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1 Introduction: The problem of natural rubber latex (NRL) allergy

1 Introduction: The problem of natural rubber latex (NRL) allergy

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Recent research on natural rubber latex (NRL) allergy


then discusses the current knowledge about the mechanisms of development of

allergic immune responses and the role of different NRL allergens and glove

powder. The third section also deals with changes in glove manufacture upon

responding to the demand for increased use of protective gloves, chemical

allergens, cross-reactions, diagnostic procedures in patient care and the

newly discovered role of genetic factors in NRL allergy. Presentation and

clinical pictures of NRL allergies are also discussed. Section 18.4 describes

changes in the incidence and prevalence of NRL allergy and the changing

epidemiology, revealing an ongoing gradual decrease in new cases of Type

1 NRL allergy in many parts of the world. The peak of the NRL allergy

‘epidemic’, which hit in the 1980s and 1990s, seems to have passed in

healthcare in the western world, but problems do still exist, in particular in

developing countries and in the non-medical fields.

Section 18.5 handles the key issues in reducing NRL allergy, discussing

changes in glove manufacture, education, development of international

standards and means to reliably measure the allergenic potential of NRL

products as well as regulatory activities and numerous published position

papers. Future trends in NRL allergy research are assessed in Section 18.6.

Central findings and advances in recent research efforts on NRL allergy are

summarised in Section 18.7. Suggestions for further information are proposed

in Section 18.8.


Medical background to NRL allergy

18.2.1 Basic concepts in immunology

Immunology is generally considered as the discipline of the body’s defense

against infections. The responses mounted against infectious agents, such as

bacteria, viruses or fungi, are known as immune responses. The responses can

be specific and are then defined as adaptive immune responses, developing

as adaptation to particular pathogens. The adaptive immune response can

lead to a phenomenon known as immunological memory and confer lifelong

protective immunity against reinfection by the same pathogen.

In addition, the body is ready for non-specific or innate immune responses

which in the front line combat the wide range of pathogens surrounding

us. This system is not specific for any individual pathogen nor does it lead

to immunological memory. Central components of this front-line defense

are ubiquitous phagocytic cells (macrophages), able to engulf and digest

microorganisms. Another important compartment in the non-specific host

defense is the complement system, a collection of several plasma proteins

that can be activated directly by pathogens or indirectly by pathogen-bound

antibody, leading to various effector functions important in the neutralisation

and elimination of the invaders.


Chemistry, Manufacture and Applications of Natural Rubber

A vital part of the immune responses is the production of specific

antibodies belonging to one or several of the five major immunoglobulin

classes (IgG, IgA, IgM, IgD and IgE). They can combine with a large variety

of substances, known as antigens, and participate in the inactivation and

elimination of the unwanted invaders. An antigen is simply defined as a

substance (often a protein or polypeptide) that can stimulate the production of


A crucially important compartment in the immune responses is composed of

white blood cells or lymphocytes. The immunologically relevant lymphocytes

include T-cells, further divided into cytotoxic and helper type T-cells (Th1

and Th2) as well as regulatory T-cells, and B-cells, eventually maturing to

plasma cells which are responsible for antibody production. Lymphocytes

very efficiently recognise pathogenic microorganisms, target them and, in

collaboration with adaptive and innate immunity mechanisms, fight against


18.2.2 Deviation of immune responses towards allergic

(hypersensitivity) reactions

The immune defense system sometimes ‘goes wrong’, i.e. leads to adverse

or pathologic reactions, known as allergies or hypersensitivity reactions in

which immune responses are typically mounted against harmless environmental

antigens such as pollen, food or drugs.

Hypersensitivity reactions in immunology and immunopathology were

already classified about 50 years ago by Gell and Coombs (1963) into four

types. As seen in Table 18.1, Type I reactions are immediate-type allergic

reactions (developing in minutes after exposure) mediated by IgE-class

antibodies, Type II are mediated by IgG-class antibodies, Type III by immune

complexes composed usually of IgG-class antibodies and corresponding

antigens. Type IV reactions, known also as delayed hypersensitivity reactions

(developing typically in 24−48 hours after exposure), are caused by T-cells.

In NRL allergy, Type II and Type III allergies seem to play minor roles.

