Anda di halaman 1dari 78

Why do we Sleep?

No Idea
• Sleep to avoid attracting predators in the night
• Highly conserved. All vertebrates sleep
• “Unlearning” mechanism whereby sleep erases
unwantedthoughts or erroneous information

Benefits of Sleep
• Replenishes glucose and neurotransmitters in the
brain
• Sleep determines our waking success in terms of:
• Mood, Alertness, Energy, Thinking, Productivity,
and Safety
• Promotes General Health and Longevity
Evolution of Sleep
• Rest but no sleep
– amphibians, fish
• Non-REM sleep only
– lower reptiles
• A little REM
– chameleons, crocodiles, birds (when babies)
– echidna
• REM and NonREM
– All placental mammals
Development of Sleep
• Babies spend 16 hours sleeping, initially
half in REM. REM sleep in infants
represents a larger percentage of the total
sleep at the expense of stages III and IV.
Until age 3-4 months, newborns transition
from wake into REM sleep. Thereafter,
wake begins to transition directly into
NREM.
• Over lifespan, total sleep decreases
• Over lifespan, proportion of REM decreases
In elderly persons, the time spent in stages
III and IV sleep decreases by 10–15% and the
time in stage II increases by 5% compared to
young adults, representing an overall decrease in
total sleep duration.
Latency to fall asleep and the number and
duration of overnight arousal periods increase.
Thus to have a fully restorative sleep, the total
time in bed must increase. If the elderly person
does not increase the total time in bed,
complaints of insomnia and chronic sleepiness may
occur.
Sleep Facts
• Adults need an average 8.2 hours of sleep per
24 hours1
• Impairment of performance occurs with as little as 2
hours less sleep than normal per night2
• Sleep debt from restricting sleep to 5 hours a night
accumulates with time, and awareness of sleepiness
declines2
• The significance of circadian timing is rarely addressed
when considering the effects of shift work
• National Heart, Lung, and Blood Institute
Working Group on Problem Sleepiness. 1997.
• Carskadon MA, et al. Sleep restriction. In:
Monk T, ed. Sleep, Sleepiness and
Performance. 1991.
Purpose of Sleep
• Excessive sleep deprivation kills rats
• Sleep deprivation makes people more tired
How Much Sleep Is Enough?
• The amount that allows you to feel alert when
rested and relaxed (eg, grand rounds)

• There is little variation of sleep need (8.2 hours) among


individuals

• 1 night with 2 hours less than your usual sleep is


sufficient to produce significant decrements in waking
performance

• After several nights of 5-hour sleep, most adults do not


realize they are pathologically sleepy
Carskadon MA, et al. In: Monk T, ed. Sleep,
Sleepiness and Performance. 1991.
• Sleep-reversible state of consciousness
• Brain relatively more responsive to internal than to external
stimuli (visual, auditory, and other environmental stimuli) during
the transition from wake to sleep
• Historically, sleep a passive state initiated through
withdrawal of sensory input.
• Currently, withdrawal of sensory awareness believed to be a
factor in sleep, but an active initiation mechanism that facilitates
brain withdrawal recognized.
Why Do We Feel Sleepy?
The 2-Process Model
• 2 processes combined determine sleep propensity
and the duration of sleep
– Homeostatic sleep drive:
• Process driven by amount of time awake
• Linear and cumulative—one gets progressively more tired
with each passing hour (“sleep load” increases)
– Circadian rhythm:
• Process driven by biological clock (time of day)
• Cyclical—periods of sleepiness occur at roughly the same
times each day
Combined Sleep Processes
Increases The physiological Sleep
pressure to sleep Sleep
progresses linearly
The
biological
Sleepiness

pressure to
sleep
occurs
cyclically

Wake Wake

Decreases
Noon Midnight Noon Midnight

Time (48 hours)


• Sleep is an active process that cycles at an ultradian rhythm
of about 90 minutes.

