![Univariate analysis for FSFI total score by variable. RT: radiotherapy, CCRT: concurrent chemoradiotherapy. FIGO: International Federation of Gynecology and Obstetrics, HRT: hormone replacement therapy. Int J Gynecol Cancer, 2014; 24(4):800-5[18].](https://www.researchgate.net/publication/333786069/figure/fig2/AS:769744617627649@1560532826716/Univariate-analysis-for-FSFI-total-score-by-variable-RT-radiotherapy-CCRT-concurrent_Q320.jpg)
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254
Cur Op Gyn Obs, 2(1): 254-261 (2019)
Clinicopathological Risk Factors Affecting Sexual
Function after Radiotherapy for Cervical Cancer
Patients
Harding Y1*, Ooyama T1 and Ueda S2
1Department of Obstetrics and Gynecology, Graduate School of Medical Science, University of the Ryukyus, 207
Uehara, Nishihara Okinawa 903-0215, Japan
2Department of Clinical Pharmacology and Therapeutics, Graduate School of Medical Science, University of the
Ryukyus, 207 Uehara, Nishihara Okinawa 903-0215, Japan
*Correspondence: Yuko Harding, St. Mary’s College, Faculty of Nursing, Maternity Nursing, Advanced Midwifery
Course, M.S program in nursing, 422 Tsubukuhonmachi, Kurume, Fukuoka Pref. 830-8558, Japan,
Tel: +81-942-35-7271 Ext 237; E-mail: yukohardinaha@yahoo.co.jp
Received date: April 23, 2019; Accepted date: June 03, 2019; Published date: June 08, 2019
Abstract
Aim: To specify the clinicopathological risk factors that influence sexual function after radiotherapy for cervical
cancer.
Methods: This observational and cross-sectional study includes a population of 60 adult women diagnosed with stage
I to III cervical cancer who underwent radiotherapy. Sexual function was assessed using a self-reported standardized
questionnaire, the Female Sexual Function Index (FSFI). Age, clinical stage, tumor diameter, type of radiotherapy, use
of hormone replacement therapy, and period of time elapsed since the completion of radiotherapy at the time of data
collection were documented using participants’ medical records. Multivariate logistic regression was used to identify
independent risk factors for decreased sexual function.
Results: The median age of participants was 53 years (Interquartile range, IQR, 45-60 years). Using the FSFI total
score compared by variable, sexual dysfunction was significantly more prevalent among women in FIGO stage III than
those in stage I /II (P = 0.038), and at ≥ 12 months after the completion of radiotherapy than at < 12 months after
completion (P = 0.008). Multivariate analysis revealed that sexual morbidity was significantly more likely in stage III
women (OR 4.60, 95% CI, 1.07, 24.39, P = 0.040), or where radiotherapy had occurred more than 12 months before
(OR 4.78, 95% CI, 1.17, 25.20, P = 0.028).
Conclusion: FIGO stage III and a period of ≥ 12 months after radiotherapy are associated with reduced sexual
function. In medical consultations with women in these categories, adequate treatment should be provided where
appropriate.
Keywords: Cervical cancer, Radiotherapy, FIGO stage I-III, Sexual function, FSFI
Abbreviations: FSFI: the Female Sexual Function Index; FSD: Female Sexual Dysfunction; HRT: Hormone Replacement
Therapy; EBRT: External Beam Radiotherapy Technique; HDR-ICBT: High-Dose-Rate Intracavitary Brachytherapy;
FIGO: the International Federation of Gynecology and Obstetrics; RT: Radiotherapy alone; CCRT: Concurrent
Chemoradiotherapy
Research Article
ISSN: 2637-4617
Current Opinion in Gynecology and Obstetrics
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Cur Op Gyn Obs, 2(1): 254-261 (2019)
Introduction
In Japan, 9,794 women were diagnosed with cervical
cancer in 2008 and 2,712 women died of the disease in
2012 [1]. Surgery and radiotherapy are the basic treatment
modalities for cervical cancer, but since 1999, concurrent
chemoradiotherapy has been recommended as the
standard treatment for locally advanced cancers [2,3]. The
number of surviving patients has now increased, as has
the prevalence of late radiation-induced side effects [4,5].