18.2.3 Sensitisation in Type I allergy

Individuals have first to be exposed to the antigen (allergen) and become

‘sensitised’ to it by producing IgE-class antibodies. Sensitisation alone does

not lead to clinical allergies, only upon re-exposure to the same antigen may

an allergic reaction develop. Allergens are in most cases delivered through

mucous membranes on the epithelia of eyes, nose, airways, gut or genitalia,

where they can be picked up by specialised antigen-presenting cells, in

particular so-called dendritic cells.

Recent research on natural rubber latex (NRL) allergy


Table 18.1 Classification of hypersensitivity (allergic) reactions according to Gell

and Coombs (1963) in relation to NRL allergy

Type I

Immunoglobulin IgE

class or

mediating cell

Type II

Type III

Type IV







Soluble antigen Cell-associated Soluble antigen



bound by





antigen; in NRL


allergy NRL


Soluble antigen

(e.g. chemical

or cellassociated




Mast cell

activation and

release of



reactants (e.g.,


Activation of


system and











and induces

release of



(cytokines and


Typical allergic

reaction in NRL




allergic rhinitis,




Minor role in

NRL allergies



allergy to


Minor role in

NRL allergies



serum sickness)

Allergic contact


(caused in

NRL allergy

by rubber


18.2.4 IgE-mediated (Type I) allergies

Characteristically, most immunoglobulins circulate in the blood, but IgEantibodies are localised mainly in tissues, being bound to the surface of mast

cells and also to some extent to so-called basophilic cells via high-affinity

IgE receptor molecules (FceRI). When specific IgE antibodies, now bound

on the FceRI receptors, catch their corresponding antigens (allergens), these

complexes are cross-linked and cause the release of inflammatory mediators

from characteristic granules of mast cells. These mediators, in particular

histamine, induce the allergic reactions. The commonest Type I manifestation

is known as contact urticaria.

In the development of allergic reactions, activation of Th2-type helper

T-cells and the production of typical allergy-associated cytokines (in

particular interleukin 4, interleukin 5 and interleukin 13) seem to be crucial.

Interestingly, exposure of individuals to very low amounts of allergens

favours the activation of these allergy-related pathways, e.g., the dominance

of Th2-type cells over Th1-cells.


Chemistry, Manufacture and Applications of Natural Rubber

Allergen introduced into the bloodstream can cause anaphylaxis, an

uncommon but severe and potentially fatal form of IgE-mediated allergy. In

severe anaphylaxis, increase in vascular permeability results from massive

release of histamine from mast cells further leading to sudden loss of blood

pressure, constriction of airways and shock. The reaction can usually be

controlled by the immediate injection of epinephrine.

18.2.5 Genetic factors in Type I allergies

Both genetic and environmental components contribute to the risk of the

development of allergic diseases. Atopy is defined as a genetically determined

tendency to produce high amounts of IgE-class antibodies to a large variety

of environmental antigens. The prevalence of atopy in various populations

varies considerably; estimates from 10 to 40% have been presented. Several

genes, including genes in the HLA (human leukocyte antigen) class II region

have been suspected to govern the susceptibility to various manifestations

of allergic diseases.

18.2.6 Type IV allergic reactions

Type IV hypersensitivity, or delayed hypersensitivity reactions, are mediated

by antigen-specific effector T-cells, namely T-helper-1 (Th1) and CD8

cytotoxic T-cells. These cells function in essentially the same way as they

do in response to pathogens. The provoking antigens are typically highly

reactive small molecules, such as tuberculin or various chemicals. These

substances react with locally accessible self-proteins, creating hapten−protein

and hapten−peptide complexes. Hapten denotes a small molecular weight

substance that is not big enough to be bound by antibodies or cell receptors.

These complexes are then presented to the major histocompatibility complex

(MHC) molecules (a set of molecules displayed on cell surfaces being

responsible for lymphocyte recognition and antigen presentation) and

recognised by T-cells as foreign antigens.

Direct contact in the skin with certain antigens or haptens can cause local

inflammatory reaction, known as allergic contact dermatitis. Like in Type

I allergies, the first phase involves sensitisation, i.e. uptake, processing and

presentation of the antigen by local antigen-presenting cells. In the second

phase, Th1-cells that have been primed by a previous exposure to the antigen

become activated and release mediators ending up in local inflammatory

cell infiltration, accumulation of fluid and protein and, finally, allergic

manifestations in the affected skin.

