Transcript Document

Pelvic Inflammatory Disease
By: Kallianpur Vaibhav Vinayanand.
ML- 610
2012
Upper Genital Tract Infections
The Cervix is
considered the
boundary between
the lower and upper
genital tracts.
Upper genital tract
infections affect
primarily the cervix,
uterus, or fallopian
tubes
Severe infections
may affect one or
both ovaries.
Topic Defined: Pelvic Inflammatory
Disease (PID)
 Infection of the upper female genital tract.
 Refers to the clinical syndrome among women
resulting from infection
 Includes endometritis (infection of the uterine
cavity)
 Salpingitis (infection of the fallopian tubes)
 Mucopurulent Cervicitis (infection of the
cervix),
 Oophoritis (infection of the ovaries).
Pathway of
Ascendant Infection
Cervicitis
Endometritis
Salpingitis/
oophoritis/ tuboovarian abscess
Peritonitis
Pathologic Processes of PID
• PID has a broad clinical spectrum that
includes
a) acute PID
b) silent PID
c) atypical PID
d) the PID residual syndrome or chronic PID
and
e) postpartum/postabortal PID
PID Classification
Subclinical/
silent
60%
Mild to
moderate
symptoms
36%
Overt
40%
Severe
symptoms
4%
PID Specifically defined:
• Individual cases of PID can also be more
specifically defined by
– a) the site (s) of disease (i.e.,
endometritis, salpingitis, salpingooophoritis)
– b) the etiologic agent (s) involved
(those that cause chlamydial
endometritis, gonococcal salpingitis,
nonchlamydial/nongonococcal salpingooophoritis).
Relevance to Women’s Health:
• Commonly occurs in women <35 years.
• Rarely occurs before menarche, after menopause
or during pregnancy.
• About 1.2 million women are treated for PID.
• Over 100,000 women with PID are hospitalized
each year.
• About 15% are acutely ill that require intensive
inpatient treatment.
• Approximately 85,000 women with mild or
moderate PID who currently are being
hospitalized, treating them as outpatients may
save around $500 million each year.
Relevance to Women’s Health
Is one of the major causes of
gynecologic morbidity
Infertility
Ectopic pregnancy
Chronic pelvic pain
Diagnosis and treatment must be
prompt to avoid these conditions.
PID: Etiology
PID results from microorganisms
transmitted during intercourse.
Certain procedures that open the cervix
and allow possible bacteria to pass
through (D&C, abortion, cesarean birth,
miscarriage, I.U.D. insertion)
The infection is usually multifactorial,
involving aerobic and anaerobic
organisms
PID: Risk Factors
 Multiple sexual partners or partner with multiple
sexual partners
 Intercourse with partner with untreated urethritis
 Previous history of PID
 Use of an IUD
 Presence of bacterial vaginosis or an STD
 Nulliparity
 Recent instrumentation of the uterus
 Douching
 Cigarette smoking
 Sex with menses
Causative Agents of PID
• Neiserria Gonorrhoeae and Chlamydia
trachomatis are the 2 major causative
organisms.
• Chlamydia trachomatis is the predominant
STD organism causing PID.
• In the U.S., the role of Neisseria Gonorrhoeae
as the primary cause of PID has decreased.
• Other agents: Mixed infection caused by both
aerobic and anaerobic organisms
• Recent studies demonstrate the presence of
Bacterial Vaginosis and trichomoniasis in cases
of confirmed PID
C. trachomatis Infection (PID)
Causative Agents of PID
• Cytomegalovirus (CMV) has been found in the
upper genital tracts of women with PID.
• Enteric gram-negative organisms (E-coli)
• Peptococcus species
• Streptococcus agalactiae
• Bacteroides fragilis
• Mycoplasma hominis
• Gardnerella vaginalis
• Haemophilus influenzae
Signs & Symptoms of PID
 The patient presents with lower abdominal
pain, fever, vaginal discharge, and/or abnormal
uterine bleeding.
 Symptoms frequently occur during or after
menses.
 Peritoneal irritation produces marked
abdominal pain with or without rebound
tenderness
 The abdomen should be palpated gently to
prevent abscess rupture
Chlamydial Pyosalpinx
• Pelvic inflammatory disease, proven Chlamydial
Pyosalpinx.