• Normal sleep is divided into NREM & REM


• NREM has 4 stages
i) Stage I (Light sleep or slow wave sleep)
ii) Stage II
iii) Stage III (SWS)
iv) Stage IV (Deep or delta wave sleep) (SWS)
• In adults, sleep of 8-8.4 hours is considered fully
restorative. In some cultures, total sleep often is
divided into an overnight sleep period of 6-7 hours and a
midafternoon nap of 1-2 hours.
• Stage I is considered a transition between wake and
sleep. It occurs upon falling asleep and during brief
arousal periods within sleep and usually accounts for 5-
10% of total sleep time. Stage II occurs throughout the
sleep period and represents 40-50% of total sleep time.
Stages III and IV delta sleep occur mostly in the first
third of the night. They are distinguished from each
other only by the percentage of delta activity and
represent up to 20% of total sleep time. REM
represents 20-25% of total sleep time.
Normal Sleep Patterns in Young Adults
TheThe
ForWaking
One
the first
frequency
cycle
purpose REM
usually
ofofsleep
of period
transitions
Stages
REM-nonREM
analysis, of
alters during
overnight thebeen
sleep has night - in
The
the
the proportion
early
night hours
3may of
of sleep
be REM
SWS
less sleep
sleepfalls
dominates,
than therapidly
in whereas
firstREM
into
divided
lasts NREM
into
about sleep
equal
90-100 followed
time periods:
minutes by third
and
sleep
of
10 the plateaus
occurs more
night, which
minutes in at 25%
often in until
the it falls further
the highest percentageThe
comprises while
duration,
second part of sleep. in
of
REM
and,
portion and
4-5 then
cycles
of REM followed
sleep occur by
during
duringthird
nightofalters with age
old
NREM; age. Children
sleep in the have
middle more sleep
the night; and -sleep
time in in
and REM Stage
AWAKE the
NREM
normal
the last
newborn
last 8-may
babies
thirdto exceed
ofREM
9-hoursleep 60
the night, lasts
sleep for 50%,ofpre-mature
the majority which is REM.
stage
infants
minutes. 4
80% sleep
& in than
adults adults.
for 20%. NREM
Awakening after a full night's sleep is usually from REM
period during night
sleep.
REM
Sleep Stages

1 2 3 4 5 6 7 8
Hours of Sleep

Adapted from Berger RJ. The sleep and dream cycle. In: Kales A, ed. Sleep
Physiology & Pathology: A Symposium. Philadelphia: J.B. Lippincott; 1969.
Sleep spindles
Human Sleep Stages begin
appearing in
Awake—low voltage-random, fast the second
month of life
50µV with a density
greater than
1 sec
that seen in
Drowsy—8 to 12 cps-alpha waves adults . After
the first year,
the spindles
begin
Stage 1—3 to 7 cps-theta waves decreasing in
Theta Waves density and
progress
toward adult
patterns. K
complexes
begin by the
sixth month of
life.
Human Sleep Stages
Stage 2—12 to 14 cps-sleep spindles and K complexes
sleep spindle K complex

Stage 3/4—1/2 to 2 cps-delta waves>75µV

REM Sleep—low voltage-random, fast with sawtooth waves*

*
*
Brain Waves in Sleep
• Waking
– low amplitude, high frequency
• Stage 1
– mostly theta waves
• Stage 2
– sleep spindles
• brief period of high amp,high f
– K-complex
• Stage 3
– appearance of delta waves
• Stage 4 (slow wave sleep)
– mostly delta
• REM
– like Stage 1, but with REM
Physiology of Sleep I
Circadian Cycle
• The Biological Clock…the regular bodily rhythms
that operates on a 24-hour cycle
• Independent of environmental stimulus
• Maintain appropriate sleep and wakefulness cycle
SCN (Suprachiasmatic Nucleus)
• Photoreceptors that containing Melanopsin
• Synchronization of the circadian cycle with the
day/night cycle
• Regulates body temperature, hormone
secretion, urine production, and blood pressure to match
the Circadian Cycle
• Stimulation of Pineal gland that releases
Melatonin
– Neuro-hormone that promotes sleep
Diencephalic sleep zone (Post hyp+ ant hyp N)
Medullary synchronizing zone (RF at level of
NTS)
Basal forebrain sleep zone
Serotonin agonist- suppression of sleep
Serotonin antagonist (ritanserin)- SWS inc
Adenosine- Sleep increase, Role of Coffee?
PGD2- medial POA of hyp- SWS + Rem inc
PGE2- Wake
Resrpine depletes serotonin and catecholmine,
blocks SWS and REM but increases PGO spike
Barbiturates Dec SWS
Functional
dissociation b/w
brainstem and
cerebral cortex

