 0.001, I2 = 82.6%) (Figures 2B and 2C). Meta-analysis of Group 2 (Figure 3) assessed 23 studies with 3,552 participants and showed that females comprised 63% (n=2,200) of the total allergic population (95% CI 0.60–0.67, p < 0.001, I2 = 60.3%).

Subgroup analysis of the 11 studies within Group 1 that assessed only adults encompassed 2,935 participants and showed no difference between adult males and females in the prevalence of beta-lactam allergy (RR 0.97, 95% CI 0.92–1.03, p = 0.966, I2 = 0.0%). Analysis of the 18 studies that assessed both adults and children encompassed 7,120 participants and showed no difference between males and females in the prevalence of beta-lactam allergy (RR 1.02, 95% CI 0.99–1.05, p =1.000, I2 = 0.0%) (Figure 4).

Figure 4:

Figure 4:

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Forest plot of subgroup analysis defined by participant age group. CI, Confidence interval; DL, DerSimonian-Laird; HKSJ, Hartung-Knapp-Sidik-Jonkman; I2, I-squared statistic

The severity of allergic reactions was reported by sex in 9 studies assessing 939 participants. We found no significant difference in the severity of allergic reactions to beta-lactams between males and females (RR 1.02, 95% CI 0.99–1.05, p = 1.000, I2 = 0.0%) (Figure 5). Specific drug classes within beta-lactam antibiotics were also assessed, with 6 studies focused on cephalosporins (970 participants) and 17 on penicillins and aminopenicillins (35,619 participants). There was no significant difference between males and females for allergy to specifically cephalosporins (RR 1.0, 95% CI 0.90–1.11, p = 0.956, I2 = 0.0%) or penicillins (RR 1.01, 95% CI 0.99–1.02, p = 0.989, I2 = 0.0%) (Figure 6).

Figure 5:

Figure 5:

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Forest plot of subgroup analysis defined by severe beta-lactam allergy reaction. CI, Confidence interval; DL, DerSimonian-Laird; HKSJ, Hartung-Knapp-Sidik-Jonkman; I2, I-squared statistic

Figure 6:

Figure 6:

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Forest plot of subgroup analysis defined by beta-lactam antibiotic sub-class. CI, Confidence interval; DL, DerSimonian-Laird; HKSJ, Hartung-Knapp-Sidik-Jonkman; I2, I-squared statistic

Oral challenge results were reported by sex in 13 studies which performed a challenge on 2,295 participants. There were 171 participants with positive oral challenge, of which 73% (n=125) were female. We found a significantly higher risk of positive oral challenge in females than in males (RR 1.40, 95% CI 1.18 –1.66, p < 0.001, I2 = 77.8%) (Figure 7). Of the 13 studies, 2 included only low-risk patients and performed oral challenges on all participants. The other 11 performed oral challenges only on participants with negative skin test results. The definition of positive oral challenge was based on reactions with variable symptoms, including hypotension, skin involvement (rash, urticaria, flushing), gastrointestinal, and pulmonary symptoms.

Figure 7:

Figure 7:

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Forest plot of subgroup analysis defined by positive oral challenge. Weight are from random-effects model; continuity correction applied to studies with zero cells. CI, Confidence interval; DL, DerSimonian-Laird; HKSJ, Hartung-Knapp-Sidik-Jonkman; I2, I-squared statistic.

Discussion

To our knowledge, this is the first systematic review and meta-analysis to assess the prevalence of immediate beta-lactam allergy in males and females. The studies in our meta-analysis included either high-risk patients with suspected beta-lactam allergy or patients with confirmed allergy who were seen in an Allergy department in a specific time frame. We performed separate analyses on 2 groups of studies, one which performed allergy testing during the study (Group 1) and one in which a positive allergy test was required for study inclusion (Group 2). As Group 1 performed allergy testing during the study and had a larger population, this set of studies provided a higher quality of data. Within Group 1, we observed two main outcomes. First, we found no difference in the prevalence of positive beta-lactam allergy test between sexes when assessing studies that performed both skin tests and oral challenges. However, we found that the subgroup analysis of oral challenges alone did show a higher risk of positive beta-lactam allergy test in females. When assessing both Group 1 and Group 2, we observed two additional outcomes. We found that a higher proportion of females than males were enrolled in beta-lactam allergy studies, and that there is a higher number of total overall confirmed beta-lactam allergies in the literature for women. Our findings suggest both sex-based and gender-based differences in the prevalence of immediate beta-lactam allergy, which may be influenced both by biological factors such as sex hormones as well as behavioral factors such as healthcare utilization and exposure to allergens.