• Right tube is swollen and tortuous (arrow)
(Holmes, 1999, Plate 17; reprinted with permission from McGraw Hill.)
Cervicitis
The cervix appears
red and bleeds easily
when touched with a
spatula or cotton
swab.
Mucopurulent
discharge is yellowgreen
Contains >10
polymorphonuclear
WBCs per oil
immersion field (using
Gram stain)
Acute Salpingitis
Onset is usually shortly after menses.
Lower abdominal pain becomes
progressively more severe, with
guarding, rebound tenderness, and
cervical motion tenderness.
Involvement is usually bilateral.
Nausea and vomiting occur with severe
infection.
In the early stages, acute abdominal
signs are often absent
Acute Salpingitis (PID)
Bowel sounds are
present unless
peritonitis with ileus
has developed.
Fever, leukocytosis,
and mucopurulent
cervical discharge are
common
Irregular bleeding
and bacterial
vaginosis often
accompany the pelvic
infection.
Acute Salpingitis (PID)
 Pelvic infection due to N. Gonorrhoeae is
usually more acute than that due to C.
trachomatis
 Onset is rapid, and pelvic pain develops shortly
after menses starts.
 Although the pain is often localized to one
side, both tubes are probably infected.
 The infection produces a diffuse exudate,
leading to agglutination, adhesions, and tubal
occlusion.
 Peritonitis may occur, causing upper
abdominal pain and adhesions
Acute Salpingitis: Chlamydia & Gonorrhea
 C. trachomatis produces symptoms that often
seem mild, but it can cause more damage
than N. Gonorrhoeae in the long term.
 Chlamydial organisms may remain in tubal
mucosa for many months before clinical
manifestations of acute disease appear.
 Untreated or inadequately treated acute
infection can lead to chronic salpingitis, with
tubal scarring and possible adhesion
formation.
 Chronic pelvic pain, menstrual irregularities,
and infertility are long-term sequelae
Complications of PID
 Tubo-ovarian abscess develops in about 15% of
women with salpingitis.
 It can accompany acute or chronic infection
 The tube and ovary can become completely
matted together.
 May require prolonged hospitalization,
sometimes with surgical percutaneous
drainage.
 Rupture of the abscess is a surgical emergency
 Rapidly progressing from severe lower
abdominal pain to N & V, generalized
peritonitis, and septic shock
Tubo-ovarian abscess
Pyosalpinx, in which one or both
fallopian tubes are filled with pus, may
also be present.
 Hydrosalpinx (fimbrial obstruction and tubal
distention with nonpurulent fluid) develops if
treatment is late or incomplete.
 The consequent mucosal destruction leads to
infertility.
 Hydrosalpinx is generally asymptomatic but
can cause pelvic pressure, chronic pelvic pain,
or dyspareunia.
 Women with HIV infection are more likely to
have tubo-ovarian abscess
Tubo-ovarian abscess
• Here at least the ovaries, tubes and uterus can
still be recognized as separate structures
Fitz-Hugh-Curtis syndrome
Can be a complication of gonococcal or
chlamydial salpingitis.
Characterized by right upper quadrant
pain in association with acute salpingitis,
indicating perihepatitis.
Acute cholecystitis may be suspected,
but signs and symptoms of PID are
present or develop rapidly.
Diagnostic Studies:
•
•
•
•
•
•
•
CBC with differential
Erythrocyte Sedimentation Rate
Cervical cultures
Blood Cultures
Urine Pregnancy Test
Rapid Plasma Reagin (RPR)
Cervical infection due to N. Gonorrhoeae
can also be diagnosed by Gram stain
showing intracellular gram-negative
diplococci
Diagnostic studies
 Leukocytosis is typical.
 Pelvic ultrasonography may be used when a
patient cannot be adequately examined
because of tenderness or pain
 When a pelvic mass may be present, or when
no response to antibiotic therapy occurs
within 48 to 72 h. - Laparoscopy should be performed only if the
diagnosis is uncertain or if the patient does not
promptly improve with medical therapy
CDC’s Minimum Criteria for
Empiric Treatment of PID
• Lower Abdominal Tenderness &
Rebound
• Adnexal Tenderness
• Cervical Motion Tenderness
Diagnosis
And one or more minor criteria
• Temperature over 100.9F or 38.3 C
• White Blood Cell count > 10,000
• Elevated ESR
• Elevated C-reactive protein
• Pus in cul-de-sac
• Pelvic abscess or inflammatory complex
• Cervical Mucus findings
• Gram Stain: Gram Positive diplococci
• Intracellular parasites
Diagnosis
ESR and C-reactive protein are elevated
in many disorders and are therefore not
specific for PID.