Intralamin Rostral
Histamine
Cerebral ar Posteroinfundibualr
cortex nuclei of region
thalamus
Inhibitory signal
Ant Hyp POA Brainstem RF & Post Hyp

1) Dec in ascending
cholinergic pathway
2) Dec cortical Pontine reticular
responsiveness Centre inhibited
GABA + Ach
NREM is an active state that is maintained
partly through oscillations between the
thalamus and the cortex. The 3 major
oscillation systems are sleep spindles, delta
oscillations, and slow cortical oscillations.
Sleep spindles, a hallmark of stage II sleep,
are generated by bursts of hyperpolarizing
GABAnergic thalamic reticular neurons. These
bursts inhibit thalamocortical projection
neurons.
The functions of NREM sleep speculative,
several theories have been put forth.
- One theory : that decreased metabolic
demand facilitates replenishment of glycogen
stores.
-Another theory, which utilizes neuronal
plasticity, suggests that the oscillating
depolarizations and hyperpolarizations
consolidate memory and remove redundant or
excess synapses.
During NREM sleep, the metabolic
demand of the brain decreases. This is
supported by oxygen positron emission
tomography (PET) studies, which show
that, during NREM sleep, the blood flow
throughout the entire brain
progressively decreases.
REM sleep is generated by
mesencephalic and pontine cholinergic
neurons, hence these are referred to as
REM-on neurons. As REM sleep initiates,
monoadrenergic locus ceruleus (NA) and
serotonergic raphe neurons become
inactive and are called REM-off neurons.
Control of REM by Pontine Nuclei
Physiologic correlates of Sleep states
NREM- HR & BP inc & reverse during REM
Cardiac dysrhythmia- REM sleep
fR regular- NREM Opp during REM
High PCO2 during NREM due to dec in VE
SWS- inc GH, dec TSH, ACTH cortisol axis
NREM Sleep- Attenuated thermoregulatory fn to
cold and heat, REM complete unresponsiveness
REM Sleep

• EEG is remarkably similar to awakestate


• Each sleep cycle is 90 minutes
• Increasing REM intervals
• Characterization:
• Rapid Eye Movement (REM)
•Increase in Blood Pressure, Heart Rate, and
Metabolism
• Paralysis of large muscles (Tone of sk ms in neck dec)
• Genital Arousal
• Dreaming and Visual Hallucinations
• Lack of self-reflection
• Lack of Volitional Control
• periodic skeletal muscle twitches, pupil dilation, and
increased respiratory rate
• “Active Brain in an Inactive Body”
PET studies also show that, during REM
sleep, blood flow increases in the thalamus
and the primary visual, motor, and sensory
cortices, while remaining comparatively
decreased in the prefrontal and parietal
associational regions. The increase in blood
flow to the primary cortical regions may
explain the vivid nature of REM dreaming,
while the continued decrease in blood flow
to the prefrontal cortex may explain the
unquestioning acceptance of even the most
bizarre dream content.
An essential method in human
clinical and basic sleep research is
polysomnography. It is
composed of measuring
electroencephalogram (EEG),
electrooculogram (EOG) and
electromyogram (EMG)
Figure :Placement of electrodes of polysomnographic
measurement
The Description of Brain Waves
• Two parameters
– frequency
• the number of waves per second, measured as Hertz,
Hz
– amplitude
• the height of waves, measured in EEG recordings as
microvolts, or V
• Synchronization
• synchronized: waves are aligned with each other in
time
• desynchronized: waves occur randomly with each
other in time
Physiological Measures
• Brain waves
– Electroencephalograph (EEG)
• Beta waves 14 - 30 Hz, <20 V
• Alpha waves 8 - 13 Hz, 25-100 V
• Theta waves 4 - 7 Hz, 20 V
• Delta waves .5 - 4 Hz, 20-200 V
• Eyemovements
– Electrooculagraph (EOG)
• Muscle tension
– Electromyograph (EMG)
Additional Bodily Changes
• Decreased threshold of awareness of
external events
• Vestibular activation during REM
• Autonomic arousal in REM
• Genital arousal in REM
Impact and Recognition of Sleep
Deprivation
What Is Good Performance?
• Motivation
• Ability to see the “big picture”
• Memory for details
• Prompt decision making
• Accurate and consistent motor performance
• Good communication
• Contingency planning
• Professionalism
Clinical Signs of Excessive Sleepiness
• Irritability, moodiness, and disinhibition
• Frontal lobe signs
– Apathy, impoverished speech, flattened affect
– Impaired memory
– Inflexible thinking and impaired planning skills—an
inability to be novel or to multitask
• Intrusive sleepiness
– Microsleeps (5 to 10 seconds) cause lapses in attention
– Nodding off when sedentary
– REM phenomena (hypnagogic hallucinations)

