Category: 8. Health

Data

Administrative data on drug stock-outs were obtained from Zimbabwe’s MoHCC, whose Pharmacy Services Department collects the data. Facility authorities submit their stock information quarterly to the MoHCC, and the Ministry collates the dataset into a single database. The data contain information on SP availability at each facility in all the districts. The information is collected to monitor drug availability at the health facilities, which includes stock in hand, drugs used, and stock-outs. The data used in the current paper were collected quarterly per facility and district from 2011 to 2015.

The DHS dataset is collected from developing countries every five years and has been conducted in Zimbabwe since 1988. The dataset contains information on demographic and socioeconomic variables, healthcare services utilisation, maternal and child health outcomes, and maternal and child mortality. A total of 9,955 women were interviewed, yielding a 96.2% response rate. However, we only included information on women who gave birth between 2011 and 2015, for which stock-out data were available. Data on 2010 health outcomes were not included, as there were no data on stock-outs for the same year. After excluding individuals with missing observations, the data analysis was based on 3,432 observations. The survey data were prone to missing observations due to recall and non-response bias. Robustness checks were performed to examine whether the missing observations in the analysis resulted in biased estimates and the results are part of the supplementary information.

We first added facility GPS coordinates to the stock-out data by merging master facility data, which contained information on facility location and stock-out data to link facility and household survey data. To combine the drug stock-out data and the ZDHS data, we then used the facility and survey cluster GPS coordinates. A total of 296 facilities were merged into the clusters in the ZDHS in the analysis. The ZDHS cluster coordinates and the facility coordinates were merged based on the assumption that people in the same cluster use the same facility. The ZDHS GPS coordinates were displaced 2 km in urban areas and 5 km to 10 km in rural areas. The displacement of coordinates was done carefully, to ensure that clusters did not overlap with other administrative areas (see [22]). To correct the impact of coordinate displacement, we used a 10 km buffer zone by considering only the facilities within a 10 km radius. We combined the 2015 ZDHS and drug stock-out data in the analysis. We used 2015 cross-sectional data, but child’s year of birth provided a retrospective time dimension within the survey. Drug stock-out data, were, however are collected quarterly for each facility. The time dimension in the stock-out data was linked to the birth timing in the DHS cross-section.

Analysis

We used the Ordinary Least Square (OLS) model to examine the relationship between malaria prophylaxis stock-outs and birth- and maternal outcomes in Zimbabwe. We also included regional and birth-year fixed effects in the analysis to capture regional and birth-year variations. Clustered standard errors are used to account for common variations inside survey clusters. Therefore, we measured associations, and not causal relationships – specifically between stock-outs and birthweight for neonates and maternal anaemia. Given that haemoglobin levels are only monitored during data collection in 2015 and not earlier during pregnancy, when women are more vulnerable to malaria, the paper focused on mothers who had given birth or were pregnant in 2015. This is because these women were more likely to be affected by malaria infections than women who were not pregnant at the time of the survey. However, one major weakness of this analysis is that haemoglobin levels might have adapted to post-birth experiences in potentially biased ways. The results on the association between malaria prophylaxis stock-outs and maternal anaemia are reported in Tables B and C of the supplementary information and are presented as explanatory rather than definitive. The model for malaria prophylaxis stock-outs relationship with health outcomes was specified as follows:

where ({y}_{ict}) was the birthweight or haemoglobin level of individual i in cluster c at time t, ({stockout}_{ct}) was the SP stock-out at cluster c (where the cluster was equal to the facility) in period t. ({X}_{ict}) was the matrix of other control variables in the model, which were education, parity, preterm delivery, wealth index, BMI, currently pregnant, work status, birth interval, interacted ANC and stock-outs, interacted IPTp districts and stock-outs and HIV status, ({alpha }_{2}) was the vector of parameters, ({varepsilon }_{ict}) represented the error term, ({theta }_{i}) represented regional fixed effects, and ({phi }_{t}) represented birth year fixed effects.

After this analysis, we used the recentered influence functional (RIF) unconditional quantile regression model to estimate the association between malaria prophylaxis stock-outs and health outcomes along different quantiles of the birthweight distribution. The unconditional quantile regression model shows the marginal effects of explanatory variables on the unconditional quantile of the dependent variable [15, 35]. RIFs of the unconditional quantile provide a robust analysis of every unconditional quantile [35], useful for policy implementation [1]. According to Firpo et al. [15], the model is simple and easy and can be used for other distributional statistics like the Gini coefficient and conditional quantile. The unconditional quantile regression model focuses on unconditional quantiles when independent regressors are present, which differs from the conditional quantile used in the presence of endogenous regressors [15]. In this regard, conditional quantile regression shows heterogeneity in parameters that characterise the relationship between conditional quantiles of dependent variables and independent variables [1]. The effects of independent variables in unconditional quantile regression are a weighted average of conditional quantile regression. The RIF unconditional quantile regression was specified as follows:

where y was the dependent variable, (alpha) represented the constant, and ({beta }_{j}) represented the unconditional quantile partial effect of changes in X in the model. ({X}_{i}) showed the independent variables used in the paper including interacted variables, (p) showed the quantiles, and ({varepsilon }_{i}) represented a normally distributed error term. We used bootstrapped standard errors. Although the RIF approach allows for estimation of the covariates across the outcome distribution in the population (rather than conditional on covariates), it may limit generalisability in contexts where the underlying distribution of covariates differs substantially from the study sample.

Description of variables

The independent variables used in this analysis are birth interval, parity, preterm delivery, stock-out index, wealth index, work status, education, geographical location, BMI, currently pregnant and HIV status. These variables were selected from the prior literature.

