R E S E A R C H A R T I C L E Open Access
Criteria in diagnosing nocturnal leg cramps:
a systematic review
, Mathieu de Greef
, Wim Krijnen
and Cees van der Schans
Background: Up to 33% of the general population over 50 years of age are affected by nocturnal leg cramps. Currently
there are no generally accepted clinical characteristics, which identify nocturnal leg cramps. This study aims to identify
these clinical characteristics and to differentiate between them and the characteristics of restless leg syndrome and
periodic limb disorder.
Method: A systematic literature study was executed from December 2015 to May 2016. This study comprised of a
systematic literature review of randomized clinical trials, observationalstudiesonnocturnalandrestcrampsoflegsand
other muscles, and other systematic and narrative reviews. Two researchers independently extracted literature data and
analyzed this using a standardized reviewing protocol. Modified versions of the Cochrane Collaboration tools assessed
the risk of bias. A Delphi study was conducted to assess agreement on the characteristics of nocturnal leg cramps.
Results: After systematic and manual searches, eight randomized trials and ten observational studies were included. On
thebasisoftheseweidentifiedsevendiagnostic characteristics of nocturnal leg cramps: intense pain, period of duration
from seconds to maximum 10 minutes, location in calf or foot, location seldom in thigh or hamstrings, persistent
subsequent pain, sleep disruption and distress.
Conclusion: The seven above characteristics will enhance recognition of the condition, and help clinicians make a clear
distinction between NLC and other sleep-related musculoskeletal disorder among older adults.
Keywords: Cramps, Nocturnal, Diagnosis, Aged, Sleep-wake transition disorder, Restless legs syndrome
Nocturnal Leg Cramps (NLC) is a musculoskeletal dis-
order characterized by suddenly occurring, episodic, per-
sistently painful, involuntary contractions of the calf,
hamstrings or foot muscles at night . Up to 33% of the
general population over 50 years of age have complaints
related to NLC . In 20% of these cases, cramps also
occur during rest periods in the daytime . Sleep distur-
bances, which may seriously affect well-being and quality
of life, are common among patients with NLC [4, 5].
Symptoms, as well as prevalence and incidence, progress
with advancing age [1, 6]. There is no consensus about
aetiology of NLC, however it is suggested that shortened
muscle length among older less physically active people is
a risk factor . Medical pathologies associated with NLC
are chronic liver and renal failure (haemodialysis), vascular
diseases, magnesium or calcium deficiency, dehydration
and varicose veins [2, 7]. A pre-stretching protocol by
physical therapists, as well as medical treatment blocking
the medial branch of the deep peroneal nerve after lumbar
surgery, may be effective in treating NLC [8, 9].
In contrast to the restless leg syndrome (RLS) and the
idiopathic periodic limb movement disorder (PLMD),
diagnosing NLC is hindered due to lack of a categorical
definition of NLC. Moreover, different types of muscular
cramps such as idiopathic, rest, leg, or pregnancy-related
cramps are similar to NLC symptoms and are often con-
fused in the literature .
Diagnostic criteria for RLS are clearly stated as follows:
uncomfortable and unpleasant sensations in the legs, feet
or arms associated with an urge to move; relief of symp-
toms by moving the affected limb; occurrence during rest
in the evening or at night [11, 12]. The International
* Correspondence: email@example.com
Research Group Healthy Ageing, Allied Health Care and Nursing, Hanze
University of Applied Sciences, Groningen, The Netherlands
SOMT University Campus, Institute for Master Education in Musculoskeletal
Therapies, Amersfoort, The Netherlands
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Hallegraeff et al. BMC Family Practice (2017) 18:29
Restless Leg Syndrome Study Group approved the validity
of a rating scale for RLS, which reflects the severity of the
discomfort . Idiopathic PLMD symptoms include the
repetitive jerking movements of the leg for approximately
20-30 seconds during sleep, with the complaints when
awake being more intense than during sleep. PLMD can
be classified into mild, moderate, and severe levels as mea-
sured by the Periodic Limb Movement Index. Additionally,
both RLS and PLMD may co-exist . No consensus has
been reached regarding the diagnostic criteria for NLC, or
how to differentiate them from the RLS and PLMD criteria
. Primarily based on the patient history, the diagnosis
of NLC may be confused with RLS or PLMD .
