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VOLUME ONE HUNDRED AND FIFTEEN
ADVANCES IN
PARASITOLOGY
SERIES EDITOR
D. ROLLINSON J. R. STOTHARD
Life Sciences Department Department of Tropical
The Natural History Museum, Disease Biology
London, United Kingdom Liverpool School of Tropical
[email protected] Medicine, Liverpool, United Kingdom
[email protected]
EDITORIAL BOARD
T. J. C. ANDERSON K. KING
Department of Genetics, Texas Department of Zoology,
Biomedical Research Institute, University of Oxford,
San Antonio, TX, United States Oxford, United Kingdom
M. G. BASÁÑEZ M. G. ORTEGA-PIERRES
Professor of Neglected Tropical Professor of the Department of Genetics
Diseases, Department of Infectious and Molecular Biology,
Disease Epidemiology, Faculty of Centro de Investigación y de
Medicine (St Mary’s Campus), Estudios Avanzados IPN,
Imperial College London, Mexico City, Mexico
London, United Kingdom
D. L. SMITH
D. D. BOWMAN Johns Hopkins Malaria Research
Director Cornell CVM MPS—Veterinary Institute & Department of Epidemiology,
Parasitology, Professor of Parasitology, Johns Hopkins Bloomberg School
C4-119 VMC, Dept Micro & Immunol, of Public Health, Baltimore,
CVM Cornell University, Ithaca, MD, United States
NY, United States
R. B. GASSER R. C. A. THOMPSON
Head, WHO Collaborating Centre
Faculty of Veterinary and Agricultural
for the Molecular Epidemiology
Sciences, The University of Melbourne,
of Parasitic Infections, Principal
Parkville, VIC, Australia
Investigator, Environmental
A. L. GRAHAM Biotechnology CRC (EBCRC),
Professor of Ecology & Evolutionary Biology, School of Veterinary and Biomedical
Co-Director of the Global Health Program, Sciences, Murdoch University,
Princeton University, Princeton, Murdoch, WA, Australia
NJ, United States
X.-N. ZHOU
J. KEISER Professor, Director, National Institute of
Head, Helminth Drug Development Unit, Parasitic Diseases,
Department of Medical Parasitology and Chinese Center for Disease Control
Infection Biology, Swiss Tropical and Public and Prevention, Shanghai,
Health Institute, Basel, Switzerland People’s Republic of China
VOLUME ONE HUNDRED AND FIFTEEN
ADVANCES IN
PARASITOLOGY
Edited by
DAVID ROLLINSON
Life Sciences Department
The Natural History Museum,
RUSSELL STOTHARD
Department of Tropical
Disease Biology
Liverpool School of Tropical
Medicine, Liverpool, United Kingdom
Academic Press is an imprint of Elsevier
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First edition 2022
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Typeset by STRAIVE, India
Contents
Contributors vii
1. An update on female and male genital schistosomiasis and

a call to integrate efforts to escalate diagnosis, treatment and
awareness in endemic and non-endemic settings: The time is now 1
Amaya L. Bustinduy, Bodo Randriansolo, Amy S. Sturt, Seke A. Kayuni,
Peter D.C. Leustcher, Bonnie L. Webster, Lisette Van Lieshout,
J. Russell Stothard, Hermann Feldmeier, and Margaret Gyapong
1. Introduction 3
2. Pathogenesis and clinical manifestations 9
3. Immunology 12
4. Diagnosis of genital schistosomiasis 13
5. Co-infections and co-morbidities 21
6. Immigrants and returned travellers 24
7. Management of FGS and MGS 25
8. Disability, stigma and community awareness 29
9. Programme integration 30
10. Conclusions and way forward 33
Acknowledgements 33
References 33
2. Vertebrates as uninfected disseminators of helminth

eggs and larvae 45
Neil J. Morley
1. Introduction 46
2. Terminology and definitions of helminth zoochory 48
3. Features of different vertebrates that affect their ability to disseminate
parasites 49
4. Endozoochory 54
5. Ectozoochory 127
6. Long-distance dispersal 138
7. Conclusion 143
References 146
v
vi Contents
3. Anthelmintic resistance in ruminants: challenges and solutions 171

J. Charlier, D.J. Bartley, S. Sotiraki, M. Martinez-Valladares, E. Claerebout,
G. von Samson-Himmelstjerna, S.M. Thamsborg, H. Hoste, E.R. Morgan,
and L. Rinaldi
1. Concerted action for combatting anthelmintic resistance in ruminants 173
2. Prevalence and impact of anthelmintic resistance 175
3. Gastrointestinal nematodes: current and future diagnosis 179
4. Diagnosis of anthelmintic resistance 185
5. Towards a sustainable use of anthelmintics 193
6. Prospects of new anthelmintics 197
7. Complementary control approaches 198
8. Facilitating behavioural change 206
9. Conclusions 210
Acknowledgements 211
References 211
Further reading 226
Contributors
D.J. Bartley
Disease Control, Moredun Research Institute, Penicuik, United Kingdom
Amaya L. Bustinduy
Department of Clinical Research, London School of Hygiene & Tropical Medicine,
J. Charlier
Kreavet, Kruibeke, Belgium
E. Claerebout
Ghent University, Faculty of Veterinary Medicine, Laboratory of Parasitology, Merelbeke,
Belgium
Hermann Feldmeier
Charite University Medicine Berlin, Institute of Microbiology, Infectious Diseases and
Immunology, Berlin, Germany
Margaret Gyapong
Institute of Health Research, University of Health and Allied Sciences, Ho, Ghana
H. Hoste
INRAE, UMR 1225 IHAP INRAE/ENVT, Toulouse University, Toulouse, France
Seke A. Kayuni
Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool,
United Kingdom; MASM Medi Clinics Limited, Blantyre, Malawi
Peter D.C. Leustcher
Centre for Clinical Research, North Denmark Regional Hospital, Hjoerring; Department of
Clinical Medicine, Aalborg University, Aalborg, Denmark
M. Martinez-Valladares
Instituto de Ganaderı́a de Montaña (CSIC-Universidad de León), Departamento de Sanidad
Animal, León, Spain
E.R. Morgan
Institute for Global Food Security, Queen’s University Belfast, Belfast, United Kingdom
Neil J. Morley
School of Biological Sciences, Royal Holloway, University of London, Egham, Surrey,
United Kingdom
Bodo Randriansolo
Association K’OLO VANONA, Antananarivo, Madagascar
L. Rinaldi
University of Naples Federico II, Unit of Parasitology and Parasitic Diseases, Department of
Veterinary Medicine and Animal Production, CREMOPAR, Napoli, Italy
vii
viii Contributors
S. Sotiraki
Veterinary Research Institute, Hellenic Agricultural Organisation ELGO-DIMITRA,
Thessaloniki, Greece
J. Russell Stothard
Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool,
United Kingdom
Amy S. Sturt
Section of Infectious Diseases, Veterans Affairs Palo Alto Health Care System, Palo Alto,
United States
S.M. Thamsborg
Veterinary Parasitology, University of Copenhagen, Frederiksberg C, Denmark
Lisette Van Lieshout
Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
G. von Samson-Himmelstjerna
Institute for Parasitology and Tropical Veterinary Medicine, Veterinary Centre for
Resistance Research, Freie Universit€at Berlin, Berlin, Germany
Bonnie L. Webster
Natural History Museum, London, United Kingdom
CHAPTER ONE
An update on female and male

genital schistosomiasis and
a call to integrate efforts
to escalate diagnosis, treatment
and awareness in endemic
and non-endemic settings:
The time is now
Amaya L. Bustinduya,∗, Bodo Randriansolob, Amy S. Sturtc,
Seke A. Kayunid,e, Peter D.C. Leustcherf,g, Bonnie L. Websterh,
Lisette Van Lieshouti, J. Russell Stothardd, Hermann Feldmeierj,
and Margaret Gyapongk
a
Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United
Kingdom
b
Association K’OLO VANONA, Antananarivo, Madagascar
c
Section of Infectious Diseases, Veterans Affairs Palo Alto Health Care System, Palo Alto, United States
d
Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
e
MASM Medi Clinics Limited, Blantyre, Malawi
f
Centre for Clinical Research, North Denmark Regional Hospital, Hjoerring, Denmark
g
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
h
Natural History Museum, London, United Kingdom
i
Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
j
Charite University Medicine Berlin, Institute of Microbiology, Infectious Diseases and Immunology, Berlin,
Germany
k
Institute of Health Research, University of Health and Allied Sciences, Ho, Ghana
∗
Corresponding author: e-mail address: [email protected]
Contents
1. Introduction 3
1.1 Selection criteria 3
1.2 Epidemiology and geographical distribution of genital schistosomiasis 3
1.3 Life cycle and transmission 4
1.4 FGS and MGS in less common Schistosoma species 7
1.5 The importance of different hybrids of S. haematobium group species
(including minor species contributing to FGS/MGS) 8
2. Pathogenesis and clinical manifestations 9
2.1 Female genital schistosomiasis (FGS) 9
2.2 Male genital schistosomiasis (MGS) 11
Advances in Parasitology, Volume 115 Copyright #2022 Elsevier Ltd 1