Sex leads to differences in genetic and hormonal factors which can strongly influence the immune system. Previous studies have reported on the impact of sex and differential prevalence between females and males in atopic diseases such as asthma, allergic rhinitis, and eczema85. Similar findings have been shown in food allergy, with a 2009 literature review which showed the prevalence of IgE-mediate food allergy in adults as favoring females over males with a ratio of 1.9:1. This sex difference attenuates with the onset of menopause, suggesting that estrogen plays a role in food allergy3. Females are known to have more robust immune responses to infection and vaccination than men2,86. Several studies assessing multiple vaccines have also shown an increased risk of vaccine-related anaphylaxis in females4,87–89.

It has been shown that sex hormones regulate several key mediators involved in driving the immunological mechanisms that lead to hypersensitivity reactions85. Immediate beta-lactam allergy is IgE-mediated, and it is known that estrogen promotes B-cell survival and enhances IgE production, while testosterone has been found to do the opposite. In addition, estrogen and progesterone can regulate mast cells, with several studies showing that estradiol can promote mast cell degranulation with IgE-mediated release of histamine and leukotriene C490. Estrogen receptor-α signaling has also been shown to promote the release of interleukin 33, which in turn can promote T helper 2 cell immune responses associated with allergic response91. These biological factors of sex may help to explain our finding that females are at higher risk of having a positive oral challenge to beta-lactams.

The finding of increased prevalence of positive beta-lactam allergy test in females was seen only in our subgroup analysis of oral challenge and did not occur when including assessment of beta-lactam allergy via skin test. There may be a few reasons for this discrepancy. First, oral challenge is the current gold standard for diagnosis of beta-lactam allergy and therefore has both higher negative and positive predictive value than skin testing92–94. As there are no commercially available standardized reagents containing all major and minor penicillin determinants, there was also variation within the included studies in the minor determinants used for penicillin skin testing68. In addition, the inclusion of subjective symptoms such as flushing, itching, and nausea as criteria for identifying a positive drug challenge may have elevated the likelihood of positive oral challenge in female patients. Past studies have shown that subjective symptoms are more likely to be reported by females, with increased occurrence of the nocebo effect in females during a blind oral challenge as well40,95–97. Future studies should include placebo-controlled oral challenges to better evaluate our findings.

We also propose that gender-based differences rooted in behavioral and social factors could contribute to the increased prevalence of beta-lactam allergy in women. We found that a higher proportion of females than males were enrolled in beta-lactam allergy studies. Women have been shown to have higher healthcare utilization and are more likely to seek their healthcare provider’s advice than men, which could suggest that male patients are simply not presenting for allergy testing even though they may have a true beta-lactam allergy98,99. This subsequently affects recruitment for clinical studies, as many studies choose to sample by convenience and enroll directly from patients seen at their institution. In questionnaire-based studies for asthma and food allergy, women were more likely to report asthma symptoms and food allergies than men100,101. Women are also more likely to self-report drug allergy than men, suggesting these results are attributable to an overall female dominance of self-reported allergic disease102,103.

Gender differences in lifestyle, including profession, environmental exposures, and dietary choices, have also been known to influence the prevalence of allergies. Women tend to make up a greater proportion of the workforce in haircare, textile, caretaker, and food production industries, increasing their exposure and leading to an elevated risk of sensitization104. For example, muscle relaxant drug allergy is more prevalent in women, and is thought to be associated with increased exposure to cross-reactive compounds such as ammonium ion epitopes found in cosmetic products105. Women have also been shown to have higher rates of both medication dispensation and utilization than men, with the largest sex difference found for dispensation of systemic antibiotics106. This increased exposure to antibiotics, including beta-lactams, could lead to a higher risk of sensitization in women. A previous systematic review and meta-analysis on the frequency of self-reported drug allergy also showed that the prevalence of self-reported drug allergy is higher in females than males107. All of these factors may help to explain why providers see more females presenting with concern for beta-lactam allergy than males.

