Continuous Glucose Monitoring Feedback in the Subsequent Development of Gestational Diabetes: A Pilot, Randomized, Controlled Trial in Pregnant Women.

OBJECTIVE: This study evaluated the effects of receiving glucose feedback from continuous glucose monitoring (CGM) by intermittent scanning (unblinded group), and CGM with masked feedback (blinded group) in the subsequent development of gestational diabetes mellitus (GDM). STUDY DESIGN: This was a prospective, single-center, pilot, randomized controlled trial including n = 206 pregnant women in the first trimester of pregnancy with no prior diagnosis of type 1 or type 2 diabetes. The participants were randomized into the unblinded group or blinded group and wore the CGM in the first trimester of pregnancy (9-13 weeks), the second trimester of pregnancy (18-23 weeks), and late-second to early-third trimester (24-31 weeks). The primary outcome was GDM rate as diagnosed by the 75-g oral glucose tolerance test (OGTT) at 24 to 28 weeks. RESULTS: Over 47 months, 206 pregnant women were enrolled at 9 to 13 weeks. The unblinded group had a higher prevalence of women who developed GDM (21.5 vs. 14.9%; p > 0.05), compared to the blinded group. In the unblinded group compared to the blinded group, plasma glucose values were higher at 1 hour (median 7.7 [interquartile range {IQR}: 6.3-9.2] vs. 7.5 [6.3-8.7]) and 2 hours (6.3 [5.8-7.7] vs. 6.2 [5.3-7.2]), but lower at 0 hour (4.2 [4.0-4.5] vs. 4.3 [4.1-4.6]; p > 0.05). All these differences were not statistically significant. CONCLUSION: Glucose feedback from CGM wear in the first to the third trimester of pregnancy without personalized patient education failed to alter GDM rate. KEY POINTS: · Continuous glucose monitoring (CGM) is feasible for use in pregnant women.. · No significant difference in gestational diabetes rates with or without CGM feedback.. · Future clinical trials should incorporate CGM education and personalized guidance to enhance study outcomes..

Tranexamic acid, as an adjunct to oxytocin prophylaxis, in the prevention of postpartum haemorrhage in women undergoing elective caesarean section: A single-centre double-blind randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of tranexamic acid (TXA) in reducing blood loss during elective caesarean sections in women with and without risk factors for postpartum haemorrhage (PPH). DESIGN: A double-blind, randomised placebo-controlled trial. SETTING: An academic tertiary referral centre in Singapore. POPULATION: Multiethnic women aged 21 years or older undergoing elective caesarean section. METHODS: Randomisation to intravenous TXA or normal saline (placebo) 10 minutes before skin incision. MAIN OUTCOME MEASURES: Calculated estimated blood loss (cEBL), derived from blood volume and haematocrit levels. RESULTS: Between June 2020 and October 2021, 200 women were randomised to the placebo or TXA groups. Women who received prophylactic TXA had a significantly lower mean cEBL compared with those receiving placebo (adjusted mean difference -126.4 mL, 95% CI -243.7 to -9.1, p = 0.035). The effect was greatest in those at high risk for PPH, with a reduction in cEBL (mean difference -279.6 mL, 95% CI -454.8 to -104.3, p = 0.002) and a lower risk of cEBL ≥500 mL (risk ratio [RR] 0.54, 95% CI 0.36-0.83, p = 0.007) and cEBL ≥1000 mL (RR 0.44, 95% CI 0.20-0.98, p = 0.016). Subgroup analysis showed benefit for women with preoperative haemoglobin <10.5 g/dL (mean difference -281.9 mL, 95% CI -515.0 to -48.8, p = 0.019). There was no significant difference in need for additional medical or surgical interventions. There were no maternal or neonatal adverse outcomes. CONCLUSION: Prophylactic TXA should be considered in women with risk factors for PPH, and those most likely to benefit are those with preoperative haemoglobin <10.5 g/dL.

Conservative surgical approach towards placenta accreta spectrum disorders for uterine preservation.

