The global prevalence of musculoskeletal disorders among firefighters: a systematic review and meta-analysis

ABSTRACT This systematic review and meta-analysis study aimed to explore the global prevalence of musculoskeletal disorders (MSDs) among firefighters. A systematical search was performed in three international academic databases (Scopus, PubMed and Web of Science). Overall, 31 articles were included in this review. The pooled prevalence of total MSDs in firefighters was identified as 41% (95% confidence interval [CI] [33, 50]). The prevalence of MSDs in neck, shoulders, upper back, lower back, upper extremity and lower extremity was 9% (95% CI [7, 10]), 11% (95% CI [8, 15]), 8% (95% CI [5, 12]), 31% (95% CI [27, 34]), 13% (95% CI [9, 17]) and 16% (95% CI [14, 18]), respectively. No statistically significant relationship was observed between prevalence of MSDs and year of study, mean age, size of sample, duration of prevalence, region or income level. Demographic, occupational and medical condition factors were identified that can create these disorders among firefighters.


Introduction
Today, musculoskeletal disorders (MSDs) are one of the most common occupational disorders and the cause of disabilities in industrialized and developing countries [1].As such, MSDs are a leading concern in the field of health [2].According to research conducted in the USA, 65% of all new cases of disorders in the workplace are related to MSDs [3].Based on a report from the International Labor Organization (ILO), MSDs are the second most prevalent occupational disorder among 160 million work-related disorders occurring annually worldwide [4][5][6].MSDs have been defined as a disorder or injury to the musculoskeletal system (muscles, ligaments, tendons, joints, nerves, blood vessels and soft tissues) that includes pain, tension, pressure and inflammation [7].The National Institute for Occupational Safety and Health (NIOSH) defines MSDs as a group of conditions that involve nerves, tendons, muscles and supporting structures, such as the intervertebral discs.These disorders represent a wide range of conditions that vary in severity, ranging from mild to chronic and debilitating.Examples of occupational MSDs include carpal tunnel syndrome, neck tension syndrome and lower back pain (LBP) [8].MSDs are also considered a collective term for several conditions under a range of subgroups, including: clinical disorders (such as tendonitis and vibration white finger [VWF]); lesser known clinical conditions (such as cervical tendon syndrome); and non-specific disorders (such as cumulative trauma disorders or injuries caused by repetitive stressors) [8].
Numerous factors are involved in the development of musculoskeletal injuries, including those derived from: physical, organizational and social aspects of work and the workplace; physical and social aspects of living outside the workplace (exercise); and physical and physiological characteristics of the person [9,10].Among these, the most important factors that CONTACT Saeid Yazdanirad saeedyazdanirad@gmail.comcause MSDs are inappropriate postures, repetitive and rapid movements, excessive force exertion, psychological factors, genetics and, in general, inappropriate body conditions and workstations [5,7,8].Given this diversity it is not surprising that the bodily sites where MSDs occur can vary.Khan and Singh [11], in a study on the prevalence of MSDs in 51 railway industry workers, highlighted some areas of the body, such as the shoulder (51%), neck (47%), knee (47%) and lower back (43%), to have a higher prevalence of MSDs than other areas of the body.Similar results were found in a study of 100 construction workers where the highest prevalence of MSDs was found in the neck and then the shoulder (28 and 23%, respectively), followed by the lower back (15%) and elbow (14%) [12].The prevalence of shoulder MSDs was found to be even higher (72%) in a Malaysian study of janitorial workers [13].Conversely, rather than the upper body (i.e., neck and shoulder), a cross-sectional study of 392 health specialty students by Hendi et al. [14] suggested that most symptoms of MSDs occurred in the lower back (33%).Likewise, investigating the prevalence of MSDs in 603 tobacco farmers, Kongtawelert et al. [15] found the lower back (37%) to be the most prevalent bodily site of MSDs followed by the knee (29%), shoulder (23%), wrist (20%) and hip (8%).In a less physically active population, drawn from employees from banks and insurance companies who primary worked with display screens, the lower back (77%) was again found to be the leading bodily site of MSD symptoms [16].Interestingly, perhaps spanning both trends, a survey to determine the prevalence of MSDs in schoolteachers identified the lower back and shoulder (73 and 67%, respectively) as the bodily sites where the most symptoms of MSDs occurred [17].These examples demonstrate that across nations and occupational workplaces there is high diversity in bodily sites where worker MSDs occur.
Occupational MSDs impart high costs to the healthcare system of many countries [18].Direct costs include costs paid to the physician and hospital, including rehabilitation, insurance, etc. [18].Indirect costs include disability of the injured person and their loss of wages, costs incurred by the employer in hiring and training new staff in place of the incapacitated person, and administrative costs, including related costs of compensation and quality of life costs associated with the suffering of the injured person and their family [18].
In Canada, work-related MSDs (WMSDs) are responsible for 10% of short-term rehabilitation costs and 39% of long-term rehabilitation costs [19].According to the NIOSH [3,20], MSDs have been reported to account for nearly 48% of all workrelated illnesses and rank second in the health problems category, costing more than USD 1200 million directly and 90 million indirectly.Research in Europe suggests that nearly 40 million employees (more than 30%) have suffered from MSDs; approximating 0.5-2% of the gross domestic product of the European Union [21].
Acknowledging the high prevalence of WMSDs in general, community firefighters, in particular, may face a greater risk of suffering these disorders.Firefighters are responsible for responding to a wide range of dynamic demands in their role that go beyond fire control.These tasks comprise rescue in ice water, trench, marine and aircraft, motor vehicle crashes, train derailment, vehicle extrication and hazardous material containment [22,23].The firefighting profession is a hard job and is classified as a high-risk and dangerous job with great demands placed on the musculoskeletal system [24].These demands are mainly due to the austere environmental/working conditions (e.g., temperatures above 50 °C) and prolonged levels of demanding physical exertion while carrying a heavy burden of > 20 kg of personal protective equipment (PPE) [25,26].As such, it is not surprising that WMSDs are one of the main health concerns among firefighters [22,27].In a critical review of 17 studies reporting on firefighter injuries, Orr et al. [24] reported prevalence rates ranging from 7 to 74% with the lower back the most commonly reported bodily site with the highest prevalence of injury (ranging from 20 to 32%).A systematic review and meta-analysis on Canadian firefighters, however, found the prevalence of pain in the shoulder, back and knee to be 23, 27 and 27%, respectively [22].In a study of 840 female firefighters spanning 14 different countries, North American firefighters, who presented with the highest prevalence rates of WMSDs, reported rates of 51% in the lower limbs and 49% in the lower back [28].
Meta-analysis studies are often carried out in order to achieve accurate results with high statistical power resulting from the increased sample sizes drawn from the collation of data from different studies and reducing the confidence interval of these measurements [29].Considering this, while notable research has been performed to explore the prevalence of MSDs in firefighters worldwide, the findings of this volume of work have been reported sporadically.Hence, the current study aimed to explore the global prevalence of MSDs among firefighters using a systematic review and metaanalysis.In addition, factors associated with firefighter MSDs were explored.