Work status was a dummy variable denoted by working (for women with a paying job or a business) and not working women. Working women were expected to have better health outcomes than non-working while the geographical location was a binary variable denoted by rural if the location is one and urban if the location is zero. The wealth index was another variable measured in ZDHS using principal component analysis from the household’s assets. Women from wealthy families tend to have enhanced health outcomes compared to those from less wealthy households.

Another variable was education, which depicted the number of years in which the highest qualification was acquired, and educated women were more likely to have improved health outcomes than their uneducated counterparts. Preterm delivery also affects birth and maternal outcomes. Preterm delivery was defined as birth before the 37th week of pregnancy, children born before 37 weeks are preterm represented by one in the analysis and zero if a child is born after 37 weeks of pregnancy. Preterm neonates tend to have lighter birth weights than the non-preterm neonates. Parity was another variable representing the number of children that the woman has ever given birth to, either stillborn or born alive. On the other hand, birth interval shows the spacing between pregnancies by the mother which affects the health of the children and it was represented by the number of children a woman gave birth to within a year in this paper. Women with short birth intervals were more likely to have compromised birth and maternal outcomes.

While there are many causes of anaemia in pregnant women, including iron deficiency and genetic factors, malaria is considered one of the major causes [46]. The WHO [43] defines anaemia as a condition where the number of red blood cells is below the recommended level. Haemoglobin level is used as a measure of maternal anaemia. Birthweight was used to measure the association of neonatal health outcomes with malaria prophylaxis stock-outs. According to the WHO (2019c), babies weighing more than 0.5 kg and less than 2.5 kg are considered to have low birthweight, which is undesirable for a child’s subsequent growth trajectory. Given that birthweight can either be affected directly via placental malaria or indirectly via maternal anaemia, we assumed that we detect the direct effects of malaria on birthweight, as maternal anaemia is mostly measured after pregnancy in the ZDHS. In addition, we created the stock-out index by calculating the proportion of stock-out days per quarter per facility, and then averaged these proportion of days drugs are stocked out at a facility for two quarters over time to get stock-out for the two final trimesters of pregnancy (see supplementary information A.2). Drug stock-outs increase the likelihood of receiving no or fewer SP doses than recommended, increasing the probability of malaria infections [14, 25]. Therefore, SP stock-outs were expected to be negatively associated with birthweight and maternal haemoglobin levels.

Specialty

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Attitudes of the Lithuanian public and experts towards the return of IGF

The results of the quantitative study revealed a high level of interest of the Lithuanian population in obtaining information relevant to their health from the biobank. Our survey results align with the attitude surveys of the public and biobank participants from some other countries [14], the overall rate of those interested is substantially high.

The findings from our study as well as from some other countries reveal that people desire various health-related insights, including information on the risk of untreatable monogenic diseases like Huntington’s disease (PAG approach), the risk of monogenic diseases in offspring (such as possessing a pathogenic variant associated with cystic fibrosis) (PAG approach), and even slight genetic risks for multifactorial diseases like type 2 diabetes (DTC GT approach) [1, 3]. For instance, in the U.S. study, 95% of the 4,659 respondents agreed that they would like to know about health risks related to treatable diseases (e.g., asthma), and 90% expressed interest in learning about risks related to untreatable diseases (e.g., Alzheimer’s disease) [3]. Similarly, in a Japanese study, more than 80% of the population biobank participants expressed a desire to receive information encouraging lifestyle changes, a number even higher than those who wished to receive clinically significant findings (over 50%) [1].

Despite the expressed willingness of the general population to know the information related to their individual health, which was revealed during the biobanking activities, it is important to underline that the results of the qualitative research carried out by the authors revealed a less than uniform attitude of the experts regarding the appropriateness of returning these findings. While experts unanimously agreed that biobank participants should be informed about findings indicating an increased risk of a treatable monogenic disease like Lynch syndrome (MAG approach), they held varying opinions regarding the disclosure of other findings, such as those related to Huntington’s disease (PAG approach), possession of a pathogenic variant associated with cystic fibrosis (PAG approach), and type 2 diabetes (DTC GT approach). The experts, regardless of their professional field, presented arguments both for and against returning findings like possession of pathogenic variant associated with Huntington’s disease or cystic fibrosis to the biobank participants. They highlighted the challenges in establishing a clear policy for informing biobank participants about these findings and changed their views on the appropriateness of returning them accordingly during the interviews. This undoubtedly reflects the complexity of the issue and the need for a debate on the return of IGF. A slightly clearer division of opinion between the domains was observed with regard to the return of the type 2 diabetes finding. When discussing this finding, the most significant differences of opinion were found between the experts according to their area of expertise. Medical geneticists, natural scientists and ethicists considered it inappropriate to return such a finding to a biobank participant. This reflects more a concern that findings that may not be sufficiently informative may cause misunderstanding and confusion for the biobank participant. Conversely, legal and data protection experts considered the return of such a finding to the biobank participant to be appropriate. The latter experts’ position is more reflective of the public’s view.

Similar findings regarding the divergence between public and expert opinions on other findings than the MAG approach suggests, have been observed in contexts unrelated to biobanking. For example, a study on the Danish population in the context of clinical genome sequencing reveals that the general public’s preferences for reporting differ significantly from those of professionals, as indicated in the ACMG guidelines. The general population places greater importance on findings from the PAG approach, which includes severe but clinically non-actionable findings, compared to the MAG approach favored by professionals. This may suggest the need for a new policy that combines elements of both the MAG and PAG approaches to better align with public preferences while maintaining professional standards [15].