ISSN 0065-308X All rights reserved.
https://doi.org/10.1016/bs.apar.2021.12.003
2 Amaya L. Bustinduy et al.
3. Immunology 12
3.1 Vaginal environment in FGS 12
3.2 Immune activation during pregnancy 13
4. Diagnosis of genital schistosomiasis 13
4.1 FGS diagnostics 13
4.2 Molecular diagnostics (nucleic acid amplification tests) 17
4.3 MGS diagnostics 19
4.4 Immunopathology in MGS 20
5. Co-infections and co-morbidities 21
5.1 Human immunodeficiency virus (HIV) 21
5.2 Human papillomavirus (HPV) and FGS 22
6. Immigrants and returned travellers 24
7. Management of FGS and MGS 25
7.1 FGS treatment 25
7.2 Treatment of MGS 28
7.3 Pregnancy 28
8. Disability, stigma and community awareness 29
8.1 Case study: Ghana 29
9. Programme integration 30
10. Conclusions and way forward 33
Acknowledgements 33
References 33
Abstract
The last decades have brought important insight and updates in the diagnosis, man-
agement and immunopathology of female genital schistosomiasis (FGS) and male
genital schistosomiasis (MGS). Despite sharing a common parasitic aetiological agent,
FGS and MGS have typically been studied separately. Infection with Schistosoma
haematobium manifests with gender-specific clinical manifestations and consequences
of infection, albeit having a similar pathogenesis within the human genital tract.
Schistosoma haematobium is a known urinary bladder carcinogen, but its potential caus-
ative role in other types of neoplasia, such as cervical cancer, is not fully understood.
Furthermore, the impact of praziquantel treatment on clinical outcomes remains largely
underexplored, as is the interplay of FGS/MGS with relevant reproductive tract infections
such as HIV and Human Papillomavirus. In non-endemic settings, travel and immigrant
health clinics need better guidance to correctly identify and treat FGS and MGS. Our
review outlines the latest advances and remaining knowledge gaps in FGS and MGS
research. We aim to pave a way forward to formulate more effective control measures
and discuss elimination targets. With a growing community awareness in health prac-
titioners, scientists and epidemiologists, alongside the sufferers from these diseases,
we aspire to witness a new generation of young women and men free from the
downstream disabling manifestations of disease.
An update on female and male genital schistosomiasis 3
1. Introduction
As a neglected tropical disease (NTD), interventions against schisto-
somiasis are featured within the recently outlined WHO 2021–30
Roadmap (WHO, 2021a). Preventive chemotherapy against urogenital
and intestinal schistosomiasis-related morbidity is strongly encouraged and
disease-specific control targets are also defined. However, the detection
and management of disease sequelae within the female and male genital
tracts due to urogenital schistosomiasis, remain unaddressed. In this review,
we seek to highlight the importance and often overlooked connections
between female genital schistosomiasis (FGS) and male genital schistosomi-
asis (MGS), addressing disease-specific needs and challenges in endemic and
non-endemic settings, respectively. Our review presents a comprehensive
summary of the recent published evidence about FGS and MGS to ulti-
mately inform policy makers to support integrative approaches for disease
management.
1.1 Selection criteria

References were searched in PubMed and Medline databases using the key
words ‘female genital schistosomiasis’, ‘male genital schistosomiasis’, ‘genital
or urogenital schistosomiasis’, ‘praziquantel’, for the last 10 years (2011–21)
with the terms ‘AND’, ‘OR’. A total of 324 articles were identified.
Abstracts were reviewed for suitability and were included in this review if
they pertained to any discipline related to FGS and MGS. A total of 123 arti-
cles related specifically to FGS published in the last decade were screened
and 85 were reviewed. No clinical trials were identified. For MGS, 56 arti-
cles were retrieved and only 32 were found to be related to the topic. A sea-
rch for articles covering both FGS and MGS retrieved 29 results but only
3 studied both diseases jointly. Historical articles were included where
relevant
1.2 Epidemiology and geographical distribution of genital

schistosomiasis
The global distribution of FGS is estimated to be around 50 million people
limited to S. haematobium endemic areas in sub-Saharan Africa (SSA)
(Christinet et al., 2016). Urinary schistosomiasis (viz. S. haematobium eggs
in urine) and FGS often co-exist, and are commonly referred to as urogenital
schistosomiasis. For example, a Tanzanian study reported concurrent FGS
diagnosed by histopathology in 62% of 543 women with urinary schistoso-

miasis (Poggensee et al., 1998). Overall, there are fewer studies evaluating
FGS compared with the broader disease definition of urogenital schistoso-
miasis, including urine-based diagnostics with and without genital involve-
ment. Thus, accurate geographical estimates for FGS are lacking and remain
an extrapolation from the broader disease manifestations. Estimates for
MGS are scarce and also rely on extrapolation of a wider range of clinical
manifestations attributed to S. haematobium (Kayuni et al., 2019a).
Genital schistosomiasis is an inflammatory parasitic disease caused when
eggs from the waterborne blood fluke S. haematobium, are lodged within the
reproductive organs. Genital schistosomiasis affects both females and males
(Colley et al., 2014; Kjetland et al., 2012; Yu et al., 2013). FGS and MGS are
not yet included in the global burden of disease estimates of 1.44 million
disability-adjusted life years (DALYs) attributed to schistosomiasis, despite
the well-known disabling morbidities associated with FGS (DALYs and
Collaborators, 2018). Control efforts for schistosomiasis, noting urogenital
and intestinal manifestations, broadly focus on decreasing heavy intensity
infections leading to severe morbidity in school-aged children in the urinary
tract, and in the liver and spleen, respectively (Savioli et al., 2017; WHO,
2020). This approach neglects to recognize manifestations related to genital
disease that are often difficult to quantify such as infertility, ectopic pregnan-
cies, sexual dysfunction and menstrual disorders (Bustinduy et al., 2017;
Helling-Giese et al., 1996a; Kjetland et al., 2008; Stothard et al., 2020b).
WHO has recognized the hidden manifestations of FGS as a public health
problem whereas MGS remains unacknowledged, not only by its sufferers
but also overlooked in health statistics captured across the continent of
Africa and other schistosome endemic locations (WHO, 2020). Fig. 1 shows
the limited number of countries with reported FGS and MGS studies.
The recognition of gender differences is necessary, as they may impact
exposure, transmission, manifestation and treatment for genital schistosomi-
asis (Ozano et al., 2020). Importantly, there are several differences in disease
awareness and social stigma for each disease manifestation (Mazigo
et al., 2021).
1.3 Life cycle and transmission

The life cycle of the waterborne Schistosoma species is complex but can be
highly efficient when certain temperature and humidity environmental
conditions are met; this can result in universal exposure and infection in
Fig. 1 Countries with FGS (A) and MGS (B) case reports and studies in S. haematobium
endemic areas in sub-Saharan Africa published to date. Panel (A) is adapted from
Sturt, A.S., Webb, E.L., Francis, S.C., Hayes, R.J., Bustinduy, A., 2020a. Beyond the barrier:
female genital schistosomiasis as a potential risk factor for HIV-1 acquisition. Acta
Trop. 209, 105524 and Panel (B) is adapted from Kayuni, S., Lampiao, F., Makaula, P.,
Juziwelo, L., Lacourse, E.J., Reinhard-Rupp, J., Leutscher, P.D.C., Stothard, J.R., 2019b. A sys-
tematic review with epidemiological update of male genital schistosomiasis (MGS): a call for
integrated case management across the health system in sub-Saharan Africa Parasite
Epidemiol. Control 4, e00077.
communities that have unsafe water contact (Satayathum et al., 2006). In

Africa, two main Schistosoma species infect humans, S. haematobium and
S. mansoni (Lai et al., 2015). While cross-specific worm pairings occur
within a co-infected host, it is likely that successful mating between these
two species is very rare although such mixed worm pairs may lead to ectopic
egg deposition (e.g. S. mansoni eggs in urine) and associated pathology
(Stothard et al., 2020a) (Fig. 2).
Schistososoma mansoni primarily causes hepatosplenic and intestinal
disease, while S. haematobium is strongly associated with urogenital manifes-
tations. In mixed heavy infections, S. mansoni eggs can be excreted in the
urine (mansonuria), contributing to urinary tract disease. This is most likely
resultant from mixed worm pairings between S. haematobium and S. mansoni,
with S. mansoni females being carried by S. haematobium males to the uro-
genital system (Doehring et al., 1986). Schistosoma haematobium infections
are endemic in Africa, the Middle East, and now also in Corsica (France)
(WHO, 2020), while S. mansoni is distributed in Africa, the Middle East
and also the Americas (Colley et al., 2014). While co-infection with both
Fig. 2 The life cycle of S. haematobium. Adapted from Countdown (https://countdown.

lstmed.ac.uk).
parasites is common, its epidemiological occurrence is only rarely reported,

even by WHO. In 2012, for example, 163 million men and women in Africa
were infected with either of these two Schistosoma species with about a quar-
ter having dual infections. Some 57 million (35%) are school aged children
(Lai et al., 2015). Much of the pathological description of S. haematobium’s
related disease has focused on urinary abnormalities, ignoring the less obvi-
ous genital complications of the disease (Bustinduy et al., 2021).
FGS is defined by the detection of parasite eggs or DNA in genital tissue
or in secretions. Schistosoma eggs (also referred to as ova) are immunogenic,
and once tissue-entrapped they invoke granulomatous inflammation. The
accumulation of eggs in genital tissues over time results in subsequent mor-
bidity and organ dysfunction (Kjetland et al., 2014). Worm migration pat-
terns of adult schistosomes and the accessibility of genital organs via the
pelvic venous plexus explain why genital manifestations are so common
in S. haematobium infections and their disease sequelae more noticeable in
sexually active adults. Signs and symptoms therefore overlap with many sex-
ually transmitted infections (Poggensee et al., 2000). Depending on where
Fig. 3 Schistosoma haematobium egg deposition in the female and male genital tracts
causing female and male genital schistosomiasis. Graphic components courtesy of
https://smart.servier.com/.
eggs are released, clinical pathology develops in the vulva and vagina, cervix,
uterus, fallopian tubes and the ovaries (Kjetland et al., 2012) (Fig. 3). All gen-
ital organs may be affected simultaneously, and their dynamics change
through time concurrent with administration with praziquantel, the only
available deworming medication that is active against Schistosoma spp.
(WHO, 2020).
Male genital schistosomiasis (MGS) is a specific chronic manifestation of
schistosomiasis, associated with presence of Schistosoma eggs and pathologies in
male genital fluids and organs of men inhabiting or visiting schistosomiasis-
endemic areas. Of the 54 countries in Africa, only 20 of them have formally
reported FGS and 17 countries have MGS reported cases in the literature
(Kayuni et al., 2019b; Sturt et al., 2020a).
1.4 FGS and MGS in less common Schistosoma species

