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Abstract Background A vaginal fistula is a devastating condition, affecting an estimated 2 million girls and women across Africa and Asia. There are numerous challenges associated with providing fistula repair services in developing countries, including limited availability of operating rooms, equipment, surgeons with specialized skills, and funding from local or international donors to support surgeries and subsequent post-operative care. Finding ways of providing services in a more efficient and cost-effective manner, without compromising surgical outcomes and the overall health of the patient, is paramount. Shortening the duration of urethral catheterization following fistula repair surgery would increase treatment capacity, lower costs of services, and potentially lower risk of healthcare-associated infections among fistula patients. There is a lack of empirical evidence supporting any particular length of time for urethral catheterization following fistula repair surgery. This study will examine whether short-term (7 day) urethral catheterization is not worse by more than a minimal relevant difference to longer-term (14 day) urethral catheterization in terms of incidence of fistula repair breakdown among women with simple fistula presenting at study sites for fistula repair service. Methods/Design This study is a facility-based, multicenter, non-inferiority randomized controlled trial (RCT) comparing the new proposed short-term (7 day) urethral catheterization to longer-term (14 day) urethral catheterization in terms of predicting fistula repair breakdown. The primary outcome is fistula repair breakdown up to three months following fistula repair surgery as assessed by a urinary dye test. Secondary outcomes will include repair breakdown one week following catheter removal, intermittent catheterization due to urinary retention and the occurrence of septic or febrile episodes, prolonged hospitalization for medical reasons, catheter blockage, and self-reported residual incontinence. This trial will be conducted among 512 women with simple fistula presenting at 8 study sites for fistula repair surgery over the course of 24 months at each site. Discussion If no major safety issues are identified, the data from this trial may facilitate adoption of short-term urethral catheterization following repair of simple fistula in sub-Saharan Africa and Asia. Trial registration ClinicalTrials.gov Identifier NCT01428830.

Abstract Background Maternal outcomes in most countries of the developed world are good. However, in many developing/resource-poor countries, maternal outcomes are bleaker: Every year, more than 500,000 women die in childbirth, mostly in resource-poor countries. Those who survive often suffer from severe and long-term morbidities. One of the most devastating injuries is obstetric fistula, occurring most often in south Asia and sub-Saharan Africa. Fistula treatment and care are available in many countries across Africa and Asia, but there is a lack of reliable data around clinical factors associated with the success of fistula repair surgery. Most published research has been retrospective. While these studies have provided useful information about the care and treatment of fistula, they are limited by the design. This study was designed to identify practices in care that could lead to the design of prospective and randomized controlled trials. Methods Self-administered questionnaires were completed by 40 surgeons known to provide fistula treatment services in Africa and Asia at private and government hospitals. The questionnaire was divided into three parts to address the following issues: prophylactic use of antibiotics before, during, and after fistula surgery; urethral catheter management; and management practices for patients with urinary incontinence following fistula repair. Results The results provide a glimpse into current practices in fistula treatment and care across a wide swath of geographic, economic, and organizational considerations. There is consensus in treatment in some areas (routine use of prophylactic antibiotics, limited bed rest until the catheter is removed, nonsurgical treatment for postsurgical incontinence), while there are wide variations in practice in other areas (duration of catheter use, surgical treatments for postsurgical incontinence). These findings are based on a small sample and do not allow for recommending changes in clinical care, but they point to issues for possible clinical trial research that would contribute to more efficient and effective fistula care. Conclusions The findings from the survey allowed us to consider clinical practices most influential in the cost, efficacy, and safety of fistula treatment. These considerations led us to formulate recommendations for eight randomized controlled trials on the following subjects: 1) Efficacy/safety of short-term catheterization; 2) efficacy of surgical and nonsurgical therapies for urinary incontinence; 3) technical measures during fistula repair to reduce the incidence of post-surgery incontinence; 4) identification of predictive factors for "incurable fistula"; 5) usefulness of urodynamic studies in the management of urinary incontinence; 6) incidence and significance of multi-drug resistant bacteria in the fistula population; 7) primary management of small, new fistulas by catheter drainage; and 8) antibiotic prophylaxis in fistula repair.