After radiotherapy for cervical cancer directly affecting
sexual organs and hormonal status, all are succeptable to
a high risk for sexual compromise. Both the reproductive
organs and hormones are affected, exposing patients to
a high risk of female sexual dysfunction (FSD), resulting
from both physical and psychological changes. Previous
studies have found that radiotherapy for cervical cancer
results in FSD [6-8], which is defined as disorders of
libido, arousal, orgasm, and sexual pain [9,10]. Sudden
premature ovarian failure and vaginal shortening and
stenosis after radiotherapy results in dyspareunia (sexual
pain disorders) [11-13]; dyspareunia influences FSD
affecting approximately 43% of women under the age of
60 in the U.S and contributing to personal psychological
distress [14,15] or poor body image [16]. In addition, the
associated psychological impact of the disease, combined
with the physical sensations from the disease itself and
the treatment side effects, may contribute to both a
lower interest in sex, and consequently, a reduction in
the frequency of sexual activity.
Very little attention has been placed on the
sexual difficulties that women can experience after
radiotherapy to the sexual organs [17]. In our previous
study in 2014, by Female Sexual Function Index (FSFI)
self-reported questionnaires, there was a significant
difference in median (range) FSFI total score in patients
after RT or RS and healthy women. The median FSFI
total score in patients after RT was significantly lower
than that in healthy women.Six sexual domains (desire,
arousal, lubrication, orgasm, satisfaction, pain) were all
significantly affected inpatients after RT (The International
Journal of Gynecological Cancer. 2014; 24: 800-805)
[18]. However, to the best of our knowledge, only a few
studies have evaluated how sexual dysfunction after
radiotherapy is associated with multiple clinical factors,
such as age, clinical stage, tumor diameter, type of
radiotherapy, hormone replacement therapy (HRT), and
the period after completion of radiotherapy. Clarifying
the clinicopathological factors associated with FSD could
lead to the development of more accurate interventions
for cervical cancer survivors.
The aim of this study was to specify the
clinicopathological factors that influence sexual problems
after radiotherapy for cervical cancer by the use of a
globally validated questionnaire.
Materials and Methods
This observational and cross-sectional study used
a standardized questionnaire, the Female Sexual
Function Index (FSFI). All participants were outpatients
at the University of the Ryukyus Hospital who had
undergone definitive pelvic radiotherapy or concurrent
chemoradiotherapy for cervical cancer and had follow-up
appointments between June 2011 and April 2012. Women
were excluded from the study for the following reasons:
presence of metastases or recurrence; treatment with
postoperative adjuvant radiotherapy or radiotherapy for
hemostasis during the study period; no sexual partner;
psychiatric disorder; current use of antidepressant
or psychotropic medicine; history of depression;
alcohol or drug addiction; major hematologic, renal, or
hepatic abnormalities; uncontrolled diabetes; serious
cardiovascular disease; pre-existing health problems;
and a physical or psychological handicap. The study
was reviewed and approved by the institution’s Ethics
Committee. Written informed consent was obtained
from all participants prior to the study.
In planning this research, we estimated that at least
43% of women (by analysis of data from the National
Health and Social Life Survey, a probability sample study
of sexual behavior in a demographically representative,
1992 cohort of U.S. adults) [14] would demonstrate FSD
at enrollment. A sample size of participants was defined
as being large enough to achieve a 43% incidence rate
with a statistical power of 80% and a confidence level of
95%.
All participants were treated with anterior-posterior
and posterior-anterior parallel-opposed ports or a 4-field
external beam radiotherapy technique (EBRT). A 50 Gy
dose of EBRT was delivered in 25 fractions. The center
shield (4 cm wide at the midline) was set up after delivering
20-40 Gy. High-dose-rate intracavitary brachytherapy
(HDR-ICBT) was delivered once per week at a fractional
dose of 6 Gy and given 3 or 4 times at point A. Patients
treated with concurrent chemoradiotherapy received
cisplatin 20 mg/m2 for 5 days every 3 weeks or 40 mg/
m2 weekly concomitantly with radiotherapy. A dilator
for protecting vaginal contracture or shortening after
radiotherapy was not used as a standard practice. Clinical
stage was determined according to the International
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Cur Op Gyn Obs, 2(1): 254-261 (2019)
Federation of Gynecology and Obstetrics (FIGO) 1994
classification system. Participants were asked about their
use of HRT. Conjugated estrogens or estradiol with and
without medroxyprogesterone acetate were used. All
participants underwent a standardized evaluation for
sexual function by the FSFI which focuses on arousal,
desire, lubrication, orgasm, satisfaction, and pain [19].
