Bystander effects, pharmacokinetics, and linker-payload stability of EGFR-targeting antibody-drug conjugates Losatuxizumab vedotin and Depatux-M in glioblastoma models.

PURPOSE: Antibody-drug conjugates (ADCs) are targeted therapies with robust efficacy in solid cancers, and there is intense interest in using EGFR-specific ADCs to target EGFR-amplified glioblastoma (GBM). Given the molecular heterogeneity of GBM, bystander activity of ADCs may be important for determining treatment efficacy. In this study, the activity and toxicity of two EGFR-targeted ADCs, Losatuxizumab vedotin (ABBV-221) and Depatuxizumab mafodotin (Depatux-M), with similar auristatin toxins, were compared in GBM patient-derived xenografts (PDXs) and normal murine brain following direct infusion by convection enhanced delivery (CED). METHODS: EGFRviii-amplified and non-amplified GBM PDXs were used to determine in vitro cytotoxicity, in vivo efficacy, and bystander activities of ABBV-221 and Depatux-M. Non-tumor bearing mice were used to evaluate pharmacokinetics and toxicity of ADCs using LC-MS/MS and immunohistochemistry. RESULTS: CED improved intracranial efficacy of Depatux-M and ABBV-221 in three EGFRviii-amplified GBM PDX models (Median survival: 125 to >300 days vs 20-49 days with isotype-control AB095). Both ADCs had comparable in vitro and in vivo efficacy. However, neuronal toxicity and CD68+ microglia/macrophage infiltration were significantly higher in brains infused with ABBV-221, with the cell-permeable MMAE, as compared to Depatux-M, with the cell-impermeant MMAF. CED infusion of ABBV-221 into brain or incubation of ABBV-221 with normal brain homogenate resulted in significant release of MMAE, which is consistent with linker instability in the brain microenvironment. CONCLUSION: EGFR-targeting ADCs are promising therapeutic options for GBM when delivered intra-tumorally by CED. However, the linker and payload for the ADC must be carefully considered to maximize the therapeutic window.

Factors associated with patent foramen ovale-related stroke: SAFAS study.

BACKGROUND: Persistent foramen ovale (PFO) contributes to cryptogenic stroke and is associated with stroke recurrence, although the exact mechanism of ischemic events is not fully understood. Several biomarkers have been developed for the prediction of atrial fibrillation after stroke, but there are currently only limited data on their potential value for the diagnosis of PFO-related stroke. METHODS: This study was a prospective single-center study that included all patients hospitalized between March 31, 2018, and January 18, 2020, in the stroke department of the Dijon University Hospital for ischemic stroke without obvious cause and without a history of atrial fibrillation. PFO was systematically screened by transthoracic echocardiography and images were reviewed by an independent cardiologist blinded from clinical data. PFO was defined according to the CLOSE trial criteria: PFO associated with interatrial septal aneurysm or significant interatrial shunt (> 30 microbubbles in the left atrium within three cardiac cycles after right atrial opacification). The potential association of PFO-related stroke with biomarkers of cardiac fibrosis and inflammation such as galectin-3, GDF-15, ST-2, osteoprotegerin and NT-proBNP was tested using multivariate backward stepwise logistic regression. RESULTS: Of the 240 patients included in the SAFAS study, 229 had complete echocardiographic data, and 23 (10%) had PFO-related stroke. Patients with PFO-related stroke were significantly younger (58±14 vs. 69±14, P<0.001), had less frequent previous arterial hypertension (30 vs. 60%, P=0.008), and more frequent cerebellar territory involvement (26 vs. 9%, P=0.014) compared to the other patients. In addition, they had less frequently left atrial dilatation (left atrial index volume>34mL/m2 [9 vs. 35%, P=0.009]). After ROC curve analysis for definition of thresholds, PFO-related stroke patients more often had galectin-3<9.5ng/mL (59 vs. 27%, P=0.002), ST2<13380pg/ml (23 vs. 50%, P=0.007), GDF-15<1200ng/mL (59 vs. 27%, P=0.002), osteoprotegerin<1133pg/mL (82 vs. 58%, P=0.033) and NT-proBNP<300pg/mL (88 vs. 55%, P=0.009). After multivariate analysis, only galectin-3<9.5ng/mL (OR [95% CI] 3.4 [1.18; 9.8], P=0.024) and osteoprotegerin<1133pg/L (OR [95% CI] 5.0 [1.1; 22.9], P=0.038) were independently associated with PFO-related stroke. CONCLUSION: Patients in whom cryptogenic stroke is attributed to a significant PFO have a specific clinical and biological phenotype. Low levels of galectin-3 and osteoprotegerin may help identify patients with PFO-related strokes.