Although uncommon, genital manifestations of the disease are not always
directly related to infections with S. haematobium alone. In a Tanzanian
study, 5% (19/359) of women who underwent gynaecological exam had
S. mansoni eggs detected in cervical tissue and 52.6% (10/19) had both
S. haematobium and S. mansoni eggs present in genital samples (Poggensee
et al., 2001a). In S. mansoni endemic areas in Brazil there are reported
FGS cases affecting the fallopian tubes (Faria et al., 2010) and presenting
as ovarian tumours (Cavalcanti et al., 2011; Feldmeier et al., 1998).
There are several reports of MGS caused by species other than
S. haematobium; for example, a case of testicular schistosomiasis leading to

secondary infertility was reported in a S. mansoni endemic area in Nigeria
(Adisa et al., 2012) and prostate involvement reported in a patient with
Schistosoma japonicum living by the Yangtze river in China (Yu et al., 2013).
1.5 The importance of different hybrids of S. haematobium

group species (including minor species contributing
to FGS/MGS)
There are currently 23 Schistosoma species, 13 of which are found in
sub-Saharan Africa, which are split into three species groups.
S. haematobium resides within the S. haematobium species group, which con-
sists of nine closely related species all of which share the characteristic of ter-
minal spined ova. Apart from S. haematobium two other species within this
group are considered to be human pathogens S. guineensis and S. intercalatum,
both of which cause intestinal schistosomiasis in specific foci in central
African regions. Other species within the group are considered pathogens
of mammalian livestock and/or wildlife. Of note is the occurrence of
S. haematobium hybrids; S. haematobium-guineensis, S. haematobium-bovis,
S. haematobium-curassoni, S. haematobium-mattheei, the latter three involve
livestock Schistosoma species and raise concerns over zoonoses and animal
reservoir hosts. Mixed species combinations are likely to result in ectopic
egg excretion and/or deposition, though there is still much to learn about
these hybrid forms, together with their potential impact on schistosomiasis
control. This has been observed for co-infections between S. haematobium
and S. mansoni where the species are urogenital and intestinal forms,
respectively.
Schistosoma intercalatum and Schistosoma guineensis have not been specifi-
cally reported to be involved FGS or MGS, either alone or in combination
with an underlying S. haematobium. However, this association has never
actually been investigated. This absence, together with that of any morbidity
impact of S. haematobium hybrid forms is more likely to represent a deficit in
application of precise species-specific diagnostic methods per se rather than
these species’ inability to colonize veins surrounding the genitalia and
deposit eggs therein.
The same molecular genetic markers that have been used to characterize
these species and hybrid forms collected from their human hosts, could be
applied for a more in-depth analysis of clinical materials associated with FGS
and MGS. This could involve the evaluation of ejaculate or cervicovaginal
samples with molecular diagnostics, to gauge the extent to which existing
S. haematobium-hybrids contribute to genital schistosomiasis. A further

research need is an improved understanding of not just the epidemiology
of S. haematobium-hybrids, but also their role in inflammation, and
organ-specific responses, including FGS and MGS (Baay et al., 2004;
Kayuni et al., 2019a; Leutscher et al., 2009).
2. Pathogenesis and clinical manifestations

2.1 Female genital schistosomiasis (FGS)
FGS was specifically recognized in the medical literature over 100 years ago
(Madden, 1899), but it is still often incorrectly reported and seldom treated.
This is partly due to overlapping symptoms with sexually transmitted infections
(Christinet et al., 2016; Kjetland et al., 2012). As a neglected gynaecological
condition in SSA, FGS is not frequently considered in clinical practice, with
both patients and practitioners alike unaware of the disease and its downstream
sexual and reproductive health consequences (Ngwenya, 2016).
The pathogenesis of FGS is the result of a complex inflammatory
immune response driven by the antigens released from both viable eggs,
which have been entrapped in genital tissue, and adult worms located in
small veins of the pelvis (Fig. 3). Inflammation occurs in all strata of the gen-
ital tissue including the small blood vessels ( Jourdan et al., 2011a, 2013).
Schistosomiasis related inflammation extends beyond egg-deposition site
eventually affecting entire organs (Ramarokoto et al., 2014; Schanz et al.,
2010). Lesions in the vulva, vagina and the cervix are easiest to detect
and can be identified with a colposcope (Yirenya-Tawiah et al., 2011).
Deeper lesions in the uterus, the Fallopian tubes and the ovaries are challeng-
ing to assess (Andrianjafitrimo et al., 2019) but the ensuing pathology is asso-
ciated with chronic morbidity and can sometimes be life-threatening
(Kjetland et al., 2010; Norseth et al., 2014; Schanz et al., 2010; Swai
et al., 2006) and often negatively impacts women’s reproductive health
(Laroche et al., 2016; Laxman et al., 2008).
Studies in Niger, Malawi and Zimbabwe have found that up to 75% of
women with urinary schistosomiasis also have S. haematobium eggs distrib-
uted in the genital tissues (Kjetland et al., 1996, 2005; Poggensee et al., 1998;
Renaud et al., 1989). However, just as importantly, at least 20% of women
with Schistosoma genital involvement did not have eggs present in the urine
(Poggensee et al., 1998). These data highlight the non-linear relationship
between egg detection by different diagnostic methods and established
genital morbidity.
Vulvar or vaginal ulcerations and papillomata have been associated with

FGS (Goldsmith et al., 1993; Laven et al., 1998; Yirenya-Tawiah et al.,
2011). These may lead to stigmatization if the findings are misinterpreted
as being caused by a sexually transmitted infection (Goldsmith et al.,
1993). Consequences of FGS may include post-coital pain and bleeding
which are not uniquely identifiable as associated with schistosomiasis. Of
special concern, women with FGS in rural Zimbabwean had a twofold
greater odds of prevalent HIV infection (Kjetland et al., 2006).
Recent population-based and ecological studies have linked FGS with
female infertility and sub-fecundity in endemic communities (Kjetland
et al., 2010; Miller-Fellows et al., 2017; Woodall and Kramer, 2018).
More recently, the Bilharzia and HIV (BILHIV) study in Zambia (Sturt
et al., 2020b), found a twofold increase in delayed conception in women
with FGS as diagnosed by DNA-based detection methods (Mills, 2021).
FGS occurs in women of all age groups, including young girls, and is
associated with important, frequently debilitating and stigmatizing morbid-
ity. Women with FGS report spontaneous or post-coital bleeding, vaginal
discharge, pain during sexual intercourse, pelvic pain, irregular menstruation
and infertility (Kjetland et al., 2008, 2010). Across studies in Zambia and
Zimbabwe, a higher proportion of young women were found to have more
detectable Schistosoma DNA in their genital tract than older women
(Kjetland et al., 2009; Sturt et al., 2020b). Additionally, young girls with uri-
nary S. haematobium may present with gynaecological symptoms prior to
their sexual debut, in particular bloody or foul-smelling vaginal discharge
(Hegertun et al., 2013). These symptoms are frequently attributed to STIs
by health care providers, contributing to the associated stigma. As a conse-
quence, many women are not encouraged to pursue medical help at health
centers and are seeking help from traditional healers (Madagascar KAP study,
Randriansolo, B, personal communication). Vagino-vesical fistulae in
women are unlikely to heal if concomitant schistosomiasis is left untreated
(Richter et al., 2008).
2.1.1 Pregnancy and placental involvement

The placenta may also be involved during chronic Schistosoma infection,
however foetal outcomes of prematurity or lower birth weight are primarily
due to the effect of schistosomiasis on the mother, in conjunction with pro-
tein loss and anaemia (Schleenvoigt et al., 2014). Maternal iron deficiency
during pregnancy is also associated with iron deficiency among infants

(Abioye et al., 2019; Friedman et al., 2007; Mombo-Ngoma et al., 2017;
Siegrist and Siegrist-Obimpeh, 1992). Importantly, the effect of underlying
FGS on pregnancy outcomes has not been explored.
2.2 Male genital schistosomiasis (MGS)

The first case of MGS was reported in 1911 (Madden, 1911). This was
followed by several case reports, post-mortem and histopathological research
studies in the subsequent decades (Corachan et al., 1994; Gelfand et al., 1970;
Leutscher et al., 2000). Like FGS, MGS is underreported and often not rec-
ognized by medical providers in endemic areas. Schistosome eggs passing
through or being entrapped in the tissues of prostate, seminal vesicles, vas
deferens, epididymis and testis, trigger immune reactions and granulomata
formation (Kayuni et al., 2019b). In addition to granulomatous inflammation,
post-mortem and histopathological studies have shown egg-induced lesions
such as fibrosis and calcifications which can also be detected on radiological
examinations (Al-Saeed et al., 2003; Ramarakoto et al., 2008; Vilana
et al., 1997).
In MGS, changes of sperm consistency or blood in semen
(haematospermia) are often presenting symptoms (Corachan et al.,
1994). A particular observation in retuning travellers, haematospermia can
present in the early stages of MGS (Barlow and Meleney, 1949; Feldmeier
et al., 1999; Schwartz et al., 2002) and in some instances at a young age
(Rambau et al., 2011). Symptoms associated with semen quality and outflow
include, coital or ejaculatory pain, abnormal ejaculates, and occasional spe-
rmaturia (presence of spermatozoa in urine). Additionally, orchitis, prostatitis,
dyspareunia, and hydrocele are also associated with MGS. Other potential
symptoms include pelvic pain, erectile and ejaculatory dysfunction or para-
phimosis. To date, the epidemiology, diagnostic testing, specific clinical man-
ifestations and case management of MGS are not well or widely described.
There are little data regarding the current burden of and morbidity among
local inhabitants in endemic areas of SSA.
The aetiology of symptom underreporting in MGS is likely multi-
factorial including stigma associated with genital tract infections and the
potential impact on fertility-despite the quality of the semen being
preserved (Leutscher et al., 2009). Studies in Madagascar and Malawi have
demonstrated resolution of symptoms after anti-schistosomal therapy
(Kayuni et al., 2019a,b; Leutscher et al., 2000, 2009). This finding has
increased interest in including men-at-risk of schistosomiasis during mass
drug administration campaigns in endemic areas.
3. Immunology
3.1 Vaginal environment in FGS
Chronic egg deposition in genital tissues results in the clinical manifestations
associated with FGS (Kjetland et al., 2005). However, studying the natural
history of S. haematobium egg deposition in human genital tissue through to
the formation of cervicovaginal lesions is not ethically permissible and there
are no well described clinical manifestations during acute infection in
humans (Odegaard and Hsieh, 2014). These limitations restrict the current
knowledge to an extrapolation r from animal models. A murine FGS model
has been created through the microinjection of viable S. haematobium eggs
into the vaginal walls of female BALB/c mice (Richardson et al., 2014).
Eight weeks after vaginal egg injection, mice developed egg-associated
granulomata surrounded by eosinophils, neutrophils, and lymphocytes.
Both Schistosoma infection and subsequent egg patency stimulate
immune responses, though divergent in character. Acute schistosomiasis,
also known as Katayama Syndrome is thought to occur in response to the
migration of the immature schistosomula and evokes an initial T helper type
1 (Th1) response (Ross et al., 2007). As the schistosomes mature and pro-
duce eggs, a T helper type 2 (Th2) response prevails, stimulated primarily by
antigens present on schistosome eggs (Pearce and MacDonald, 2002). Both
Th1 and Th2 responses can be associated with morbidity (Fallon, 2000),
while granuloma formation (Pearce and MacDonald, 2002) and clinically
detected hepatic fibrosis in S. mansoni are associated with a Th2 response
(Mutengo et al., 2018). However, a carefully orchestrated balance between
Th1 and Th2 responses is required as an unopposed Th1 response has been
associated with mortality in murine hosts (Fallon, 2000; Fallon et al., 2000).
Studying local cytokines and chemokines can provide additional infor-
mation regarding downstream biological processes associated with
Schistosoma egg deposition. Murine studies emphasize the importance of
studying the immune environment local to egg deposition (Fu et al.,
2012; Richardson et al., 2014). For example, a Luminex multiplex
bead-based immunoassay was used to evaluate cytokine responses in a study
of mice with urinary S. haematobium infection highlighted a Th2 cytokine
bias (interleukin [IL]- 4, IL-13, and IL-5) in the local bladder environment
(Fu et al., 2012). However, when similar techniques were used to evaluate
cytokine concentrations in systemic circulation of mice with FGS, only