Further reading on the medical background of immunology and allergy

can be found in Janeway’s Immunobiology, (Murphy, 2012).

Recent research on natural rubber latex (NRL) allergy



Mechanisms of development and clinical

presentation of NRL allergy

18.3.1 Background, historical aspects and evolution of

NRL allergy to an ‘epidemic’

Highlighting historically interesting milestones and trends in the use of

NRL may be helpful when assessing the current problems of NRL allergy.

William Stewart Halsted, a renowned US surgeon of Johns Hopkins Hospital,

is generally credited with introducing protective rubber gloves to surgery

in the mid-1890s (cited by Rankin, 2006, p. 420). With the invention of the

vulcanisation process, the use of rubber became widespread, resulting in

its use in the manufacture of over 40,000 different products today. Allergic

reactions to NRL were not noticed until some 30 years later, in the first

reported case of allergy to dental cofferdam (Stern, 1927). Then, some

half a century later, the allergy issue broke through in reports showing that

protective gloves are able to cause allergic reactions (Nutter, 1979; Förström,

1980). A few years later, allergic reactions to NRL were determined to be

IgE-mediated (Köpman and Hannuksela, 1983; Turjanmaa et  al., 1984).

Sensitisation to NRL turned out to be common in healthcare workers and

in pediatric patients with spina bifida and other patients with congenital

anomalies and histories of multiple surgical procedures (Turjanmaa, 1987;

Slater 1989; Turjanmaa and Reunala, 1989; reviewed by Turjanmaa et al.,

1996). The seriousness of this ‘new’ allergy became a subject of substantial

media coverage and other publicity, especially after anaphylactic reactions

to NRL had been published (Turjanmaa et al., 1984; Slater, 1989; Ownby

et al., 1992, Kelly et al., 1994).

Following the introduction in the US of ‘Universal Precautions’ (Centers

for Disease Control, 1987), directed at minimisation of HIV infection (AIDS)

and hepatitis, glove use increased tremendously (reviewed, e.g., in Sussman

et al., 2002). This increase in demand for gloves resulted in changes in NRL

harvesting and manufacturing practices that may have altered the protein

content and thereby allergen content of gloves. It has been proposed, for

example, that liquid NRL was often collected from younger trees than before,

the production of NRL was accelerated by injection of stimulants into the

trees and the period of storage before manufacture was shortened. Early

on in the history of NRL allergy, some authors (White, 1994; Yip et  al.,

1994) suggested that the increased production in response to the sudden

upsurge in demand for NRL gloves often led to inadequate leaching, which

is the main method used to reduce the content of water-soluble allergens

(reviewed in Palosuo et al., 2011, p. 235). Also, the earlier common re-use

and washing of surgical and examination gloves had largely discontinued.

Thus, a stream of high-protein and often powdered NRL gloves entered the


Chemistry, Manufacture and Applications of Natural Rubber

markets. Consequently, the industry had to respond to the new problem and

the rising demand for ‘safer’ gloves. It is well known that the escalating

glove use was then associated with a remarkable rise in reports of allergic

reactions to NRL gloves among healthcare workers, first reports appearing

in Europe and a few years later in the US (Turjanmaa, 1987, reviewed in

Turjanmaa and Reunala, 1988; Slater, 1994; Hunt et al., 1995, reviewed in

Charous et al., 2002a,b).

Additional factors further affecting the magnitude of the problems were

not fully understood but included, for example, increasing general awareness

of the disease, better diagnostic preparedness and education of healthcare

professionals. On the other hand, guidelines and recommendations produced

by various scientific associations and regulatory bodies in the midst of the

‘epidemic’ started to work in the other direction, i.e. to decrease unnecessary

exposure of people to NRL products and thereby to decreasing sensitisation

and appearance of new cases.

It should be kept in mind that the scientific reports on NRL allergy focused

almost exclusively on medical gloves. Compared with the huge number of

publications on NRL gloves, only few studies were conducted on problems

related to other NRL products like toy balloons, dental dams, condoms, sport

bands or mattresses (Yunginger et  al., 1994; Chardin et  al., 2000; Crippa

et al., 2006; Kostyal et al., 2009).