Generally, nocturnal pain can be a symptom of a ser-
ious pathology such as Parkinson disease, cardiovascular
and renal diseases, lumbar canal stenosis, osteroarthritis,
peripheral neuropathy or cirrhosis. It is important to
differentially diagnose NLC when is present as a nonspe-
cific musculoskeletal disorder, or related to serious
This study focuses on strengthening the available cri-
teria in order to prevent the misdiagnosis of NLC, for
RLS or PLMD. The first aim of this literature review is
to identify characteristics for diagnosing NLC. The sec-
ond aim is to differentiate these diagnostic characteris-
tics from other sleep-related disorders, such as RLS and
PLMD, for application in clinical care.
A systematic review was done to identify diagnostic criteria
of NLC. The methodology is specified in our PROSPERO-
registered protocol (16467) and conforms to Preferred
Reporting Items for Systematic Reviews and Meta-analyses
(PRISMA) guidelines . In order to differentiate between
NLC, on the one hand, and RLS and PLMD, on the other,
an additional Delphi methodology was used. In this study a
focus group of 27 experts assessed the relevance of the
An experienced librarian assisted in the development of
a search strategy to identify recognized terminology.
Four electronic databases were used including MED-
LINE, Cinahl, EMBASE and PEDro (1990 to May 2016).
The search included all commonly used terms for
NLC such as ‘cramps’,‘muscle cramps’,‘nocturnal leg
cramps’,‘leg cramps’,‘night leg cramps’,‘rest cramps’,
‘sleep-wake transition disorders/classification’,‘aged’,
‘randomized controlled trial’,‘observational study’,‘clin-
ical study’,‘systematic review’,‘meta-analysis’,‘validation
Inclusion criteria included randomised clinical trials, or
observational studies reflecting NLC, muscle cramp, leg
cramp, or rest cramp. The studies had to use the diag-
nostic criteria and classification in older adults aged over
50 years. A time frame spanning the previous 25 years.
Studies with non-English abstracts were excluded.
Two authors (JMH and MHGdG) independently ex-
tracted, screened, and reviewed all titles and abstracts of
the retrieved articles. The articles were interpreted and
classified into randomised clinical trials and observa-
tional studies. Reference lists of any recent reviews were
hand searched in order to identify additional studies and
help in excluding any duplicates.
The characteristics, diagnostic features and population
characteristics of the investigated populations were sum-
marised and catalogued. Randomised clinical trials and
observational studies were screened for descriptions of
diagnostic terms or classification criteria for NLC during
sleep among adults aged over 50. For each included
study, descriptive data regarding the participants and
diagnostic terms were extracted. A flowchart was made
to show the process of the literature search .
Cochrane checklists for randomised clinical trials and
observational studies were appraised using the methodo-
logical quality (risk of bias) of the included studies. To
discuss any discrepancies between the two reviewers,
consensus meetings were arranged. Complete agreement
was reached after discussions with a third reviewer
(CvdS) in all of the cases.
The Delphi methodology was performed to examine the
relevance of the extracted diagnostic criteria found in
the systematic review. A questionnaire with closed-
ended questions on a five-point Likert scale (always –
mostly –sometimes –never - not known) was presented
to a focus group of experts. The questionnaire was de-
veloped based on the results of the literature search and
comprised the following items: (1) Are you known with
NLC; (2) NLC has a sudden onset; (3) NLC is only
present at night; (4) Pain and/or intense pain is the main
characteristic; (5) NLC duration varies from seconds to
10 minutes; (6) NLC location is thigh, calf or foot; (7)
After reduction of NLC there will be pain afterwards; (8)
NLC might be associated with sleep disruption; (9) NLC
is associated with medication use / comorbidity; (10)
NLC might be associated with distress. The designated
criteria for inclusion were established by more than 50%
Hallegraeff et al. BMC Family Practice (2017) 18:29 Page 2 of 9
of the respondents. Geriatric experts were randomly
chosen on the basis of their expertise in geriatric health.