Dinges D, et al. In: Monk T, ed. Sleep,


Sleepiness and Performance. 1991.
Rosekind MR, et al. Behav Med. 1996.
Results of Deprivation
Less than 3 hrs/night:
• Increase in Blood Pressure
• Increase in blood Glucose level
• Decrease in Leptin level
• Hypertension, Obesity, Heart Attack, and Stroke
Less than 6 hrs/night:
• Increase in Cytokine level
• Inflammation of arteries, Hypertension, and Stroke
• Increase in production of C-Reactive Proteins by
the Liver
• Breaks down heart chambers
• Increase in risk of Type-II Diabetes
• Reduction of resistance to Viral Infections
laboratory studies indicate that nocturnal
sleep periods reduced by as little as 1.3 to
1.5 hours for 1 night result in reduction of
daytime alertness by as much as 32% as
measured by the Multiple Sleep Latency
Test (MSLT).
Physiological effects
of sleep deprivation
include: hypoxemia,
insulin resistance,
elevated sympathetic
activity, and blunted
arousal response.
Most vulnerable

Circadian Rhythm
times to feel
sleepy are 5-8
Increases AM and 2-4 PM
(independent of
lunch)
Most likely times
to feel alert are
Sleepiness

10 AM to 12
noon, and again in
the evening

Decreases
12 24

Time (h)

University of Virginia Center for Biological Timing.


Available at:
Performance Errors
Meter Reading Errors
Sweden N = 74,927
11,000

10,000

9000
No. of Errors

8000

7000

6000

5000

4000

Time of Day

Midnight 6 AM Noon 6 PM Midnight

Mitler MM, et al. Sleep. 1988.


Vehicle Accident Data
Fatigue-Related Accidents
1200 International Data N = 6052

1100
1000
900
800
No. of Accidents

700
600
500
400
300
200
100
Time of Day

Midnight 6 AM Noon 6 PM Midnight

Mitler MM, et al. Sleep. 1988.


Overlay of Vehicle Accident Data, Performance
Errors, and Circadian Rhythm

Midnight 6 AM Noon 6 PM Midnight


Survey of Pediatric On-Call House
Staff and Faculty
House Staff Faculty Members Statistical
(on call every (sleep undisturbed) signifi-
4th night) N = 85 cance
N = 70
Response rate 87% 87%
Average hours sleep 2.7 ± 0.9 6.5 ± 0.8
Fell asleep at stop light 44% 12.5% P<.001
Fell asleep while driving* 23% 8% NS
Fell asleep at the wheel† 49% 13% P<.001

*While car in motion


† Marcus CL, et al. Sleep. 1996.
While car in motion or at stop light
National Survey of 963 Emergency
Medicine Residents
Motor Vehicle Accidents
8% had
>1 MVAs N = 963
(mean = 1.3 (1554 polled,
accidents) 62% response rate)

76 (8%) 26%
74%

74% of MVAs
were
related
to night shift
MVA = motor vehicle accident

Steele MT, et al. Acad Emerg Med. 1999.


National Survey of 963 Emergency
Medicine Residents (continued)
Near-Crashes N = 963
(62% response rate)

80%
553
(58%)

20%

58% had >1 near-crashes 80% of near-crashes were


(mean = 2.6 near-crashes) related to night shift

Steele MT, et al. Acad Emerg Med. 1999.


