Management Approaches in WHO Grade III Meningioma: A National Oncology Trainees' Collaborative for Healthcare Research (NOTCH) UK Multi-Centre Retrospective Study.

AIMS: WHO Grade 3 (G3) meningiomas are rare tumours with limited data to guide management. This retrospective study documents UK management approaches across 14 centres over 11 years. MATERIALS AND METHODS: Patients with WHO G3 meningioma between 01/01/2008 and 31/12/2018 were identified. Data were collected on demographics, management strategy, adjuvant radiotherapy, approach in recurrence setting and survival. RESULTS: 84 patients were identified. 21.4% transformed from lower-grade disease. 96.4% underwent primary surgical resection, with 20.8% having evidence of residual disease on their post-op MRI. 59.3% of patients underwent adjuvant radiotherapy (RT) following surgical resection. Overall median PFS and OS were 12.6 months and 28.2 months, respectively. Median OS in the group who underwent complete surgical resection was 34.9 months, compared to 27.5 months for those who had incomplete resection (HR 0.58, 95% CI 0.27-1.23, p = 0.15). Median OS was 33.1 months for those who underwent adjuvant RT and 14.0 months for those who did not (HR 0.48, 95% CI 0.27-0.84, p = 0.004). Median adjuvant RT dose delivered was 60Gy (range 12Gy-60Gy), 45.8% of adjuvant RT was delivered using IMRT. At disease relapse, 31% underwent salvage surgery and 29.3% underwent salvage RT. Of those treated with salvage RT, 64.7% were re-treats and all were treated with hypofractionated RT. CONCLUSION: Surgery continues to be the preferred primary management strategy. Post-operative MRI within 48 hours is indicated to assess presence of residual disease and guide further surgical options. Adjuvant radiotherapy plays an important part of the management paradigm in these patients with the data supporting an attached survival advantage. Further surgery and re-irradiation is an option in the disease recurrence setting with radiosurgery frequently utilised in this context.

Novel CTD tag establishes shark fins as ocean observing platforms.

Animal-borne tags are effective instruments for collecting ocean data and can be used to fill spatial gaps in the observing network. We deployed the first conductivity, temperature, and depth (CTD) satellite tags on the dorsal fin of salmon sharks (Lamna ditropis) to demonstrate the potential of sharks to monitor essential ocean variables and oceanographic features in the Gulf of Alaska. Over 1360 km and 36 days in the summer of 2015, the salmon shark collected 56 geolocated, temperature-salinity profiles. The shark swam through a plume of anomalously salty water that originated from the "Blob" and encountered several mesoscale eddies, whose subsurface properties were altered by the marine heatwave. We demonstrate that salmon sharks have the potential to serve as submesoscale-resolving oceanographic platforms and substantially increase the spatial coverage of observations in the Gulf of Alaska.

Influence of Blood Flow Restriction on Neuromuscular Function and Fatigue During Forearm Flexion in Men.

ABSTRACT: Montgomery, TR Jr, Olmos, A, Sears, KN, Succi, PJ, Hammer, SM, Bergstrom, HC, Hill, EC, Trevino, MA, and Dinyer-McNeely, TK. Influence of blood flow restriction on neuromuscular function and fatigue during forearm flexion in men. J Strength Cond Res 38(7): e349-e358, 2024-To determine the effects of blood flow restriction (BFR) on the mean firing rate (MFR) and motor unit action potential amplitude (MUAPAMP) vs. recruitment threshold (RT) relationships during fatiguing isometric elbow flexions. Ten men (24.5 ± 4.0 years) performed isometric trapezoidal contractions at 50% maximum voluntary contraction to task failure with or without BFR, on 2 separate days. For BFR, a cuff was inflated to 60% of the pressure required for full brachial artery occlusion at rest. During both visits, surface electromyography was recorded from the biceps brachii of the dominant limb and the signal was decomposed. A paired-samples t test was used to determine the number of repetitions completed between BFR and CON. ANOVAs (repetition [first, last] × condition [BFR, CON]) were used to determine differences in MFR vs. RT and MUAPAMP vs. RT relationships. Subjects completed more repetitions during CON (12 ± 4) than BFR (9 ± 2; p = 0.012). There was no significant interaction (p > 0.05) between the slopes and y-intercepts during the repetition × condition interaction for MUAPAMP vs. MFR. However, there was a main effect of repetition for the slopes of the MUAPAMP vs. RT (p = 0.041) but not the y-intercept (p = 0.964). Post hoc analysis (collapsed across condition) indicated that the slopes of the MUAPAMP vs. RT during the first repetition was less than the last repetition (first: 0.022 ± 0.003 mv/%MVC; last: 0.028 ± 0.004 mv/%MVC; p = 0.041). Blood flow restriction resulted in the same amount of higher threshold MU recruitment in approximately 75% of the repetitions. Furthermore, there was no change in MFR for either condition, even when taken to task failure. Thus, BFR training may create similar MU responses with less total work completed than training without BFR.