After completing the systematic search and manual
searches of the reference lists of the systematic reviews
and narrative reviews and after removing duplicates and
records not meeting the inclusion criteria, in the screen-
ing a total of 221 papers were yielded of which 162 were
irrelevant and had to be excluded due to not meeting ti-
tles and abstracts. This resulted in 59 records that were
appropriate for further evaluation. Subsequently, 41 full-
text articles were excluded because they did not describe
diagnostic criteria of NLC in older adults. No primary
studies with the focus on diagnosing were found. Eight
randomised clinical trials and ten observational studies
were eligible for analysing classification characteristics of
NLC. Full consensus between MHG and WPK was
reached regarding the included citations. Figure 1 presents
the selection of the studies through the review process.
Two randomised clinical trials [14, 15] had high and
unclear risk of bias due to a lack of internal validity,
however the description of the included NLC patients
The groups were treated equally in all studies, and the
randomisation procedure was performed well, except in
one instance. Among the observational studies two
showed low risk of bias [4, 16]. In all studies, the popu-
lations were well defined.
See Tables 1 and 2 for risk of bias and Table 3 for the
description of the study characteristics.
The total number of participants in the 18 included
studies was 36,515 of which the study of Garrison et al.
2015 included 31,339 participants. Overall, 51% of the
participants were male and mean age of participants was
64 years (range 51-75 years).
Comorbidities were categorized in five domains:
Fig. 1 Flow diagram of the systematic review, modified from Moher et al., 2009 
Hallegraeff et al. BMC Family Practice (2017) 18:29 Page 3 of 9
Heart and vascular diseases: coronary artery disease,
peripheral vascular disease, hypertension, varicose
veins, ankle oedema, vascular occlusive disease and
Kidney diseases: renal dialysis, haemodialysis,
uraemia, hypocalcaemia and hypokalaemia.
Neurological diseases: neuropathies, motor neuron
disease, radiculopathy or hereditary cramp
syndromes, neuromuscular or neurological diseases,
peripheral neuropathy, Amyotrophic Lateral
Sclerosis, poliomyelitis, lumbar spinal radiculopathy,
lumbar canal stenosis and stroke.
Musculoskeletal disorders: arthritis and myopathies.
Metabolic disorders: Diabetes Mellitus, plasma
electrolyte abnormalities hepatic, liver cirrhosis,
postphlebitic syndrome volume depletion,
Table 1 Risk of bias of the included randomised clinical trials (9-item Cochrane checklists for randomised trials
Connolly 1992 
Coppin 2005 
Garrison 2011 
Hallegraeff 2012 
Jansen 1997 
Roffe 2002 
Serrao 2001 
Young 1993 
Coppin 2005 , Garrison 2011 , Hallegraeff 2012 , Jansen 1997  and Roffe 2002  showed low risk of bias
Table 2 Risk of bias of the included observational studies (9-item Cochrane checklist for observational studies)
Exposure Outcome Blinding Follow-
Loss to follow
Angeli 1996 
Baskol 2004 
Garrison 2015 
Garrison 2012 
Hawke 2013 
Hawke 2013 
Hirai 2000 
Naylor 1994 
Nishant 2014 
Oboler 1991 
Baskol 2004 , Garrison 2015 , Hawke 2013  and Hawke 2013  showed low risk of bias
Hallegraeff et al. BMC Family Practice (2017) 18:29 Page 4 of 9
Table 3 Characteristics of the included studies
Number of participants
Diagnostic criteria Comorbidities associated with
NLC and medication use
Connolly 1993 
Efficacy of quinine
Nocturnal leg cramps. Aged > 50.
Foot, lower part of leg, sometimes
thigh. Sleep interruption.
Coronary artery disease, Peripheral
vascular disease, Hypertension, Diabetes
Coppin 2005 
Effect of calf stretching
Nocturnal leg cramps, aged > 60,
painful and involuntary. Muscle
spasms. Disrupt sleep. Disruption.
Most commonly in the leg, relief
Renal dialysis, asthma and hypertension.
Medication: diuretics, nifedipine,
salbutamol and terbutaline
Garrison 2011 
The effect of magnesium in
individuals with leg cramps
Leg cramps, aged > 50, at rest
(bed or night). Legs and feet.
Painful muscle contractions.
Participants with comorbidities excluded
Hallegraeff 2012 
Effect of pre sleep stretching
Nocturnal leg cramps, aged > 55,
Suddenly, episodic. Involuntary.