18.3.2 Mechanisms of development of allergic immune

responses to NRL proteins

Type I (immediate hypersensitivity) reactions

The immune responses in the typical Type 1 allergy encompass production

of specific antibodies belonging to immunoglobulin class IgE. Before

that, specific immune cells, T- and B-lymphocytes, have recognised the

allergen(s), become activated and enabled the production of antibodies.

IgE class antibodies attach via their high-affinity Fc receptors (FceRI) to

mast cells and basophilic cells. When meeting their corresponding antigens

(allergens) these antibody-coated cells release within minutes of exposure

vasoactive amines like histamine, leukotrienes, prostaglandins and other

types of mediators, which are responsible for the allergic reactions. Type I

reactions most frequently present as cutaneous reactions, typically as contact

urticaria (Tables 18.1 and 18.2).

Type IV (delayed hypersensitivity) reactions

Type IV allergies are cell-mediated reactions where allergens are presented

to CD4-positive T-cells (so-called ‘helper’ T-cells), leading to production

Recent research on natural rubber latex (NRL) allergy


Table 18.2 Symptoms of IgE-mediated (Type I) NRL allergy

∑ Symptoms usually develop within minutes of exposure and vary from mild

local reactions to severe systemic reactions

∑ The most frequently reported manifestation is contact urticaria

∑ Systemic reactions, e.g., anaphylactic shock, are usually connected to release of

the antigen to circulation and/or exposure through mucous membranes

∑ Allergic rhinitis and asthma can occur after inhalation of NRL allergens

Table 18.3 Main risk groups for NRL allergy

∑ Healthcare workers

∑ Children with spina bifida or other congenital anomalies with histories of

multiple surgeries at an early age

∑ People with hand dermatitis

∑ Atopic individuals

∑ Genetic background of atopic individuals is possible risk factor

of inflammatory cytokines, e.g., various interleukins, and recruitment of

CD8-positive T-cells (so-called ‘cytotoxic’ T-cells). On subsequent (or

prolonged) exposure, the immune system is primed to react again against

the same antigen. The reactions are delayed, occurring over 24−48 hours

after exposure, resulting in pruritic, eczematous reactions, usually defined

as allergic contact dermatitis.

18.3.3 Clinical presentation and risk factors

When the number of reported cases of contact urticaria to NRL gloves

had dramatically increased, the clinical spectrum and severity of Type I

NRL allergy had also widened (reviewed by Ownby, 2002) with reports of

rhinoconjunctivitis, asthma and intraoperative anaphylaxis (Table 18.2). NRL

had become recognised as a major cause of occupational asthma (Vandenplas,

1995; McDonald et al., 2000) and the main risk factors for developing NRL

allergy were determined (Table 18.3). The highest risk was associated with

professions in healthcare, in addition to children with spina bifida or other

congenital anomalies subjected to surgical procedures.

Genetic background has also been brought in as an additional possible risk

factor among atopic individuals. Accordingly, Rihs et al. (2002) had shown

that certain HLA (human leukocyte antigen) haplotypes (HLA-DQ8 and

HLA-DQ8-DR4) are positively associated with specific immune responses

to the major NRL allergen Hev b 6.02 (hevein) in healthcare workers with

NRL allergy, but not in patients with spina bifida. In addition, according to

Brown et al. (2005), the observed significant association of interleukin 13

and interleukin 18 promoter polymorphisms with NRL allergy may suggest

a location for genetic control in the induction of NRL allergy in healthcare


Chemistry, Manufacture and Applications of Natural Rubber

workers. The overall weight of the genetic factors as risk factors awaits still

further studies.

18.3.4 Diagnosis of NRL allergy

Reliable diagnostic procedures are required not only to correctly diagnose

the diseases but also to obtain reliable figures for prevalence rates that can

be compared in different parts of the world. Diagnosis of NRL allergy is

optimally based on compatible clinical history, skin prick testing using

preferably a standardised reagent, and measurement of IgE antibodies in

the blood (Turjanmaa et al., 1997; Turjanmaa, 2001). However, a prevailing

shortcoming is the considerable differences in diagnostic procedures in

various parts of the world. An important detail has been the lack of generally

accepted reagents for skin prick testing, a problem especially manifest in the

US, where the Food and Drug Association has not accepted any reagents for

this purpose as recently discussed again by Accetta Pedersen et al. (2012).