differences in RANTES were detected (Richardson et al., 2014).
While the immunology of human Schistosoma infections has been widely
explored, data regarding the immunologic microenvironment in FGS are
limited. In human studies, women with S. haematobium infection, in the
absence of evaluation for genital involvement, have also been shown to have
altered levels of IL-15 in cervicovaginal lavage as well as differences in the
expression of genes associated with regulating extracellular matrix deposi-
tion, angiogenesis, and protease activity in the cervical mucosa (Dupnik
et al., 2019). Recent data on the immunology of FGS suggest the impor-
tance of an evaluation stratified by a measure of the burden of schistosome
infection. In the BILHIV study in Zambia when participants with a medium
to high Schistosoma DNA concentration was detected in any genital speci-
men (cervical or vaginal swab or cervicovaginal lavage (CVL)), higher con-
centrations of Th2 (IL-5) and pro-inflammatory (TNF-α) cytokines were
detected in CVL after adjusting for multiple comparisons and potential
confounders (Sturt et al., 2021a).
3.2 Immune activation during pregnancy

There are currently no studies on pregnancy outcomes or placental involve-
ment in women infected with S. haematobium (Bustinduy et al., 2017).
Studies in the Philippines have shown elevated inflammatory cytokines
(Kurtis et al., 2011) and high levels of endotoxin, a systemic immune activa-
tion marker, in pregnant women whose placentas were concomitantly
infected with Schistosoma japonicum compared to non-infected women
(McDonald et al., 2014). Furthermore, women with high levels of endotoxin
had adverse pregnancy outcomes including prematurity (McDonald et al.,
2014). Despite clear differences in the pathophysiology of S. haematobium
and S. japonicum, which target different organ systems there appears to be
common pro-inflammatory pathways. Further research is needed in women
with FGS to understand gestational issues and in the case of pregnant women
infected with S. haematobium pre-gestational female genital schistosomiasis.
4. Diagnosis of genital schistosomiasis

4.1 FGS diagnostics
Conventional FGS diagnosis is challenging, as it relies on costly equipment
and high-level specialized training seldom available in resource-limited set-
tings. This hinders the accurate estimation of disease burden and challenges
study comparisons due to differences in FGS case definitions. For example,

egg visualization in the genital mucosa is sufficient but not necessary for FGS
diagnosis. Concerns of increasing the risk of HIV acquisition have
preempted the routine use of biopsies for FGS diagnosis (Kjetland et al.,
2012). As a consequence, well conducted histopathological studies are
scarce. Recently, the wider availability of molecular diagnostic assays
allowed methods like PCR to aid in the diagnostic accuracy of FGS, as well
as for MGS, by identifying Schistosoma DNA within samples acquired from
the genital tract (Downs et al., 2013; Kjetland et al., 2009; Kayuni et al.,
2019a; Pillay et al., 2014; Sturt et al., 2020b, 2021a).
4.1.1 Traditional colposcopy

A visual FGS diagnosis involves using a colposcope to obtain a magnified and
illuminated view of the cervix and vaginal walls and fornices (Norseth et al.,
2014). FGS-associated lesions in the vulva/vagina and the cervix are the
most visible and have therefore been described in detail (Norseth et al.,
2014). Characteristic clinical findings associated with FGS include grainy
sandy patches, homogenous sandy patches and rubbery papules (Kjetland
et al., 2014; Norseth et al., 2014; Randrianasolo et al., 2015). Abnormal
vessels have also been described in FGS ( Jourdan et al., 2013) (Fig. 4).
The grains of the sandy patches are approximately 0.05 mm 0.2 mm
long, are shaped like grains of rice, they may be single Schistosoma ovum
or exist in clusters of up to 300 (Randrianasolo et al., 2015). These individual
grains (viz. eggs) are deep or superficially situated in the mucosa, with a char-
acteristic yellow, off-white or golden colour. The deeply situated grains
merge into sub-mucosal plaque-like formations with uneven edges and sha-
des of texture. Sometimes, the mucosa is mottled beneath the surface. The
mucosal surface over the deeply grained patches is smooth and grains are not
mobile. The superficial grains have a distinct shape and colour. Grains can
Fig. 4 FGS atlas of visual diagnosis (WHO, 2015). From left to right: Grainy sandy pat-
ches, homogeneous sandy patches, abnormal vessels and rubbery papules.
often be distinguished easily from each other even when they are clustered
together (WHO, 2015).
The homogeneous yellow sandy patches are defined as sandy looking
areas with no visible grains when using the 15 times magnification setting
on the colposcope, appearing as homogenous, yellow areas (Kjetland et al.,
2005). Rubbery papules were initially found and described in Madagascar
(Randrianasolo et al., 2015), but have been described elsewhere (Ekpo
et al., 2017). They are spheroid, pustuloid, firm (hence rubbery), beige papules
that may give the cervicovaginal mucosa an irregular surface. The rubbery
papules may stand alone, or can be found concurrently with sandy patches.
They are often surrounded by various degrees of vascularisation at their base
(Randrianasolo et al., 2015).
Traditional colposcopes are expensive pieces of equipment that are sel-
dom available in resource-constrained settings, where access to electricity
and adequate infrastructure is limited. Furthermore, they require specialist
training to operate. Where colposcopy is not possible, The Female Genital
Schistosomiasis Pocket Atlas has been developed by the WHO as a visual aid
and is free of charge. This resource was created to raise awareness about
FGS and to facilitate clinical diagnosis by clinical health-care professionals
working particularly in rural areas where schistosomiasis is endemic (WHO,
2015) (Fig. 4).
Alternative means of visual diagnosis in-lieu of colposcopy or medical
expertise are urgently needed to increase FGS surveillance at scale. There
are attempts to develop artificial intelligence visual reading algorithms based
on a computer colour analysis (Holmen et al., 2015b). The computer anal-
ysis identifies the region of interest (the ectocervical mucosa) and splits the
image in multiple colour channels, based on the characteristic colour prop-
erties of the FGS lesions (yellow sandy patches). This method shows prom-
ising results in terms of accuracy, but the specificity needs to be refined
(Holmen et al., 2015a).
4.1.2 Hand-held colposcopy and other hand-held devices

The use of simple electronic devices such as handheld cameras, mobile
phone cameras, or other can be an alternative to document FGS lesions with
acceptable results and have been used in an ongoing study in Madagascar
(Randriansolo, B. Personal communication).
Handheld colposcopy has been widely used for the diagnosis of cervical
cancer in remote settings. A recent systematic review of different available
handheld devices for the diagnosis of cervical cancer screening included
Fig. 5 Images obtained by hand-held colposcopy from women in Zambia and Malawi.
They were all PCR positive for Schistosoma haematobium from genital samples. Outlined
areas highlight homogeneous sandy patches (A, C, D), grainy sandy patches (E, F) and
clusters of eggs (B).
smartphones, a digital camera and several handheld colposcopes, their avail-

ability, price and image quality. The study concluded that two handheld
colposcopes, the Gynocular and Mobile ODT could be potentially useful
for FGS diagnosis (Softeland et al., 2021). In two studies in Malawi and
Zambia, hand-held colposcopy (Mobile ODT) enabled the detection of
FGS lesions as shown in Fig. 5 (Bustinduy, AL. BILHIV study, Personal
communication).
4.1.3 Ultrasound scans and other radiological imaging

The role of advanced imaging modalities such as ultrasonography, CT scan,
and MR scan can aid in assessing the severity and complications of schisto-
some infection (Sah et al., 2015). Ultrasound is a non-invasive imaging
method that cannot detect schistosome infection but rather is used to assess
Schistosoma-induced pathology (Skelly, 2013). Despite the use of more sen-
sitive transvaginal probes, specific schistosomiasis related lesions of the
female reproductive tract are difficult to diagnose by ultrasound
(Ramarakoto et al., 2008). Ultrasound may be helpful in diagnosing com-

plications related to genital schistosomiasis such as sterility, vesico-vaginal
fistulae (Ben-Chetrit et al., 2015; Richter et al., 2008; Schanz et al.,
2010; Schleenvoigt et al., 2014) and gestation issues such as ectopic pregnan-
cies due to granulomatous tubal obstruction (Laroche et al., 2016; Laxman
et al., 2008; Sheorey et al., 2004).
4.1.4 Parasitology diagnosis

It is possible to identify eggs upon microscopy of genital samples through
wet preps or pap smears. However, this technique is not frequently used,
as several studies have demonstrated its low sensitivity ( Jourdan et al.,
2011b; Pillay et al., 2016; Poggensee et al., 2001b).
4.2 Molecular diagnostics (nucleic acid amplification tests)