Correction: Migration of nanoparticles across a polymer-polymer interface: theory and simulation.

Correction for 'Migration of nanoparticles across a polymer-polymer interface: theory and simulation' by Nigel Gibbions et al., Soft Matter, 2021, 17, 7294-7310, https://doi.org/10.1039/D1SM00671A.

Novel Developments to Enable Treatment of CNS Diseases with Targeted Drug Delivery.

The blood-brain barrier (BBB) is a major hurdle for the development of systemically delivered drugs against diseases of the central nervous system (CNS). Because of this barrier there is still a huge unmet need for the treatment of these diseases, despite years of research efforts across the pharmaceutical industry. Novel therapeutic entities, such as gene therapy and degradomers, have become increasingly popular in recent years, but have not been the focus for CNS indications so far. To unfold their full potential for the treatment of CNS diseases, these therapeutic entities will most likely have to rely on innovative delivery technologies. Here we will describe and assess approaches, both invasive and non-invasive, that can enable, or at least increase, the probability of a successful drug development of such novel therapeutics for CNS indications.

Optimized automated cardiac MR scar quantification with GAN-based data augmentation.

BACKGROUND: The clinical utility of late gadolinium enhancement (LGE) cardiac MRI is limited by the lack of standardization, and time-consuming postprocessing. In this work, we tested the hypothesis that a cascaded deep learning pipeline trained with augmentation by synthetically generated data would improve model accuracy and robustness for automated scar quantification. METHODS: A cascaded pipeline consisting of three consecutive neural networks is proposed, starting with a bounding box regression network to identify a region of interest around the left ventricular (LV) myocardium. Two further nnU-Net models are then used to segment the myocardium and, if present, scar. The models were trained on the data from the EMIDEC challenge, supplemented with an extensive synthetic dataset generated with a conditional GAN. RESULTS: The cascaded pipeline significantly outperformed a single nnU-Net directly segmenting both the myocardium (mean Dice similarity coefficient (DSC) (standard deviation (SD)): 0.84 (0.09) vs 0.63 (0.20), p < 0.01) and scar (DSC: 0.72 (0.34) vs 0.46 (0.39), p < 0.01) on a per-slice level. The inclusion of the synthetic data as data augmentation during training improved the scar segmentation DSC by 0.06 (p < 0.01). The mean DSC per-subject on the challenge test set, for the cascaded pipeline augmented by synthetic generated data, was 0.86 (0.03) and 0.67 (0.29) for myocardium and scar, respectively. CONCLUSION: A cascaded deep learning-based pipeline trained with augmentation by synthetically generated data leads to myocardium and scar segmentations that are similar to the manual operator, and outperforms direct segmentation without the synthetic images.

Convection enhanced delivery of EGFR targeting antibody-drug conjugates Serclutamab talirine and Depatux-M in glioblastoma patient-derived xenografts.