Cell-to-cell heterogeneity in ion channel conductance impacts substrate vulnerability to arrhythmia.

Determining whether an ectopic depolarization will lead to a self-perpetuating arrhythmia is of critical importance in determining arrhythmia risk, so it is necessary to understand what factors impact substrate vulnerability. This study sought to explore the impact of cell-to-cell heterogeneity in ion channel conductance on substrate vulnerability to arrhythmia by measuring the duration of the vulnerable window in computational models of one-dimensional cables of ventricular cardiomyocytes. We began by using a population of uniform cable models to determine the mechanisms underlying the vulnerable window phenomenon. We found that in addition to the known importance of GNa, the conductances GCa,L and GKr also play a minor role in determining the vulnerable window duration. We also found that a steeper slope of the repolarizing action potential during the vulnerable window correlated with a shorter vulnerable window duration in uniform cables. We applied our understanding from these initial simulations to an investigation of the vulnerable window in heterogeneous cable models. The heterogeneous cables displayed a great deal of intra-cable variation in vulnerable window duration, highly sensitive to the cardiomyocytes in the local environment of the ectopic stimulus. Coupling strength modulated not only the magnitude of the vulnerable window duration but also the extent of intra-tissue variability in vulnerable window duration.NEW & NOTEWORTHY We investigate the impact of cell-to-cell heterogeneity in ion channel conductance on substrate vulnerability to arrhythmia by measuring the vulnerable window duration in computational cardiomyocyte cable models. We demonstrate a wide range of intra-cable variability in vulnerable window duration (VWD) and show how this is changed by ion channel block and coupling strength perturbations.

A CD25-biased interleukin-2 for autoimmune therapy engineered via a semi-synthetic organism.

BACKGROUND: Natural cytokines are poorly suited as therapeutics for systemic administration due to suboptimal pharmacological and pharmacokinetic (PK) properties. Recombinant human interleukin-2 (rhIL-2) has shown promise for treatment of autoimmune (AI) disorders yet exhibits short systemic half-life and opposing immune responses that negate an appropriate therapeutic index. METHODS: A semi-synthetic microbial technology platform was used to engineer a site-specifically pegylated form of rhIL-2 with enhanced PK, specificity for induction of immune-suppressive regulatory CD4 + T cells (Tregs), and reduced stimulation of off-target effector T and NK cells. A library of rhIL-2 molecules was constructed with single site-specific, biorthogonal chemistry-compatible non-canonical amino acids installed near the interface where IL-2 engages its cognate receptor ßγ (IL-2Rßγ) signaling complex. Biorthogonal site-specific pegylation and functional screening identified variants that retained engagement of the IL-2Rα chain with attenuated potency at the IL-2Rßγ complex. RESULTS: Phenotypic screening in mouse identifies SAR444336 (SAR'336; formerly known as THOR-809), rhIL-2 pegylated at H16, as a potential development candidate that specifically expands peripheral CD4+ Tregs with upregulation of markers that correlate with their suppressive function including FoxP3, ICOS and Helios, yet minimally expands CD8 + T or NK cells. In non-human primate, administration of SAR'336 also induces dose-dependent expansion of Tregs and upregulated suppressive markers without significant expansion of CD8 + T or NK cells. SAR'336 administration reduces inflammation in a delayed-type hypersensitivity mouse model, potently suppressing CD4+ and CD8 + T cell proliferation. CONCLUSION: SAR'336 is a specific Treg activator, supporting its further development for the treatment of AI diseases.

Interleukin-2 (IL-2) is a protein that functions as a master regulator of immune responses. A key function of IL-2 is the stimulation of immune-regulatory cells that suppress autoimmune disease, which occurs when the body's immune system mistakenly attacks healthy tissues. However, therapeutic use of IL-2 is limited by its short duration of action and incomplete selectivity for immune-suppressive cells over off-target immune-stimulatory cells. We employ a platform that we have previously developed, which is a bacterial organism with an expanded DNA code, to identify a new version of IL-2, SAR444336 (SAR'336), with an extended duration of activity and increased selectivity for immune-suppressive cells. In mice and monkeys, SAR'336 was a specific activator of immune suppression, with minimal effect on immune cells that stimulate autoimmunity. Our results support further development of SAR'336 for treatment of autoimmune disorders.