Materials and methods
The current systematic review and meta-analysis study (PROS-PERO ID: CRD42022303049) was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist [30].

Inclusion and exclusion criteria
Studies reporting on a MSD within populations that included firefighters were included and entered into the investigation.No filtration for publication year, age or sex/gender were used.Furthermore, review studies, editorial letters, conference papers or case studies, studies in a language other than English, studies without reporting inclusion criteria and studies without reporting prevalence were excluded.

Study screening
All articles found via the searching of the databases were introduced into Endnote and duplicates were omitted.In the next step, the titles and abstracts of the collected articles were independently checked by two reviewers (A.K.H. and S.Y.).In this step, articles clearly not of relevance to this study were omitted (e.g., World Trade Center rescue worker injury and illness surveillance, New York, 2001).The remaining articles were then checked according to the eligibility criteria by two reviewers (A.K.H. and S.Y.).Articles meeting the inclusion criteria and failing to meet the exclusion criteria were kept to inform this review.

Assessment of article quality
For assessment of study quality, the Joanna Briggs Institute (JBI) checklist for papers reporting prevalence data was used [31] with the evaluation carried out by two authors (A.K.H. and S.Y.).This checklist includes nine questions with four options: 'yes', 'no', 'uncertain' and 'not applicable'.The JBI tool evaluates the prevalence of studies on the basis of criteria comprising the suitability of the sample, suitability of sampling, sufficiency of population size, characteristics of the study population, adequacy of data analysis, credibility of the used methods, validity of identification, suitability of the statistical analysis and sufficiency of the response rate.In this tool, the number of positive answers was calculated and given a score of '1'.Thus, papers were able to be classified into three categories, comprising low quality (scores 1 and 2 out of 9), moderate quality (scores 3-6 out of 9) and high quality (scores 7-9).