Background: EGFR targeting antibody-drug conjugates (ADCs) are highly effective against EGFR-amplified tumors, but poor distribution across the blood-brain barrier (BBB) limits their efficacy in glioblastoma (GBM) when administered systemically. We studied whether convection-enhanced delivery (CED) can be used to safely infuse ADCs into orthotopic patient-derived xenograft (PDX) models of EGFRvIII mutant GBM. Methods: The efficacy of the EGFR-targeted ADCs depatuxizumab mafodotin (Depatux-M) and Serclutamab talirine (Ser-T) was evaluated in vitro and in vivo. CED was performed in nontumor and tumor-bearing mice. Immunostaining was used to evaluate ADC distribution, pharmacodynamic effects, and normal cell toxicity. Results: Dose-finding studies in orthotopic GBM6 identified single infusion of 2 µg Ser-T and 60 µg Depatux-M as safe and effective associated with extended survival prolongation (>300 days and 95 days, respectively). However, with serial infusions every 21 days, four Ser-T doses controlled tumor growth but was associated with lethal toxicity approximately 7 days after the final infusion. Limiting dosing to two infusions in GBM108 provided profound median survival extension of over 200 days. In contrast, four Depatux-M CED doses were well tolerated and significantly extended survival in both GBM6 (158 days) and GBM108 (310 days). In a toxicity analysis, Ser-T resulted in a profound loss in NeuN+ cells and markedly elevated GFAP staining, while Depatux-M was associated only with modest elevation in GFAP staining. Conclusion: CED of Depatux-M is well tolerated and results in extended survival in orthotopic GBM PDXs. In contrast, CED of Ser-T was associated with a much narrower therapeutic window.

Biodistribution Analysis of an Anti-EGFR Antibody in the Rat Brain: Validation of CSF Microcirculation as a Viable Pathway to Circumvent the Blood-Brain Barrier for Drug Delivery.

Cerebrospinal fluid (CSF) microcirculation refers to CSF flow through brain or spinal parenchyma. CSF enters the tissue along the perivascular spaces of the penetrating arteries where it mixes with the interstitial fluid circulating through the extracellular space. The potential of harnessing CSF microcirculation for drug delivery to deep areas of the brain remains an area of controversy. This paper sheds additional light on this debate by showing that ABT-806, an EGFR-specific humanized IgG1 monoclonal antibody (mAb), reaches both the cortical and the deep subcortical layers of the rat brain following intra-cisterna magna (ICM) injection. This is significant because the molecular weight of this mAb (150 kDa) is highest among proteins reported to have penetrated deeply into the brain via the CSF route. This finding further confirms the potential of CSF circulation as a drug delivery system for a large subset of molecules offering promise for the treatment of various brain diseases with poor distribution across the blood-brain barrier (BBB). ABT-806 is the parent antibody of ABT-414, an antibody-drug conjugate (ADC) developed to engage EGFR-overexpressing glioblastoma (GBM) tumor cells. To pave the way for future efficacy studies for the treatment of GBM with an intra-CSF administered ADC consisting of a conjugate of ABT-806 (or of one of its close analogs), we verified in vivo the binding of ABT-414 to GBM tumor cells implanted in the cisterna magna and collected toxicity data from both the central nervous system (CNS) and peripheral tissues. The current study supports further exploration of harnessing CSF microcirculation as an alternative to systemic delivery to achieve higher brain tissue exposure, while reducing previously reported ocular toxicity with ABT-414.

Clinical evaluation of large volume subcutaneous injection tissue effects, pain, and acceptability in healthy adults.

Determining feasibility and tolerability of large volume viscous subcutaneous injection may enable optimized, intuitive delivery system design. A translational early feasibility clinical study examined large volume subcutaneous injection viability, tolerability, acceptability, tissue effects and depot location for ~1, 8, and 20 cP injections at volumes up to 10 ml in the abdomen and 5 ml in the thigh in 32 healthy adult subjects. A commercial syringe pump system delivered 192 randomized, constant rate (20 µl/s) injections (6/subject) with in-line injection pressure captured versus time. Deposition location was qualified via ultrasound. Tissue effects and pain tolerability were monitored through 2 hours post-injection with corresponding Likert acceptability questionnaires administered through 72 hours. All injection conditions were feasible and well-tolerated with ≥79.3% favorable subject responses for injection site appearance and sensation immediately post-injection, increasing to ≥96.8% at 24 hours. Mean subject pain measured via 100 mm visual analog scale increased at needle insertion (6.9 mm, SD 10.8), peaked during injection (26.9 mm, SD 21.7) and diminished within 10 minutes post-removal (1.9 mm, SD 4.2). Immediate injection site wheal (90.9%) and erythema (92.6%) formation was observed with progressive although incomplete resolution through 2 hours (44.6% and 11.4% remaining, respectively). Wheal resolution occurred more rapidly at lower viscosities. Most subjects (64.5%) had no preference between abdomen and thigh. Correlations between tissue effects, injection pressure and pain were weak (Pearson's rho ± 0-0.4). The large volume injections tested, 1-20 cP viscosities up to 10 ml in the abdomen and 5 ml in the thigh, are feasible with good subject acceptability and rapid resolution of tissue effects and pain.