OBJECTIVE: We previously described a technique for repair of the myometrial defect at repeat Caesarean section which increases residual myometrial thickness thereby potentially reducing future niche-related complications. Here we describe how this technique can be modified for use for placenta accreta spectrum disorders, in line with emerging evidence that this is more a disorder of myometrial deficiency than morbid adherence. DESIGN: The surgical performance of peripartum hysterectomy was compared with that of the modified technique in all women having repeat Caesarean delivery for placenta accreta spectrum disorder in a tertiary unit in Singapore between December 2019 and October 2021. METHODS: Modification of the original technique involved the systematic delivery of the placenta starting from its most posterior attachment after uterine exteriorization. This is followed by the identification, mobilization, and apposition of the boundaries of myometrial defects as described previously. RESULTS: Ten women had Caesarean hysterectomy and ten had Caesarean section using the modified approach. Age and gestational age at delivery were similar for the two groups. Women in the modified technique group had had fewer prior Caesarean sections and had a lower body mass index. Operating time, estimated blood loss and need for transfusion were all lower in the myometrial repair group but without statistical significance. There were no visceral injuries in the repair group but there was one bladder injury in the hysterectomy group. CONCLUSION: The modified approach provides an effective alternative to peripartum hysterectomy with favourable surgical profile and allows uterine conservation with restoration of myometrial thickness.

Repair of the myometrial scar defect at repeat caesarean section: a modified surgical technique.

BACKGROUND: To investigate whether the existing surgical technique for uterine closure at repeat lower segment Caesarean section (LSCS) can be modified to achieve adequate residual myometrial thickness (RMT) to ensure scar integrity and reduce complications in future pregnancy. METHODS: Women with a significant scar defect at repeat LSCS had the anterior uterine wall closed by a single experienced obstetrician with a technique focused on recognition, mobilisation and apposition of the retracted myometrial edges at the boundary of the defect. This was aimed at anatomical restoration of the lower segment. The RMT at the scar area was assessed by postnatal pelvic ultrasound scan at three months. RESULTS: Thirty women with a history of at least one previous CS, incidentally found to have a large defect at operation underwent the technique with prior consent. A postnatal scan showed a mean residual myometrial thickness of 8.4 mm (SD ±1.3 mm; range 5.6-11.0 mm). The average operating time was 91 mins and the average blood loss 728 ml. Two women who underwent the repair have gone on to have a further uneventful CS. CONCLUSION: This modified technique resulted in scan evidence of an RMT indicative of uterine wall stability postnatally and offers the potential for reducing the risk of rupture and placenta accreta spectrum (PAS) in future pregnancy.

A comparison of in vitro cytotoxicity assays in medical device regulatory studies.

Medical device biocompatibility testing is used to evaluate the risk of adverse effects on tissues from exposure to leachates/extracts. A battery of tests is typically recommended in accordance with regulatory standards to determine if the device is biocompatible. In vitro cytotoxicity, a key element of the standards, is a required endpoint for all types of medical devices. Each validated cytotoxicity method has different methodology and acceptance criteria that could influence the selection of a specific test. In addition, some guidances are more specific than others as to the recommended test methods. For example, the International Organization for Standardization (ISO1) cites preference for quantitative methods (e.g., tetrazolium (MTT/XTT), neutral red (NR), or colony formation assays (CFA)) over qualitative methods (e.g., elution, agar overlay/diffusion, or direct), while a recent ISO standard for contact lens/lens care solutions specifically requires a qualitative direct test. Qualitative methods are described in United States Pharmacopeia (USP) while quantitative CFAs are listed in Japan guidance. The aim of this review is to compare the methodologies such as test article preparation, test conditions, and criteria for six cytotoxicity methods recommended in regulatory standards in order to inform decisions on which method(s) to select during the medical device safety evaluation.

Practical synthesis of capromorelin, a growth hormone secretagogue, via a crystallization-induced dynamic resolution.

A practical synthesis of capromorelin (1), a growth hormone secretagogue, is described that utilizes as a key step a crystallization-induced dynamic resolution (CIDR) of (±)-3a-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3(3aH)-one [(±)-2] by L-tartaric acid salt formation, yielding (R)-2.L-tartaric acid in high chemical yield (>85%) and with diastereomeric excess (de) of ∼98%. Treatment of (R)-2.L-tartaric acid with ammonium hydroxide provided (R)-2 without loss of chiral purity. In situ generated (R)-2 was coupled with (R)-3-(benzyloxy)-2-(2-(tert-butoxycarbonyl)-2-methylpropanamido)propanoic acid [(R)-3] to give predominantly a single diastereomer of N-Boc-protected capromorelin [(1R,3aR)-4]. This process was used to prepare bulk quantities of capromorelin from (±)-2 to support preclinical toxicology studies.