The impact of cancer metastases on COVID-19 outcomes: A COVID-19 and Cancer Consortium registry-based retrospective cohort study.

BACKGROUND: COVID-19 can have a particularly detrimental effect on patients with cancer, but no studies to date have examined if the presence, or site, of metastatic cancer is related to COVID-19 outcomes. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, the authors identified 10,065 patients with COVID-19 and cancer (2325 with and 7740 without metastasis at the time of COVID-19 diagnosis). The primary ordinal outcome was COVID-19 severity: not hospitalized, hospitalized but did not receive supplemental O2, hospitalized and received supplemental O2, admitted to an intensive care unit, received mechanical ventilation, or died from any cause. The authors used ordinal logistic regression models to compare COVID-19 severity by presence and specific site of metastatic cancer. They used logistic regression models to assess 30-day all-cause mortality. RESULTS: Compared to patients without metastasis, patients with metastases have increased hospitalization rates (59% vs. 49%) and higher 30 day mortality (18% vs. 9%). Patients with metastasis to bone, lung, liver, lymph nodes, and brain have significantly higher COVID-19 severity (adjusted odds ratios [ORs], 1.38, 1.59, 1.38, 1.00, and 2.21) compared to patients without metastases at those sites. Patients with metastasis to the lung have significantly higher odds of 30-day mortality (adjusted OR, 1.53; 95% confidence interval, 1.17-2.00) when adjusting for COVID-19 severity. CONCLUSIONS: Patients with metastatic cancer, especially with metastasis to the brain, are more likely to have severe outcomes after COVID-19 whereas patients with metastasis to the lung, compared to patients with cancer metastasis to other sites, have the highest 30-day mortality after COVID-19.

Blood flow restriction increases necessary muscle excitation of the elbow flexors during a single high-load contraction.

PURPOSE: To investigate the effects of blood flow restriction (BFR) on electromyographic amplitude (EMGRMS)-force relationships of the biceps brachii (BB) during a single high-load muscle action. METHODS: Twelve recreationally active males and eleven recreationally active females performed maximal voluntary contractions (MVCs), followed by an isometric trapezoidal muscle action of the elbow flexors at 70% MVC. Surface EMG was recorded from the BB during BFR and control (CON) visits. For BFR, cuff pressure was 60% of the pressure required to completely occlude blood at rest. Individual b (slope) and a terms (gain) were calculated from the log-transformed EMGRMS-force relationships during the linearly increasing and decreasing segments of the trapezoid. EMGRMS during the steady force segment was normalized to MVC EMGRMS. RESULTS: For BFR, the b terms were greater during the linearly increasing segment than the linearly decreasing segment (p < 0.001), and compared to the linearly increasing segment for CON (p < 0.001). The a terms for BFR were greater during the linearly decreasing than linearly increasing segment (p = 0.028). Steady force N-EMGRMS was greater for BFR than CON collapsed across sex (p = 0.041). CONCLUSION: BFR likely elicited additional recruitment of higher threshold motor units during the linearly increasing- and steady force-segment. The differences between activation and deactivation strategies were only observed with BFR, such as the b terms decreased and the a terms increased for the linearly decreasing segment in comparison to the increasing segment. However, EMGRMS-force relationships during the linearly increasing- and decreasing-segments were not different between sexes during BFR and CON.

Creating cell-specific computational models of stem cell-derived cardiomyocytes using optical experiments.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have gained traction as a powerful model in cardiac disease and therapeutics research, since iPSCs are self-renewing and can be derived from healthy and diseased patients without invasive surgery. However, current iPSC-CM differentiation methods produce cardiomyocytes with immature, fetal-like electrophysiological phenotypes, and the variety of maturation protocols in the literature results in phenotypic differences between labs. Heterogeneity of iPSC donor genetic backgrounds contributes to additional phenotypic variability. Several mathematical models of iPSC-CM electrophysiology have been developed to help understand the ionic underpinnings of, and to simulate, various cell responses, but these models individually do not capture the phenotypic variability observed in iPSC-CMs. Here, we tackle these limitations by developing a computational pipeline to calibrate cell preparation-specific iPSC-CM electrophysiological parameters. We used the genetic algorithm (GA), a heuristic parameter calibration method, to tune ion channel parameters in a mathematical model of iPSC-CM physiology. To systematically optimize an experimental protocol that generates sufficient data for parameter calibration, we created simulated datasets by applying various protocols to a population of in silico cells with known conductance variations, and we fitted to those datasets. We found that calibrating models to voltage and calcium transient data under 3 varied experimental conditions, including electrical pacing combined with ion channel blockade and changing buffer ion concentrations, improved model parameter estimates and model predictions of unseen channel block responses. This observation held regardless of whether the fitted data were normalized, suggesting that normalized fluorescence recordings, which are more accessible and higher throughput than patch clamp recordings, could sufficiently inform conductance parameters. Therefore, this computational pipeline can be applied to different iPSC-CM preparations to determine cell line-specific ion channel properties and understand the mechanisms behind variability in perturbation responses.