FSFI is a brief, multidimensional self-reporting
instrument to assess sexual function occurring over the
previous 4 weeks in women. The scale consists of 19
items and has received initial psychometric evaluation
by Rosen et al. [19], in addition to studies related to its
reliability, convergent validity, and discriminant validity
[20]. The FSFI has been validated for internal consistency
and test-retest reliabilities, which are shown to be
within the acceptable range. It provides a total score
as well as domain scores in six areas: Desire (2 items),
Arousal (4 items), Lubrication (4 items), Orgasm (3 items),
Satisfaction (3 items), and Pain (3 items). Response
options were organized according to a Likert-type scale
of 1 to 5 for items 1, 2, 15, and 16. For the remaining
items, the response options ranged from 0 to 5, because
the option “no sexual activity” was included. The score
of each domain is obtained by adding individual scores,
then multiplying the obtained score by the corresponding
factor. The total score (full scale score or overall score)
is then obtained by adding together all the scores of
each domain. The measurement of total sexual function
can range between 2 and 36; a low score indicates the
existence of multiple problems related to sexual function,
and a high score represents good sexual function. In the
present study, we used the published FSFI to distinguish
women with or without FSD. Participants signed a written
informed consent and completed the FSFI questionnaire
(Refer to [18]).
Data were analyzed using JMP (ver. 14.2; SAS Institute
Inc., Cary, NC, U.S.). Age, FIGO stage, tumor diameter,
type of radiotherapy, HRT, and the time period since
the completion of radiotherapy were expressed as
observation numbers and percentages. The chi-square
test was used for categorical variables. The patient
variables: age significance and time period elapsed
since the completion of radiotherapy at data collection,
FSFI total score and each domains’ sexual functional
score status were evaluated by Mann-Whitney U test
to investigate the difference in the groups between the
FSFI total score ≤ 5 and > 5, which were categorized by a
median score. The age variable was divided into two, with
53 years old being the median score. The time period
passed since the completion of radiotherapy at the time
of data collection variable was divided into two groups: <
12 months and ≥ 12 months,
Participants
returned survey
n = 89; 75%
Blank survey returned
n = 23
Declined to participate: 10
Missing response: 13
Complete
survey returned
n = 66; 55%
Survey not returned
n = 30
Participants included
in final analysis
N = 60; 50%
Excluded
n = 6
Not meeting inclusion criteria
No partner: 2
Metastases: 1
Recurrence: 1
Operation with adjuvant
radiotherapy: 1
Radiotherapy for
hemostasis: 1
Participants in cervical
cancer after RT
identified
N = 199
N=119
Figure 1: Flow chart of participant data collection.
The inclusion and exclusion process of the study
participants shows the selection of cervical cancer
participants. *HRT, Hormone replacement therapy.
Using the FSFI total score and based on receiver
operating characteristics analysis (ROC), and the area
under the curve (AUC, 0.627).
The results are presented as the median and
interquartile range. In the univariate analysis for the FSFI
total score and subscale scores by variables, the P values
are from the Mann-Whitney tests analyzed. Univariate
and multivariate logistic regression analysis was used for
factors predicting FSD after radiotherapy. P values < 0.05
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Cur Op Gyn Obs, 2(1): 254-261 (2019)
were considered significant. Sample size calculation used
the EPI-INFO 7.0 statistical package.
Results
A flow chart of participant FSFI data collected is shown
in figure 1. During the study period, 119 patients received
radiotherapy at our institution, and 60 eligible patients
met the inclusion criteria. Eligible patients were classified
in groups according to their FSFI total score, either ≤ 5
(50%, n = 30), or > 5 (50%, n = 30), and comparisons were
made between the groups.