At rest or sleep. Calf, hamstrings
or foot. Muscles are tender and
hard. Intense painful. From
seconds to minutes. Distress.
Sleep disruption. Maximum ten
Varicose veins and arthritis. Physical
inactivity and inadequate stretching and
reduced muscle and tendon length.
Medication: diuretics, lithium, steroids,
Jansen 1997 
Efficacy of hydro quinine in muscle
Involuntary muscle contraction.
Painful Sudden onset. Muscle
hardening, maximum duration
Roffe 2002 
The effect of magnesium in chronic
Leg cramps. Painful contractions
of any muscle group in the leg.
Sudden onset. Successive
improvement. Palpable hardening
of the muscle. Distress.
Arthritis, peripheral vascular disease,
varicose veins, ankle oedema
Serrao 2001 
To evaluate the efficacy and safety of
gabapentin in the treatment of muscle
Sudden, involuntary, painful
contractions. Maximum of 10
minutes. Sleep disturbance.
Neuropathy, radiculopathy, Isaac’s
syndrome, multiple sclerosis, Parkinson’s
disease, vascular disease
Young 1993 
The effect of naftidrofuryl in
individuals with rest cramps
Rest cramps. Night-time cramps.
Foot, calf muscles. Distress.
Angeli 1996  To define the features, prevalence, and
pathophysiology of therapy for muscle
and small muscles cramps in cirrhotic
A-symmetric involuntary contractions
or stiffness in calves and feet. At rest
or at night
Cirrhosis, vascular occlusive disease,
peripheral neuropathy, diabetes mellitus,
severe renal failure and postphlebitic
Baskol 2004 
The prevalence of muscle cramps in
non-alcoholic cirrhosis patients.
Muscle cramps. Aged > 50. Involuntary.
Painful, visible contraction. Sudden
onset. At rest or sleep. From seconds
to minutes. Affects quality of life. At
least once per week. Sleep disruption.
Liver cirrhosis, diuretic, alcohol use,
volume depletion, hyponatremia,
haemodialysis, hypothyroidism, uraemia.
Motor neuron disease, radiculopathy or
hereditary cramp syndromes
Hallegraeff et al. BMC Family Practice (2017) 18:29 Page 5 of 9
hyponatremia, hypothyroidism, hyper- and
hypothyroidism and acute extracellular volume
depletion including excessive perspiration.
The analysis of 18 primary studies revealed twelve differ-
ent diagnostic criteria used: ‘rest, sleep or night’(n= 16);
‘painful’(n= 12); ‘aged > 50’(n=8); ‘involuntary’(n= 10);
‘sudden onset’(n=7; ‘posterior calf, foot or thigh’(n=8);
‘sleep disruption’(n=7); ‘persisting pain afterwards’(n=4);
‘duration from seconds to several minutes’(n=5);‘distress’
(n=4); ‘stiffness’(n=1) and ‘asymmetrical cramps’(n=1)
Clinical classification characteristics
After counting the number of times the criteria were de-
scribed, and after comparing the twelve criteria to RLS
Table 3 Characteristics of the included studies (Continued)
Seasonally variation of symptom
burden of leg cramps in the general
Painful involuntary muscle cramps
in the legs or feet during rest. It
Garrison 2012 
Evaluating the association between
diuretics, statins and long-acting β2
Nocturnal leg cramps. Painful legs
or feet. During rest or sleep
Medication: diuretics and long-acting β2
Hawke 2013 
Impact of NLC on health related
quality of life.
Nocturnal leg cramps. Pain afterwards.
Sleep disruption. Aged >60 with sleep
disruption. Reduced quality of life.
Gradually lessens. Sudden, involuntary
painful contraction. At night and rest.
Relief by stretching.
Participants with comorbidities known to
cause cramp excluded
Hawke 2013 
Factors associated with night-time calf
Reduced strength dorsiflexion foot.
Distress. Lesser quality of life.
Interference of activities of daily living.
Hamstring tightness. Foot or leg coldness
Participants with comorbidities known to
cause cramp were excluded
Hirai 2000 
NLC in general population and in
patients with varicose veins
Age not stated
Muscle cramps. Aged >50. Intense
painful with sudden onset in calf,
foot or thigh. Maximum duration
10 minutes. At least once per week.