Endometrial biopsy with aerobic and
anaerobic culture may assist in the
diagnosis.
All three major criteria and at least one
minor criterion must be present to
diagnose PID.
Endometritis (thickened heterogenous endometrium)
Hydrosalpinx (anechoic tubular structure)
Hydrosalpinx.
Pyosalpinx (tubular structure with debris in adnexa
Tuboovarian abscess resulting from tuberculosis
Right hydrosalpinx with an occluded left fallopian tube
Differential Diagnosis
Condition
Characteristic Signs/Symptoms
Acute Appendicitis
Anorexia, N & V, decreased or absent bowel signs,
unilateral pain limited to right or left lower
quadrant
Ectopic Pregnancy
Unilateral pain; missed menstrual period usually
warrants hCG test
Ruptured Ovarian Cyst
Unilateral pain
Endometriosis
Constant pain begins 2-7 days before menses
Urinary Tract Infection
Dysuria, abnormal urinalysis. No cervical motion
tenderness
Renal calculus
Severe unilateral pain, hematuria
Adnexal torsion
Unilateral pain
Proctocolitis
Anorectal pain, tenesmus, rectal discharge or
bleeding
Hemorrhaging corpus
luteum
Unilateral pain
Treatment Goals & Benefits
Therapeutic goals include complete
resolution of the infection and
prevention of infertility and ectopic
pregnancy.
Management Outpatient
Regimen A:
Initial Treatment at Diagnosis
• Ofloxacin 400 mg orally BID for 14 days
(95% cure)
Or
• Levofloxacin 500 mg orally once daily for
14 days
With or without:
• Metronidazole 500 mg orally twice a day
for 14 days.
Management Outpatient: Regimen B
• Ceftriaxone 250 mg IM in a single dose
Or
• Cefoxitin 2 g IM in a single dose and Probenecid, 1
g orally administered concurrently in a single dose
Or
• Other parenteral third-generation cephalosporin
(ceftizoxime or cefotaxime)
Plus
• Doxycycline 100 mg PO BID for 14 days (75%
cure)
With or without
• Metronidazole 500 mg PO BID for 14 days
Management Inpatient
•Toxic
appearance
•Unable to take
oral fluids
•Unclear DX
•Appendicitis
•Ectopic
Pregnancy
•Ovarian torsion
•Pelvic abscess
•Pregnancy
•HIV positive
•Adolescents
•Outpatient
TX failure
•Unreliable
patient
Inpatient Treatment Regimens:
General: Treat for at least 48 hours IV
Regimen A
• Cefotetan 2g IV q12 hours
OR
• Cefoxitin 2g IV q6 hours
Plus
• Doxycycline 100 mg orally or IV every 12
hours
Inpatient Treatment
Regimen B
• Clindamycin 900 mg IV q8 hours
Plus
• Gentamicin 2 mg/kg IV loading dose,
then 1.5 mg/kg IV q8h
• Discharge Regimen (after IV antibiotics)
• Doxycycline 100mg PO BID for 10 days
or
• Clindamycin 450mg PO QID for 14 days
Alternative Parenteral Regimens
• Ofloxacin 400 mg IV q 12 hours
Or
• Levofloxacin 500 mg IV once daily
With or without
• Metronidazole 500 mg IV every 8 hours
Or
• Ampicillin/Sulbactam 3 g IV every 6 hours
Plus
• Doxycycline 100 mg orally or IV every 12 hours
Prognosis
• Therapy using antibiotics alone is
successful in 33-75% of cases.
• If surgical therapy is warranted, the
current trend in therapy is conservation
of reproductive potential with simple
drainage and copious irrigation or
unilateral adnexectomy, if possible.
• Further surgical therapy is needed in 1520% of cases so managed.
Prognosis
• Chronic pelvic pain occurs in approximately
25% of patients with a history of PID.
• This pain is thought to be related to cyclic
menstrual changes, but it also may be the
result of adhesions or Hydrosalpinx.
• Impaired fertility is a major concern in
women with a history of PID.