The clinicopathological characteristics of the study
patients are listed in table 1. The median (Interquartile
range, IQR) age of all cervical cancer participants was
53 (45-60) years. In addition, the median (IQR) age of
patients with an FSFI total score of ≤ 5 and > 5, was 51
(42-60) years, and 55 (46-60) years, respectively. Fourteen
of the 30 patients (47%) in the ≤ 5 group were older
than 53 years and 53% in the > 5 group. The FIGO stage
distribution was as follows: in the ≤ 5 group, 11, 9, and
10 patients in stages I, II, and III, respectively; in the >
5 group, 13, 13, and 4 patients, respectively. There was
therefore a higher proportion of stage III patients in the
FSFI total score ≤ 5 group (P = 0.169). The median (IQR)
period after treatment completion was 30 (11-58) months.
We observed a significantly higher number of patients
in the > 5 group who had completed the treatment 12
months prior to data collection (P = 0.006). No significant
differences in characteristics were observed in age, tumor
diameter, type of radiotherapy, and HRT use.
FSFI median (IQR) total score among all participants in
stage I−III were 5.0 (3.6-16.7) (Table 1). Though it is not in
the table here, the FSFI median subscale scores in stage
III / I−III were 1.2 (1.2-2.0) / 1.8 (1.2-2.4) for Desire, 0 (0-1.0)
/ 0 (0-2.3) for Arousal, 0 (0-0.6) / 0 (0-3.3) for Lubrication,
0 (0-0.8) / 0 (0-3.2) for Orgasm, 2.4 (1.6-2.5) / 2.4 (2.4-3.6)
for Satisfaction and 0 (0-0.6) / 0 (0-1.6) for Pain. The FSFI
median subscale scores except Desire and Satisfaction in
stage III as well as all patients in stage I-III were all zero.
And then there are no significant different subscale score
except Satisfaction between in stage III and in stage I
and II. The median (IQR) for Satisfaction in stage III was
significantly lower than in stage I and II (p = 0.013); Refer
to [18] about the FSFI subscale score in stage I / II.
In univariate analysis for FSFI total score by variable
(Figure 2), sexual function was not influenced by age,
tumor diameter, type of radiotherapy, or HRT, but the
median FSFI total score was significantly lower in women
with FIGO stage III (P = 0.038) and in those who completed
the survey > 12 months after treatment completion (P =
0.008).
Univariate and multivariate logistic regression analysis
for factors predicting female sexual dysfunction after
radiotherapy is shown in table 2. In univariate analysis,
only those more than 12 months after the completion
of radiotherapy (OR 6, 95% CI, 1.63, 29.13, P = 0.006) are
shown to be independent risk factors for sexual morbidity.
However, in multivariate analysis, stage III (OR 4.60, 95%
CI, 1.07, 24.39, P = 0.040) and more than 12 months after
the completion of radiotherapy (OR 4.78, 95% CI, 1.17,
25.20, P = 0.028) are shown to be independent risk factors
for sexual morbidity.
Table 1: Participant characteristics.
Characteristics FSFI total
score ≤5
FSFI total
score >5
P-value
(n=30) (n=30)
Age (years)
Median 51 55 0.553
IQR 42-60 46-60
≤53 16 14 0.606
>53 14 16
Clinical stage
(FIGO1997)*
I 11 13 0.169
II 9 13
III 10 4
Tumor
diameter
≤4 cm 10 8 0.573
>4 cm 20 22
Radiotherapy
RT 7 3 0.161
CCRT 23 27
HRT (yes) 7 10 0.39
Months after
treatment
Median 37 23 0.09
IQR 17-70 5-57
<12 3 12 0.006
≥12 27 18
Total FSFI
Median 3.6 15.5 < 0.001
IQR 3.6-4.2 6.0-22.1
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Cur Op Gyn Obs, 2(1): 254-261 (2019)
RT, radiotherapy alone, CCRT, concurrent
chemoradiotherapy. FIGO, International Federation of
Gynecology and Obstetrics, HRT, hormone replacement
therapy. FSD, Female sexual dysfunction, FSFI (Female
sexual function Index) median (IQR, interquartile range)
total score among all participants were 5.0 (3.6-16.7).