The general public and the experts in Lithuania agreed that the finding indicating an increased risk of developing a treatable monogenic disease (Lynch syndrome), discovered during the biobanking activity, should be offered/returned to the biobank participant. However, it is important to note that the Lynch syndrome case scenario within our research study involved a pathogenic variant with relatively high penetrance, which is not always the case and may depend significantly on family history [16]. Therefore, it would still be valuable to explore how both experts and the public perceive low-penetrance monogenic variants, as this is crucial for understanding how opportunistic screening can lead to false positives, overdiagnosis, unnecessary surveillance, and distress.

Lithuanian experts also emphasized the need to validate findings in an accredited laboratory and assess their clinical validity, even though this criterion was not explicitly mentioned in the interview guide. The reason for raising this point is that it poses a significant challenge to both the findings and their practical application, given the substantial resource demands involved in validating all potentially relevant variants in a biobank before they can be returned.

Both issues—the agreement on the disclosure of high-penetrance, serious monogenic diseases and the importance of clinical validity—are already, to some extent, reflected in the current Lithuanian strategy for the return of health-related findings to a biobank participant. Nevertheless, the analysis of the empirical data leads to a number of points to be addressed and improved. Firstly, as the results have shown the disagreements may arise between experts on the assessment of specific findings against the established strategy. However, it may be even more difficult for biobank participants to understand what health information they can obtain from a biobank. In other words, once a biobank participant has been informed of a finding, he or she may still be surprised that he or she has agreed to be aware of the finding. Secondly, Lithuanian experts and citizens considered other criteria not set out in Lithuanian legislation (e.g. invasiveness of the preventive measure) to be important in the decision to know/return a particular finding. Thirdly, experts and the public highlighted that while all the criteria discussed (severity of disease, likelihood of disease, effectiveness of the preventive measure and invasiveness) may be relevant when considering whether to return/know a particular finding, each of these criteria may have a different weight in this decision. It is therefore important to consider the interplay between all criteria when deciding whether to know/offer a particular finding.

Measures to improve the IGF strategy in Lithuania

Based on the results of empirical research, as well as the discussion of these findings, the authors of this paper believe that specifying the current strategy for returning IGF to biobank participants in Lithuania—while still following the MAG approach—should be considered the primary goal for improving the return of IGF from biobanks. This could be done in at least two ways.

Development and use of a list of genes and diseases

The genes and diseases included in this list should be selected based on criteria deemed important by Lithuanian experts and the public. The advantages and challenges of using such a list in biobank activities are presented in Table 8.

The list of genes and diseases is recommended and/or applied in several scientific clinical projects in other European countries that aim to integrate genome sequencing into clinical practice [17, 18]. In recent years, this method has also been adopted in biobanks [19, 20]. One of the advantages of using a gene and disease list is that it makes it easier for all individuals involved in biobank activities (e.g., biobank administrators, participants, and funders) to understand which findings might be detected and returned to biobank participants. For participants, reviewing the gene and disease list can be helpful in reducing unrealistic expectations about the information they might receive, such as avoiding the misconception that not finding any results means they are in good health. For biobank administrators and researchers, this list is a convenient tool for limiting the number of findings that may be returned during biobank operations. Moreover, it simplifies the process for those managing and funding the biobank to calculate and plan the necessary human and financial resources to effectively implement the return of findings [21]. It is also worth noting that the adaptation and application of a gene and disease list require minimal changes to the legal regulations in Lithuania.

Despite the advantages of applying a gene and disease list, there are also challenges associated with its implementation. First, creating and regularly updating such a list requires expert knowledge, time, and financial resources, which are very limited for conducting biobank activities in Lithuania. One possible solution to this challenge is to use existing gene and disease lists. For example, this approach has been adopted by the Estonian Biobank, which uses the gene and disease list prepared and continuously updated by the American College of Medical Genetics and Genomics (ACMG) [22,23,24,25,26] as one of the methods for evaluating findings. However, it is important to note that while the ACMG gene and disease list is becoming a standard for the return of findings in various scientific projects, the specific needs of a biobank—considering factors such as the focus of planned research, the characteristics of the biobank’s participant population, the intensity of communication with participants, and the resources available for implementing a return of findings strategy—might make a narrower or broader list of genes and diseases more appropriate [21].

A further challenge in applying a gene and disease list lies in the limited capacity of researchers to curate and interpret findings. Gene lists may indicate which results warrant consideration for return, but they do not determine which policy should be implemented. For example, policies may require researchers to actively screen all listed genes for pathogenic variants—an approach that may prove unfeasible in many research contexts—or to report such findings only if they are incidentally discovered in the course of research, which could be a more practical approach.

One more complication in applying a gene and disease list concerns the assumptions regarding clinical responsibilities. In the article we referred to duties such as the duty to rescue or obligations that apply when the researcher is also a medical doctor. However, it is important to clarify that many genomics researchers are not clinicians and have no direct relationship with participants. As a result, they may not bear the same ethical or professional responsibilities as healthcare providers. This may complicate the application of clinical norms in research settings. One way to address this gap is by integrating clinical team members into the research team from the outset, thereby ensuring that appropriate expertise is available and responsibilities are clearly defined where needed.

Another challenge related to the use of a gene and disease list is that researchers might discover other findings (not included in the list) that they consider significant for the participant’s health. This challenge could be mitigated by establishing an advisory body for the biobank, which would be responsible for reviewing new cases of findings not included in the list.