• The rate of infertility increases with the
number of episodes of infection.
• The risk of ectopic pregnancy is increased in
women with a history of PID.
• Ectopic pregnancy is a direct result of damage
to the fallopian tube.
Sequelae
Infertility
– ¼ of pt have acute salpingitis
– occur 20%
– infertility rate increase direct with number of episodes of
acute pelvic infection
Sequelae
Ectopic pregnancy
– increase 6-10 fold
– 50% occur in fallopian tubes (previous salpingitis)
– mechanism ; interfere ovum transport entrapment of
ovum
Sequelae
Chronic pelvic pain
– 4 times higher after acute salpingitis
– caused by hydrosalpinx, adhesion around ovaries
– should undergo laparoscope  R/o other disease
Mortality
– acute PID 1%
– rupture TOA 5-10%
Prevention
• Randomized controlled trials suggest that
preventing chlamydial infection reduces the
incidence of PID.
• Other methods of preventing PID and STD
include reducing the number of sexual partners,
avoiding unsafe sexual practices, and using
condoms with spermicide.
• Use of mechanical barriers with spermicide also
decreases the risk of acquiring STDs.
• Notification of the female sex partners of men
infected with Chlamydia trachomatis is
recommended
Relevance of topic for
clinical NP Practice
• NPs can help reduce the risk for PID and
its sequelae.
• Timely diagnosis and appropriate
treatment of lower-genital-tract
chlamydial and gonococcal infection
among both men and women can reduce
the risk of adverse consequences among
infected individuals and can reduce the
risk of further transmission to others.
Relevance of topic for
clinical NP Practice
• Also, NPs can influence men's and
women's risk of infection by providing
effective counseling about their sexual
behavior, health- care-seeking behavior,
and contraceptive practice, and by
convincing them to comply with
management instructions.
• Finally, by ensuring timely and effective
treatment of patients' sex partners, NPs
can reduce risk of reinfection.
Relevance of topic for clinical NP Practice
• Because the partners' infections may be
asymptomatic, interviewing and
treating these persons will help reduce
further transmission of infection in the
community and may facilitate
identifying other infected persons.
Management of Sex Partners
• Treatment for sex partners of women with PID
is imperative.
• The management of women with PID should
be considered inadequate unless their sex
partners have been appropriately evaluated
and treated.
• Failure to manage her sex partner (s)
effectively places a woman at risk for recurring
infection and related complications.
• Moreover, untreated sex partners often
unknowingly transmit STD in a community
because of asymptomatic infection.
Surveillance
• At all levels, PID surveillance is affected by four
main constraints:
• PID is difficult to diagnose accurately.
• PID is diagnosed in a wide variety of clinical
settings.
• Microbiology test results are needed to
determine the etiology of PID.
Patient Education
• The NP’s role as a health educator is central to
effective management.
• NPs should explain to women the nature of
their disease and should encourage them to
comply with therapy and prevention
recommendations.
• Specifically, NPs should:
• Emphasize the need for taking all the
medication, regardless of symptoms.
•
http://www.cdc.gov/mmwr/preview/mmwrhtml/00031002.htm
Patient Education
• Review contraindications and potential side
effects.
• Identify and discuss potential compliance
problems.
• Review the medical purpose of follow-up
evaluation.
• Emphasize the need to avoid sex until
treatment is completed.
• Emphasize the need to refer sex partners for
evaluation and treatment.
• http://www.cdc.gov/mmwr/preview/mmwrhtml/00031002.htm
Patient Education
• When medical-care messages are clear,
explicit, relevant, and rigorously delivered
by providers, patients are likely to comply.
• Reinforcement of these messages can be
achieved by providing written information.
• Information on written materials for
patient distribution can be obtained from
CDC or local and state health departments
• http://www.cdc.gov/mmwr/preview/mmwrhtml/00031002.htm
Controversies Surrounding PID
 The exact incidence of PID is unknown
 The disease cannot be diagnosed reliably from
clinical signs and symptoms.
 Laparoscopy exam of the pelvic organs
continues to be the "gold standard" approach
to diagnosis of PID.
 But, because this is a surgical procedure which
requires an incision in the abdomen, the high
priority is to design and development of noninvasive techniques, with smaller costs and
fewer risks.