Data extraction
The required data were extracted by individuals after the final selected articles were determined and scored.These extracted data consisted of the first author, year of publication, country, sample size, gender, type of study, type of occupations, age of subjects, job experience, prevalence and relevant main variables.

Statistical analysis
The selection agreement level between the two authors (A.K.H. and S.Y.) was calculated via Cohen's κ [32].The κ coefficients regarding the first and second stages were 0.87 and 0.91, which demonstrate a good level of agreement between the two authors.For calculation of heterogeneity, the Q test (significance level < 0.1) and I 2 statistics (significance level > 50%) were applied [33].Heterogeneity in a subgroup was investigated.Cochran's test and I 2 statistics were employed to investigate for significant heterogeneity reduction in subgroups (study data, sample size, duration of prevalence, study type, region and income level).Region was classified into five categories: Pacific, North America, Europe, East Asia and Middle East.Age group, study date, sample size and duration of prevalence were also categorized on the basis of the median value.Study type was divided into two categories including cohort and cross-sectional.Finally, income level included middle and high.For evaluation of publication bias, visual investigation of the funnel plot and calculation of the Egger's and Begg's tests were applied [34,35].Statistical analyses were carried out using STATA version 15.

Study selection results and basic characteristics
Through the initial search, 714 papers were found.After removing the 343 duplicate studies, 371 studies remained.Among the identified articles, 67 papers did not meet the criteria for inclusion into this review, including 12 conference papers, 29 review papers, 10 meeting abstracts, five case report papers, five papers not published in English, three letters to the editors, two short surveys and one technical paper.The title and abstracts of the remaining 304 papers were screened, resulting in 273 articles being eliminated and 31 studies remaining to be included in the present study (Figure 1).
Table 1 presents the general characteristics of the included studies, all of which were introduced into the meta-analysis.Of the included studies, one study included only female participants and 12 studies included only male participants with the remaining 18 studies including both male and female participants.The majority of the research was carried out in North America (n = 13 studies), Europe (n = 10 studies) and East Asia (n = 7 studies), respectively.Other regions included the Middle East (n = 2 studies), Pacific (n = 2 studies) and Latin America (n = 1 studies).In terms of country, the majority of the research was performed in the USA (n = 8 studies), Canada (n = 6 studies) and South Korea (n = 6 studies), respectively.In relation to country income status, 28 research studies were conducted in countries with high incomes and three studies were carried out in countries classified as middle income.No studies were performed in countries classified as low income.

Quality assessment
Based on the JBI checklist, 29 studies (nearly 93.5%) presented with moderate to high quality.The remaining two studies were considered of low quality.

Factors affecting musculoskeletal disorders in firefighters
Various studies identified different factors influencing MSDs as presented in Table 1.These can be categorized into three groups: demographic factors, occupational factors and medical condition factors.Demographic factors included ethnicity, age, career length in the fire service, obesity, smoking, gender, aerobic exercise and number of children.Occupational factors consisted of job stress, uncomfortable physical environment, high mental and physical demands, highly biomechanically demanding activities, insufficient job control, job position, work time, weight lifting, restricted mobility while wearing PPE and psychosocial dimensions in workplaces (such as interpersonal conflict, job insecurity, organizational system, lack of reward, occupational climate, organizational injustice, burnout, organizational commitment and team support).Medical condition factors were post-traumatic stress disorder (PTSD), insomnia, sleep disturbances, mental disorders, lumbar disc herniation and previous ankle sprain.