Multiple pregnancy remains a relatively common occurrence, but it is associated with increased risks of adverse outcomes for the mother and her babies and presents unique challenges to healthcare providers. This review will briefly discuss multiple pregnancies, their aetiology and their problems, including preterm birth, before reviewing the processes leading to normal labour onset and how they may be different in a multiple pregnancy. The mechanisms by which mechanical factors i.e., uterine distension or 'stretch' contribute to uterine excitability and the timing of labour onset will be the major focus, and how over distention may pre-dispose multiple pregnancies to preterm birth. This includes current thinking around the role of mechano (stretch) sensitive ion channels in the myometrium and changes to other important regulators of excitability and contraction which have been identified from studies using in vitro and in vivo models of uterine stretch. Physiological stimuli arising from the fetus(es) and placenta(s) will also be discussed. In reviewing what we know about the myometrium in multiple pregnancy in humans, the focus will be on twin pregnancy as it is the most common type of multiple pregnancy and has been the most studied., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author.)

In this study, we develop a method that assigns acoustic signals with Automatic Dependent Surveillance-Broadcast (ADS-B) data to build a labeled dataset of acoustic signals from aircraft without expensive ground-truth experiments. An exploration of the resultant labeled dataset enables an assessment of the acoustic characteristics from three types of aircraft. The fusion framework is evaluated using data from an acoustic sensor and collocated ADS-B receiver in the middle of a large urban area at Southern Methodist University in Dallas, Texas. Our results demonstrate the benefit of combining multiple types of data to generate a labeled dataset leveraging open-source aircraft surveillance data. By studying three classes of aircraft, we find that the smaller fixed wing single engine (FWSE) class is mostly detected within approximately 5000 m, while the larger fixed wing multi-engine (FWME) class is commonly detected out to greater distances above 7500 m. The FWSE class has a median source frequency at 100 Hz, compared to FWME class with median source frequency at 80 Hz, while rotorcraft has a source frequency falling into a lower range of 30-100 Hz., (© 2023 Acoustical Society of America.)

The World Health Organisation (WHO) estimates 15 million babies worldwide are born preterm each year, with 1 million infant mortalities and long-term morbidity in survivors. Whilst the past 40 years have provided some understanding in the causes of preterm birth, along with development of a range of therapeutic options, notably prophylactic use of progesterone or uterine contraction suppressants (tocolytics), the number of preterm births continues to rise. Existing therapeutics used to control uterine contractions are restricted in their clinical use due to pharmacological drawbacks such as poor potency, transfer of drugs to the fetus across the placenta and maternal side effects from activity in other maternal systems. This review focuses on addressing the urgent need for the development of alternative therapeutic systems with improved efficacy and safety for the treatment of preterm birth. We discuss the application of nanomedicine as a viable opportunity to engineer pre-existing tocolytic agents and progestogens into nanoformulations, to improve their efficacy and address current drawbacks to their use. We review different nanomedicines including liposomes, lipid-based carriers, polymers and nanosuspensions highlighting where possible, where these technologies have already been exploited e.g. liposomes, and their significance in improving the properties of pre-existing therapeutic agents within the field of obstetrics. We also highlight where active pharmaceutical agents (APIs) with tocolytic properties have been used for other clinical indications and how these could inform the design of future therapeutics or be repurposed to diversify their application such as for use in preterm birth. Finally we outline and discuss the future challenges., Competing Interests: SR is a Director of Tandem Nano Ltd and co-inventor of patents relating to drug delivery using nanotechnologies. SR has received research funding from GSK/ViiV, AZ and Gilead and a consultancy from Gilead. TM is a co-inventor of patents relating to drug delivery using nanotechnologies and has carried out consultancy work for Vifor Pharma., (This journal is © The Royal Society of Chemistry.)