Naylor 1994 
Prevalence, severity and correlation
with vascular diseases
Rest cramps. Aged > 50. Distress.
Less quality of life.
Peripheral vascular disease
Nishant 2014 
Prevalence of nocturnal leg cramps
in LSCS patients and in general
Nocturnal cramps. Painful. Acute
and involuntary. At sleep or rest.
Knee flexion test might be indicative
Amyotrophic lateral sclerosis, poliomyelitis,
peripheral neuropathy, lumbar spinal
radiculopathy; metabolic disorders including
diabetes, pregnancy, uremia, liver cirrhosis,
and hyper- and hypothyroidism; acute
extracellular volume depletion including
excessive perspiration, hemodialysis, diarrhea,
and diuretic therapy; hereditary disorder.
Hypertension, hypocalcaemia, hypokalaemia,
Medications: diuretics, antidepressants,
calcium blockers, statins, and steroid,
Oboler 1991 
Prevalence and treatment regimens of
Painful and involuntary in the calf
with a visible palpable knot. At rest
Arthritis, Peripheral vascular disease,
Hypokalaemia, Coronary artery disease,
Hypertension, Kidney disease, Stroke,
Diabetes Mellitus, Hypocalcaemia.
In total 18 studies are included for analysing NLC characteristics: eight randomized clinical trials and ten observational studies
Hallegraeff et al. BMC Family Practice (2017) 18:29 Page 6 of 9
and PLMD criteria, the following criteria were deemed
not distinctive enough: ‘at rest or sleep’,‘aged’,‘involun-
tary’,‘sudden onset’,‘stiffness’and ‘asymmetrical’. As a re-
sult, the following seven criteria remained in order to
differentiate NLC from RLS and PLMD: ‘pain’,‘intense pain’,
‘period of seconds to a maximum of 10 minutes’,‘located in
posterior calf or foot’,‘subsequent pain’,‘sleep disruption’
and ‘distress’. These seven classification characteristics dif-
ferentiate from RLS and PLMD See Table 4.
This review has identified seven criteria, derived from
consensus, which can be employed as a framework to
differentiate NLC from RLS or PLMD.
Distress and sleep disruption are indicated in a limited
number of studies and are associated with negative im-
pacts on physically related aspects of the quality of life
. Similarly, ‘subsequent pain’is also a criterion as a
consequence of the occurrence of NLC. The NLC char-
acteristics that were revealed as the most discriminatory
–compared to those of RLS and PLMD –include in-
tense pain with duration of a maximum of ten minutes
in the calf or the foot, with relief of the symptoms oc-
curring with no intervention. In contrast to NLC, pain
in rest or during sleep in the calf or foot can also be due
to vascular insufficiency.
In contrast to previous studies, that included all kind of
cramps in different ages, the current review focused on
NLC among older adults aging 50 years and older there-
fore excludes other types of cramps [1–3, 28]. Naylor et al.
1994, showed the highest prevalence of NLC is in age
group 60-69 years, which is in line with our result with a
mean age of the total population in the included studies of
64 years . We also confirmed the previous findings
that vascular and renal comorbidities are the most stated
and are clinically relevant in elderly people [4, 9, 19–21,
25, 27, 29]. In addition, the use of diuretics is known to
cause muscle cramps [9, 16, 21, 24–26, 29]. Consequently,
we suggest that vascular and renal comorbidities as well
as the use of diuretics could be considered as correlational
factors for NLC. This may improve the accuracy of future
Managing the symptoms of patients with NLC can be
a challenge in daily clinical practice considering how re-
cent some developments in the diagnosis and treatment
Table 4 Involuntary musculoskeletal disorders at rest or nocturnal
with sudden onset in elderly above 50
Intensely pain ✓
From seconds to
maximum 10 minutes
Calf or foot, seldom
Sleep disruption ✓
In episodes ✓
An urge to move ✓
Reduction of symptoms
No pain ✓✓
Repeating and jerking
Duration 20-30 seconds ✓
Reduced strength of dorsiflexion of ankle, foot and toes was also found in one
study and can be associated with NLC 
The response rate of the geriatric clinicians in the focus group of the Delphi
study was 52%, all with > 50% consensus. See Table 5T5
Table 5 Delphi study items
Delphi Study Items Always Mostly Sometimes Never Not known
Are you known with NLC 30* 40 20 0 10**
•NLC has a sudden onset 33 56 11 0 0
NLC is only present at night 11 68 11 0 11
•Pain and / or intense pain is the main characteristic 10 80 0 0 10
•NLC duration varies from seconds to 10 minutes 10 80 0 0 10
•NLC location is thigh, calf or foot 33 45 11 0 11
•After reduction of NLC there will be pain afterwards 0 50 40 0 10
•NLC might be associated with sleep disruption 10 50 20 0 20
NLC is associated with medication use / comorbidity 0 11 67 0 22
•NLC might be associated with distress 10 10 60 10 10
Seven criteria differentiating NLC from RLS and PLMD. *Percentages; ** if ‘no’excluded from these survey (n=3)
Hallegraeff et al. BMC Family Practice (2017) 18:29 Page 7 of 9
of the disorder are. Therefore, we suggest that these de-
velopments indicate extending the scope of clinical care.