*Patients who had stage I / II disease in this current study
were included in the manuscript as follows: Int J Gynecol
Cancer, 2014; 24(4):800-5[18].
Discussion
If the previous FSFI total score of 26.55 is taken as
the optimal cut-off score for sexual dysfunction [21], the
FSFI total scores after radiotherapy in our study, with a
median of 5.0.
IQR, 3.6-16.7 in stage I-III were shown to be markedly
low. Using both univariate for FSFI total score by variable
and multivariate logistic regression analysis, multivariate
analysis revealed that sexual morbidity was significantly
more likely in stage III women, or where radiotherapy
had occurred more than 12 months before.
Regarding domains, among all participants, not only
in stage I and II, but also III terribly compromised their
sexual functions except in the domains of Desire and
Satisfaction. Frumovitz et al. [22] reported FSD using
FSFI, and investigated stage IA and IB cervical cancer
patients (37 surgery, 37 radiotherapy, and 40 controls).
They showed that all domains of sexual function (except
Desire) were significantly lower in patients treated with
radiotherapy. Damage to the pelvic splanchnic nerve,
fibrosis of the vagina and the paravaginal soft tissue by
radiotherapy, results in sexual insensitivity and pelvic
pain, or pain during sexual intercourse. In addition,
radiotherapy can cause early menopause by halting the
production of sex hormones by the ovaries, leading to
vaginal atrophy and dyspareunia [23,24]. Saewong S et
al. [25] reported that there was a significant reduction in
the frequency of sexual intercourse after radiotherapy
in cervical cancer survivors, and this was significantly
correlated with the FIGO stage. However, Rodrigues et al.
[26] found no statistically significant differences in sexual
function in stage IB2- IVA cervical cancer patients treated
with pelvic radiotherapy. In our institution, radiotherapy
was performed as previously described, and the median
cumulative biologic effective dose at point A (EBRT + ICBT)
was 64.8 Gy10 (range: 48-76.8 Gy10) for early disease,
and 76.8 Gy10 (range: 38.4-86.4 Gy10) for advanced
disease [27]. It is possible that this dose could be related
to the fact that greater rates of sexual dysfunction were
reported in women in FIGO stage III than in stages I /
II of the disease. These results suggest the necessity
of treating vaginal dryness and vaginal dilatation after
radiotherapy, particularly in women with an advanced
stage disease.
Using both univariate and multivariate analysis,
our study revealed that the other risk factor for sexual
dysfunction was that at the time of data collection a period
of ≥ 12 months had elapsed since the completion of
radiotherapy. Schover et al. [23] reported that in patients
Figure 2: Univariate analysis for FSFI total score by variable.
RT: radiotherapy, CCRT: concurrent chemoradiotherapy. FIGO: International Federation of Gynecology and Obstetrics,
HRT: hormone replacement therapy. Int J Gynecol Cancer, 2014; 24(4):800-5[18].
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Cur Op Gyn Obs, 2(1): 254-261 (2019)
with cervical cancer who underwent radical hysterectomy
and radiotherapy alone, significantly more problems
(such as dyspareunia, postcoital bleeding, or painful
penetration) were reported in patients 1 year after the
termination of treatment, although at six months there
was no difference in the numbers reporting problems
between all the cancer treatment groups. Jensen et al.
[12] researched 118 patients treated with radiotherapy
for cervical cancer over a 2 yr period, using the Sexual
function Vaginal changes Questionnaire (SVQ), and found
that approximately 85% had low or no sexual interest. In
particular, 12 months and longer after the termination
of treatment, there was an increase in the number of
women reporting feelings that their vagina was too small
during intercourse. This feeling became increasingly
bothersome, causing a lack of sexual activity, and
dyspareunia was frequently observed. They suggested
that FSD after radiotherapy alters sexual behavior
because of the insidious changes relating to fibrosis that
occur between 6 months and 1 year after treatment. It is,
therefore, very important to prevent these changes soon
after the completion of radiotherapy.