Serum osmolality measured in fingertip capillary blood is comparable to serum osmolality measured in venous blood.

Blood osmolality is considered the gold standard hydration assessment, but has limited application for technical and invasive reasons. Paired antecubital-venous blood and fingertip-capillary blood were collected pre- and 30 min post-drinking 600 mL water in 55 male/female participants. No bias (0.2 mOsmo/kg, limits of agreement = -2.5 to 2.8 mOsmo/kg) was found between sampling methods, with high linear correlation (Spearman's r = 0.95, P < 0.001). Capillary blood sampling offers an accurate less-invasive method for determining serum osmolality than venous blood sampling.

Sex differences in muscle contraction-induced limb blood flow limitations.

PURPOSE: To determined sex differences in absolute- and %-reductions in blood flow during intermittent muscular contractions as well as relationships between blood flow reductions and time to task failure (TTF). METHODS: Thirteen males (25 ± 4 years) and 13 females (22 ± 5 years) completed intermittent isometric trapezoidal forearm flexion at 50% maximal voluntary contraction until task failure. Doppler ultrasound was used to measure brachial artery blood flow (BABF) during the 12-s plateau phase and 12-s relaxation phase. RESULTS: Target torque was less in females than males (24 ± 5 vs. 42 ± 7 Nm; p < 0.001); however, TTF was not different between sexes (F: 425 ± 187 vs. M: 401 ± 158 s; p = 0.72). Relaxation-phase BABF at end-exercise was less in females than males (435 ± 161 vs. 937 ± 281 mL/min; p < 0.001) but contraction-phase BABF was not different (127 ± 46 vs. 190 ± 99 mL/min; p = 0.42). Absolute- and %-reductions in BABF by contraction were less in females than males (309 ± 146 vs. 747 ± 210 mL/min and 69 ± 10 vs. 80% ± 6%, respectively; both p < 0.01) and were associated with target torque independent of sex (r = 0.78 and 0.56, respectively; both p < 0.01). Absolute BABF reduction per target torque (mL/min/Nm) and TTF were positively associated in males (r = 0.60; p = 0.031) but negatively associated in females (r = - 0.61; p = 0.029). CONCLUSIONS: This study provides evidence that females incur less proportional reduction in limb blood flow from muscular contraction than males at a matched relative intensity suggesting females may maintain higher levels of muscle oxygen delivery and metabolite removal than males across the contraction-relaxation cycle of intermittent exercise.

A Qualitative Study of Racial, Ethnic, and Cultural Experiences of Minority Clinicians During Agitation Care in the Emergency Department.

STUDY OBJECTIVE: Racial and ethnic bias in health care has been documented at structural, organizational, and clinical levels, impacting emergency care, including agitation management in the emergency department (ED). Little is known about the experiences of racial and ethnic minority ED clinicians caring for racial and ethnic minority groups, especially during their agitated state. The objective of this study was to explore the lived experiences of racial and ethnic minority ED clinicians who have treated patients with agitation in the ED. METHODS: We performed semistructured individual interviews of Black, Latino, and multiracial clinicians who worked at 1 of 3 EDs from an urban quaternary care medical center in the Northeast United States between August 2020 and June 2022. We performed thematic analysis through open coding of initial transcripts and identifying additional codes through sequential iterative rounds of group discussion. Once the codebook was finalized and applied to all transcripts, the team identified key themes and subthemes. RESULTS: Of the 27 participants interviewed, 14 (52%) identified as Black, 9 (33%) identified as Hispanic/Latino, and 4 (15%) identified as multiracial and/or other race and ethnicity. Three primary themes emerged from racial and ethnic minority clinician experiences of managing agitation: witness of perceived bias during clinical interactions with patients of color who bear racialized presumptions of agitation, moral injury and added workload to address perceived biased agitation management practices while facing discrimination in the workplace, and natural advocacy and allyship for agitated patients of color based on a shared identity and life experience. CONCLUSIONS: Our study found that through their shared minority status, racial and ethnic minority clinicians had a unique vantage point to observe perceived bias in the management of agitation in minority patients. Although they faced added challenges as racial and ethnic minority clinicians, their allyship offered potential mitigation strategies for addressing disparities in caring for an underserved and historically marginalized patient population.

