Effectiveness of integrating a pragmatic pathway for prescribing liraglutide 3.0 mg in weight management services (STRIVE study): a multicentre, open-label, parallel-group, randomized controlled trial.

Background: An effective prescribing pathway for liraglutide 3 mg, an approved obesity pharmacotherapy, may improve treatment access. This trial compared a targeted prescribing pathway for liraglutide 3 mg with multiple stopping rules in specialist weight management services (SWMS) to standard SWMS care. Methods: This phase four, two-year, multicentre, open-label, parallel-group, real-world randomized clinical trial (ClinicalTrials.gov: NCT03036800) enrolled adults with BMI ≥35 kg/m2 plus prediabetes, type 2 diabetes, hypertension or sleep apnoea from five SWMS in Ireland and UK. Participants were randomly allocated (2:1, stratified by centre and BMI) to SWMS care plus a targeted prescribing pathway for once daily subcutaneous liraglutide 3 mg (intervention) with stopping rules at 16 (≥5% weight loss, WL), 32 (≥10% WL) and 52 weeks (≥15% WL) or to SWMS care alone (control) through an online randomization service. The primary outcome was WL ≥15% at 52 weeks, assessed by complete cases analysis. All randomized participants were included in safety analysis. Findings: From November 28, 2017 to February 28, 2020, 434 participants were screened, and 392 randomized (260 intervention; 132 control), while 294 (201 intervention; 93 control) included in the 52 weeks complete case analysis. More intervention than control participants achieved WL ≥15% at 52 weeks [51/201 (25.4%) vs 6/93 (6.5%); odds ratio 5.18; 95% CI 2.09, 12.88; p < 0.0001]. More adverse events occurred in the intervention (238/260, 91.5%; two deaths) than control (89/132, 67.4%; no deaths) group. Interpretation: A targeted prescribing pathway for liraglutide 3 mg helps more people achieve ≥15% WL at 52 weeks than standard care alone. Funding: Novo Nordisk A/S.

Laparoscopic adjustable gastric banding with liraglutide in adults with obesity and type 2 diabetes (GLIDE): a pilot randomised placebo controlled trial.

INTRODUCTION: Obesity drives type 2 diabetes (T2DM) development. Laparoscopic adjustable gastric banding (LAGB) has lower weight reduction than other bariatric procedures. Liraglutide, a GLP-1 receptor agonist, improves weight and glycaemic control in patients with T2DM. This study aimed to determine the efficacy and safety of liraglutide 1.8 mg in participants undergoing LAGB. METHODS: GLIDE, a pilot randomised, double-blind, placebo-controlled trial, evaluated LAGB with either liraglutide 1.8 mg or placebo in participants with T2DM and obesity. Participants were randomised (1:1) to 6-months therapy post-LAGB, with further 6 months off-treatment follow-up. The primary outcome was change in HbA1c from randomisation to the end of treatment, secondary outcomes included body weight change. A sample size of 58 (29 per group) had 80% power to detect a 0.6% difference in HbA1c between groups. RESULTS: Twenty-seven participants were randomised to liraglutide (n = 13) or placebo (n = 14). Multivariate analysis showed no difference between placebo and liraglutide arms in HbA1c at 6 months (HbA1c:0.2 mmol/mol, -11.3, 11.6, p = 0.98) however, at 12 months HbA1c was significantly higher in the liraglutide arm (HbA1c:10.9 mmol/mol, 1.1, 20.6, p = 0.032). There was no difference between arms in weight at 6 months (BW:2.0 kg, -4.2, 8.1, p = 0.50), however, at 12 months weight was significantly higher in the liraglutide arm (BW:8.2 kg, 1.6, 14.9, p = 0.02). There were no significant differences in adverse events between groups. CONCLUSIONS: Our pilot data suggest no additional improvement in glycaemic control or BW with LAGB and liraglutide therapy. However, this trial was significantly underpowered to detect a significant change in the primary or secondary outcomes. Further trials are needed to investigate whether GLP-1 agonists, and particularly with more effective weekly agents (i.e. semaglutide or tirzepatide), are of benefit following metabolic surgery. CLINICAL TRIAL REGISTRATION: EudraCT number 2015-005402-11.