Our systematic review has several limitations that are primarily due to the quality of the primary studies included. The evidence for our findings was obtained from case-control and observational cohort studies. Because of this, we were unable to identify higher-level evidence from randomized control trials to validate a sex or gender-based disparity in the prevalence of beta-lactam allergy. Therefore, the studies included were retrospective and observational in nature and used convenience or consecutive sampling. Furthermore, there was inconsistent documentation of demographic and clinical data such as patient age and clinical manifestations of index reactions. Some studies reported more vaguely by systems, including skin, gastrointestinal, cardiovascular, and respiratory symptoms. Others were more detailed and included urticaria, flushing, angioedema, diarrhea, vomiting, abdominal pain, shortness of breath, and hypotension. For studies that listed skin involvement or rash, we are unable to assess whether they excluded acute onset maculopapular exanthems and fixed drug eruptions. In addition, there may have been selection bias due to the primary study's exclusion of pregnant patients, patients with severe cardiac, renal, or pulmonary disease, and patients on beta-blockers.

The majority of the meta-analysis results reported a high heterogeneity, which can pose interpretive challenges. Meta-analyses addressing the prevalence of a disease state in diverse environments often assemble highly heterogeneous studies due to differences in study design and setting. However, this issue was, to some extent, accounted for by the random-effect model. Subgroup analyses were also performed, and a significant subgroup effect was seen for oral challenges. Oral challenge was found to modify the risk of positive beta-lactam allergy test between sexes and may explain the heterogeneity between studies that did or did not perform an oral challenge. There was no significant subgroup effect between the adults versus adults and children (p=0.113), suggesting that age group does not modify the prevalence of beta-lactam allergy between sexes. There was also no significant subgroup effect between the drug classes of cephalosporins versus penicillins (p=0.849). However, a far smaller number of participants contributed to the cephalosporin subgroup than the penicillin subgroup, which likely affects the ability of this analysis to detect subgroup differences.

Despite the heterogeneity, there are also advantages afforded by the large number of studies included in this meta-analysis. We included 69 studies in this review, increasing the statistical power of the meta-analysis and improving the precision and validity of the results. We used rigorous systematic review methods, creating a meta-analysis that is useful in providing general trends on the prevalence of beta-lactam allergy. Our research also draws attention to how few studies report results by sex and gender. Sex and Gender Equity in Research (SAGER) guidelines recommend that all studies report results by sex and gender, even if the sample size is too small to perform sex- and gender-based analysis108. Reporting by sex and gender facilitates the synthesis of results across studies, which would allow conclusions to be drawn even if primary studies have small sample sizes.

Overall, the risk of immediate beta-lactam allergy appears to be related to both sex-based and gender-based factors. This review found a significantly higher risk of positive oral challenges in females than males, suggesting that biological factors such as sex hormones may contribute to higher rates of beta-lactam allergy diagnosis in females. We also identified that female patients are more likely to be enrolled in clinical studies on beta-lactam allergy, suggesting that gender-based factors such as increased reporting of allergies and healthcare utilization may also play a role. Future directions should include expanding this work to assess the general population for sex-based differences via placebo-controlled oral challenge and skin testing, as well as including delayed hypersensitivity reactions.

Supplementary Material

Supp.File

Highlights.

What is already known about this topic?

Previous literature suggests an increased prevalence of penicillin drug allergy in female patients in both the inpatient and outpatient settings.

What does this article add to our knowledge?

We found that females had a higher risk of positive oral challenge for immediate beta-lactam allergy. We also identified a higher proportion of female participants in studies on immediate beta-lactam allergy.

How does this study impact current management guidelines?

Our findings suggest both sex-based and gender-based differences in the prevalence of immediate beta-lactam allergy.

Acknowledgements:

NBP initiated and designed the study, screened studies for inclusion, collected, analyzed, and interpreted data, and wrote the manuscript. GCK, DGG, DS, DB, AM, and FS screened studies for inclusion, collected data, and edited the manuscript. DG assisted with study design and performed the literature search. LCP, MAP, TP, and EJ interpreted data and critically reviewed the manuscript. ZW assisted in study design, performed statistical analysis, and edited the manuscript. AGE and SEC assisted in study design, led the study, interpreted data, and critically reviewed the manuscript. All authors approved the final version of the article.

We thank the authors and the participants of the included studies for their contributions.

Sources of funding:

This work was supported by the NIH NIAID K08AI141765 grant to Sergio E. Chiarella.

Abbreviations:

ADR

adverse drug reaction

DIA

drug induced anaphylaxis

RR

relative risk

CI

confidence interval

I2

I-squared statistic

IgE

immunoglobulin E

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflicts of interest:

The authors declare that they have no conflicts of interest.

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