Results of meta-analysis
The random effects model was applied because of the high heterogeneity in the results.The pooled prevalence of total MSDs among firefighters according to this meta-analysis was measured as 41% (95% confidence interval [CI] [33,50]) (Figure 2).The prevalence in countries with high incomes was calculated as 39% (95% CI [30,48]) and in countries with middle incomes was calculated as 53% (95% CI [48,58]).The pooled prevalence of total MSDs in various body regions of firefighters is shown in Figure 2a-g.Based on the results, the values of the pooled prevalence of MSD among firefighters was calculated as 9% (95% CI [7,10]) in the neck, 11% (95% CI [8,15]) in the shoulders, 8% (95% CI [5,12]) in the upper back, 31% (95% CI [27,34]) in the lower back, 13% (95% CI [9,17]) in the upper extremity and 16% (95% CI [14,18]) in the lower extremity.Table 2 presents the results of subgroup analysis for the prevalence of MSDs.Based on these results, studies after 2017 (n = 8; compared to those in or before 2017, n = 10), with sample size less than 500 (n = 11; compared to those with sample size equal to or higher than 500, n = 7), with prevalence durations less than 6 months (n = 6; compared to those with prevalence durations equal to or higher than 6 months, n = 12) and that were cohort studies (n = 3; when compared to cross-sectional studies, n = 15) had a higher prevalence of total MSDs.Similarly, where studies in which the mean age of firefighters was less than 39 years (n = 8; when compared to those with mean ages equal to or higher than 39 years, n = 10), were in Middle East countries (n = 2; compared to those in other countries, n = 16) or were in middle-income countries (n = 15; compared to those in high-income countries, n = 3) had a higher prevalence of MSDs.

Results of heterogeneity
The highest number of research studies reported the prevalence of MSDs of the lower back (n = 25 studies) while the lowest number of research studies reported the prevalence of the upper back (n = 6 studies).Table 3 presents the results of evaluating the heterogeneity of the included studies.The results showed that there was high heterogeneity in the finding of the studies performed on MSDs of various body organs.

Results of publication bias evaluation
Table 4 presents the results of evaluating publication bias by Egger's and Begg's linear regression tests.Figure 3a-g shows funnel plots used to identify the possibility of publication bias for the prevalence of MSDs in various body regions.Based on the results, there was a publication bias in research studies related to total MSDs (p < 0.001) and in relation to studies of MSDs in the shoulders, lower back, upper extremity and lower extremity (p < 0.007).However, no publication bias was observed in studies related to MSDs in the neck and upper back (p > 0.05).

Results of meta-regression
A meta-regression test was used to investigate the effect of different factors on the prevalence of total MSDs including the relationship between year of study, mean of participants' ages, size of sample, duration of prevalence, region of study and income level of studied country and the prevalence of total MSDs (Table 5).The results showed that any factor could significantly affect the prevalence of total MSDs (p > 0.05).