In smooth muscle tissues, calcium-activated chloride channels (CaCC) provide the major anionic channel. Opening of these channels leads to chloride efflux and depolarization of the myocyte membrane. In this way, activation of the channels by a rise of intracellular [Ca 2+ ], from a variety of sources, produces increased excitability and can initiate action potentials and contraction or increased tone. We now have a good mechanistic understanding of how the channels are activated and regulated, due to identification of TMEM16A (ANO1) as the molecular entity of the channel, but key questions remain. In reviewing these channels and comparing two distinct smooth muscles, myometrial and vascular, we expose the differences that occur in their activation mechanisms, properties, and control. We find that the myometrium only expresses "classical," Ca 2+ -activated, and voltage sensitive channels, whereas both tonic and phasic blood vessels express classical, and non-classical, cGMP-regulated CaCC, which are voltage insensitive. This translates to more complex activation and regulation in vascular smooth muscles, irrespective of whether they are tonic or phasic. We therefore tentatively conclude that although these channels are expressed and functionally important in all smooth muscles, they are probably not part of the mechanisms governing phasic activity. Recent knockdown studies have produced unexpected functional results, e.g. no effects on labour and delivery, and tone increasing in some but decreasing in other vascular beds, strongly suggesting that there is still much to be explored concerning CaCC in smooth muscle., (Copyright © 2021 Wray, Prendergast and Arrowsmith.)

The scale of the SARS-CoV-2 pandemic has thrust a spotlight on the sex-based differences in response to viral diseases; morbidity and mortality are greater in men than women. We outline the mechanisms by which being female offers a degree of protection from COVID19, that persists even when confounders such as comorbidities are considered. The physiological and immunological mechanisms are fascinating and range from incomplete X chromosome inactivation of immune genes, a crucial role for angiotensin converting enzyme 2 (ACE2), and regulation of both immune activity and ACE2 by sex steroids. From this flows understanding of why lung and other organs are more susceptible to COVID19 damage in men, and how their distinct immunological landscapes need to be acknowledged to guide prognosis and treatment. Pregnancy, menopause, and hormone replacement therapy bring changed hormonal environments and the need for better stratification in COVID19 studies. We end by noting clinical trials based on increasing estrogens or progesterone or anti-testosterone drugs; excellent examples of translational physiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wray and Arrowsmith.)

Physical and deployment factors that influence infrasound signal detection and assess automatic detection performance for a regional infrasound network of arrays in the Western U.S. are explored using signatures of ground truth (GT) explosions (yields). Despite these repeated known sources, published infrasound event bulletins contain few GT events. Arrays are primarily distributed toward the south-southeast and south-southwest at distances between 84 and 458 km of the source with one array offering azimuthal resolution toward the northeast. Events occurred throughout the spring, summer, and fall of 2012 with the majority occurring during the summer months. Depending upon the array, automatic detection, which utilizes the adaptive F-detector successfully, identifies between 14% and 80% of the GT events, whereas a subsequent analyst review increases successful detection to 24%-90%. Combined background noise quantification, atmospheric propagation analyses, and comparison of spectral amplitudes determine the mechanisms that contribute to missed detections across the network. This analysis provides an estimate of detector performance across the network, as well as a qualitative assessment of conditions that impact infrasound monitoring capabilities. The mechanisms that lead to missed detections at individual arrays contribute to network-level estimates of detection capabilities and provide a basis for deployment decisions for regional infrasound arrays in areas of interest.