In line with the most recent developments in component-resolved

diagnostics, extended now also to NRL allergy, it appears that diagnoses

may become more specialised in the future through the use of microarrays of

recombinant Hevea proteins (Ebo et al., 2010; Ott et al., 2010). These tools

allow further identification of immune responses to such Hevea allergens that

are likely to be relevant to the patient. Facilities for these new sophisticated

methods may, however, not yet be widely available.

18.3.5 Types of NRL allergens

Proteins or peptides eluting from NRL gloves are considered as major sources

of sensitisation, i.e., capable of generating characteristic allergic immune

responses in susceptible individuals (reviewed in Turjanmaa et al., 1996).

Other NRL-based medical devices may include, for example, catheters,

tubings, balloon cuffs and dental cofferdams which may all cause allergic

reactions. The source material for NRL products, the native liquid sap of

the rubber tree, relatively seldom sensitises exposed subjects as shown by

the low prevalence of NRL allergy in rubber tree tappers and in workers in

glove manufacture (Chaiear et al., 2001).

Knowledge of NRL allergens and their quantification in NRL products

has significantly increased during the last two decades (Palosuo et al., 2002,

2007; Tomazic-Jezic and Lucas, 2002). In the liquid latex of the rubber

tree, more than 200 different proteins or peptides have been demonstrated

of which some 50 can bind IgE (Alenius et  al., 1994; Posch et  al., 1997)

and can therefore be defined as allergens. The World Health Organisation/

International Union of Immunological Societies Allergen Nomenclature

Subcommittee (WHO/IUIS; www.allergen.org) currently (November 2012)

Recent research on natural rubber latex (NRL) allergy


recognises 14 officially acknowledged NRL allergens (Table 18.4). Most

clinically relevant NRL allergens have been cloned and produced in various

vectors by recombinant DNA techniques (Wagner and Breiteneder, 2005).

Solving three-dimensional structures of the allergen molecules and

information on their conformational IgE-binding epitopes on the surface of

the molecules will be increasingly important for studies of the allergenic

potential of the proteins. Of NRL allergens, three-dimensional structures are

so far available only for Hev b 6.02 (hevein) and Hev b 13.

Glove allergens

Manufacturing processes are harsh treatments during which most of the liquid

NRL-contained proteins break up and disintegrate. Only those which can

retain their immunological properties may end up as active molecules in the

final manufactured products. Currently, altogether, seven Hevea allergens

have unequivocally been identified in extracts of NRL gloves (Table 18.4)

(Lu et al., 1995; Palosuo et al., 2002; 2007; Yeang et al., 2004; Lee et al.,

2010). The most important glove allergens are hevein (Hev b 6.02) and an

acidic 16 Kd hevea protein (Hev b 5) and two hydrophobic proteins known

as rubber elongation factor (REF or Hev b 1) and small rubber particle

associated allergen (Hev b 3). Hevein is present in high concentration in

practically all highly or moderately allergenic gloves (Palosuo et al., 2002;

2007; Yagami et al., 2009).

Related to the presumptive sensitisation pathways, reports of Peixinho

et al. showed that concentrations of Hev b 1 and Hev b 3, major allergens

Table 18.4 WHO/IUIS acknowledged NRL allergens

Official name

Conventional name

Detected in gloves or

glove extracts

















Rubber elongation factor (REF)


Small rubber particle protein

Microhelix protein complex

Acidic 16 kDa protein

Prohevein, hevein precursor

Hevein, mature hevein

C-terminal fragment of prohevein

Patatin-like hevea-protein

Hevea profilin

Hevea enolase

Manganese superoxide dismutase

Hevea endochtinase

Hevea lipid transfer protein (LTP)

Early nodulin-specific protein, esterase



















































Chemistry, Manufacture and Applications of Natural Rubber

for patients with spina bifida, were significantly higher on external surfaces

of NRL gloves, while internal surfaces had higher levels of Hev b 5 and

Hev b 6.02, the major allergens for healthcare workers (Peixinho et  al.,

2006). Furthermore, the authors found different in vivo reactivity patterns in

healthcare workers and in patients with spina bifida to extracts of the internal

and external surfaces of gloves, which indeed suggests that sensitisation and

clinical reactions may occur by different routes of exposure (Peixinho et al.,

2008, 2012; Marchetti-Deschmann and Allmaier, 2009). Furthermore, this

new information may turn out to be helpful in designing and considering

possible new manufacturing processes.