4.2.1 Real time PCR
Due to their high specificity and sensitivity, DNA detection methods have
become a feasible option for the diagnosis of schistosomiasis (Hoekstra et al.,
2021; Utzinger et al., 2015). Specifically, for FGS, parasite DNA detection
from cervicovaginal lavage has been postulated as a highly specific diagnostic
method with potential to monitor treatment effect (Downs et al., 2013;
Randrianasolo et al., 2015; Sturt et al., 2020b). Although specificity was high,
some studies reported low sensitivities in the detection of Schistosoma DNA in
cervicovaginal lavage samples, ranging from 15% to 53% using visual methods
as the diagnostic reference for FGS (Galappaththi-Arachchige et al., 2018;
Kjetland et al., 2009). More recently, the BILHIV study in Zambia reported
a sensitivity of 80% when Schistosoma PCR was performed on vaginal and cer-
vical swabs obtained through home-based self-sampling and were compared
with detectable Schistosoma DNA in any positive genital sample as a composite
reference. The sensitivity increased to 89% when women with active schis-
tosomiasis, as defined by a positive circulating anodic antigen, were included
(Sturt et al., 2020b). Vaginal and cervical self-sampling at home for FGS
screening was well accepted by participants and can offer a scalable option
for FGS screening and surveillance (Rutty Phiri et al., 2020).
4.2.2 Isothermal diagnostics

Novel molecular diagnostics specifically isothermal (low constant tempera-
ture) molecular diagnostics such as Recombinase Polymerase Amplification
(RPA) (Archer et al., 2020b; Rosser et al., 2015; Rostron et al., 2019) and
Loop Mediated Isothermal Amplification (LAMP) (Gandasegui et al., 2018)

offer an alternative to PCR-based amplification. These assays are better suited
for use in resource-limited settings as they require only minimal equipment,
can be performed using a crude DNA extraction process that can be easily
prepared under field conditions. Results can be rapidly obtained in less than
1 h (Archer et al., 2020a; Lodh et al., 2017).
A previously developed RPA assay (the RT-ShDra1-RPA (Sh-RPA)) has
been used to detect trace levels of Schistosoma ova-derived DNA within
egg-spiked laboratory samples (able to detect a single S. haematobium egg
within 100 μL ddH2O), as well as in clinical urine samples from patients
with very low infection intensities (1–3 eggs per/10 mL) (Archer et al.,
2020b; Frimpong et al., 2021; Rosser et al., 2015; Rostron et al., 2019).
The method is simple, quick (<20 min), portable, low-footprint (can run
at temperatures from 25 to 42 °C) and can be performed using crude sample
preparations.
The Sh-RPA assay has also been piloted to detect S. haematobium DNA
in FGS samples collected as part of BILHIV study in Zambia (Sturt et al.,
2020b). The rapid and portable Sh-RPA assay was able to reliably detect
and amplify S. haematobium DNA within vaginal self-swab samples and pro-
vider obtained cervicovaginal lavage (CVL) using two crude extraction
methods that can be easily and rapidly carried out in field settings. Based
on RT-PCR as the reference test (Sturt et al., 2020b), the Sh-RPA assay
proved to be highly sensitive and specific for self-swab samples, 93.3%
and 96.6%, respectively (Archer, J et al. manuscript under review).
LAMP also has the potential for field-based/point-of-care diagnosis and
assays have been developed for the three main Schistosoma species,
S. haematobium, S. mansoni and S. japonicum. LAMP performs at tempera-
tures between 60 and 65 °C and takes from 30 to 60 min. Its set up can
be simple with low equipment requirements although its design can be com-
plex, needing up to six primers. An assay for urogenital schistosomiasis
proved sensitive and specific, 100% and 86.7%, respectively (Gandasegui
et al., 2018) but has not been tested for FGS diagnosis.
The ease of use, low-resource needs, simplicity and feasibility demon-
strated by LAMP and RPA in field conditions together with the acceptable
level of reproducibility achieved in a reference laboratory, support the use of
these isothermal assays as effective molecular diagnostics for urogenital schis-
tosomiasis in remote endemic areas. These assays have great potential for
field-based point-of-care diagnosis of FGS using self-swab samples.
4.2.3 Histopathology
Direct examination of cervical tissue obtained by biopsy from a suspicious
lesion can be promptly examined by crushing the biopsy specimen between
two glass slides. This technique, known as quantitative crushed biopsy allows
examination for S. haematobium eggs at 100 and provides indisputable evi-
dence of FGS (Poggensee et al., 2001b). However, since eggs may cluster in
the cervix, biopsy and the subsequent histopathology may miss eggs
(Helling-Giese et al., 1996b; Randrianasolo et al., 2015).
4.3 MGS diagnostics

To date, optimal MGS diagnosis remains largely undefined (Kayuni et al.,
2019b). Currently, semen microscopy is considered the standard technique
for diagnosing active MGS. Since Schistosoma eggs can be visualized and
quantified in semen, microscopy can also assess MGS infection intensity.
However, sensitivity and cultural misgivings around the submission and
handling of semen in most rural endemic areas pose challenges for MGS
diagnosis (Kayuni et al., 2019a).
Fig. 6 S. haematobium egg in semen at 400 magnification. Photo credit. S. Kayuni.

4.3.1 Parasitology and molecular diagnostics in MGS

As in FGS, the diagnosis of urinary schistosomiasis is often used as a proxy for
the presence of MGS (Downs et al., 2011). However, this practice lacks sen-
sitivity, as there are reports of schistosome eggs detected in the semen of
patients with no eggs present in the urine (Schwartz et al., 2002; van
Delft et al., 2007) (Fig. 6).
Semen samples need to be processed within 2–3 h of submission and
technicians must allow the semen to liquefy. Thereafter, a drop of well-
mixed semen can be placed on a glass slide with coverslip and light micros-
copy using 40 and 100 magnification can be used to visualize for schis-
tosome eggs. Results can be recorded as eggs visualized per ml of ejaculate
(Kayuni et al., 2019a). Different preservation techniques have been devel-
oped to increase the sensitivity of the assays (Kenguele et al., 2014).
If available, molecular tests can be performed on semen for the detection
of Schistosoma DNA (Kayuni et al., 2019a). Alternative diagnostic methods
for MGS include the detection of soluble egg antigen (SEA) and eosinophil
cationic protein (ECP) in urine and semen and circulating anodic antigen in
serum. The concentration of these proteins correlates with urinary schisto-
some egg excretion but are still not available for clinical diagnosis (Leutscher
et al., 2008).
4.4 Immunopathology in MGS

A single study in Madagascar has explored the immune activation through
seminal egg-induced inflammation in individuals with MGS (Leutscher
et al., 2005). Elevated cytokines (IL-4, IL-6, IL-10 and TNF-α) and
increased leukocytes (eosinophils, lymphocytes) were significantly elevated
in the semen of men with MGS compared to those with no Schistosoma
infection, controlling for sexually transmitted infections (Leutscher et al.,
2005). MGS infection intensity, defined by seminal egg count, was strongly
associated with elevated seminal cytokine concentrations including Th2
(IL-4), regulatory (IL-10), Th1 (IFN-γ) and pro-inflammatory (TNF-α)
immune proteins. Local inflammation is hypothesized to increase viral shed-
ding in the ejaculate from co-infected HIV positive men with MGS, hence
putting the female partner at additional risk of being infected with HIV in
particular if this woman also suffers from egg-induced lesions in the lower
genital tract (Leutscher et al., 2000; Midzi et al., 2017), but longitudinal
studies are needed to confirm this.
5. Co-infections and co-morbidities

5.1 Human immunodeficiency virus (HIV)
Two-thirds (67%) of people living with HIV-1 currently live in SSA
(UNAIDS, 2021). Despite recent advances in HIV prevention and treat-
ment, there continues to be a gender-specific HIV vulnerability, with
new HIV infections disproportionately affecting women and girls. A plau-
sible association between HIV and female genital schistosomiasis was postu-
lated at the height of the HIV pandemic (Feldmeier et al., 1994), with a
cross-sectional study showing an association between HIV-1 and FGS
(Kjetland et al., 2006b).
There is biological plausibility for an association between FGS and HIV.
HIV acquisition occurs at mucosal surfaces where an intact cervicovaginal
epithelium provides a barrier to invading pathogens (Sturt et al., 2020a).
This intact barrier can be disrupted in FGS. The heightened HIV-1 vulner-
ability seen in women with schistosome infection but not in men (Downs
et al., 2017) may suggest a role of the cervicovaginal mucosa. The organs
most commonly involved in MGS are the prostate and seminal vesicles,
internal structures not exposed during sexual contact (Kayuni et al.,
2019a,b) and therefore additional potential mechanisms for HIV-1 vulner-
ability in men with MGS are more likely due to increased viral shedding in
the ejaculate, following similar pathways as in men with sexual transmitted
infections (Cohen et al., 1997; Moss et al., 1995). In females, potential addi-
tional mechanisms include effects on granuloma vascularity ( Jourdan et al.,
2011a) and HIV-1 target cell composition ( Jourdan et al., 2011b) as well as
modulation of HIV-1 co-receptors (Kleppa et al., 2014).
A recent systematic review reported an odds ratio [OR] of 1.85 for the asso-
ciation between prevalent HIV-1 and urogenital schistosomiasis (Zirimenya
et al., 2020). A further metanalysis including both S. haematobium or
S. mansoni infection reported a slightly higher pooled OR 2.3 (95% CI
1.2–4.3) (Patel et al., 2021). Additionally, modelling data suggest that each
S. haematobium infection is association with a 2.9% (95% CI 0.2–5.8%) increase
in HIV-1 prevalence in endemic areas (Ndeffo Mbah et al., 2013). However,
there are also some data against the association of S. haematobium infection with
HIV-1 (N’Zoukoudi-N’Doundou et al., 1995).
S. haematobium seropositivity has been associated with HIV-1 acquisition
in women (Wall et al., 2018). Additionally, in a cross-sectional study in
Zambia, women with FGS were twice as likely to acquire HIV, but with
no statistical evidence for a difference likely due to and a small sample size
and thus limited power (adjusted rate ratio 2.16; 95% CI 0.21–12.30,
P ¼ 0.33) (Sturt et al., 2021b). A subsequent exploratory analysis of women
with a higher burden of Schistosoma infection suggested a potential dose-
response relationship between FGS burden and incident HIV-1 (Sturt
et al., 2021b). Larger, longitudinal studies will be needed to strengthen
the association between FGS and HIV incidence. However, to prevent
life-long complications of both diseases, programmatic integration should
not be delayed.
5.1.1 Interactions with vertically transmitted HIV