Migration of nanoparticles across a polymer-polymer interface: theory and simulation.

We proposed recently a theoretical description for hydrodynamic flows in inhomogeneous liquids in the vicinity of solid interfaces, consistent with current theoretical descriptions of the thermodynamical equilibrium of liquids in the vicinity of solid surfaces and with the Onsager formalism for linear response theory in out-of-equilibrium liquids. We showed that these equations allow for describing diffusio-osmosis along a capillary and also wetting/dewetting dynamics of liquids on a solid substrate. We now apply this physical model to the wetting/dewetting dynamics of nano-particles in polymer blends, showing how they reach equilibrium at the interface between two liquids at rest and how they migrate from the non-preferred polymer to the preferred one under applied flow.

Decreased neonatal morbidity in 'stomach-down' left congenital diaphragmatic hernia: implications of prenatal ultrasound diagnosis for counseling and postnatal management.

OBJECTIVE: To evaluate the influence of stomach position on postnatal outcome in cases of left congenital diaphragmatic hernia (CDH) without liver herniation, diagnosed and characterized on prenatal ultrasound (US), by comparing those with ('stomach-up' CDH) to those without ('stomach-down' CDH) intrathoracic stomach herniation. METHODS: Infants with left CDH who underwent prenatal US and postnatal repair at our institution between January 2008 and March 2017 were eligible for inclusion in this retrospective study. Detailed prenatal US examinations, fetal magnetic resonance imaging (MRI) studies, operative reports and medical records of infants enrolled in the pulmonary hypoplasia program at our institution were reviewed. Cases with liver herniation and those with an additional anomaly were excluded. Cases in which bowel loops were identified within the fetal chest on US while the stomach was intra-abdominal were categorized as having stomach-down CDH. Cases in which bowel loops and the stomach were visualized within the fetal chest on US were categorized as having stomach-up CDH. Prenatal imaging findings and postnatal outcomes were compared between the two groups. RESULTS: In total, 152 patients with left CDH were initially eligible for inclusion. Seventy-eight patients had surgically confirmed liver herniation and were excluded. Of the 74 included CDH cases without liver herniation, 28 (37.8%) had stomach-down CDH and 46 (62.2%) had stomach-up CDH. Of the 28 stomach-down CDH cases, 10 (35.7%) were referred for a suspected lung lesion. Sixty-eight (91.9%) cases had postnatal outcome data available for analysis. There was no significant difference in median observed-to-expected (o/e) lung-area-to-head-circumference ratio (LHR) between cases with stomach-down CDH and those with stomach-up CDH (41.5% vs 38.4%; P = 0.41). Furthermore, there was no difference in median MRI o/e total lung volume (TLV) between the two groups (49.5% vs 44.0%; P = 0.22). Compared with stomach-up CDH patients, stomach-down CDH patients demonstrated lower median duration of intubation (18 days vs 9.5 days; P < 0.01), median duration of extracorporeal membrane oxygenation (495 h vs 223.5 h; P < 0.05), rate of supplemental oxygen requirement at 30 days of age (20/42 (47.6%) vs 3/26 (11.5%); P < 0.01) and rate of pulmonary hypertension at initial postnatal echocardiography (28/42 (66.7%) vs 9/26 (34.6%); P = 0.01). No neonatal death occurred in stomach-down CDH patients and one neonatal death was seen in a patient with intrathoracic stomach herniation. CONCLUSIONS: In infants with left CDH without liver herniation, despite similar o/e-LHR and o/e-TLV, those with stomach-down CDH have decreased neonatal morbidity compared to those with stomach herniation. Progressive or variable physiological distension of the stomach over the course of gestation may explain these findings. Stomach-down left CDH is mistaken for a lung mass in a substantial proportion of cases. Accurate prenatal US characterization of CDH is crucial for appropriate prenatal counseling and patient management. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Harnessing cerebrospinal fluid circulation for drug delivery to brain tissues.