The framework introduced in this review provides a nat-
ural guide to future research within the population of
older adults with musculoskeletal disorders during rest
or sleep. Further research on the reliability and valid-
ation of the proposed theoretical framework is necessary
for clinical application and diagnostic accuracy.
In addition, two clinical test procedures were re-
ported for diagnostic application: the forceful knee
flexion test indicated findings of cramps; the examiner
applies a force to overcome knee flexion when testing
in a prone position. Most patients with lumbar disc
herniation comorbid with leg cramps also showed
positive findings during this test, and cramps could
be induced (n= 2) [26, 30]. There is a need for diag-
nostic studies in regard to these clinical tests on NLC
and it will be interesting to assess their benefits as
well [26, 30].
A potential limitation of this review is the lack of pri-
mary studies with the focus on diagnosing NLC in older
adults. Therefore, as much as possible, the risk of bias
was limited by using clearly defined inclusion criteria
and conducting a thorough screening and reviewing
process of the presented literature. Inherent in this
process was the inclusion of patients with several co-
morbidities in the separate studies. Although these co-
morbidities might have influenced the interpretation of
NLC, it does reflect the clinical relevance of patients
with this disorder.
An extensive history taking including the above seven
characteristics may rule out other disorders in diagnos-
ing idiopathic NLC. In conclusion, seven relevant clinical
characteristics have been identified to diagnose patients
with NLC, and specifically differentiate this disorder
from RLS and PLMD. These characteristics enhance the
recognition and diagnosis of this highly prevalent, mus-
culoskeletal sleep-related disorder.
NLC: Nocturnal leg cramps; PLMD: Periodic limb movement disorder; RLS: Restless
The content is solely the responsibility of the authors, who have all made
substantial contributions to the study’s conception and design, the analysis
and interpretation of the data, the draft and revision of the article and the final
approval of the version to be submitted. Mrs A. Hartman of the University
library optimized the search strategy. Also thanks to Mrs A. White and Mr D.
White who edited the manuscript and improved English expression.
This project did not receive any funding.
Availability of data and materials
The full list of extracted abstracts with reasons for exclusion may be obtained
from the corresponding author.
JMH conceived and coordinated the review, participated in search design
and analysis, and drafted the manuscript. JMH designed the search strategy
in collaboration of the library of Hanze University and reviewed the
manuscript. MHG, WP and CvdS contributed to the writing and review of the
manuscript. All authors read and approved the final manuscript.
The authors, JMH, MHG, WP and CvdS, declare that they have no competing
Consent for publication
Ethics approval and consent to participate
This study has reviewed research materials already published in the public
domain, and with no contact with human subjects; therefore it was exempt
from review by Hanze University Groningen.
Research Group Healthy Ageing, Allied Health Care and Nursing, Hanze
University of Applied Sciences, Groningen, The Netherlands.
University Campus, Institute for Master Education in Musculoskeletal
Therapies, Amersfoort, The Netherlands.
University of Groningen, University
Medical Centre Groningen, Groningen, The Netherlands.
Received: 19 September 2016 Accepted: 9 February 2017
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