Clinical evaluation of patients living with obesity.

Obesity is a significant public health concern which is implicated in cardiometabolic disease, mechanical complications and psychiatric sequelae. BMI is currently used for diagnosis; however, it has limited sensitivity for adiposity in certain circumstances. This has led to the development of risk stratification tools like the Edmonton Staging criteria and the Kings Obesity Staging Criteria: these facilitate and guide comprehensive obesity-related complication assessment. Healthcare professionals working within obesity clinics should adopt evidence-based communication strategies, including shared decision-making, motivational interviewing, and realistic goal setting. It is also vital to avoid weight-stigmatising terminology in all aspects of care, as this can negatively impact patients. Primary care plays an essential part in obesity care and should work to promptly identify cases, initiate treatment and forward on to specialist services where appropriate. Clinical evaluation of the patient living with obesity should take a holistic approach and involve input from bariatric physicians, dietitians, psychologists, and bariatric surgeons, wider members of the multi-disciplinary team should be involved where needed. Clinicians should take a detailed history, examination and order laboratory tests to investigate for complications. Overall, with appropriate evaluation, these assessments can guide patient management and facilitate long-term improvement in health.

Diagnosis and management of parathyroid carcinoma: a state-of-the-art review.

Parathyroid carcinoma is one of the least common endocrine malignancies and accounts for approximately 1% of all patients with primary hyperparathyroidism. A systematic review of peer-reviewed literature published between January 2000 and March 2022 via Medline, Embase, Cochrane Central Register of Controlled Trials, EudraCT, ClinicalTrials.gov, CINAHL and SCOPUS was conducted. Manuscripts were eligible if they included data on adult non-pregnant populations with parathyroid carcinoma. No restrictions regarding interventions, comparators or duration of follow-up were imposed. Single case reports, reviews or meta-analyses were excluded. Outcomes of interest were molecular pathogenesis, clinical presentation, differential diagnosis, treatment, follow-up and overall survival. Study quality was evaluated using the Newcastle-Ottawa Scale for observational studies. This review included 75 studies from 17 countries, reporting on more than 3000 patients with parathyroid carcinoma. CDC73 mutation has been recognised as playing a pivotal role in molecular pathogenesis. Parathyroid carcinoma typically presents with markedly increased calcium and parathyroid hormone levels. The most frequently described symptoms were bone and muscle pain or weakness. En bloc resection remains the gold standard for the surgical approach. The 5-year overall survival ranged from 60 to 93%, with resistant hypercalcaemia a significant cause of mortality. Emerging evidence indicating that targeted therapy, based on molecular biomarkers, presents a novel treatment option. The rarity of PC and need for personalised treatment warrant multidisciplinary management in a 'centre of excellence' with a track record in PC management.

Trauma-Informed Design of Supported Housing: A Scoping Review through the Lens of Neuroscience.

There is growing recognition of the importance of the design of the built environment in supporting mental health. In this context, trauma-informed design has emerged as a new field of practice targeting the design of the built environment to support wellbeing and ameliorate the physical, psychological and emotional impacts of trauma and related pathologies such as Post Traumatic Stress Disorder (PTSD). With high levels of prevalence of PTSD among people escaping homelessness and domestic violence, a priority area is the identification and application of evidence-based design solutions for trauma-informed supported housing. This study sought to examine the scope of existing evidence on the relationship between trauma, housing and design and the correlation of this evidence with trauma-informed design principles, and to identify gaps and opportunities for future research. In response to the commonly articulated limitations of the evidence-base in built environment design research, we combined a scoping review of literature on trauma, housing and design with insights from neuroscience to focus and extend understanding of the opportunities of trauma-informed design. We found that while limited in scope, there is strong alignment between existing evidence and the principles of trauma-informed design. We also identify three areas of future research related to the key domains of safety and security; control; and enriched environments.