To date, there are no longitudinal studies in children with vertically acquired
HIV that evaluate the early development of schistosomiasis-associated mor-
bidity including FGS and MGS (Bustinduy et al., 2014). In this unique sce-
nario, HIV acquisition would precede Schistosoma infection, an intrinsically
different mechanistic pathway to that of adult HIV exposure (where FGS is
hypothesized to precede HIV acquisition). The differences in immunopath-
ological responses in children with vertically acquired HIV may have a role
in shaping schistosomiasis (and HIV) disease manifestations, even if the child
is receiving successful antiretroviral therapy (Bustinduy et al., 2014).
Children’s response to egg excretion and entrapment in the presence of
HIV is also not known. Abnormal egg deposition and subsequent organ
involvement leading to early FGS and MGS is plausible, and should be
explored longitudinally in a cohort of vertically infected HIV positive infants
and children (Bustinduy et al., 2014).
Children born to pregnant women with HIV, S. haematobium and other
helminth co-infection, have a higher likelihood of being HIV positive after
their first year of life (Gallagher et al., 2005). However, the effect of HIV
infection in women with underlying FGS on the mother-to-child transmis-
sion of HIV during delivery is not yet known.
5.2 Human papillomavirus (HPV) and FGS

Human papillomavirus (HPV) is the etiological agent of cervical cancer that
is preceded by cervical dysplasia. Cervical cancer is the fourth leading cause
of death in women worldwide, with an estimated 341,800 deaths/year
(Sung et al., 2021). Despite the recognition of S. haematobium as a urinary
bladder carcinogen (Humans, 2012), few studies have looked at the role
of HPV and S. haematobium co-infection as potential synergistic agents in
cervical cancer pathophysiology.
A plausible pro-neoplastic association between HPV and S. haematobium

has been hypothesized from earlier studies (Feldmeier et al., 1996). Case
reports and cross-sectional studies have used heterogeneous methodology
and FGS definitions, making cross-study comparisons challenging (Coelho
et al., 1979; Dzeing-Ella et al., 2009; Savardekar et al., 2010; Schwartz,
1984; Slavska et al., 2011; Youssef, 1957).
Histopathological studies are limited by the tendency of Schistosoma eggs
to cluster in genital tissue yielding conflicting results. In Malawi, a review of
174 cervical biopsies in women with FGS found no association with dyspla-
sia or cervical cancer (Wright et al., 1982). A larger study analysing 10 years
of cervical cancer and nearly 7000 biopsies in Tanzania did not find an
association between FGS and cervical carcinoma, but found that women
with FGS were younger at time of diagnosis of cervical cancer (A, 1994).
This finding was replicated in South Africa where investigators found that
women with FGS and cervical cancer were 15 years younger than the local
average (van Bogaert, 2011). The women in these series had a clinical indi-
cation for biopsy and furthermore, women accessing healthcare at tertiary
centres are not representative of the population most at risk of FGS, rep-
resenting potential selection bias.
Other gynaecological studies such as Pap smears for the diagnosis of cer-
vical dysplasia have been tested for FGS diagnosis with mixed results and
have been confounded by technical issues. In Zimbabwe, 527 women
underwent visual examination of the vagina and cervix, urine microscopy,
Pap smear and STI testing (Kjetland et al., 2005). No association was found
between FGS diagnosed by visual inspection and cervical dysplasia diag-
nosed by Pap smear. However, a 5-year follow up of a small cohort of
women (n ¼ 37) with high risk HPV serotypes showed that FGS was asso-
ciated with development of cervical neoplasia, but not persistence of
high-risk HPV (Kjetland et al., 2010b). Also, no association was found
between Pap smears for cervical dysplasia and FGS in a study in South
Africa of 394 girls aged 16–23 (Pillay et al., 2016). These results should
be interpreted with caution, as 95–97% of Pap smears from women with
FGS in this study were not interpretable.
Additionally, two case control studies investigated the association
between FGS and cervical dysplasia. The first found no association between
FGS diagnosed by biopsy and HPV diagnosed by PCR, or cervical dysplasia
by Pap smear in 24 women in Ghana from an endemic schistosomiasis area
(cases) compared to women living in a non-endemic area (controls) (Szela
et al., 1993). In a Tanzanian case control study, participants (n ¼ 109) were
compared to 109 German age-matched controls (n ¼ 109). Authors defined

FGS as urine microscopy positive without known genital involvement
(Petry et al., 2003). HPV DNA detection was higher in Tanzanian cases than
in German controls (34.5% vs 26.9%). Prior or current history of schistoso-
miasis was associated with high-risk HPV serotypes (Petry et al., 2003).
A recent study in Zambia, the BILHIV study, was the first study to report a
strong association between women with FGS, diagnosed by genital PCR, and
cervical dysplasia diagnosed by visual inspection with acetic acid (OR 6.8 95%
CI: 1.58–23.37 P ¼ 0.016) (Rafferty et al., 2021). Large longitudinal studies
evaluating HPV DNA persistence and incidence in women with PCR or
biopsy confirmed FGS are lacking and are urgently needed to understand com-
mon pathophysiological pathways in the genesis of cervical cancer. Synergistic
findings would support joint FGS and HPV screening programmes.
6. Immigrants and returned travellers

Among returned travellers, both FGS and MGS diagnosis remain a
rare occurrence and are commonly underreported. Most cases present as
secondary disease manifestations related to overall sexual and reproductive
life changes. Ectopic pregnancies have been reported in female travellers
from Mali (Laroche et al., 2016), Malawi and Tanzania (Sheorey et al.,
2004) and can ensue from tubal obstruction due to bilharziomas (masses of
S. haematobium eggs) that can also be the cause of secondary infertility
(Sheorey et al., 2004). Of note, most clinical disease became patent many years
and often decades after exposure. Some women present with symptoms of
urogenital schistosomiasis such as haematuria and are mistakenly treated for
urinary tract infections (Sheorey et al., 2004). Manifestations similar to those
of sexually transmitted infections (STI), commonly vulvar lesions, can also
confound the diagnosis of FGS as in the case of two returned travellers from
Zimbabwe and Malawi with S. haematobium eggs found in biopsies from
lesions resembling vulvar warts (Carey et al., 2001; Crump et al., 2000).
More extensive manifestations of FGS with ovarian, tubal and endometrial
involvement have been reported after a visit to Malawi (Crump et al.,
2000). Schistosoma serology in these patients confirms parasite exposure
(Carey et al., 2001; Crump et al., 2000) but cannot be used as a marker of
cure since it can remain positive in the long term.
There are few case reports of MGS diagnosed in returned travellers.
Haematospermia was the most common finding in four males returning from
Malawi with two of them presenting with haematuria and testicular
paraesthesia, and one with a tender prostate. All patients had a positive
Schistosoma serology (Schwartz et al., 2002). Semen microscopy can aid in
the parasitological diagnosis of MGS patients presenting with haematospermia
(Torresi et al., 1997) but PCR is likely to increase the yield (Kayuni
et al., 2019a).
Women and men born in endemic areas and migrating to non-endemic
countries are at risk of delayed recognition of the genital manifestation of
schistosomiasis. A large review on schistosomiasis in refugees, immigrants
and returned travellers to Europe reported a large number of individuals
(166/318, 52%) who presented with chronic urogenital symptoms.
However, these symptoms were not distinguished between urinary and gen-
ital complaints (Lingscheid et al., 2017). In a report from an Italian centre,
out of 103 patients, only one patient had FGS as diagnosed by S. haematobium
eggs found in the uterus (Marchese et al., 2018). Other reported cases
include recurrent ectopic pregnancies in a woman born in Zambia and living
in Europe for decades afterwards (Laxman et al., 2008), but many cases
continue to be unpublished and unreported.
7. Management of FGS and MGS

7.1 FGS treatment
Praziquantel (PZQ) is the drug of choice for schistosomiasis and is currently
the only available treatment against human Schistosoma species (Colley et al.,
2014). PZQ is only effective against adult worms with juvenile forms
remaining viable after treatment (Doenhoff et al., 2008). Despite this limi-
tation, cure leads to cessation of egg-deposition (the pathogenic mediator in
host tissues) and this prevents additional organ damage.
PZQ is well tolerated and virtually all trials have confirmed the absence
of toxicity in the liver, kidney, and haematopoietic system. However, minor
side-effects do occur. Praziquantel was initially developed as a sedative due
to its ability to cross the blood-brain barrier. Therefore, it is not surprising
that side effects can include headache, dizziness and somnolence (Bustinduy
et al., 2021). Gastrointestinal side effects related to the gastrointestinal tract
are also common and include epigastric or generalized abdominal pain or dis-
comfort, nausea, vomiting, anorexia or loose stools. The severity of these
side-effects correlates with intensity of infection, but overall, they are generally
mild, transient, lasting between 1 and 3 h, and rarely require intervention.
WHO recommends 40–60 mg/kg of praziquantel in a single dose for
both the treatment and control of schistosomiasis through mass drug
administration programmes in school-aged children (WHO, 2020).