Discussion
This systematic review and meta-analysis provides a quantitative and global estimation of MSDs among firefighters.The results of the PRISMA approach and subsequent eligibility process led to 31 studies from 714 identified articles being included to inform the review and meta-analysis.The majority of the research was performed on male firefighters in highincome countries from the region of North America, Europe and East Asia.Given that the majority of firefighters are men and that high-income countries pay more attention to the personnel health of their workforce, it is not surprising that most studies included males and were from these countries.However, in developing countries with low incomes, particularly in the Middle East and Africa, the work conditions may be worse due to older elementary equipment.The pooled prevalence of total MSDs among firefighters, according to this meta-analysis, was 41%.The highest prevalence was observed in the lower back region (31%) and the lowest in the upper back region (8%).Other regions based on the prevalence rate in this review included the lower extremity (16%), upper extremity (13%), shoulders (11%), neck (9%) and upper back (8%).The results of this study support the aforementioned reviews by Orr et al. [24] and Nazari et al. [22] who showed that highest prevalence of MSDs in firefighters were related to the back (between 20 and 32%).When compared to other occupations, a systematic review and meta-analysis of operating room personnel likewise found that the highest prevalence of MSDs was in the lower back region (61%) [36].However, in this same review, the lowest prevalence was in the elbow region with 23% [36].These results are similar to other medical MSD reviews and meta-analysis studies.Parno et al. [37], investigating the prevalence of occupational MSDs in Iran, concluded that the lower back and elbow (50 and 17%, respectively) had the highest and lowest prevalence of these disorders in employed populations.Soroush et al. [38], similarly, found the highest prevalence of MSDs among Iranian nurses to be to the lower back region (61%) and the lowest prevalence to the elbow region (18%).These findings were echoed by the work of Govaerts et al. [39] in secondary industries of 21st-century Europe, and by Clari et al. [40] in perioperative nurses, who concluded that the most and the least prevalent WMSDs were to the back overall (60%) or lower back (62%) followed by the elbow (21 and 18%, respectively).Conversely, while Umer et al. [41] likewise found the lower back (51%) to have the highest prevalence of musculoskeletal symptoms in the construction industry, the hip/thigh (20%) presented the lowest.Miners as a population, with a prevalence of total MSDs equating to 56% [42], were found by Rabiei et al. to suffer the highest prevalence to the upper back (50%) and the lowest to  the knee (16%); differing from the other reviews.As a summation, the lower back is often the bodily site with the highest prevalence of MSDs.Conversely, there are some differences between population groups.It stands to reason that the occurrence of MSDs in various body regions would depend on the job type and its risk factors.For example, in some occupations such as medical jobs and nursing, the awkward posture, prolonged standing, static movement as well as other risk factors create a high prevalence of MSDs in regions of the lower back, neck and upper extremities [43].In the steel industry, awkward postures, carrying heavy loads and repetitive movements, etc., are risk factors associated with MSDs [44].For firefighters, their PPE can weigh more than 20 kg and their clothing can affect their movement, factors which are associated with increasing their risk of MSDs [45].In view of these findings, Seabury and McLaren [46] concluded that, when compared to privatesector workers, firefighters were 3.8 times more likely to suffer a WRMSD.
Considering the causes and natures of injuries and subsequent MSDs in firefighters, Carr-Pries et al. [47] found that the occurrence of exercise and training injuries was between 8 and 55%.The authors also concluded that exercise and training were the most common causes of firefighter injuries.This is supported by the review by Orr et al. [24] which identified that training and activities at the fire station were the leading causes of injuries as opposed to actual fire suppression.Of note, some of these reported injuries occurred acutely whereas others were chronic in nature [48].Considering these differences is of importance.For example, a firefighter may experience immediate muscle cramping and pain because of sudden movements, excessive rapid overloading or intense stretching during training or operations.Conversely, some firefighter tasks, such as load carrying and sustaining poor postural positions, can cumulatively cause musculoskeletal damage, and as such injury, over time.Further, the susceptibility of some firefighters to both acute and chronic disorders due to individual factors, like previous injuries or physical structure, warrants consideration [49].Greater attention is therefore needed in MSD prevalence investigation if these injuries are to be successfully mitigated.
The volume of evidence highlighted in this review suggests that demographic factors, occupational factors and medical condition factors present as factors associated with an increased risk of MSDs in firefighters.Demographic factors, including ethnicity, older age, longer career lengths in the fire service, higher obesity, cigarette smoking, female gender, poorer aerobic exercise and a higher number of children, increase the risk of MSDs.These findings are supported by Khanzode et al. [50], who likewise identified increased age, race, longer working periods, female sex, amount of alcohol consumed, awareness on ergonomics and cigarette smoking as increasing the risk of MSDs.Occupational factors, identified in this review, consisted of increased job stress, uncomfortable physical environments, high mental and physical demands, highly biomechanically demanding activities, insufficient job control, awkward occupationally specific body positions, increased work time, heavy load lifting, restricted mobility while wearing PPE and psychosocial dimensions in workplaces (such as interpersonal conflict, job insecurity, organizational system, lack of reward, occupational climate, organizational injustice, burnout, organizational commitment and team support).Similarly, the work by Herin et al. [51] noted awkward postures, heavy loads, repetitive movements, vibration and forceful grips to be associated with creating musculoskeletal pain among workers.Hildebrandt et al. [52]    to pain and injury.Given the findings of Kang and Kim [53], who identified that firefighter tasks (including lifting, lowering, pushing, pulling and moving heavy objects) required excessive force and often occurred in uncomfortable situations, the high prevalence of MSDs in firefighters is understandable.Moreover, some firefighter tasks are performed in undesirably high or low-temperature environments while others are associated with holding a static posture for long hours.
In regard to psychosocial factors, research by Amin et al. [54] concluded that job stress and job content (including job demands, decision latitude, job security and social support) were significantly related to MSDs in a population of nurses.Kodom-Wiredu [55] likewise identified a positive relationship between firefighter MSDs and both work demands and work tasks.However, Kodom-Wiredu [55] went on to suggest that firefighter work demands moderated work task relationships given that the higher the work demand, the more work tasks were conducted.Medical condition factors associated with an increased risk of MSDs in firefighters included PTSD, insomnia, sleep disturbances, mental disorders, lumbar disc herniation and previous ankle sprains.These findings regarding medical conditions associated with MSDs in firefighters are broadly supported by Kalkim et al. [56], who observed that MSDs had a higher prevalence in people with poor or very poor health and chronic illnesses.
Based on the results of the subgroup analysis, studies after 2017 (compared to those in or before 2017), with sample size less than 500 (compared to those with sample size equal to or higher than 500), with a prevalence duration of less than 6 months (compared to those with prevalence durations equal to or higher than 6 months) and that were cohort studies (when compared to cross-sectional studies) had a higher prevalence of MSDs.The prevalence of MSDs were expected to decrease with the advancement of technology and equipment in recent years [57], but the results of this study suggest the opposite.However, the discrepancy in findings may be due to the increasing fire services in recent years or publication bias.The prevalence of MSDs was higher in studies with sample sizes lower than 500.In these types of studies, people may enter into the research more selectively, while studies with a large sample may be a better representative of the population [58].The prevalence of MSDs in firefighters was found to be higher in the last 6 months.This finding may be due to MSDs in firefighters being relatively minor (e.g., sprains and strains [24]) and resolving over time [59].
Of note, and contrary to expectations, the prevalence of MSDs in firefighters was found to be higher in cohort studies as opposed to cross-sectional studies.However, the number of cohort studies (n = 3) compared to cross-sectional studies (n = 15) on the prevalence of MSDs among firefighters was very limited and, as such, the results should be considered with caution.Studies of firefighters with a mean age less than 39 years, when compared to studies with mean age equal to or higher than 39 years, had a greater prevalence of MSDs.It may be that older firefighters work in less physically demanding job positions (e.g., managerial as opposed to an on-the-line firefighter) and mostly act in leadership roles.However, it should be noted that Kim et al. [60] found that the prevalence of MSDs in male cameramen aged 50 years or older was significantly higher than those in the age categories 30-39 years and 40-49 years.While there are notable differences in populations and the findings of this study compared to Kim et al. [60] in age-related risk factors, more research considering firefighter age and MSD prevalence is needed.
Similar to the aforementioned, firefighters in Middle East countries, as compared to firefighters in other countries, had greater prevalence of MSDs; as did firefighters in middleincome countries as compared to firefighters in high-income countries.Firefighters in countries with low and middle income, particularly in developing countries in the Middle East and Africa, may use technologically older equipment [61] which may, in turn, increase the MSD risk and contribute to the higher prevalence of MSDs in these countries.Thus, a limitation to this review was noted whereby most of the included studies were performed in developed countries while MSD concerns may be greater in developing countries with low or medium incomes, particularly in Africa.Further limitations include very limited female participant numbers, albeit indicative of this male-dominant profession, and the limited number of cohort studies compared to cross-sectional studies.