Allergens in non-medical NRL products

Allergies to household gloves were recently investigated by Proksch et al.

(2009) who reported that, in line with many earlier largely unpublished

observations, high allergen content is rarely seen in household gloves.

Toy balloons have been addressed in some studies (Yunginger et  al.,

1994; Crippa et al., 2006; Kostyal et  al., 2009) showing that they may

contain high concentrations of NRL allergens, comparable with levels

seen in powdered NRL gloves. This fact has been considered genuinely

worrying since the main target group of exposure is children. It is well

known that the allergenic potential of toy balloons is not regulated by any


Condoms were among the first NRL products reported to cause allergic

reactions ranging from genital urticaria to anaphylaxis in subjects who had

become allergic to NRL (reviewed by Levy et al., 2001). The severity of the

adverse reactions is not unexpected, as Yunginger et al. (1994) and Docena

et  al. (2000) showed that traditional NRL condoms may contain as high

levels of allergens as powdered NRL medical gloves. Many properties of

condoms are regulated by existing standards but there have so far not been

requirements related to their residual protein or allergenic potential. Only

scattered observations are available of baby pacifiers (teats) made of NRL,

certain NRL sports equipment like sports bands (Untersmayr et al., 2008)

and rubber mattresses (Chardin et al., 2000). The common shared problem in

monitoring and controlling the allergenic properties of this type of products

is the lack of standardisation.

Chemical allergens in NRL products

Type IV reactions, typically presenting as allergic contact dermatitis, occur

in response to chemicals present in gloves, generally used as parts of the

manufacturing process. Such chemicals include, in particular, accelerators

such as thiurams, carbamates, thiazoles, thioureas and guanidines (Nettis

Recent research on natural rubber latex (NRL) allergy


et  al., 2002; reviewed by Yip and Cacioli, 2002). A large proportion of

these chemicals are leached out in the further stages of production, through

processes such as ‘wet-gel leaching’. Examples of commonly used chemicals

are listed in Table 18.5.

Although Type IV allergic contact dermatitis is not life-threatening, it

can cause significant morbidity. Allergic contact dermatitis disrupts the skin

barrier and alters the normal physiology of the skin, which may occasionally

lead to development of more serious IgE-mediated responses to NRL proteins

(Cohen et al., 1998).

18.3.6 Glove powder

Corn starch (currently the only glove powder in general use) itself is not

believed to cause allergic symptoms but plays an important role in being

an efficient carrier of allergenic molecules, enabling, for example, airborne

spreading of allergens, as originally shown more than 20 years ago (Turjanmaa

et al., 1990; Tomazic et al., 1994; Lundberg et al., 1995). The development of

methods to manufacture powder-free NRL products (discussed, for example,

in Koh et al., 2005) and their implementation has been an important turning

point in the prevention of NRL allergies. For reasons not yet fully understood,

powder-free NRL gloves tend to contain lower concentrations of proteins

and allergens than powdered products. Powdered gloves, including brands

containing only low or negligible amounts of NRL allergens, are still available

for certain applications within the healthcare and hospital environment, for

example where their superior grip properties are sought after. Their use is

generally restricted to areas where the risk of powder contamination is low

(Palosuo et al., 2011, p. 239).

18.3.7 Latex-fruit syndrome

Individuals who are allergic to certain tropical fruits, such as kiwi fruit,

bananas, chestnuts and avocados, are frequently (30−60%) allergic to NRL

as well (Blanco et al., 1994). The coinciding allergies are known as latexfruit syndrome and the mechanisms behind the cross-reactivity are based

Table 18.5 Rubber chemicals shown to cause allergic reactions (allergic contact

dermatitis, Type IV hypersensitivity reaction)

Thiazoles (e.g., 2-mercaptobenzo-thiazole, 2 MBT)

Thiurams (e.g., tetramethylthiuram monosulfide, TMTM)

Dithiocarbamates (e.g., zinc dibutyl-dithiocarbamate, ZDBC)


Thioureas (e.g., dibutylthiourea, DBTU)

Amine aldehydes

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