However, this dosing regimen reduces worm load by about 80–90% and
does not guarantee cure, except in very light infections (Downs et al.,
2013) highlighting the need for more frequent dosing. Pharmacokinetic/
pharmacodynamic studies have reported both doses advocated by WHO
to be insufficient in treating children from endemic areas, with modelling
suggesting that at least 80 mg/kg may be needed to achieve cure
(Bustinduy et al., 2020b).
There are inherent flaws in recommending the same dose of PZQ for
public health and clinical outcomes as the indicators of success are different.
In public health campaigns, the desired outcome is to reduce heavy intensity
infections to a prevalence below 1% (WHO, 2006). This approach is thought
to decrease severe morbidity, the ultimate goal of schistosomiasis control
programmes. For WHO, programmes that achieve cure rates of 75% are con-
sidered optimal (World Health Organization, 2010). However, this approach
is likely to leave untreated residual morbidity. Intensified treatments are there-
fore needed and are being evaluated in randomized controlled trials testing
repeated standard dosing of 40 mg/kg of PZQ (Webb et al., 2021). Double
initial dosing is being advocated as the minimum initial treatment needed
in any clinical scenario (Bustinduy et al., 2020a). The rationale for repeated
dosing stems from the assumption that re-infection occurs with maturation
of schistosomula within 4 weeks that become adult worms. High dose-
regimens with a triple dose of PZQ was shown to achieve cure in cases of
travel-associated FGS and is recommended by some medical societies
(Blum et al., 1998; Leslie et al., 1993; Schleenvoigt et al., 2014).
Only a few small studies, evaluating the performance of single dose PZQ
for the treatment of genital schistosomiasis have been conducted (Table 1).
Based on the available data, it is difficult to make conclusions regarding the
efficacy of single dose PZQ given at 40 mg/kg based on the heterogeneity of
methods, study outcomes, and low study power (due to small sample sizes).
None of the studies were randomized controlled trials and did not control
for re-infection. Outcome measures included resolution of infertility
(El-Mahgoub, 1982), reduction of circulating antigen in serum (Richter
et al., 1996), improvement of symptoms (Leutscher et al., 2008c; Richter
et al., 1996), resolution of cervical abnormalities (Kjetland et al., 2006a)
and clearance of Schistosoma DNA in vaginal lavage fluid (Downs et al.,
2013). The clinical pathology present at baseline and follow-up varied con-
siderably from weeks to 12 months. The reduction in the different outcome
measures used varied between zero and 73%.
Table 1 Results of treatment studies on FGS.
Reduction in outcome
Country N Outcome measure Treatment Time interval measures (%) Reference
Egypt 13 Primary infertility Niridazole for 15 months 46% El-Mahgoub
6 days (1982)
Malawi 9 1. CAAa; PZQ 2–9 weeks 1. 80% Richter et al.
2. Complaintsb; single dose 2. 34% (1996)
3. FGS lesions (40 mg/kg) 3. 50
Zimbabwe 1. Presence of FGS lesionsc PZQ 3, 12 months 1. HYSP: 21–36%; Kjetland et al.
260 2. Contact bleeding single dose GSP: 76% (2006a)
(40 mg/kg) 2. 78%
Madagascar 253 Complaintsb PZQ 6 months 52–73% Leutscher et al.
single dose (2008a)
(40 mg/kg)
Tanzania 33 1. Presence of FGS lesions; 6 months 1. 67% Downs et al.
2. Presence of eggs in cervical PZQ 2. 100% (2013)
tissue; single dose 3. 80%
3. Schistosome DNA (vaginal (40 mg/kg)
lavage fluid)
Zambia 32 1. Presence of FGS lesions; PZQ 12 months 1. 0% Samuels (2019)
2. Symptoms single dose 2. 45%
(40 mg/kg)
a
Circulating anodic antigen in serum.
b
Dyspareunia, genito-pelvic discomfort; pain during sexual intercourse, genital itching and others.
c
Homogeneous sandy patches (HYSP) and grainy sandy patches (GSP).
A recently completed RCT for the treatment of FGS in Madagascar

compared five doses of PZQ with the first three doses administered within
24–48 h, a fourth dose at 4 weeks and fifth at 10 weeks compared to standard
of care (40 mg/kg single dose) (Randriansolo, B, Personal communication).
7.2 Treatment of MGS

There are few treatment studies of men with MGS, and only in two coun-
tries; Madagascar (Leutscher et al., 2005) and Malawi (Kayuni et al., 2019a).
Men followed up after 6 months of receiving a single dose PZQ (40 mg/kg)
had a significant reduction in eggs founds in semen and urine as well as lower
levels of pro-inflammatory cytokines and leukocytospermia (Leutscher
et al., 2005). A small case series of five fishermen from Malawi with
MGS were followed up for 12 months after treatment with a single dose
of PZQ 40 mg/kg (Kayuni et al., 2019a). Resolution of symptoms including
delayed ejaculation, reduced semen volume and haematuria, were reported
after 1 year only in one subject. PCR positivity was reported at 3 months
after treatment in two of the subjects. There are currently no randomized
controlled trials comparing different treatment strategies for the treatment
of MGS (Kayuni et al., 2019b).
7.3 Pregnancy
Anti-schistosomal praziquantel treatment of pregnant women is not only
safe, but increases the infant’s iron endowment (Olveda et al., 2016).
Furthermore, it may also prevent pervasive S. haematobium infection in
women of reproductive age who may also have FGS (Bustinduy et al.,
2020b; Friedman et al., 2018; Ndibazza et al., 2010; Olveda et al., 2016;
Tweyongyere et al., 2008). Sadly, despite two randomized controlled trials
in Uganda and the Philippines demonstrating praziquantel safety in preg-
nancy, and revised WHO recommendations, the uptake in endemic settings
is still sub-optimal (Friedman et al., 2018; Ndibazza et al., 2010; Olveda
et al., 2016). In addition, a recent study of PZQ in pregnancy showed a neg-
ligible amount of PZQ is excreted in the breast milk, posing a minimal risk
to the infant and reinforcing the safety and benefits of treating pregnant and
lactating women (Bustinduy et al., 2020b). Special attention must be given
to Schistosoma treatment in pregnant and lactating women during MDA
programmes to decrease disease burden and improve pregnancy and foetal
outcomes (Bustinduy et al., 2017). This approach may prove beneficial
particularly if women have underlying FGS.
8. Disability, stigma and community awareness

Urogenital schistosomiasis is second only to malaria in terms of public
health impact and is one of the most relevant chronic infections among the
world’s poorest people (Hotez and Kamath, 2009; Utzinger et al., 2009;
Yirenya-Tawiah et al., 2016). Few countries in SSA have conducted studies
unveiling the social determinants of FGS and MGS. More specifically, recent
work reported from Cameroon (Masong et al., 2021) and Tanzania (Mazigo
et al., 2021), highlight a worrisome knowledge vacuum on FGS as a treatable
disabling gynaecological disorder. In response to the need to increase FGS
awareness at different levels, a multi-partner initiative has been recently
launched with a focus on Ghana and Madagascar, two endemic countries
for FGS (https://fastpackage.org).
In previous efforts to quantify the global burden of disease attributed
to schistosomiasis, chronic manifestations of disease such as established gen-
ital lesions have been systematically neglected (King, 2010). Disability due to
FGS and MGS will remain unrecognized globally unless the disability-
adjusted life-year (DALY) estimates integrate the disabling consequences
of genital morbidity in their ongoing calculations (DALYs and
Collaborators, 2018).
8.1 Case study: Ghana

Ghana is one of the first five countries to implement the integrated control
program for Neglected Tropical Diseases (NTDs) but with little docu-
mented evidence on FGS (Yirenya-Tawiah et al., 2016). The strategy to
reduce the burden of schistosomiasis in Ghana mainly focuses on children
while neglecting other risk groups, including reproductive-aged women
(Yirenya-Tawiah et al., 2016).
Due to inadequate knowledge about FGS among health workers (Kukula
et al., 2019), community members (Kukula et al., 2019; Yirenya-Tawiah
et al., 2016), and complexities in diagnosis (Engels et al., 2020), obtaining
information about the precise disease burden of FGS is daunting (Engels
et al., 2020). Furthermore, FGS is not included in most textbooks for nurses,
midwives, and medical students worldwide and across sub-Saharan Africa
where the disease is endemic (Engels et al., 2020). This situation further exac-
erbates the poor awareness and diagnosis of FGS and consequently, FGS is
overlooked by national health policymakers (Engels et al., 2020).
Community-based assessment of knowledge and disease burden of FGS

is challenging. For example, studies investigating FGS have been conducted
in a few areas in the country and found that community members and local
health workers had not heard of FGS as a disease entity and were not aware
of the impact of schistosomiasis on women and girls (Kukula et al., 2019;
Yirenya-Tawiah et al., 2016). A common belief was that schistosomiasis
symptoms in girls and women, such as blood in the urine, represented pro-
miscuity as it was believed they could be acquired only by sexual transmis-
sion from males (Kukula et al., 2019).
Many of the health education interventions delivered in schistosomiasis
control programmes do not include information on FGS and its impact on
sexual and reproductive health for both women and men (Yirenya-Tawiah
et al., 2011). Thus, minimal information on this aspect of the disease is avail-
able to endemic communities and the public. A study found that community
members along the Volta Basin did not perceive urogenital schistosomiasis as
an important disease and, therefore, either resorted to self-medication or no
treatment (Yirenya-Tawiah et al., 2011). Other researchers found a lower
level of knowledge for reproductive health implications for urogenital schis-
tosomiasis among females than males (Yirenya-Tawiah et al., 2016).
Stigma associated with FGS was a significant obstacle for girls and
women seeking care at health facilities (Kukula et al., 2019). Health workers
and community members consider boys and men at higher risk of schisto-
somiasis than women and adolescent girls. Because of this misconception,
when younger girls report genital tract symptoms, to the health facilities,
they are often stigmatized by health care workers and are accused of sexual
promiscuity and referred for STI treatment (Kukula et al., 2019). To avoid
stigmatization, adolescent girls prefer seeking home remedies and herbal
medicine to treat symptoms consistent with FGS (Kukula et al., 2019).
9. Programme integration
To achieve integration of FGS and MGS in diagnostic and treatment
platforms, it is paramount to understand if both diseases co-exist in any given
endemic community. Fig. 7 depicts early exposure to S. haematobium
resulting in genital disease at an unknown age, but likely early in childhood.
Exposure to sexually transmitted infections including HPV may lead to ear-
lier development of cervical cancer and increase the risk of HIV and STI
acquisition for both females and males. The role of S. haematobium on the
risk of female and male genital cancers is still largely unknown.
Fig. 7 Natural history of exposure and disease of reproductive tract infections at different
stages of life in a woman and a man. Yellow arrow represents exposure to
S. haematobium, purple arrow depicts the active sexual and reproductive life of a
woman, red arrow marks the exposure to human papillomavirus (HPV). *Not represen-
ted but also important are HIV via sexual transmission and sexually transmitted infec-
tions (STIs) once the woman becomes sexually active.
Opportunities for integration should follow the lead of established,

ongoing programmes that have been rolled out across SSA. As reproductive
tract infections, FGS and MGS can and should be integrated within global
sexual and reproductive health (SRH) efforts without delay. HIV programmes
have gained momentum across SSA and home HIV self-testing is paving the
way to increased testing in communities and access of hard-to-reach
populations and scaling up couples and partner testing ( Johnson and
Corbett, 2016). Policy organization such as UNAIDS has already taken the
lead to raise awareness regarding the important synergies between FGS and
HIV through a seminal report (UNAIDS, 2019).
In November 2020, the World Health Assembly (WHA 73) set forth
The WHO global strategy to accelerate the elimination of cervical cancer
as a public health problem by 2030. It focuses on three key pillars:
prevention through HPV vaccination; screening and treatment of
pre-cancerous lesions; and management of invasive cervical cancer.
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The Project Gutenberg eBook of I bring fresh
flowers
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Title: I bring fresh flowers
Author: Robert F. Young
Release date: December 12, 2023 [eBook #72390]
Language: English
Original publication: New York, NY: Ziff-Davis Publishing

Company, 1963
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*** START OF THE PROJECT GUTENBERG EBOOK I BRING