Conclusions
The results of this review and meta-analysis found that the prevalence of total MSDs among firefighters equated to 41%.The highest prevalence of MSDs was in the lower back region (31%) while the lowest was in the upper back region (8%).Various factors were identified as being associated with increasing the risk of these MSDs among firefighters.These factors were categorized into three groups, including demographic factors, occupational factors and medical condition factors.Given the high prevalence of MSDs in firefighters it is proposed that predictive planning and measures for decreasing these disorders are investigated and implemented.For example, developing and maintaining high levels of firefighter fitness and exploring the use of advanced equipment may be of benefit.This issue is of greater importance in developing countries with low and medium incomes that have received less research attention.

Figure 3 .
Figure 3. Funnel plot to identify the possibility of publication bias for the prevalence of musculoskeletal disorders (MSDs) in different body regions: (a) total, (b) neck, (c) shoulder, (d) upper back, (e) lower back, (f) upper extremity and (g) lower extremity.Note: ES = effect size.

Table 1 .
General characteristics of included studies.

Table 2 .
Results of subgroup analysis for the prevalence of total musculoskeletal disorders.

Table 3 .
Results of evaluating heterogeneity of the included studies.

Table 4 .
Results of evaluating publication bias.

Table 5 .
Meta-regression results for the prevalence of total musculoskeletal disorders.