The Bariatric-Metabolic Physician's Role in Managing Clinically Severe Obesity.

PURPOSE OF REVIEW: The aim of this review is to outline the obesity physician's role in managing patients with severe obesity with a particular emphasis on bariatric surgery candidates. RECENT FINDINGS: Obesity is a chronic, relapsing and progressive disease. Scoring systems that evaluate the severity of obesity based on the clinical assessment, rather than the Body Mass Index, are a valuable tool. The clinical assessment should explore the underlying contributors for weight gain and screen for obesity-related complications. Bariatric surgery remains the most effective management approach for severe and complex obesity. Nevertheless, pharmacotherapy and other non-surgical approaches play an important role. The bariatric-metabolic physician's role is paramount in delivering effective care to patients with obesity. The multiple complications of patients with clinically severe obesity highlight the complexity of their management and reinforce the need for adequate assessment and long-term follow-up to ensure optimal clinical outcomes.

Diabetic retinopathy is independently associated with increased risk of intubation: A single centre cohort study of patients with diabetes hospitalised with COVID-19.

In our study of 187 patients with diabetes hospitalised with COVID-19 we observed a more than 5 fold increased risk of intubation in patients with diabetic retinopathy. Further studies are required to understand the mechanisms that explain the associations between retinopathy and other indices of microangiopathy with severe COVID-19.

Effectiveness and cost of integrating a pragmatic pathway for prescribing liraglutide 3.0 mg in obesity services (STRIVE study): study protocol of an open-label, real-world, randomised, controlled trial.

INTRODUCTION: In the UK and Ireland, severe and complex obesity is managed in specialist weight management services (SWMS), which provide multicomponent lifestyle interventions to support weight loss, and use of medication if available. Liraglutide 3 mg (LIRA 3 mg) is an effective weight-loss medication, but weight loss in individual patients is variable, and its efficacy has not been assessed in SWMS. This study aims to investigate whether a targeted prescribing pathway for LIRA 3 mg with multiple prespecified stopping rules could help people with severe obesity and established complications achieve ≥15% weight loss in order to determine whether this could be considered a clinically effective and cost-effective strategy for managing severe and complex obesity in SWMS. METHODS AND ANALYSIS: In this 2-year, multicentre, open-label, real-world randomised controlled trial, 384 adults with severe and complex obesity (defined as body mass index ≥35 kg/m2 plus either prediabetes, type 2 diabetes, hypertension or sleep apnoea) will be randomised via a 2:1 ratio to receive either standard SWMS care (n=128) or standard SWMS care plus a targeted prescribing pathway for LIRA 3 mg with prespecified stopping rules at 16, 32 and 52 weeks (n=256).The primary outcome is to compare the proportion of participants achieving a weight loss of ≥15% at 52 weeks with a targeted prescribing pathway versus standard care. Secondary outcomes include a comparison of (1) the weight loss maintenance at 104 weeks and (2) the budget impact and cost effectiveness between the two groups in a real-world setting. ETHICS AND DISSEMINATION: The Health Research Authority and the Medicines and Healthcare products Regulatory Authority in UK, the Health Products Regulatory Authority in Ireland, the North West Deanery Research Ethics Committee (UK) and the St Vincent's University Hospital European Research Ethics Committee (Ireland) have approved the study. The findings of the study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov-Identifier: NCT03036800.European Clinical Trials Database-Identifier: EudraCT Number 2017-002998-20.

Oxytocin receptor activation in the basolateral complex of the amygdala enhances discrimination between discrete cues and promotes configural processing of cues.