Validating a conceptual framework for the core concept of "cell-cell communication".

We have created and validated a conceptual framework for the core physiology concept of "cell-cell communication." The conceptual framework is composed of 51 items arranged in a hierarchy that is, in some instances, four levels deep. We have validated it with input from faculty who teach at a wide variety of institutional types. All items making up the framework were deemed essential to moderately important. However, some of the main ideas were clearly judged to be more important than others. Furthermore, the lower in the hierarchy an item is, the less important it is thought to be. Finally, there was no significant difference in the ratings given by faculty at different types of institutions.

A conceptual framework for homeostasis: development and validation.

We have developed and validated a conceptual framework for understanding and teaching organismal homeostasis at the undergraduate level. The resulting homeostasis conceptual framework details critical components and constituent ideas underlying the concept of homeostasis. It has been validated by a broad range of physiology faculty members from community colleges, primarily undergraduate institutions, research universities, and medical schools. In online surveys, faculty members confirmed the relevance of each item in the framework for undergraduate physiology and rated the importance and difficulty of each. The homeostasis conceptual framework was constructed as a guide for teaching and learning of this critical core concept in physiology, and it also paves the way for the development of a concept inventory for homeostasis.

A review of the surgical management of heel pressure ulcers in the 21st century.

Heel ulceration, most frequently the result of prolonged pressure because of patient immobility, can range from the trivial to the life threatening. Whilst the vast majority of heel pressure ulcers (PUs) are superficial and involve the skin (stages I and II) or underlying fat (stage III), between 10% and 20% will involve deeper tissues, either muscle, tendon or bone (stage IV). These stage IV heel PUs represent a major health and economic burden and can be difficult to treat. The worst outcomes are seen in those with large ulcers, compromised peripheral arterial supply, osteomyelitis and associated comorbidities. Whilst the mainstay of management of stage I-III heel pressure ulceration centres on offloading and appropriate wound care, successful healing in stage IV PUs is often only possible with surgical intervention. Such intervention includes simple debridement, partial or total calcanectomy, arterial revascularisation in the context of coexisting peripheral vascular disease or using free tissue flaps. Amputation may be required for failed surgical intervention, or as a definitive first-line procedure in certain high-risk or poor prognosis patient groups. This review provides an overview of heel PUs, alongside a comprehensive literature review detailing the surgical interventions available when managing such patients.

Discovery of a novel Kv7 channel opener as a treatment for epilepsy.

Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.

Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo.

Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in the current study represent attractive targets for developing therapeutics aimed at modulating synaptic and axonal stability and neurodegeneration in vivo.

A physiologist's view of homeostasis.

Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the "milieu interieur," but his discussion was rather abstract. Walter Cannon introduced the term "homeostasis" and expanded Bernard's notion of "constancy" of the internal environment in an explicit and concrete way. In the 1960s, homeostatic regulatory mechanisms in physiology began to be described as discrete processes following the application of engineering control system analysis to physiological systems. Unfortunately, many undergraduate texts continue to highlight abstract aspects of the concept rather than emphasizing a general model that can be specifically and comprehensively applied to all homeostatic mechanisms. As a result, students and instructors alike often fail to develop a clear, concise model with which to think about such systems. In this article, we present a standard model for homeostatic mechanisms to be used at the undergraduate level. We discuss common sources of confusion ("sticky points") that arise from inconsistencies in vocabulary and illustrations found in popular undergraduate texts. Finally, we propose a simplified model and vocabulary set for helping undergraduate students build effective mental models of homeostatic regulation in physiological systems.