 OC may reduce the risk of PID that is not
attributable to C. trachomatis.
Relevant Research Findings
• Recently, a study conducted at the University
of Washington School of Medicine confirmed
that regular douching is associated with pelvic
inflammatory disease.
• An earlier study had shown a significant
association between vaginal douching and
ectopic pregnancy.
• Pelvic inflammatory disease is also a major
factor in ectopic pregnancy.
Research Findings
• In a comparison of 100 women with confirmed
pelvic inflammatory disease (PID) and 762
randomly selected controls, at Harborview
Medical Center in Seattle
• The investigators report that women who
douche once or twice a month were 2.5 times
more likely to have PID than those who
douched less than once a month.
• However, the risk of PID does not appear to
increase with more frequent douching.
Relevant Research Studies on PID
• It is thought that douching increases the risk
of PID by wiping out beneficial vaginal
bacteria making it possible for disease
producing bacteria to get the upper hand.
• Another theory is that douching flushes
vaginal and cervical bacteria back into the
uterine cavity where they cause trouble.
Research Study
• According to a study funded by the Agency for
Healthcare Research and Quality (AHRQ),
women with mild to moderate PID who are
treated as outpatients have recovery and
reproductive outcomes similar to those for
women treated in hospitals.
• The PID Evaluation and Clinical Health (PEACH)
study was a randomized clinical trial designed to
compare the effectiveness of inpatient and
outpatient treatment strategies in preserving
fertility and preventing PID recurrence, chronic
pelvic pain and ectopic pregnancy for women
with mild to moderate PID.
Research Study
• Women treated as outpatients received a
single injection of Cefoxitin and an oral dose
of probenecid, followed by a 14-day supply of
oral doxycycline.
• Those treated in a hospital were given
multiple intravenous doses of Cefoxitin plus
doxycycline during a minimum inpatient stay
of 48 hours.
• The women’s care then was followed for 35
months to document long-term outcomes
Research Study
• The short-term clinical improvements were
similar for women treated in inpatient and
outpatient settings.
• After 35 months of follow-up, pregnancy
rates were nearly equal between the groups,
as was the amount of time it took to
become pregnant.
• There also were no statistically significant
differences between the proportion of
women with ectopic pregnancy, chronic
pelvic pain or PID recurrence .
Relevant Research Questions
• Should suspected PID be treated
empirically or should treatment be
delayed until results of microbiological
investigations are known?
• Do parental antibiotic treatment provide
optimal effectiveness than oral antibiotic
treatment for PID?
Case Study
Case Study
History: Jane Wheels
24-year-old female who presents reporting lower abdominal
pain, cramping, slight fever, and dysuria for 4 days
P 1001, LMP 2 weeks ago (regular without dysmenorrhea).
Uses oral contraceptives (for 2 years).
Reports gradual onset of symptoms of lower bilateral
abdominal discomfort, dysuria (no gross hematuria),
abdominal cramping and a slight low-grade fever in the
evenings for 4 days. Discomfort has gradually worsened.
Denies GI disturbances or constipation. Denies vaginal d/c.
States that she is happily married in a monogamous
relationship. Plans another pregnancy in about 6 months. No
condom use.
No history of STDs. Reports occasional yeast infections.
Douches regularly after menses and intercourse; last
douched this morning.
Case Study
Physical Exam
Vital signs: blood pressure 104/72, pulse 84,
temperature 38°C, weight 132
Neck, chest, breast, heart, and musculoskeletal exam
within normal limits. No flank pain on percussion.
No CVA tenderness.
On abdominal exam the patient reports tenderness in
the lower quadrants with light palpation. Several
small inguinal nodes palpated bilaterally.
Normal external genitalia without lesions or discharge.
Speculum exam reveals minimal vaginal discharge with
a small amount of visible cervical mucopus.
Bimanual exam reveals uterine and adnexal tenderness
as well as pain with cervical motion. Uterus anterior,
midline, smooth, and not enlarged.
Case Study
Questions
1.
What should be included in the differential
diagnosis?
2.
What laboratory tests should be performed
or ordered?
Case Study
Laboratory
Results of office diagnostics:
Urine pregnancy test: negative
Urine dip stick for nitrates: negative
Vaginal saline wet mount: vaginal pH was 4.5.