Use of guidelines for evaluating criteria for returning IGF

These guidelines can serve as an alternative to the previously discussed gene and disease list or as a supplementary tool to help determine which genes and diseases should be included in the list. One example of such guidelines is the five-criteria scale proposed by Berg and colleagues for assessing the clinical significance of specific genetic conditions. This scale was developed by an interdisciplinary group of experts, including not only clinical geneticists but also specialists from other fields (e.g., cardiology, neurology, primary care), clinical laboratory professionals, and ethics experts. The criteria in this scale include the severity of disease outcomes, the probability of disease occurrence, the effectiveness of interventions, the burden of interventions, and the level of evidence, with scores for these criteria ranging from 0 to 15 in total. A higher total score across these five criteria indicates greater clinical significance of the genetic variant [27].

The scale proposed by Berg and colleagues for determining the clinical significance of findings might be appealing to those involved in biobank activities (Table 9). This is primarily because the scale provides a rationale for why a particular finding is or isn’t returned to a biobank participant. Using this tool could also contribute to a more transparent and consistent evaluation of findings. Additionally, it is easily adaptable to different return-of-findings strategies and contexts. For example, while Berg and colleagues suggest focusing solely on genes associated with monogenic health disorders, the tool can be readily adapted to evaluate genes associated with complex diseases if needed. It is also worth noting that, like the gene and disease list, integrating this scale into the return-of-findings strategy in Lithuania would require only minimal legal adjustments.

One of the major challenges with using this scale is that the interpretation of its criteria and the assignment of scores might vary among experts from different fields. Therefore, it would be advisable to establish an interdisciplinary advisory body for the biobank to assist in evaluating specific findings using this scale.

Given the significant variation in Lithuanian experts’ opinions regarding the return of non-clinically actionable health information and the high level of willingness expressed by the general population, the residents to receive such information, it is important to continue developing discussions and conducting empirical research on this topic. For instance, understanding why the Lithuanian public wants non-clinically actionable health information and the psychological aspects of returning such information could be valuable. This issue, along with the broader question of IGF returning, could be examined not only within the context of biobanks but also in the broader context of healthcare.

Study limitations

We recognize that the empirical study outlined above has certain limitations. One significant limitation of the qualitative study is that many scientists involved in the research, who work with samples and health data stored in the biobank, also hold additional roles related to the biobank, such as founders or managers. While the perspectives of these experts are particularly valuable, their views on the investigated aspects may differ from those of scientists who do not have an inter-dependent relationship with the biobank. Therefore, it would be essential to explore the viewpoints of this other group of researchers in future studies.

The quantitative study also presents several limitations. Firstly, the survey was conducted among members of the Lithuanian population who voluntarily agreed to participate, resulting in a relatively low response rate of 22.7%. While this outcome was anticipated, we aimed to enroll as large as possible sample from the invited ones. However, it remains uncertain if the views of those who chose not to participate might have affected the study results.

Secondly, the study focused on hypothetical scenarios rather than actual human behavior. It is important to note that individual behavior may vary based on contextual factors, such as personal experiences with the healthcare facility associated with the biobank or the specific circumstances under which they were invited to participate.

Thirdly, since this study involved the general population in Lithuania than biobank participants and most surveyed individuals reported their health as fair or good, the findings may be more applicable to population-based biobanks rather than disease focused ones.

Finally, while the sample was designed to be representative concerning gender, age, place of residence, and education, there were challenges in ensuring the participation of older adults (65+) and those with lower education levels (e.g., primary education). These groups tend to be less technologically literate and less likely to use computers, resulting in their underrepresentation in the survey, and data weighting did not help to overcome this problem.

Although most referrals to the specialized vulva clinic were made by specialists, little more than half of the suggested diagnoses could be confirmed, which is in line with other results and represents a major potential for improvement in diagnostic approaches [8, 12]. While the overall correctness of suggested diagnosis was disappointingly low, there were marked differences among specific vulvar disorders and the clinical background of referring specialists. Significant inconsistencies in vulvar diagnosis were also found between referring physicians and dermatologists in a recent study [13]. The higher diagnostic accuracy observed in dermatologists may be attributable to the referral bias where mainly complex or refractory cases are referred and not the straightforward vulvar cases. A referral bias is also reflected by the difference referrals with a diagnosis or a suspected diagnosis (68.5% from gynecologists vs. 91.7% from dermatologists). Further, most vulvar pathologies are dermatoses, which are familiar to dermatologists as they also appear on other areas of the body. Dermatologists typically conduct a full body examination, including the oral cavity, and at least inquire about any genital involvement. Many dermatoses, such as eczema or psoriasis, can affect the vulva, but they are usually not limited to the genitalia, which generally provides the dermatologist with a clue for the diagnosis. In contrast, gynecologists have significantly less exposure to vulvar and gynecologic dermatology, as vulvar diseases are addressed only at a limited number of specialized centres in Switzerland.

There is a potential referral bias: dermatologists might be confident with their dermatological diagnoses but not with the exclusion of an underlying gynecological disease, whereas gynecologists are confident with their exclusion of a genital pathology but not so with their dermatological diagnoses. The learning objectives of the Swiss OB/GYN specialty program include the detection, prevention and treatment as well as the follow-up of diseases of the female genital organs, however there is no specific emphasis in vulvar dermatology. The inclusion of learning objectives in vulvar dermatology should be implemented in the National OB/GYN specialty programs (Fig. 2).