In relation to HRT after radiotherapy, results from
previous reports are conflicting. Jensen et al. [12]
reported that although lubrication, dyspareunia, orgasm,
sexual satisfaction, and vaginal dimensions were not
significantly related to HRT intake, patients receiving HRT
had a significantly lower risk of having reduced sexual
interest and of becoming sexually inactive. Denton et
al. [13] reported that vaginal estrogens were effective
in reducing dyspareunia and alterations in the vaginal
epithelium and prevented vaginal narrowing. Although
we initially hypothesized that hormonal status would
play an important role in changing sexual function after
treatment for cervical cancer, we could not find any
relationship between HRT and FSD. Lack of attention to
hormone related variables such as onset, type of HRT,
and iatrogenic menopause after radiotherapy may have
blunted the positive protective impact of HRT on sexual
function. Therefore, it is considered necessary to conduct
a prospective study of sexual function that includes an
evaluation of hormonal status.
One of the strengths of this study is that it objectively
evaluated sexual function using a comparable worldwide
validated scale, and used multivariate analysis to assess
the self-reported sexual function of Japanese women
treated with radiotherapy for cervical cancer. However,
our study is limited by the low data collection rates on a
single item questionnaire, and in relation to the fact that
Japanese are invariably reserved in discussions related
to sexuality. Because this study is cross-sectional, and is
an observational study, we cannot assess the changes,
in the participant’s sexual function before and after
radiotherapy. Moreover, we cannot accurately evaluate
Table 2: Univariate andmultivariate logistic regression analysis for factors predicting female sexual dysfunction after
radiotherapy.
Variable N Ref N Univariate analysis Multivariate analysis
Crude OR
(95%Cl)
*P-value Adjusted OR ‡P-value
(95%Cl)
Age (years)
53<
30 ≤53 30 0.77(0.28, 2.11) 0.605 0.29(0.05, 1.31) 0.109
FIGO stage
III
14 I /II 46 3.25(0.94, 13.28) 0.064 4.60 (1.07, 24.39) 0.04
Tumor diameter (cm)
4<
42 ≤4 18 0.73(0.23, 2.20) 0.573 0.64 (0.12, 3.48) 0.602
Radiotherapy
CCRT
50 RT 10 0.37(0.07, 1.48) 0.161 0.23 (0.02, 1.82) 0.169
HRT
No
43 Yes 17 1.64(0.53, 5.30) 0.389 2.44 (0.53, 12.09) 0.251
Months after treatment
12≤
45 <12 15 6(1.63, 29.13) 0.006 4.78 (1.17, 25.20) 0.028
OR, odds ratio, CI, confidence interval, Ref, Reference.
*The results obtained from logistic regression analysis indicating risk factors for sexual dysfunction.
‡P-value of whole model test was 0.0170. Female sexual dysfunction was categorized by the total score: 5< (No) or ≤5
(Yes). OR reviled Yes/ No.
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Cur Op Gyn Obs, 2(1): 254-261 (2019)
patients’ individual influences from their surroundings,
or their relationship with partners. Because of these
issues, our results may not be generalizable with other
populations of cervical cancer patients.
Conclusion
Female sexual morbidity following cervical cancer
treatment should be managed with interventions, [17]
including counseling by specialists. It is also considered
that women should receive routine clinical assessments
to assess any sexual dysfunction and the rehabilitation
necessary after receiving radiotherapy, and that these
should be targeted at women according to their FIGO
staging and the length of time since they completed
radiation therapy.
Declaration
Ethics approval and consent to participate
This study protocol was reviewed and approved by
the University of the Ryukyus Review Board, and written
informed consent was obtained from all participants. The
study was conducted in accordance with the Declaration
of Helsinki.
Consent for publication
We give our consent for information about ourselves
and our article to be published in Current Opinion in
Gynecology and Obstetrics.
Competing interest
The authors declare that there are no conflicts of
interest.
Funding
This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-
profit sectors except the trip money for oral presentation
at the conference from Japan Society of Private Colleges
and Universities of Nursing.
Authors’ contributors
YH participated in the conception and design,
acquisition of data, analysis and interpretation of data,
drafting the article, revising it for intellectual content, and
final approval of the completed article. TO participated in
acquisition of data, revising it for intellectual content, and
final approval of the completed article. SU participated in
the conception and design, analysis and interpretation of
data, revising the article for intellectual content, and final
approval of the completed article.
Acknowledgements
We gratefully acknowledge the work of past and
present members of our laboratory.
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