Oxytocin (OT) is a neuropeptide which influences the expression of social behavior and regulates its distribution according to the social context - OT is associated with increased pro-social effects in the absence of social threat and defensive aggression when threats are present. The present experiments investigated the effects of OT beyond that of social behavior by using a discriminative Pavlovian fear conditioning protocol with rats. In Experiment 1, an OT receptor agonist (TGOT) microinjected into the basolateral amygdala facilitated the discrimination between an auditory cue that signaled shock and another auditory cue that signaled the absence of shock. This TGOT-facilitated discrimination was replicated in a second experiment where the shocked and non-shocked auditory cues were accompanied by a common visual cue. Conditioned responding on probe trials of the auditory and visual elements indicated that TGOT administration produced a qualitative shift in the learning mechanisms underlying the discrimination between the two compounds. This was confirmed by comparisons between the present results and simulated predictions of elemental and configural associative learning models. Overall, the present findings demonstrate that the neuromodulatory effects of OT influence behavior outside of the social domain.

Auditory Tones and Foot-Shock Recapitulate Spontaneous Sub-Threshold Activity in Basolateral Amygdala Principal Neurons and Interneurons.

In quiescent states such as anesthesia and slow wave sleep, cortical networks show slow rhythmic synchronized activity. In sensory cortices this rhythmic activity shows a stereotypical pattern that is recapitulated by stimulation of the appropriate sensory modality. The amygdala receives sensory input from a variety of sources, and in anesthetized animals, neurons in the basolateral amygdala (BLA) show slow rhythmic synchronized activity. Extracellular field potential recordings show that these oscillations are synchronized with sensory cortex and the thalamus, with both the thalamus and cortex leading the BLA. Using whole-cell recording in vivo we show that the membrane potential of principal neurons spontaneously oscillates between up- and down-states. Footshock and auditory stimulation delivered during down-states evokes an up-state that fully recapitulates those occurring spontaneously. These results suggest that neurons in the BLA receive convergent input from networks of cortical neurons with slow oscillatory activity and that somatosensory and auditory stimulation can trigger activity in these same networks.

The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity.

There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity.

FRAX® counseling for bone health behavior change in women 50 years of age and older.

PURPOSE: To evaluate the use of FRAX® (Fracture risk assessment tool) for changes in bone health risk factors and treatment decision-making. DATA SOURCES: A convenience sample of seventeen women, 50 years and older, English-speaking, generally healthy, with the ability to perform weight-bearing exercise, presenting for a DXA scan in a Midwestern city between August 2009 and November 2009, and not already being treated for osteoporosis or osteopenia. Self-administered diet and exercise questionnaires were completed by participants, followed by individual counseling related to FRAX® absolute risk and NOF guidelines. Questionnaires were repeated at approximately three months later, along with a short survey regarding the information's impact. CONCLUSIONS: FRAX® increased a participant's perception of future risk for osteoporosis and desire to change bone health habits. About 50% actually made changes in calcium and vitamin D consumption and weight-bearing exercise. FRAX® could not be applied to those with osteopenia of the spine only; and a variety of bone health risk factors not covered by FRAX® were identified. IMPLICATIONS FOR PRACTICE: The FRAX® risk assessment tool can be useful to motivate clients to change bone health behavior. However, it has limitations in its use as a tool for whether or not to prescribe bisphosphonates.

Association between pregnancy complications and small-for-gestational-age birth weight defined by customized fetal growth standard versus a population-based standard.