For lichen sclerosus the concordance between referral and final diagnosis was high, which is likely due to the characteristic clinical signs of this disease [14] and supports the claim that both clinical expertise and experience in vulvar disorders play an important role in diagnostic outcome. However, in line with further results [8, 14,15,16,17,18], the frequent fear of dysplasia/vulvar cancer in suspected lichen sclerosus cases, likely motivated referral for re-evaluation in a tertiary center. In addition, reluctance to use strong topical steroids for a prolonged period is a well-known reason to refer women with lichen to a specialist clinic [8, 19, 20]. The suspicion of dysplasia, eczema, and lichen planus also proved to be most often correct, which should probably be attributed to their clear diagnosis, either by biopsy or by specific characteristics of clinical presentation [14]. However, eczema had relatively often been mistaken for lichen sclerosus, which was the most frequently corrected diagnosis through histopathological evaluation of biopsies. The great variety of other inflammatory diseases and subtle differences in their classification probably explain the considerable difference between suspected and final diagnoses in this group [2, 9, 21]. Although these diseases are commonly seen in gynecologists’, dermatologists’, and general practitioners’ daily clinical routines [10, 18, 22, 23], infectious diseases were often falsely diagnosed, which is likely also a consequence of the broad spectrum of clinical symptoms [1, 14, 24, 25]. Vulvodynia is an exclusion diagnosis, i.e. all relevant diagnostic tests have to be completed before the final diagnosis can be made [26, 27]; this was often not the case before the patient was referred. Unspecific symptom descriptions likely also contributed to the underestimation of this diagnosis [26,27,28].

With only 44% of patients reporting similar key symptoms when they saw a referral physician as at the first consultation in the specialized center, the agreement between symptoms on the two occasions was relatively vague. Although some of the discrepancy may be a result of reporting bias, symptoms or their intensity may also have changed and consequently have been reported differently at the two appointments. In addition, physicians will likely have explored symptoms in many ways, ranging from no direct question on symptoms at all to a highly complex exploration via a predefined symptom list. A guideline as to what and how information on symptoms should be collected might help to improve diagnostic quality [10, 12, 29].

While it took a long time after onset of symptoms for patients to be referred to the specialized vulva clinic, the tests needed to permit final diagnosis were completed rather quickly. The mean time between symptom onset and final diagnosis in our study was 46.1 months, with 1.0 month from the 1st consultation in the vulva clinic until final diagnosis, which is in line with other findings [18].

Differences in the time to diagnosis might be due to a deliberate, partial investigation of vulvar disease prior to referral, with the final diagnosis—especially when more sophisticated approaches such as vulvar colposcopy, dermoscopy, or biopsies are needed—being left to the specialized vulva clinic [8, 9, 29]. However, if gynecologists consider themselves to be specialists supporting women with vulvar complaints, it would be beneficial to improve their expertise to allow more reliable diagnoses or early pre-defined referral to a center offering the diagnostics tools and experience needed. The high number of vulva disorders that are a manifestation of a skin disease accords with their frequent correct initial diagnosis by referring dermatologists [18].

One reason for the limited diagnostic quality of the initial evaluation of vulvar diseases might be based on the variety, how different diagnostic tests are used in clinical practice. While bacterial/mycosal smears were frequently made, biopsies were only rarely taken, and no patterns could be detected in the performance of such biopsies among referring physicians. While some physicians, tended to steer the diagnostic process to a clear diagnosis, others referred women at some point of the diagnostic process to the tertiary vulva care center. Here, either a clear definition of how tertiary centers could ideally cooperate with primary caregivers, or better training in when, how and where biopsies should be taken would be helpful in improving diagnostic success in vulvar diseases.

In line with this finding, the cotton swab test, which, in addition to excluding other causes of vulvar pain [2, 26, 30], is mandatory for the diagnosis of vulvodynia, was only carried out in about 15.4% of women before they were referred to the tertiary center. As vulvodynia is among the most frequent vulvar disorders [31] the systematic realization of this test would help to increase diagnostic accuracy in a large proportion of vulvar diseases. As vulvar pain can also be a comorbidity of other vulvar diseases [26, 32, 33], it is important to exclude any other pain-inducing disease.

In agreement with the literature, the almost 4 years’ latency from symptoms to referral was seen more often in diseases with a fluctuating character, such as eczema and lichen sclerosus [14]. A delayed diagnosis of a dermatoses can lead to significant physical, psychological, and medical complications, depending on the specific condition. A long delay often of several years in diagnosing lichen sclerosus and lichen planus can result in progressive scarring, atrophy, and adhesions, which may lead to functional impairment and distress (e.g., narrowing of the vaginal or urethral opening) as well as an increased risk of the development of squamous cell carcinoma [34]. Furthermore, misdiagnosis can lead to unnecessary treatments, potentially worsening the patient’s condition or causing irreversible changes to the vulva appearance.

Latency was also high in diseases such as vulvodynia and other inflammatory diseases. Time from initial symptoms to final diagnosis was shortest for infectious diseases, which might be a result of sudden strong clinical symptoms, which motivated both patients and physicians towards an early solution. In contrast, the time from the onset of the first symptoms to the diagnosis of lichen sclerosus was the longest in our cohort, averaging nearly 7 years, which is longer than the 4 years reported in a survey study by Krapf et al., where women indicated they received the correct diagnosis after this duration [35].

In 225 women a diagnosis could already be formulated at the first consultation by confirming or rejecting the suspected diagnosis of a referring doctor, with 90.4% of the women receiving a final diagnosis after a maximum of two consultations. These data show that when the right approach is chosen, most vulvar diagnoses can be made very straightforwardly. While physicians can only influence patients to seek medical support to a rather limited extent, they can use this resource to facilitate earlier diagnosis and, consequently, earlier treatment.

The most common pitfalls in the diagnosis of vulvar diseases and solutions for overcoming challenges to correct diagnosis are summarized in Fig. 2 [1, 14, 28, 36]. To guarantee best diagnostic quality, if histopathological evaluation is required it should be performed by a dermato-histopathologist with experience in vulvar pathology [37]. Specific immunohistochemical markers for neuroproliferative vestibulodynia might offer future options in the classification and patho-etiology of vulvar pain [38]. Specialists supporting women who have vulvar diseases should also follow well-defined approaches to treating vulvar disorders, for example, approaches to managing vulvovaginal symptoms [29] or vulvar disorders [14]. For a standardized diagnostic method, health professionals should adhere to existing diagnostic protocols, such as the European Guideline for the Management of Vulval Conditions [14].