Microscopy showed WBCs >10 per HPF, no clue
cells, no trichomonads, and the KOH wet mount
was negative for budding yeast and hyphae.
3. What is the presumptive diagnosis?
4. How should this patient be managed?
5. What is an appropriate therapeutic
regimen?
Case Study
Partner Management
Sex partner: Joseph (spouse)
First exposure: 4 years ago
Last exposure: 1 week ago
Frequency: 2 times per week
(vaginal only)
6. How should Joseph be managed?
Case Study
Follow-Up
On follow up 3 days later, Jane was improved clinically.
The culture for gonorrhea was positive. The nucleic
acid acid amplification test (NAAT) for chlamydia was
negative.
Joseph (Jane’s husband) came in with Jane at follow-up.
He was asymptomatic but did admit to a "one-night
stand" while traveling. He was treated. They were
offered HIV testing which they accepted.
7. Who is responsible for reporting this case to the
local health department?
8. What are appropriate prevention counseling
recommendations for this patient?
Question:
1. Pelvic inflammatory disease (PID)
in women is most commonly
caused by:
A) Leptotrichia buccalis
B) Treponema pallidum
C) Chlamydia trachomatis
D) Bacillus anthracis
E) Borelia burgdorferi
Answer
The correct answer is #C.
Chlamydia Trachomatis
Question:
2. IUD use has been linked with:
A. pelvic inflammatory disease
B. tubal infections
C. uterine infections
D. all of the above
E. none of the above
Answer
The correct answer is #D.
All of the above
Question
3. Which of the following conditions
is not a risk factor for pelvic
inflammatory disease (PID)?
A. Smoking
B. Multiple sexual partners
C. Young age at first intercourse
D. Hepatitis B
E. Intrauterine device (IUD)
insertion
Answer
The correct answer is D:
• Hepatitis B is not a known risk factor
for PID.
Question:
4.) Which of the following is not used
to treat symptoms associated with
pelvic inflammatory disease (PID)?
A: Azithromycin
B: Ceftriaxone
C: Ampicillin
D: Ofloxacin
E: Cefoxitin
Answer
The correct answer is A:
• No data suggest that Azithromycin is an
appropriate oral regimen for the tx of PID.
• Most patients are now managed as outpatients.
• One outpatient regimen is Cefoxitin and
probenecid taken orally in a single dose.
• Alternatively, ceftriaxone (less active against
anaerobic bacteria compared to Cefoxitin) can be
taken once IM with doxycycline orally twice daily
for 14 days.
• Another regimen is ofloxacin taken orally for 14
days with either clindamycin or metronidazole,
which also are taken orally for 14 days.
Question
5.) (T/F): The major criteria for the
diagnosis of pelvic inflammatory
disease (PID) include
– Leukocytosis
– elevated C-reactive protein (CRP)
– elevated erythrocyte
sedimentation rate (ESR)
– fever.
Answer
The correct answer is False:
The major criteria for the diagnosis of PID
include:
– Cervical motion tenderness
– Adnexal tenderness
– Lower abdominal tenderness.
ESR, CRP, and laboratory documentation of
Neisseria gonorrhea or Chlamydia trachomatis
cervical infection, among others, can aid in
increasing the specificity of diagnosis
Question:
6.) (T/F): All of the following are
indications for hospitalization for
treatment of pelvic inflammatory
disease (PID):
– failed outpatient therapy
– Inability to tolerate oral therapy
– Pregnancy
– pelvic abscess.
Answer
The correct answer is True:
These are circumstances in which women
should be hospitalized for treatment of PID.
Other conditions that may require
hospitalization are:
• uncertain diagnosis
• severe illness
• Severe N & V
• Immunodeficiency (HIV,
immunosuppressive medications).
Question:
7.) (T/F): In the initial workup,
laparoscopy should be used to
confirm the diagnosis of pelvic
inflammatory disease (PID).
Answer
The correct answer is False:
• Laparoscopy is costly and not
always available.
• It should be used if the diagnosis is
in doubt
Question
8.) (T/F): Consider hospitalizing
patients who do not improve
clinically after 72 hours with
outpatient therapy for pelvic
inflammatory disease (PID).
Answer
The correct answer is True:
• While most patients are now
treated on an outpatient basis, these
patients should be admitted to the
hospital and treated appropriately
Any Questions???
THANK YOU FOR YOUR ATTENTION !!