Sleep Deprivation and Medical Performance
Patient Care Is Jeopardized
• During laparoscopic surgery after a night on call with an
average sleep time of 1.5 hours1:
– Fine motor control degrades
– More time taken to complete surgery
– More complications postop
• Prescribing errors made connected with physical and
mental well being2:
– Tired
– Hungry
– Unwell •

Grantcharov TP, et al. BMJ. 2001.
Dean B, et al. Lancet. 2002.
Studies on Impact of Sleep Deprivation

• Why do studies in the clinical setting produce mixed results


when laboratory studies clearly show the impact of sleep
deprivation on performance?
– Lack of well-rested residents for control groups
• Studies essentially compare effects of chronic partial sleep restriction
(residents not on call) versus chronic partial sleep restriction plus short-term
sleep loss (residents on call or immediately post call)
– Differences in general health status and sleep/wake habits
– Failure to control for caffeine and food intake, recent physical
activity, and ambient temperatures
– Effects on specific tasks may be overcome by motivation and
focused attention; more difficult to measure continuous
performance
Impact of Sleep Deprivation on
Resident Health
• Increased risk of obstetrical complications for pregnant
residents versus other working women1
– Premature labor is twice as common
– Preeclampsia is twice as likely
• High rates of depression occur among residents2
– 30% of first-year residents report depressive symptoms
for an average of 5 months
– Some reported to have suicidal ideation with plan
– Among married residents, 46% in depressed group versus 7%
in the nondepressed group had marital problems (none of the
depressed individuals had ever had martial problems prior to
depression onset)
1. Osborn LM, et al. J Fam Pract. 1990.
2. Valko RJ, et al. Dis Nerv Syst. 1975.
The Cultural Environment
“We believe that long hours are an inherent part of our
profession, and if we don’t train in the way we will
work in the future, we will not be able to function
adequately. This is analogous to pilots; if they don’t
practice flying at night, how can we expect them to
fly at night?”

“Who are we? The answer is that we are physicians, a


highly selected group, and we are not representative
of the population as a whole.”
Preventive and Operational
Countermeasures
Preventive and Operational
Countermeasures
Scheduling
• Limit continuous performance schedules to
12-16 hours
• Time off duty to protect sleep and sanity

Working With Circadian Rhythm


• Know the times of greatest impairment and
maximum alertness

Avoid Alcohol
Preventive and Operational Countermeasures
Education
• No substitute for sleep
• Avoid driving between 2 AM and 9 AM
• Behavioral changes may indicate dangerous levels
of fatigue
• Need for performance backups during times
of impairment
• Interaction between alcohol and sleep loss can
be deadly
• Benefits of prophylactic naps
Does Napping Help?
Night shift workers after 2-hour nap prior to shift
• Prevented sleepiness
• Later naps produced a deeper sleep, but workers
awakened with grogginess due to sleep inertia

ER residents after 1-hour nap prior to a night shift


• EEGs show clearly enhanced awake activity
• Reduced stress
• Workload perceived as less onerous
Dinges DF, et al. Sleep. 1997.
Rosekind MR, et al. Behav Med. 1996.
Frey R, et al. Crit Care Med. 2002.
Preventive and Operational Countermeasures

Pharmacology
• Caffeine—widely available, widely
accepted
– Boosts alertness
– Tolerance to benefits develops quickly
– Erodes sleep quality
– Undesirable side effects on mood
– Less-predictable GI absorption; active longer
than half-life suggests
Preventive and Operational Countermeasures

Pharmacology
• Alcohol
– Induces sleep initially
– Increases fragmentation
– Overall, a bad choice for sleep
Sleep Disorders
• Narcolepsy (high levels of REM)
• Hypersomnia (high levels of NREM)
• Parasomnias
– Night terrors
– Sleepwalking
– Sleeptalking
• Insomnias
Sleep Disorders
Non-REM Sleep Disorders (Stage IV)
• Enuresis (Bed-wetting)
• Sleep - Walking
• Sleep - Talking
• Sleep – Eating
• Night Terror
• Insomnia
REM Sleep Disorders
• Sleep Apnea
• Narcolepsy
Narcolepsy
• Clinical symptoms: the narcoleptic tetrad
– excessive sleepiness during the day
– cataplexy
• abrupt loss of muscle tone, without loss of awareness
– sleep paralysis
• muscle paralysis of sleep
– hypnagogic hallucination
• Waking usually transitions into NREM sleep followed by
REM and then followed by NREM
• The first REM period of the night may be less than 10 minutes
in duration, while the last may exceed 60 minutes.
• One cycle of REM-nonREM lasts about 90-100 minutes and, 4-
5 cycles occur during normal 8- to 9-hour sleep period during
night
The Cycles of Sleep Stages
For the purpose of analysis, overnight
sleep has been divided into 3 equal time
periods: sleep in the first third of the
night, which comprises the highest
percentage of NREM; sleep in the
middle third of the night; and sleep in
the last third of the night, the
majority of which is REM. Awakening
after a full night's sleep is usually from
REM sleep.
The frequency of sleep Stages
alters during the night - in the
early hours of sleep SWS
dominates, whereas REM sleep
occurs more often in the second
part of sleep. The portion of REM
sleep during night alters with age -
in newborn babies REM sleep lasts
for 50%, pre-mature infants 80%
& in adults for 20%.
The proportion of REM sleep
falls rapidly and plateaus at
25% until it falls further in
old age. Children have more
sleep time and stage 4 sleep
than adults.
Preventive and Operational Countermeasures