Altered maturation of the primary somatosensory cortex in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and results from the loss of the fragile X mental retardation protein (FMRP). Many fragile X-related cognitive and behavioral features emerge during childhood and are associated with abnormal synaptic and cellular organization of the cerebral cortex. Identifying the roles of FMRP in cortical development will provide a basis for understanding the pathogenesis of the syndrome. However, how the loss of FMRP influences the developmental trajectory of cortical maturation remains unclear. We took advantage of the stereotyped and well-characterized development of the murine primary somatosensory cortex to examine cortical maturation during a time-window that corresponds to late embryonic and early postnatal development in the human. In the Fmr1 knockout mouse, we find a delay in somatosensory map formation, alterations in the morphology profile of dendrites and spines of layer 4 neurons and a decrease in the synaptic levels of proteins involved in glutamate receptor signaling at times corresponding to the highest levels of FMRP expression. In contrast, cortical arealization, synaptic density in layer 4 and early postnatal regulation of mRNAs encoding synaptic proteins are not altered in Fmr1 knockout mice. The specificity of the developmental delay in Fmr1 knockout mice indicates that the loss of FMRP does not result in a general stalling of cerebral cortex maturation. Instead, our results suggest that inaccurate timing of developmental processes caused by the loss of FMRP may lead to alterations in neural circuitry that underlie behavioral and cognitive dysfunctions associated with FXS.

Retrospective Study Comparing Treatment Outcomes in Obstetric Patients With Iron Deficiency Anemia Treated With and Without Intravenous Ferric Carboxymaltose.

Introduction Iron deficiency anemia is associated with an increased risk of adverse maternal and perinatal outcomes. Intravenous iron preparation containing ferric carboxymaltose has been shown to be a safe and effective way of increasing hemoglobin (Hb) and mean corpuscular volume (MCV) levels and reducing the need for blood transfusion. In our center, it used to be given as an inpatient procedure because of the risks of potential drug reactions. In 2021, we initiated the administration of intravenous ferric carboxymaltose as an outpatient procedure. We compared the outcomes of patients between 2021 and 2023 after the initiation of outpatient administration of intravenous ferric carboxymaltose in 127 obstetric patients with iron deficiency anemia in the second and third trimesters. Methods In this study conducted in a large maternity unit in Singapore between 2021 to 2023, we compared the changes in maternal hematological parameters among obstetric patients with iron deficiency anemia presenting to the day care unit in the second or third trimester with a Hb level of <8 g/dl treated with a single dose of ferric carboxymaltose injection (Ferinject) against a control group who were referred for treatment but defaulted on and declined treatment. Results Ferric carboxymaltose significantly increased the Hb and MCV levels at delivery in obstetric patients with iron deficiency. The mean Hb at delivery was 10.8 g/dL in the case group compared to 8.8 g/dL in the control group. The percentage of patients with Hb ≥10.0 g/dL was 73.4% in the case group compared to 27.8% in the control group. The incidence of adverse side effects was low and mild (2/127; 1.6%). None of the patients received were hospitalized because of ferric carboxymaltose. Conclusion A single injection dose of ferric carboxymaltose as an outpatient antenatal procedure was easily administered and well tolerated. Obstetric patients with iron deficiency anemia who received intravenous ferric carboxymaltose had a significantly higher level of Hb than those who did not.

Uterine Manipulation May Not Influence Ongoing Pregnancy: Case Report and Literature Review.

Abdominal pain is a very common presentation in early pregnancy. Its cause may be gynecological or totally nonpregnancy related. While acute appendicitis is the most common nonobstetric cause of pain in pregnant women, diagnosis and differentiation from other causes, including ectopic pregnancy, remain challenging. In clinical situations of uncertainty, laparoscopy is a useful diagnostic tool, but uterine manipulation should be avoided if an intrauterine pregnancy is a possibility. In this report, we describe a case of complicated appendicitis in very early pregnancy where the patient ended with a full-term healthy pregnancy despite undergoing a diagnostic laparoscopy with inadvertent uterine manipulation.

Multidisciplinary Obstetric Simulation Training: Experience at KK Women's and Children's Hospital (KKH), Singapore, a Tertiary Referral Centre.