Shame and hesitancy to seek medical support, possibly also due to cultural background are factors hampering timely diagnosis on the patient’s side [39]. Active investigations of vulvar complaints in an atmosphere facilitating discussion of delicate topics should therefore be a standard component of taking a gynecological history [12]. Specific attention has to be paid to multiple conditions.

Strengths and limitations

The strengths of our study are the large study group and the inclusion of study participants over a period of 4 years in a real-life setting. Limitations include the retrospective data collection based on a type of documentation that was not expressly designed for the present evaluation. Despite the presence of multiple symptoms, only the leading symptom was used to compare the initial situation and the situation in the tertiary center. The intensity of several important symptoms might have changed over time and consequently have resulted in an overestimation of discrepancies. Although there was no systematic internal quality assessment of the diagnosis, we considered final diagnoses from the tertiary center to be correct. As referring physicians individually decided which information should be included in the referral letter, individual effort invested in the correctness and completeness of reports might have varied strongly and not all details of investigations occurring before referral might have been brought to the attention of the tertiary center. Another limitation is the comparison of correct diagnoses of gynecologists compared to dermatologists as the vast majority, nearly 70%, of the referrals were from gynecologists and only 7.4% from dermatologists.

However, this first systematic evaluation of suspected diagnoses before patients were referred to a tertiary hospital vulva clinic and later outcomes of additional diagnostic steps provides valuable targets for the improvement of diagnoses in primary health support.

To gain an initial representative understanding of how media debate analyses have been used and are useful for bioethics, as well as which methodological approaches were used to different ends, we conducted a rapid scoping review of the literature. This review offers a systematic and resource-efficient overview of studies analysing health-related media debates [26], highlighting the different methodologies applied in the field. It provides a broad perspective of the study landscape, helping to illustrate our methodological and theoretical considerations. As such, the rapid scoping review serves as a foundation for identifying methodological requirements and challenges and to develop perspectives for methodologically founded investigations of media debates in bioethics. Given the conceptual focus of this paper, an in-depth examination of individual studies that other review methodologies provide is beyond this paper’s scope. Instead, the rapid scoping review efficiently captures the research objectives and the methodological approaches necessary to underline our conceptual arguments in this paper.

Methodology

We systematically searched relevant articles in PubMed, Web of Science (Core Collection), and Scopus (see Table 1 for search algorithms and Fig. 1 for the article selection process). We included English-language articles that used an established methodology (e.g., qualitative or quantitative content analysis, thematic analysis) to analyse the content of traditional mass media or social media on a health topic (broadly defined, including One Health, public health, health research, and medical education) with a reference to bioethics (regarding topic, affiliation of authors, scope of journal etc.). Following our above-introduced definition of media debates, we excluded analyses of fictional content (e.g., assessment of child TV programs), social media analyses focusing on private conversations (e.g., closed Facebook groups) and studies that analysed the content of advertisements. Non-English-language studies were also not included.

From the included publications, we collected the following data from titles, abstracts, and other publication meta-data: (1) research field of the periodical; (2) first author’s field of affiliation; (3) topic of the paper; (4) unit of analysis (e.g. social media posts, newspaper articles); (5) methodology to analyse media content (qualitative, quantitative, mixed methods, Machine Learning-based); (6) presence of data triangulation; and (7) the contribution to bioethics. No full-text analysis was conducted.

Interdisciplinary landscape

To assess the interdisciplinary landscape of the 191 included publications, we extracted information on topics, methodologies, and academic fields. Topics were identified by applying Philipp Mayring’s methodology of a summarizing content analysis, which includes a step-wise paraphrasing and abstraction of content [27]. The most frequent topics were public health-related, including infectious diseases (24.6% of articles, Fig. 2A), mental health (13.1%) as well as nutrition, obesity and diet (6.8%). Other frequent topics addressed technological innovation in healthcare, including new technologies & therapies (9.9%), reproductive health (7.9%), and genomics (6.8%). Further, topics addressing the health system, including stakeholder perspectives (9.4%), health research & research ethics (8.9%), as well as health policy & health care systems (8.4%) were addressed. Various other health topics were addressed, too. Figure 2B shows that most analyses were conducted based on debates in news media (61.3%). Figure 2C indicates the variety of academic fields represented in health-relevant media debate analyses. Medicine was the most-represented field, followed by the social sciences and bioethics. Moreover, 15.2% of the articles were published in interdisciplinary journals. Our rapid scoping review further shows that the number of relevant publications has steadily increased since 2008 (Fig. 2D).

Contribution to bioethical inquiries

Based on the considerations on the threefold significance of public media debate analyses for bioethics and initial findings from the rapid scoping review, we defined four categories of how media debate analyses have contributed to bioethical inquiries so far (Fig. 3). They show the different content-related potentials of the investigation of media debates in bioethics as well as their methodological range. While we conceptualized the first three categories as mutually exclusive, the fourth category (ethical evaluation of media debate) was sometimes coded in addition to one of the other categories. In the following, we will describe these categories by giving illustrative examples and emphasizing characteristics as identified through the rapid scoping review.

Description of empirical context

Around one in three included publications (n = 61, 31.9%) did not engage explicitly in any ethical rationale or discussion but provided descriptive information on the content of media debates. Methodologically, qualitative and quantitative approaches were similarly represented. Additionally, four articles in this category used Machine Learning-based text categorization methodologies. For example, Indra and colleagues analysed social media posts about obesity, physical activity, and diets in the context of healthy lifestyles [28]. They performed sentiment analysis and topic modelling on these posts to identify the tone of the debate and the topics covered as determined by word frequencies, combinations, and relative proximities.