OBJECTIVE: To derive coefficients for developing a customized growth chart for a Mid-Western US population, and to estimate the association between pregnancy outcomes and smallness for gestational age (SGA) defined by the customized growth chart compared with a population-based growth chart for the USA. METHOD: A retrospective cohort study of an ultrasound database using 54,433 pregnancies meeting inclusion criteria was conducted. Coefficients for customized centiles were derived using 42,277 pregnancies and compared with those obtained from other populations. Two adverse outcome indicators were defined (greater than 7 day stay in the neonatal unit and stillbirth [SB]), and the risk for each outcome was calculated for the groups of pregnancies defined as SGA by the population standard and SGA by the customized standard using 12,456 pregnancies for the validation sample. RESULTS: The growth potential expressed as weight at 40 weeks in this population was 3524 g (standard error: 402 g). In the validation population, 4055 cases of SGA were identified using both population and customized standards. The cases additionally identified as SGA by the customized method had a significantly increased risk of each of the adverse outcome categories. The sensitivity and specificity of those identified as SGA by customized method only for detecting pregnancies at risk for SB was 32.7% (95% confidence interval [CI] 27.0-38.8%) and 95.1% (95% CI: 94.7-95.0%) versus 0.8% (95% CI 0.1-2.7%) and 98.0% (95% CI 97.8-98.2%)for those identified by only the population-based method, respectively. CONCLUSION: SGA defined by customized growth potential is able to identify substantially more pregnancies at a risk for adverse outcome than the currently used national standard for fetal growth.

Leiomyomas at routine second-trimester ultrasound examination and adverse obstetric outcomes.

OBJECTIVE: To estimate the risk of adverse pregnancy outcomes associated with the presence of leiomyomas. METHODS: This was a retrospective cohort study of all consecutive singleton pregnancies from 1990 to 2007 undergoing routine second-trimester fetal anatomic ultrasound survey. The presence or absence of leiomyomas was noted at second-trimester ultrasound examination. Primary and secondary obstetric outcomes were obtained as the individual progressed to delivery. Women with at least one leiomyoma at the time of second-trimester anatomic survey were compared with women without leiomyomas. Primary outcomes were intrauterine fetal death, breech presentation, placenta previa, cesarean delivery, placental abruption, preeclampsia, intrauterine fetal growth restriction, preterm premature rupture of membranes, and preterm birth. Univariable and multivariable analyses were performed. RESULTS: Of 72,373 women who underwent routine second-trimester anatomic survey, 64,047 women had complete obstetric follow-up data. The incidence of leiomyomas was 3.2% (n=2,058). Breech presentation (5.3% compared with 3.1%, adjusted odds ratio [OR] 1.5, 95% confidence interval [CI]1.3-1.9), placenta previa (1.4% compared with 0.5%, adjusted OR 2.2, 95% CI 1.5-3.2), cesarean delivery (33.1% compared with 24.2%, adjusted OR 1.2, 95% CI 1.1-1.4), placental abruption (1.4% compared with 0.7%, adjusted OR 2.1, 95% CI 1.4-3.0), preterm premature rupture of membranes (3.3% compared with 2.4%, adjusted OR 1.3, 95% CI 1.0-1.7), preterm birth less than 37 weeks (15.1% compared with 10.5%, adjusted OR 1.5, 95% CI 1.3-1.8), and less than 34 weeks (3.9% compared with 2.8%, adjusted OR 1.4, 95% CI 1.0-1.8), and intrauterine fetal death in women with a fetus with growth restriction (3.9% compared with 1.5%, adjusted OR 2.5, 95% CI 1.2-5.0) were significantly associated with the presence of leiomyomas. CONCLUSION: Women with leiomyomas are at low risk for obstetric complications compared with women without leiomyomas. LEVEL OF EVIDENCE: II.

Inhibition dominates the early phase of up-states in the basolateral amygdala.

Slow oscillations (<1 Hz) in neural activity occur during sleep and quiet wakefulness in both animals and humans. Single-cell recordings in cortical neurons have shown that these oscillations are driven by a combination of excitatory and inhibitory synaptic inputs. During up-states, although the ratio between them varies between cells, excitation and inhibition follow similar time courses. Neurons in the basolateral amygdala (BLA) also show slow oscillations between the resting membrane potential (down-state) and depolarized potentials (up-states). Delivery of footshock during the down-state fully reproduces up-states in these cells. Here we report that up-states in BLA principal neurons up-states begin with an excitatory drive that is rapidly (within ∼50 ms) overwhelmed by inhibitory input. This excess of inhibitory drive is short lasting (300-400 ms), after which up-states are maintained by a tight balance between excitation and inhibition. This initial large inhibitory input restricts action potential generation and reduces the firing frequency of these cells. These results indicate that, in contrast to cortical neurons, up-states in BLA neurons show an initial period of strong cortically driven feed-forward inhibition. For the remainder of the up-state, feedback inhibition then acts to balance excitatory input.