Solid lipid nanoparticles (SLNs) have proved to be effective nanocarriers with many advantages over other non-lipid-based systems. The development of new SLN formulations is often hindered through poor drug loading capacity and time-consuming optimisation of lipid/stabiliser combinations. One challenge in the development of new SLN formulations is understanding the complex interactions between amphiphilic stabilisers and hydrophobic lipids; the nature of these interactions can significantly impact SLN properties, including the internal polarity within the nanoparticle core. Herein, we report the use of pyrene to probe the internal lipid microenvironment inside SLNs. We investigate the effect of using different poloxamer stabilisers on the internal polarity of SLNs formed using the common solid lipid, Compritol 888 ATO. We show that the polarity of the internal lipid environment is modified by the length of the poly(propylene oxide) (PPO) block of the poloxamer stabiliser, with longer PPO blocks producing SLNs with less polar lipid cores. Blending of stabilisers could also be used to tune the polarity of the core lipid environment, which may allow for adjusting the polarity of the lipid to assist the loading of different therapeutics., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Preterm birth is recognized as the primary cause of infant mortality worldwide. Twin pregnancies are significantly more at risk of preterm birth than singleton pregnancies. A greater understanding of why this is and better modes of treatment and prevention are needed. Key to this is determining the differing pathophysiological mechanisms of preterm birth in twins, including the role of the myometrium and premature uterine contraction. We performed RNA sequencing (RNA-Seq) of human myometrium from singleton and twin pregnancies at term (> 37+0 weeks) and preterm (< 37+0 weeks), collected during pre-labour Caesarean Section. RNA-Seq libraries were prepared from polyA-selected RNA and sequenced on the Illumina HiSeq 4000 platform. Differentially expressed genes (DEGs), GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment were conducted using R software. Significance was determined with a false discovery rate-adjusted P value of <0.05. Only 3 DEGs were identified between gestational age-matched singleton and twin myometrium and only 1 DEG identified between singleton term and twin preterm tissues. Comparison of singleton preterm myometrium with twin term myometrium however, revealed 75 down-regulated and 24 up-regulated genes in twin myometrium. This included genes associated with inflammation and immune response, T cell maturation and differentiation and steroid biosynthesis. GO and KEGG enrichment analyses for biologically relevant processes and functions also revealed several terms related to inflammation and immune response, as well as cytokine-cytokine receptor interaction and chemokine receptor signalling. Data indicate that little or no differences exist in the transcriptome of singleton and twin myometrium when matched for gestational age. The significant up- and down-regulation of genes identified between preterm singleton and twin myometrium at term may point to transcriptome changes associated with the chronic levels of uterine stretch in twin pregnancy or genes associated with the myometrium transitioning to labour onset., Competing Interests: The authors have declared that no competing interests exist.

A method for estimating the yield of explosions from shock-wave and acoustic-wave measurements is presented. The method exploits full waveforms by comparing pressure measurements against an empirical stack of prior observations using scaling laws. The approach can be applied to measurements across a wide-range of source-to-receiver distances. The method is applied to data from two explosion experiments in different regions, leading to mean relative errors in yield estimates of 0.13 using prior data from the same region, and 0.2 when applied to a new region.

Characterisation of G protein-coupled receptors (GPCR) relies on the availability of a toolbox of ligands that selectively modulate different functional states of the receptors. To uncover such molecules, we explored a unique strategy for ligand discovery that takes advantage of the evolutionary conservation of the 600-million-year-old oxytocin/vasopressin signalling system. We isolated the insect oxytocin/vasopressin orthologue inotocin from the black garden ant (Lasius niger), identified and cloned its cognate receptor and determined its pharmacological properties on the insect and human oxytocin/vasopressin receptors. Subsequently, we identified a functional dichotomy: inotocin activated the insect inotocin and the human vasopressin V 1b receptors, but inhibited the human V 1a R. Replacement of Arg8 of inotocin by D-Arg8 led to a potent, stable and competitive V 1a R-antagonist ([D-Arg8]-inotocin) with a 3,000-fold binding selectivity for the human V 1a R over the other three subtypes, OTR, V 1b R and V 2 R. The Arg8/D-Arg8 ligand-pair was further investigated to gain novel insights into the oxytocin/vasopressin peptide-receptor interaction, which led to the identification of key residues of the receptors that are important for ligand functionality and selectivity. These observations could play an important role for development of oxytocin/vasopressin receptor modulators that would enable clear distinction of the physiological and pathological responses of the individual receptor subtypes., Competing Interests: The authors declare no competing financial interests.