As argued above, even though they are descriptive, such investigations may still be of relevance for bioethical inquiries: They can provide an empirical basis for further bioethical analyses, even if no such analysis is provided in the publication itself. A pertinent example is a quantitative content analysis by Zimmermann and colleagues about the content, evaluations, and stakeholder influence in newspaper coverage of predictive genetic testing in Switzerland and the United Kingdom [29]. Contrasting their findings with other studies in the field of science communication, they showed how the debate fostered a more active public engagement with the topic than previous science communication topics and how the debate was much less salient in German-speaking Switzerland as compared to the United Kingdom.

Description of ethical aspects

As a second category, we identified 52 publications (27.2%) which explicitly described ethical aspects of health topics while not engaging in any more in-depth investigation and evaluation of ethical aspects. For example, Zimmermann and colleagues analysed what ethical issues pertinent in scholarly debates about predictive genetic testing were reported on in British newspapers. They quantified what ethical issues were particularly salient in newspaper reporting, identified what ethical issues were underrepresented, and discussed what ethical issues the public should be more explicitly informed about and why [30]. This allowed a detailed description of how ethical aspects within a specific context were represented in a pertinent media debate. In this way, this example illustrates the above-outlined significance of media debate analysis through a reflection of morality.

Further, such descriptions of ethical aspects covered in media debates touch upon the societal relevance of media debate analyses. For example, Chandler and colleagues qualitatively analysed online comments in response to news articles reporting on a Canadian patient who had been in a vegetative state for several years and was reported to communicate via fMRI neuroimaging [31]. The findings illustrated important moral deliberations in the online comments, including the quality of life of this patient, the question of withdrawing life support and options of the patient consenting to this, and the accuracy of diagnosing brain death. In concluding that “[t]hese public perspectives are relevant to the obligations of clinicians, lawyers, and public policymakers to patients, families, and the public” [31], the authors refer to the practical and ethical significance of their analysis.

Methodologically, publications in this category mostly followed traditional methodologies of media content analyses, including quantitative content analysis (n = 21, 40.4%) and qualitative content analysis (n = 16, 30.8%, see Fig. 3).

Identification and evaluation of moral problems

More than a quarter of the reviewed publications (n = 51, 26.7%) identified and evaluated moral problems regarding health-related topics in addition to describing the content of media debates. Such publications employed more qualitative (24/51, 47.1%) than quantitative procedures (12/51, 23.5%). Some 12 publications in this category (23.5%) analysed other data sources in addition to media content. This seems plausible since qualitative approaches and data triangulation offer more possibilities to examine a topic in-depth, and, in this course, to identify and evaluate ethical problems. For example, Rosenberg and colleagues analysed qualitative semi-structured interviews in addition to expert comments in Finnish media to demonstrate the social impact of the orphan drug Nusinersen [32]. By combining these two analyses, they outlined competing attitudes and values and showed that these may be classified differently depending on the situation.

As an example of a qualitative content analysis, Ross Arguedas investigated the media coverage of orthorexia nervosa [33]. Applying inductive thematic analysis, the author identified different framings of orthorexia but also a heterogeneous assignment of responsibility depending on the explanation of the causes of the eating disorder. Further, exemplifying a quantitative content analysis, Zimmermann and colleagues investigated solidarity and personal responsibility as important normative reference points in newspaper coverage in Germany and German-speaking Switzerland [34]. Using quantitative content analysis, they identified different contexts and areas of application of these two concepts. Finding that the limits of solidarity were only rarely mentioned in newspaper coverage about COVID-19, they called for a more distinct consideration of these limits to sustain solidarity as a resource in further crises.

Ethical evaluation of media debates

Finally, around one in three included publications (n = 59, 30.9%) discussed and evaluated the media debate itself from a normative perspective. For example, they identified blind spots, shortcomings, and tendencies in the media debate by focusing on how the media and the debate were embedded in a broader social and societal context. Such publications thus identified moral problems that arise or are reinforced because of the media debate.

For example, Aspler and colleagues conducted a content analysis of 286 articles from Canadian newspapers to investigate how the fetal alcohol spectrum disorder is presented in the media debate [35]. Starting from inductive coding, they identified six major themes. In discussing these findings, they focused especially on exaggeration and misinterpretation in the debate and highlighted the risks of harmful stereotypical beliefs about indigenous people, confusion about health choices during pregnancy, and the unhelpful fueling of debates about sensitive issues surrounding women’s choices.

Some 32 of the 59 publications in this category (59.2%) were additionally assigned to other categories. For example, the above-mentioned study by Aspler and colleagues also aims to identify and evaluate moral problems [35]. This is not surprising since a certain thematic focus is usually necessary for a substantial ethical evaluation of the media debate.

In terms of methodology, the investigations in this category are diverse. Quantitative and qualitative approaches are equally spread. For example, Bosch and Wasserman chose a quantitative approach to analyse the tabloid media coverage of COVID-19 in South Africa [36]. Starting from the proposition that tabloid newspapers are often criticized for their sensation- and entertainment-orientated journalism, they investigated 1050 online news stories in the tabloid Daily Sun and found that the majority of the coverage was topic-oriented and neutral. Thus, using a quantitative approach to the evaluation of media debate, they show how the societal and practical significance of media debates can be addressed in media debate analyses.