Prenatal cortisol exposure impairs adrenal function but not glucose metabolism in adult sheep.

Adverse environmental conditions before birth are known to programme adult metabolic and endocrine phenotypes in several species. However, whether increments in fetal cortisol concentrations of the magnitude commonly seen in these conditions can cause developmental programming remains unknown. Thus, this study investigated the outcome of physiological increases in fetal cortisol concentrations on glucose-insulin dynamics and pituitary-adrenal function in adult sheep. Compared with saline treatment, intravenous fetal cortisol infusion for 5 days in late gestation did not affect birthweight but increased lamb body weight at 1-2 weeks after birth. Adult glucose dynamics, insulin sensitivity and insulin secretion were unaffected by prenatal cortisol overexposure, assessed by glucose tolerance tests, hyperinsulinaemic-euglycaemic clamps and acute insulin administration. In contrast, prenatal cortisol infusion induced adrenal hypo-responsiveness in adulthood with significantly reduced cortisol responses to insulin-induced hypoglycaemia and exogenous adrenocorticotropic hormone (ACTH) administration relative to saline treatment. The area of adrenal cortex expressed as a percentage of the total cross-sectional area of the adult adrenal gland was also lower after prenatal cortisol than saline infusion. In adulthood, basal circulating ACTH but not cortisol concentrations were significantly higher in the cortisol than saline-treated group. The results show that cortisol overexposure before birth programmes pituitary-adrenal development with consequences for adult stress responses. Physiological variations in cortisol concentrations before birth may, therefore, have an important role in determining adult phenotypical diversity and adaptability to environmental challenges.

Deep Brain Stimulation for an Unusual Presentation of Myoclonus Dystonia Associated with Russell-Silver Syndrome.

Background: Myoclonus dystonia syndrome typically results from autosomal dominant mutations in the epsilon-sarcoglycan gene (SGCE) via the paternally expressed allele on chromosome 7q21. There is evidence that deep brain stimulation (DBS) is beneficial for this genotype, however, there are few prior case reports on DBS for myoclonus dystonia syndrome secondary to other confirmed genetic etiologies. Case Report: A 20-year-old female with concomitant Russell-Silver syndrome and myoclonus dystonia syndrome secondary to maternal uniparental disomy of chromosome 7 (mUPD7) presented for medically refractory symptoms. She underwent DBS surgery targeting the bilateral globus pallidus interna with positive effects that persisted 16 months post-procedure. Discussion: We present a patient with the mUPD7 genotype for myoclonus dystonia syndrome who exhibited a similar, if not superior, response to DBS when compared to patients with other genotypes. Highlights: This report outlines the first described case of successful deep brain stimulation treatment for a rare genetic variant of myoclonus dystonia syndrome caused by uniparental disomy at chromosome 7. These findings may expand treatment options for patients with similar conditions.

Surveillance of Vermont wildlife in 2021-2022 reveals no detected SARS-CoV-2 viral RNA.

Previous studies have documented natural infections of SARS-CoV-2 in various domestic and wild animals. More recently, studies have been published noting the susceptibility of members of the Cervidae family, and infections in both wild and captive cervid populations. In this study, we investigated the presence of SARS-CoV-2 in mammalian wildlife within the state of Vermont. 739 nasal or throat samples were collected from wildlife throughout the state during the 2021 and 2022 harvest season. Data was collected from red and gray foxes (Vulpes vulples and Urocyon cineroargentus, respectively), fishers (Martes pennati), river otters (Lutra canadensis), coyotes (Canis lantrans), bobcats (Lynx rufus rufus), black bears (Ursus americanus), and white-tailed deer (Odocoileus virginianus). Samples were tested for the presence of SARS-CoV-2 via quantitative RT-qPCR using the CDC N1/N2 primer set and/or the WHO-E gene primer set. Surprisingly, we initially detected a number of N1 and/or N2 positive samples with high cycle threshold values, though after conducting environmental swabbing of the laboratory and verifying with a second independent primer set (WHO-E) and PCR without reverse transcriptase, we showed that these were false positives due to plasmid contamination from a construct expressing the N gene in the general laboratory environment. Our final results indicate that no sampled wildlife were positive for SARS-CoV-2 RNA, and highlight the importance of physically separate locations for the processing of samples for surveillance and experiments that require the use of plasmid DNA containing the target RNA sequence. These negative findings are surprising, given that most published North America studies have found SARS-CoV-2 within their deer populations. The absence of SARS-CoV-2 RNA in populations sampled here may provide insights in to the various environmental and anthropogenic factors that reduce spillover and spread in North American's wildlife populations.