Infrasound from a four-stage sounding rocket was recorded by several arrays within 100 km of the launch pad. Propagation modeling methods have been applied to the known trajectory to predict infrasonic signals at the ground in order to identify what information might be obtained from such observations. There is good agreement between modeled and observed back azimuths, and predicted arrival times for motor ignition signals match those observed. The signal due to the high-altitude stage ignition is found to be low amplitude, despite predictions of weak attenuation. This lack of signal is possibly due to inefficient aeroacoustic coupling in the rarefied upper atmosphere.

For successful birth, contractions need to become progressively stronger. The underlying mechanisms are unknown, however. We have found that a novel mechanism, hypoxia-induced force increase (HIFI), is switched on selectively, at term, and is essential to strengthening contractions. HIFI is initiated as contractions cyclically reduce blood flow and produce repeated hypoxic stresses, with associated metabolic and transcriptomic changes. The increases in contractility are a long-lasting, oxytocin-independent, intrinsic mechanism present only in the full-term pregnant uterus. HIFI is inhibited by adenosine receptor antagonism and blockade of cyclooxygenase-2 signaling, and partially reproduced by brief episodes of acidic (but not alkalotic) pH. HIFI explains how labor can progress despite paradoxical metabolic challenge, and provides a new mechanistic target for the 1 in 10 women suffering dysfunctional labor because of poor contractions.

Blast waves produced by 60 high-explosive detonations were recorded at short distances (few hundreds of meters); the corresponding waveforms show charge-configuration independent coda-like features (i.e., similar shapes, amplitudes, and phases) lasting several seconds. These features are modeled as reflected and/or scattered waves by acoustic reflectors/scatters surrounding the explosions. Using explosion pairs, relative coda phase delays are extracted and modeled as changes in sound speed due to changes in air temperature. Measurements from nearby weather towers are used for validation.

In this short review, we discuss how recent insights into myometrial physiology may be taken forward and translated into much-needed novel therapies for problems associated with labour. We consider excitation-contraction coupling in the myometrium and how this relates to our understanding of the changes that occur to produce myometrial contractions and successful labour. We then discuss how this information has already been used in the development of drugs to either stimulate or relax the myometrium, to address the needs of women with either slow (dystocic) labours or threatened preterm labours, respectively. We next present the data showing how basic physiological findings pertaining to hypoxia and lactate production have been taken and translated into a tool for predicting and thus better managing difficult labours. We then highlight examples of where physiological research has started to provide mechanistic insight into clinical problems associated with labour and parturition (obesity, diabetes, advanced maternal age, postdate and twin pregnancies) and suggest how these findings could be translated into new therapies for difficult labours.

Cyclotides are plant peptides comprising a circular backbone and three conserved disulfide bonds that confer them with exceptional stability. They were originally discovered in Oldenlandia affinis based on their use in traditional African medicine to accelerate labor. Recently, cyclotides have been identified in numerous plant species of the coffee, violet, cucurbit, pea, potato, and grass families. Their unique structural topology, high stability, and tolerance to sequence variation make them promising templates for the development of peptide-based pharmaceuticals. However, the mechanisms underlying their biological activities remain largely unknown; specifically, a receptor for a native cyclotide has not been reported hitherto. Using bioactivity-guided fractionation of an herbal peptide extract known to indigenous healers as "kalata-kalata," the cyclotide kalata B7 was found to induce strong contractility on human uterine smooth muscle cells. Radioligand displacement and second messenger-based reporter assays confirmed the oxytocin and vasopressin V1a receptors, members of the G protein-coupled receptor family, as molecular targets for this cyclotide. Furthermore, we show that cyclotides can serve as templates for the design of selective G protein-coupled receptor ligands by generating an oxytocin-like peptide with nanomolar affinity. This nonapeptide elicited dose-dependent contractions on human myometrium. These observations provide a proof of concept for the development of cyclotide-based peptide ligands.