Ultrasound-detected subchorionic hemorrhage and the obstetric implications.

OBJECTIVE: To estimate the association between the ultrasonographic diagnosis of subchorionic hemorrhage and adverse pregnancy outcomes. METHODS: This was a retrospective cohort study of all consecutive women undergoing routine ultrasonography before 22 weeks with a singleton gestation at one institution from 1994 to 2008. Presence or absence of subchorionic hemorrhage defined the two study groups. The primary outcomes were abruption, intrauterine growth restriction defined as birth weight less than the 10th percentile, and nonanomalous intrauterine fetal demise after 20 weeks. Secondary outcomes included preeclampsia, preterm premature rupture of membranes, and preterm delivery before 37 weeks and before 34 weeks of gestation. Univariable, bivariate, and multiple logistic regression analyses were performed. RESULTS: Of the 63,966 women in the patient population, 1,081 had subchorionic hemorrhage (1.7%). Women with a subchorionic hemorrhage were at increased risk of abruption (n=432, 3.6% compared with 0.6%, adjusted odds ratio 2.6, 95% confidence interval 1.8-3.7) and of preterm delivery (n=6,601, 15.5% compared with 10.5%, adjusted odds ratio 1.3, 95% confidence interval 1.1-1.5), even after adjusting for bleeding during pregnancy, chronic hypertension, body mass index, race, diabetes mellitus, tobacco use, and previous preterm delivery. CONCLUSION: Women with ultrasound-detected subchorionic hemorrhage before 22 weeks of gestation are at increased risk of placental abruption and preterm delivery but are not at increased risk of other adverse pregnancy outcomes. LEVEL OF EVIDENCE: II.

Effect of placenta previa on fetal growth.

OBJECTIVE: To estimate the association between placenta previa and abnormal fetal growth. STUDY DESIGN: Retrospective cohort study of consecutive women undergoing ultrasound between 15 and 22 weeks. Groups were defined by the presence or absence of complete or partial placenta previa. The primary outcome was intrauterine growth restriction (IUGR), defined as a birthweight <10th percentile by the Alexander growth standard. Univariable, stratified, and multivariable analyses were used to estimate the effect of placenta previa on fetal growth restriction. RESULTS: Of 59,149 women, 724 (1.2%) were diagnosed with a complete or partial previa. After adjusting for significant confounding factors (black race, gestational diabetes, preeclampsia, and single umbilical artery), the risk of intrauterine growth restriction remained similar (adjusted odds ratio, 1.1; 95% confidence interval, 0.9-1.5). The presence of bleeding did not impact the risk of growth restriction. CONCLUSION: Placenta previa is not associated with fetal growth restriction. Serial growth ultrasounds are not indicated in patients with placenta previa.

Single umbilical artery and its associated findings.

OBJECTIVE: To estimate whether the presence of a single umbilical artery is associated with intrauterine growth restriction (IUGR), fetal demise, or major congenital anomalies. METHODS: We performed a retrospective cohort study of all consecutive singleton pregnancies undergoing routine anatomic survey between 1990 and 2007 at a major tertiary medical center. Two dedicated research nurses obtained complete pregnancy outcome data in an ongoing manner. Pregnancies with a diagnosis of single umbilical artery were compared with those with two umbilical arteries. The primary outcomes were IUGR (less than 10th percentile), renal, and cardiac anomalies. Multivariable logistic regression was used to refine the risk association between single umbilical artery and adverse pregnancy outcomes while adjusting for confounding effects. RESULTS: Of 72,373 pregnancies, 64,047 (88.5%) had pregnancy follow-up information and were available for this analysis. There were 392 cases of single umbilical artery (0.61%) diagnosed at anatomic survey; slightly lower than previously reported. Single umbilical artery as compared with double umbilical artery was associated with increased risk of renal anomalies (adjusted odds ratio [OR] 3.0, 95% confidence interval [CI] 1.9-4.9, P<.01) and cardiac anomalies (adjusted OR 20.3, 95% CI 13.5-30.4, P<.01). Single umbilical artery was also associated with an increased risk of IUGR (adjusted OR 2.1, 95% CI 1.6-2.7, P<.01), even after excluding all fetuses with known anomalies. CONCLUSION: Our data suggest an increased risk of IUGR when the diagnosis of single umbilical artery is made, making a clinical recommendation for serial growth assessments in the setting of single umbilical artery reasonable.