ALTercations at telomeres: stress, recombination and extrachromosomal affairs.

Approximately 15% of human cancers depend on the alternative lengthening of telomeres (ALT) pathway to maintain telomeres and proliferate. Telomeres that are elongated using ALT display unique features raising the exciting prospect of tailored cancer therapies. ALT-mediated telomere elongation shares several features with recombination-based DNA repair. Strikingly, cells that use the ALT pathway display abnormal levels of replication stress at telomeres and accumulate abundant extrachromosomal telomeric DNA. In this review, we examine recent findings that shed light on the ALT mechanisms and the strategies currently available to suppress this telomere elongation mechanism.

Management of Pediatric Anterior Cruciate Ligament Injuries: A Critical Analysis.

¼ Overall evidence for the treatment of an anterior cruciate ligament (ACL) injury in a pediatric or skeletally immature patient remains lows.¼ An ACL reconstruction is recommended with concomitant repairable chondral and meniscus injury or with symptoms of persistent instability despite high-quality rehabilitation.¼ Treatment decision for pediatric ACL reconstruction should use a shared decision-making model weighing the risks and benefits of both a nonoperative vs. surgical treatment.

Impact of Chorionic Somatomammotropin In Vivo RNA Interference Phenotype on Uteroplacental Expression of the IGF Axis.

While fetal growth is dependent on many factors, optimal placental function is a prerequisite for a normal pregnancy outcome. The majority of fetal growth-restricted (FGR) pregnancies result from placental insufficiency (PI). The insulin-like growth factors (IGF1 and IGF2) stimulate fetal growth and placental development and function. Previously, we demonstrated that in vivo RNA interference (RNAi) of the placental hormone, chorionic somatomammotropin (CSH), resulted in two phenotypes. One phenotype exhibits significant placental and fetal growth restriction (PI-FGR), impaired placental nutrient transport, and significant reductions in umbilical insulin and IGF1. The other phenotype does not exhibit statistically significant changes in placental or fetal growth (non-FGR). It was our objective to further characterize these two phenotypes by determining the impact of CSH RNAi on the placental (maternal caruncle and fetal cotyledon) expression of the IGF axis. The trophectoderm of hatched blastocysts (9 days of gestation, dGA) were infected with a lentivirus expressing either a non-targeting sequence (NTS RNAi) control or CSH-specific shRNA (CSH RNAi) prior to embryo transfer into synchronized recipient ewes. At ≈125 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies. Nutrient uptakes were determined, and tissues were harvested at necropsy. In both CSH RNAi non-FGR and PI-FGR pregnancies, uterine blood flow was significantly reduced (p ≤ 0.05), while umbilical blood flow (p ≤ 0.01), both uterine and umbilical glucose and oxygen uptakes (p ≤ 0.05), and umbilical concentrations of insulin and IGF1 (p ≤ 0.05) were reduced in CSH RNAi PI-FGR pregnancies. Fetal cotyledon IGF1 mRNA concentration was reduced (p ≤ 0.05) in CSH RNAi PI-FGR pregnancies, whereas neither IGF1 nor IGF2 mRNA concentrations were impacted in the maternal caruncles, and either placental tissue in the non-FGR pregnancies. Fetal cotyledon IGF1R and IGF2R mRNA concentrations were not impacted for either phenotype, yet IGF2R was increased (p ≤ 0.01) in the maternal caruncles of CSH RNAi PI-FGR pregnancies. For the IGF binding proteins (IGFBP1, IGFBP2, IGFBP3), only IGFBP2 mRNA concentrations were impacted, with elevated IGFBP2 mRNA in both the fetal cotyledon (p ≤ 0.01) and maternal caruncle (p = 0.08) of CSH RNAi non-FGR pregnancies. These data support the importance of IGF1 in placental growth and function but may also implicate IGFBP2 in salvaging placental growth in non-FGR pregnancies.