Objective: Over half of twin pregnancies in US and UK deliver prematurely but the reasons for this are unclear. The contractility of myometrium from twin pregnancies has not been directly investigated. The objective of this research was to determine if there are differences in the contractile activity and response to oxytocin, between myometrium from singleton and twin pregnancies, across a range of gestational ages. Furthermore, we wished to determine if contractile activity correlates with increasing level of stretch, using neonatal birth weights as a marker of uterine stretch., Methods: This was an in vitro, laboratory based study of myometrial contractility in women pregnant with one or two babies, using biopsies obtained from non-labouring women undergoing Caesarean section. Spontaneous, oxytocin-stimulated and depolarization induced contractile activity was compared., Results: Direct measurements of myometrial contractility under controlled conditions show that the frequency of contractions and responses to oxytocin are significantly increased in twins compared to singletons. The duration of contraction however was significantly reduced. We find that contractile activity correlates with increasing levels of stretch, using neonatal birth weights as a surrogate for uterine stretch, with response to oxytocin being significantly positively correlated with birth weight., Conclusions: We have found significant differences in contractile properties between myometrium from singleton and twin pregnancies and that increasing uterine stretch can alter the contractile properties of myometrium. We discuss the implication of these findings to preterm delivery and future studies.

Prolongation of pregnancy i.e. going more than 10 days over the estimated due date, complicates up to 10% of all pregnancies and is associated with increased risk to both mother and fetus. Despite the obvious need for contractions of the uterus to end pregnancy, there have been no studies directly examining the role of uterine smooth muscle, myometrium, in the aetiology of prolonged pregnancy. This study tested the hypothesis that the intrinsic contractile characteristics of myometrium taken from women with prolonged pregnancy (>41 weeks and 3 days) was reduced compared to those delivering at term (39-41 weeks). We recruited women undergoing Caesarean Section (CS) delivery either pre-labour (n = 27) or in labour (n = 66) at term or postdates. The contractile ability of the postdates myometrium, whether spontaneous or elicited by oxytocin or high-K solution, was significantly reduced compared to term myometrium. These differences remained when adjusted for parity and other maternal characteristics. The findings remained significant when expressed per cross sectional area. Histological examination revealed no differences between the two groups. The contractile differences were however related to intracellular Ca transients suggesting an effect of [Ca] on reduced force production in the postdates group. In summary, myometrium from prolonged pregnancies contracts poorly in vitro even when stimulated with oxytocin and in active labour. Responses to high K(+) and measurements of Ca suggest that alterations in excitation contraction coupling, rather than any histological changes of the myometrium, may underlie the differences between term and postdates myometrium. We show that postdates pregnancy is associated with poor myometrial activity and suggest that this may contribute to increased myometrial quiescence and hence, prolonged gestation.

Objective: To quantify the scope and yield of targeted syphilis screening in nonmedical settings in 7 US cities affected by recent syphilis outbreaks among men who have sex with men (MSM)., Methods: Data were collected from syphilis screening activities targeting MSM between 1999 and 2004, conducted in bathhouses or other commercial sex venues, MSM-oriented bars, mobile vans, and other nonmedical settings by the public health departments of Chicago, Houston, Miami/Fort Lauderdale, Los Angeles, NY, and San Francisco., Results: Of 14,143 syphilis screening tests (STS) conducted during community outreach campaigns at a variety of MSM oriented venues, 132 (0.9%) new cases of syphilis were identified. One hundred five (0.8%) new cases of early syphilis were found, including 23 cases of symptomatic syphilis. Screening in jails produced the highest prevalence of early syphilis (1.3%, 51 cases/3853 STS), followed by sex venues, including bathhouses (1.2%, 29 cases/2511 STS)., Conclusions: These data suggest that even nontraditional, highly targeted screening programs conducted during outbreak situations do not detect many persons with syphilis, even though many of the screening venues were locations where men with syphilis met their sex partners. The low prevalence of infectious syphilis identified during these screening events suggests that the direct impact of these programs on decreasing syphilis transmission may be negligible. However, the secondary benefits, such as increasing awareness of syphilis and prompting earlier treatment due to symptom recognition, may be substantial.