Background Multidisciplinary simulation training in the management of acute obstetric emergencies has the potential to reduce both maternal and perinatal morbidity. It is a valuable tool that can be adapted for targeted audiences of different specialities at all experience levels from medical students to senior consultants. Methods In this study, pre- and post-course questionnaires of learners with varying levels of clinical experience from Obstetrics and Gynaecology (O&G), Anaesthesia, Neonatology, Emergency Medicine, midwifery, and nursing who undertook two simulation courses (namely the Combined Obstetrics Resuscitation Training course, CORE, and the CORE Lite), which comprised lectures and simulation drills with manikins and standardized patients, between 2015 and 2023 were compared. This also included a period when training was affected by the coronavirus disease 2019 (COVID-19) pandemic.  Results The results showed that both simulation courses increased confidence levels among all learners in the management of obstetric emergencies.  Pre-course, participants were most confident in the management of neonatal resuscitation and severe pre-eclampsia, followed by postpartum haemorrhage. They were least confident in the management of vaginal breech delivery, uterine inversion, and twin delivery. Post-course, participants were most confident in the management of neonatal resuscitation and shoulder dystocia, followed by postpartum haemorrhage. They were least confident in the management of uterine inversion and maternal sepsis, followed by vaginal breech delivery and twin delivery. Whilst we saw a huge improvement in confidence levels for all obstetric emergencies, the greatest improvement in confidence levels was noted in vaginal breech delivery, twin delivery, and uterine inversion. Conclusion The simulation courses were effective in improving the confidence in the management of obstetric emergencies. While it may be difficult to measure the improvement in clinical outcomes as a result of simulation courses alone, the increase in confidence levels of clinicians can be used as a surrogate in measuring their preparedness in facing these emergency scenarios.

ApoE isoform-specific regulation of regeneration in the peripheral nervous system.

Apolipoprotein E (apoE) is a 34 kDa glycoprotein with three distinct isoforms in the human population (apoE2, apoE3 and apoE4) known to play a major role in differentially influencing risk to, as well as outcome from, disease and injury in the central nervous system. In general, the apoE4 allele is associated with poorer outcomes after disease or injury, whereas apoE3 is associated with better responses. The extent to which different apoE isoforms influence degenerative and regenerative events in the peripheral nervous system (PNS) is still to be established, and the mechanisms through which apoE exerts its isoform-specific effects remain unclear. Here, we have investigated isoform-specific effects of human apoE on the mouse PNS. Experiments in mice ubiquitously expressing human apoE3 or human apoE4 on a null mouse apoE background revealed that apoE4 expression significantly disrupted peripheral nerve regeneration and subsequent neuromuscular junction re-innervation following nerve injury compared with apoE3, with no observable effects on normal development, maturation or Wallerian degeneration. Proteomic isobaric tag for relative and absolute quantitation (iTRAQ) screens comparing healthy and regenerating peripheral nerves from mice expressing apoE3 or apoE4 revealed significant differences in networks of proteins regulating cellular outgrowth and regeneration (myosin/actin proteins), as well as differences in expression levels of proteins involved in regulating the blood-nerve barrier (including orosomucoid 1). Taken together, these findings have identified isoform-specific roles for apoE in determining the protein composition of peripheral nerve as well as regulating nerve regeneration pathways in vivo.

Scope and Suction: Hysteroscopic-guided Suction Evacuation of Cesarean Scar Pregnancy - A Safe and Efficacious Treatment for Selected Patients.

Objectives: This study aimed to evaluate hysteroscopic-guided suction evacuation for the treatment of cesarean scar pregnancy (CSP). Materials and Methods: This was a retrospective analysis of CSP over 2 years. This study was conducted at KK Women's and Children's Hospital (KKH), Singapore, thirty-seven patients with a CSP. Hysteroscopic-guided suction evacuation to treat CSP used alone or in combination with laparoscopy depending on residual myometrial thickness (RMT) and future fertility requirements. Results: The majority of women (29) were diagnosed under 9-week gestation. Just over a third (13) had an RMT of more than 3 mm. Women with an RMT <3 mm had added laparoscopy. In total, 22 women had hysteroscopic-guided suction evacuation with 9 having it performed under laparoscopic guidance because the RMT was under 3 mm. The remaining patients underwent either laparoscopic repair (5 cases) or vaginal repair (1 case) done under laparoscopic guidance. Conclusion: Hysteroscopic-guided suction evacuation of CSP has the potential to become part of the routine management for uncomplicated cases of CSP in women with an RMT of greater than 3 mm who do not wish for future pregnancy. Its use, in combination with other minimally invasive techniques, can be extended to more complex cases where the RMT is <3 mm and future fertility is desired.