FRESH FLOWERS ***
I Bring Fresh Flowers
By ROBERT F. YOUNG
A touching tale of an Astronette—and why the

gentle rain from Heaven has the quality of mercy.
[Transcriber's Note: This etext was produced from

Amazing Stories February 1964.
Extensive research did not uncover any evidence that
the U.S. copyright on this publication was renewed.]
You know Rosemary Brooks. You have known her for many years.
It is said that when she was a little girl her favorite poem was
Barbara Frietchie, and it is told how she would sometimes poke her
pretty head out of her bedroom window, survey the suburban street
with her blue-sky eyes, and cry, "Shoot, if you must, this old gray
head, but spare your country's flag!"
Yes, you know Rosemary. You know her very well.
Like all little girls, Rosemary grew up. But Rosemary did not change.
This is not to say that she did not turn into an attractive young lady.
She turned into a most attractive one indeed. Fragilely beautiful, airy
of tread, she should have been the reigning rose of every dance she
went to, but she was not. Rarely did the young men of her
acquaintance ask her to dance, and never did one of them approach
her and say, "Come into the garden, Rosemary, for the black bat,
night, has flown." She did not go to very many dances in any event,
and looking back, one realizes that the few she did attend, she
attended primarily to please her mother. The reason behind
Rosemary's wallflowerhood is simple: the young men of her
acquaintance knew that with her, God and the United States of
America came first, and that accompanying her through life, or even
accompanying her home from a dance for that matter, meant being
relegated to a back seat. It is alright for little girls to be Barbara
Frietchies, you see, but not for big ones.
During her short and dedicated life, Rosemary poked her pretty head
out of quite a number of windows. After the Barbara Frietchie
window came the Girl Scouts of America window, and after the Girl
Scouts of America window came the Young Peoples' Civil War
Society window, and after the Young Peoples' Civil War Society
window came the Citizens for Patriotic Progress window. Last of all
came the Astronette Training Center window.
Set up by Project Rain Dance in 1969 after prejudice against women
going into space had abated, the Astronette Training Center had for
its purpose the finding, training, and conditioning of six female pilots
for a series of six manned weather-control satellite shots, the first of
which was scheduled to take place some time in February of '71.
After exhaustive screening, one hundred volunteers were accepted.
Fifteen of them passed the exacting physical and psychological
tests, and from the ranks of the fifteen, the six astronettes were
chosen. Incredibly, when one considers her delicateness (and fails to
consider her patriotic fervor), Rosemary not only made the grade but
was selected to accompany the first weather-control satellite to be
placed in orbit.
All of this is history now—faded words on newsprint, old
photographs, a dozen dusty articles in as many magazines—but at
the time, it captured the attention of the whole wide world. It is said
that Madison Avenue nearly went out of its mind trying to circumvent
the regulation that prohibited astronettes from underwriting
testimonials to toothpaste, cosmetics, and cigarettes. This is not to
be wondered at. If Rosemary could have been legally enticed, for
example, into letting her picture appear in a cigarette ad, cigarette
consumption probably would have doubled overnight. It is one thing
to be an obscure Barbara Frietchie and quite another to be a famous
one, and the patriotic devotion shining in a person's eyes can,
through the thaumaturgy of photography and touch-up, be
transmuted into a sensual gleam.
February of '71 arrived at last, as all months must, and a specific
date was set for the launching. Psychological winter had come and
gone, but no singing of birds could be heard. Even as far south as
Canaveral, gray skies were the rule, and gray rain fell intermittently.
Countdown was begun regardless. And then, miraculously it
seemed, the skies cleared, and the day of the launching dawned
bright and clear. There is a photograph of Rosemary standing in her
snow-white spacesuit at the base of the gantry, her space helmet
resting in the crook of her arm. The photograph is in color, and the
blueness of her eyes is not one whit different in shade and texture
from the blueness of the sky behind her. This is as it should be.
Looking at her hair, one thinks of sunrises and sunsets. This is as it
should be too. When remembering Rosemary, it is fitting that one
should think of the sun and the sky. It is equally fitting that one
should think of the snow and the rain. For Rosemary is nothing if she
is not all of these things.
The launching was a good one. The Rainbow 6 rode its Saturn
booster like a bird on jet-fire wings, and the bright star of its passage
seemed to linger in the morning sky long after the booster had fallen
away. The television cameras caught the action beautifully, and the
American public, reminded once again that the noblest thing a
person can do is to risk his life for his country, looked on in awe and
admiration. The orbit was a good one too: apogee—203 miles;
perigee—191 miles. Rosemary radioed back that she was A-okay.
She was supposed to complete three orbits, then climb into the
escape capsule, jettison it and herself, re-enter the atmosphere, and
parachute into the Atlantic. There, a task force waited eagerly to pick
her up. Her mission was to orientate the satellite's weather-factor
instruments to the existent cloud patterns and jet streams. Once this
was accomplished, the telemetric readings would, through the
medium of the Main Weather Control Station in Oregon, dictate
future weather. Weather control had been in effect since the middle
sixties, but the telemetric readings of the unmanned weather-control
satellites, owing to faulty orientation, had fallen far short of the one-
hundred percent accuracy needed to make the regulation of rain and
sunshine something more than a half-realized dream, and it was
hoped that the present satellite, given a human boost, would bring
the dream to fruition.
One can picture Rosemary high in the sky, faithfully carrying out her
assignment. One can see her sitting there before the instrument
panel of the Rainbow 6 looking at dawns and sunsets and stars. One
can see the slow drift of cloud and continent beneath her. Australia
now, and now the vast blueness of the Pacific ... and now the west
coast rising out of mists of distances and air, and beyond it, the vast
green blur of the land that gave her birth. Little Barbara Frietchie
riding on a star.... Far beneath her now, highways wind; rivers run
down to seas. Patternings of field and forest blend into pale blue-
greens. Fresh-water lakes look up at her with blue and wondering
eyes. Now the sea of night drifts forth to meet her. Bravely she sets
sail upon the dark waves in her little silvery ship. Brief night, soft
sunrise, new day.
I bring fresh showers for the thirsting flowers,

From the seas and the streams;
I bear light shade for the leaves when laid
In their noonday dreams.
Little Barbara Frietchie riding on a star....

Jettisoning took place exactly on schedule. The weather-control
satellite continued on its orbital way, and Rosemary plummeted
earthward in the escape capsule. That much, at least, is known. But
what took place during re-entry—whether the retro rockets failed to
fire, whether the attitude controls malfunctioned, or whether the heat
shield proved to be defective—is not known and never will be known.
All that is known is that Rosemary became a falling star.
The nation mourned. The whole wide world mourned. Project Rain
Dance was discontinued. It would have been discontinued in any
event, for Rosemary had obviated any further need for it. She had
done her job well, Rosemary had, and in the doing of it, she had
placed the weather in the palm of mankind's out-stretched hand.
That spring, the rains were soft and warm and the flowers grew
riotously upon the face of the earth. Grass knew a greenness it had
never known before, and trees dressed each day in lovelier and
lovelier dresses. The rains fell in the cities and on the plains. In
valleys and in little towns. On fields and forests and lawns. And when
the land had drunk its fill, the sun came out as warm and as bright as
Rosemary's hair, and the sky turned as blue as her eyes.
Yes, you know Rosemary, and you are in love with her in a way. If
you are not, you should be. She is the sun coming up in the morning
and the sun going down at night. She is the gentle rain against your
face in spring. She is the snow falling on Christmas Eve. She is
every glorious rainbow you see in the rain-washed sky. She is that
pattern of tree-shade over there. Each morning, when you are lying
fast asleep in your trundle bed, she tiptoes into your room, her
golden sandals soundless on the bedroom floor, and wakes you with
a golden kiss. Sunlight is her laughter, her voice the patter of the rain
—Soft you now!—she speaks:
I am the daughter of the earth and water,

And the nursling of the sky;
I pass through the pores of the ocean and shores;
I change, but I cannot die....
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FRESH FLOWERS ***
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Instant Download Advances in Parasitology, Volume 115 Russell Stothard PDF All Chapter

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1. An update on female and male genital schistosomiasis and

2. Vertebrates as uninfected disseminators of helminth

3. Anthelmintic resistance in ruminants: challenges and solutions 171

An update on female and male

Advances in Parasitology, Volume 115 Copyright #2022 Elsevier Ltd 1

1.1 Selection criteria

1.2 Epidemiology and geographical distribution of genital

diagnosed by histopathology in 62% of 543 women with urinary schistoso-

1.3 Life cycle and transmission

communities that have unsafe water contact (Satayathum et al., 2006). In

Fig. 2 The life cycle of S. haematobium. Adapted from Countdown (https://countdown.

parasites is common, its epidemiological occurrence is only rarely reported,

1.4 FGS and MGS in less common Schistosoma species

S. haematobium; for example, a case of testicular schistosomiasis leading to

1.5 The importance of different hybrids of S. haematobium

S. haematobium-hybrids contribute to genital schistosomiasis. A further

2. Pathogenesis and clinical manifestations

Vulvar or vaginal ulcerations and papillomata have been associated with

2.1.1 Pregnancy and placental involvement

during pregnancy is also associated with iron deficiency among infants

2.2 Male genital schistosomiasis (MGS)

cytokine concentrations in systemic circulation of mice with FGS, only

3.2 Immune activation during pregnancy

4. Diagnosis of genital schistosomiasis

study comparisons due to differences in FGS case definitions. For example,

4.1.1 Traditional colposcopy

4.1.2 Hand-held colposcopy and other hand-held devices

smartphones, a digital camera and several handheld colposcopes, their avail-

4.1.3 Ultrasound scans and other radiological imaging

(Ramarakoto et al., 2008). Ultrasound may be helpful in diagnosing com-

4.1.4 Parasitology diagnosis

4.2 Molecular diagnostics (nucleic acid amplification tests)

4.2.2 Isothermal diagnostics

Loop Mediated Isothermal Amplification (LAMP) (Gandasegui et al., 2018)

4.3 MGS diagnostics

Fig. 6 S. haematobium egg in semen at 400 magnification. Photo credit. S. Kayuni.

4.3.1 Parasitology and molecular diagnostics in MGS

4.4 Immunopathology in MGS

5. Co-infections and co-morbidities

5.1.1 Interactions with vertically transmitted HIV

5.2 Human papillomavirus (HPV) and FGS

A plausible pro-neoplastic association between HPV and S. haematobium