Monitoring: Self-Assessment Tools


• Epworth Sleepiness Scale (ESS)1
• Pittsburgh Sleep Quality Index (PSQI)2
• Beck Depression Inventory (BDI)3 and Zung Self-
Rating Depression Scale (SDS/ZDS)4
• Maslach Burnout Inventory (MBI)5

• Johns MW. Sleep. 1991.


• Buysse DJ, et al. J Psychiatric Res.1989.
• Beck AT, et al. Manual for the Beck Depression
Inventory. 2nd ed. 1996.
• Zung WW. Arch Gen Psychiatry. 1965.
• Maslach C, et al. The Maslach Burnout Inventory.
3rd ed. 1996.
Epworth Sleepiness Scale
Situation Chance of dozing (0-3)
Sitting and reading 0 1 2 3
Watching television 0 1 2 3

Sitting inactive in a public place—for example, a theater 0 1 2 3


or meeting
As a passenger in a car for an hour without a break 0 1 2 3
Lying down to rest in the afternoon 0 1 2 3
Sitting and talking to someone 0 1 2 3
Sitting quietly after lunch (when you’ve had no alcohol) 0 1 2 3

In a car, while stopped in traffic 0 1 2 3


Total Score

0 = would never doze 2 = moderate chance of dozing


1 = slight chance of dozing 3 = high chance of dozing
Johns MW. Sleep. 1991.
Preventive and Operational Countermeasures

Pharmacology
• Modafinil—schedule IV wake-promoting
agent
– Headache
– Nausea
– Rhinitis
• Pemoline—schedule IV stimulant
– Insomnia
– Hepatic dysfunction
– Anorexia/weight loss
Physician’s Desk Reference. 2002.
Preventive and Operational Countermeasures

Pharmacology
• Dextroamphetamine—schedule II stimulant
– Palpitations
– Tachycardia
– Elevation of blood pressure
– Overstimulation
• Methylphenidate—schedule II stimulant
– Nervousness
– Insomnia
– Anorexia
Physician’s Desk Reference. 2002.
Preventive and Operational Countermeasures
Pharmacology
• Triazolam, zolpidem, zaleplon—schedule IV short-
acting sedative hypnotics
– Headache
– Drowsiness
– Dizziness
– Nausea

Physician’s Desk Reference. 2002.


Summary

• In response to the new ACGME standards, this


presentation has:
– Reviewed the impact of sleep loss and fatigue on cognitive
function and performance
– Described the signs of fatigue and sleepiness from
sleep deprivation
– Outlined preventive and operational countermeasures

• While there are short-term countermeasures available,


ultimately, the only cure for sleep deprivation is sleep.
Sleep initiation may begin with the
emergence of inhibitory signals from the
anterior hypothalamic preoptic nucleus
directed caudally toward the brainstem
reticular core and posterior hypothalamus.
The preoptic nucleus inhibits the
histaminergic posterior hypothalamic
tuberoinfundibular region through GABA and
probably acetylcholine.
The tuberoinfundibular region projects
rostrally to the intralaminar nuclei of the
thalamus and to the cerebral cortex. Inhibition of
the tuberoinfundibular region is a critical step
toward falling asleep because it results in
functional disconnection between the brain stem
and the more rostral thalamus and cortex. A
decrease in ascending thalamic cholinergic
transmissions occurs in association with
decreasing cortical responsiveness. In addition to
inhibiting higher cortical consciousness, the
tuberoinfundibular tract projects caudally into
the pontine reticular system and inhibits afferent
transmissions from ascending cholinergic tracts.