The study of Patterson and colleagues applied both qualitative and quantitative content analysis to investigate how media coverage in the UK represented ‘binge’ drinking [37]. They found a “disproportionate focus on women’s ‘binge’ drinking” and discussed the potential effects of reinforcing harmful gender stereotypes. Furthermore, they formulated concrete suggestions on how media framing could be improved by a more comprehensive media engagement of public health advocates. Hence, this investigation is a very significant example illustrating how the societal and practical significance of media debates can be addressed in a field with different methodological approaches and different concrete research questions.

Family Handout/PA Media

Family Handout/PA Media

‘Darkest day’

Jeremy Durkin/PA Media

Announcing a new article publication for BIO Integration journal. This article provides a systematic review of music therapy research progress and clinical applications in stroke rehabilitation.

Music therapy, through techniques such as Melodic Intonation Therapy (MIT) and Rhythmic Auditory Stimulation (RAS), offers distinct advantages by activating alternative neural pathways and promoting neuroplasticity, which significantly improves emotional regulation, cognitive function, language expression, and motor function in stroke patients.

According to clinical evidence, music therapy notably decreases depression and anxiety; promotes neuroplasticity; activates brain regions associated with language and motor function; and improves gait stability and limb coordination. However, current research faces challenges such as insufficient sample sizes, unclear long-term effects, and a lack of standardized protocols.

Future studies should incorporate technologies such as artificial intelligence and virtual reality to explore personalized music therapy interventions and establish multi-center collaborative clinical research systems, thereby promoting standardized application of music therapy in stroke rehabilitation.

July 4, 2025

KATHMANDU – The number of dengue-infected patients visiting hospitals in the Kathmandu Valley has been gradually rising recently, and this could be just the beginning.

Experts warn that a sharp spike in cases is likely once the ongoing rainfall stops for a few days.

In the worst-case scenario, over 60,000 people could get infected with the dengue virus in the next three months, according to a projection prepared by the Epidemiology and Disease Control Division.

The division, which is responsible for the epidemic and outbreak control in the country, said that the figure is just an estimate, which is made for the preparation for possible worst-case scenarios.

“Every year, we made a projection of the worst-case scenario, which is required for internal preparedness,” said Dr Chandra Bhal Jha, director at the division. “Our projection does not mean the estimated number of people will be infected with the deadly virus. The infection number depends on the measures we take to lessen the risks.”

Dengue is a viral disease transmitted by female Aedes aegypti and Aedes albopictus mosquitoes. According to the World Health Organisation, the same vector also transmits chikungunya, yellow fever, and the Zika virus.

Since January, 1,673 people from 73 districts have tested positive for the dengue virus. The deadly virus has not yet been reported in four out of 21 mountain districts—Rasuwa of Bagmati province, Manang of Gandaki province, and Humla and Dolpa of Karnali province.

In 2024, 15 people died, and 41,865 others were infected as the virus spread to 76 districts. In 2023, 88 persons died and more than 54,000 were infected by the virus, which had spread to all 77 districts. At the time, hospitals in Kathmandu Valley were overwhelmed with dengue patients, and pharmacies had run out of paracetamol, the most widely used medicine to treat fever.

Experts say reported cases may represent only a small fraction of the true scale of infection, as around 90 percent of the infected people are asymptomatic, and many deaths and infections often go unreported.

Many people infected with dengue show mild symptoms, which do not need any treatment or can be managed with paracetamol at home.

Since dengue became endemic in Nepal years ago, meaning people get infected throughout the year, health officials no longer classify it as an outbreak of a deadly virus.

Officials at the division said that they have alerted all concerned health agencies about the looming crisis, supplied testing kits, and allocated a budget to carry out a dengue search-and-destroy drive.

“We have already sent Rs 80 million to local levels to carry out the dengue search and destroy drive,”said Jha. “Health workers and health facilities are asked for necessary preparation as the disease could break out at any time. We have also requested help from other sectors and the general public to destroy dengue breeding grounds. ”

Officials say an outbreak could occur in any place at any time, as most districts across the country have reported dengue cases.

Experts say that instead of counting the number of infected people, concerned authorities must focus on implementing mitigating measures.

Experts warn that the rising temperatures, coupled with monsoon rainfall, create the perfect environment for dengue-spreading vectors to breed. They say that unless the general public is made aware of the problem and takes it seriously, the spread of the dengue virus will not lessen. They asked the authorities concerned to learn from past experiences while taking preventive measures.

“Focus should be made on behavioural change, which needs continuous efforts and investments,” said Dr Sher Bahadur Pun, chief of the Clinical Research Unit at Sukraraj Tropical and Infectious Disease Hospital. “Breeding grounds of dengue-spreading mosquitoes could be anywhere, including schools, hospitals, private houses and others, and without the participation of the general public in dengue control efforts, we cannot expect control of infection of the deadly disease.”

Doctors say along with launching a search-and-destroy drive on a regular basis, authorities should also focus on strengthening the capacity of health facilities to prevent them from being overwhelmed in the event of a possible massive outbreak, experts say.

Dengue-transmitting mosquitoes breed in clean water and bite people in daylight. Uncovered water tanks and discarded objects such as plastic cups and bottles could be breeding grounds for dengue-carrying mosquitoes.

According to doctors, mild to high fever, severe muscle pain, rashes, severe headache and pain in the eyes are some symptoms of dengue. Doctors advise those with these symptoms to seek immediate treatment. While there is no specific cure for the disease, early detection and access to proper medical care can lower fatalities.

Nepal reported its first dengue case in a foreigner in 2004 in Chitwan district. Since then, an increasing number of dengue infections, including major outbreaks, have been reported from many districts.

The World Health Organisation says there is no specific cure for severe dengue, but early detection and access to proper medical care can save lives.