Is chorionic villus sampling associated with hypertensive disorders of pregnancy?

OBJECTIVE: Our objective is to evaluate for potential associations between chorionic villus sampling (CVS) and hypertensive disorders of pregnancy. METHODS: Using our genetic database, we compared the rates of hypertensive disorders between women who underwent CVS at 10-13 and 6/7 weeks with those seen for other indications at similar gestational ages who had no invasive procedure. Only singleton and euploid pregnancies were included. Statistical methods including univariable and multivariable logistic regression, supplemented by stratified analyses were used for comparisons. RESULTS: Among 11 012 pregnant women seen between 1990 and 2006 in our center and meeting the inclusion criteria, information on hypertensive disorders of pregnancy were available in 9386, and 9098 met the inclusion criteria. The overall incidence of hypertensive disorders was 421/9098 (4.6%), with 138/5096 (2.7%) in the CVS group and 283/4002 (7.1%) in the control group [adjusted odds ratio (adjOR) 0.47, 95% confidence interval (CI), 0.38-0.59]. Similar findings were seen on stratified analyses for gestational age of procedure and the type or severity of hypertensive disorder, and other potential confounders. CONCLUSION: The rate of hypertensive disorders of pregnancy is significantly lower in women having CVS compared with the control group. Placental disruption from CVS is not associated with preeclampsia or gestational hypertension.

The C5a anaphylatoxin receptor CD88 is expressed in presynaptic terminals of hippocampal mossy fibres.

BACKGROUND: In the periphery, C5a acts through the G-protein coupled receptor CD88 to enhance/maintain inflammatory responses. In the brain, CD88 can be expressed on astrocytes, microglia and neurons. Previous studies have shown that the hippocampal CA3 region displays CD88-immunolabelling, and CD88 mRNA is present within dentate gyrus granule cells. As granule cells send dense axonal projections (mossy fibres) to CA3 pyramidal neurons, CD88 expression could be expressed on mossy fibres. However, the cellular location of CD88 within the hippocampal CA3 region is unknown. METHODS: The expression of CD88 within the hippocampal CA3 region was characterized using dual-immunolabelling of hippocampal sections prepared from Wistar rats. Immunolabelling for CD88, using a monoclonal antibody, was combined with immunolabelling for markers of astrocytes (GFAP), microglia (IBA1), presynaptic proteins (synaptophysin and synapsin-1) and preterminal axons (neurofilament). In addition, electron microscopy was performed on peroxidase-visualized CD88-immunolabelling to determine its cellular localisation within the CA3 region. RESULTS: Dense CD88-immunolabelling was observed within the stratum lucidum of the CA3, consistent with the presence of CD88 on mossy fibres. Labelling for CD88 rarely co-localized with astrocytes or microglia, but was highly co-localized with presynaptic proteins. Electron microscopy revealed CD88-immunolabelling was localized to large presynaptic terminals within the stratum lucidum. CONCLUSION: These results demonstrate that CD88 is expressed on presynaptic terminals of mossy fibres within the CA3 region of the hippocampus. Although the role of CD88 on mossy fibres remains to be established, their involvement in synaptic/cellular plasticity, and in cognitive disorders such as Alzheimer's disease deserves investigation.