Initially thought to be useful only to reach tissues in the immediate vicinity of the CSF circulatory system, CSF circulation is now increasingly viewed as a viable pathway to deliver certain therapeutics deeper into brain tissues. There is emerging evidence that this goal is achievable in the case of large therapeutic proteins, provided conditions are met that are described herein. We show how fluid dynamic modeling helps predict infusion rate and duration to overcome high CSF turnover. We posit that despite model limitations and controversies, fluid dynamic models, pharmacokinetic models, preclinical testing, and a qualitative understanding of the glymphatic system circulation can be used to estimate drug penetration in brain tissues. Lastly, in addition to highlighting landmark scientific and medical literature, we provide practical advice on formulation development, device selection, and pharmacokinetic modeling. Our review of clinical studies suggests a growing interest for intra-CSF delivery, particularly for targeted proteins.

Efficient polynomial analysis of magic-angle spinning sidebands and application to order parameter determination in anisotropic samples.

Chemical shift tensors in 13C solid-state NMR provide valuable localized information on the chemical bonding environment in organic matter, and deviations from isotropic static-limit powder line shapes sensitively encode dynamic-averaging or orientation effects. Studies in 13C natural abundance require magic-angle spinning (MAS), where the analysis must thus focus on spinning sidebands. We propose an alternative fitting procedure for spinning sidebands based upon a polynomial expansion that is more efficient than the common numerical solution of the powder average. The approach plays out its advantages in the determination of CST (chemical-shift tensor) principal values from spinning-sideband intensities and order parameters in non-isotropic samples, which is here illustrated with the example of stretched glassy polycarbonate.

Clinical Evaluation of an Investigational 5 mL Wearable Injector in Healthy Human Subjects.

An investigational wearable injector (WI), the BD Libertas Wearable Injector (BD Libertas is a trademark of Becton, Dickinson and Company), was evaluated in an early feasibility clinical study for functional performance, tissue effects, subject tolerability, and acceptability of 5 mL, non-Newtonian ~ 8 cP subcutaneous placebo injections in 52 healthy adult subjects of 2 age groups (18-64 years and ≥ 65 years). Randomized WI subcutaneous injections (n = 208, 4/subject) were delivered to the right and left abdomen and thigh of each subject, 50% (1 thigh and 1 abdomen) with a defined movement sequence during injection. Injector functional performance was documented. Deposition was qualified and quantified with ultrasound. Tissue effects and tolerability (pain) were monitored through 24 hours with corresponding acceptability questionnaires administered through 72 hours. WI (n = 205) automatically inserted the needle, delivered 5 mL ± 5% in 5.42 minutes (SD 0.74) and retracted. Depots were entirely (93.2%) or predominantly (5.4%) localized within the target subcutaneous tissue. Slight to moderate wheals (63.9%) and erythema (75.1%) were observed with ≥ 50% resolution within 30-60 minutes. Subject pain (100 mm Visual Analog Scale) peaked mid-injection (mean 9.1 mm, SD 13.4) and rapidly resolved within 30 minutes (mean 0.4 mm, SD 2.6). Subjects' peak pain (≥ 90.2%), injection site appearance (≥ 92.2%) and injector wear, size, and removal (≥ 92.1%) were acceptable (Likert responses) with 100% likely to use the injector if prescribed. Injection site preference was divided between none (46%), abdomen (25%), or thigh (26.9%). The investigational WI successfully delivered 5 mL viscous subcutaneous injections. Tissue effects and pain were transient, well-tolerated and acceptable. Neither injection site, movement or subject age affected injector functional performance or subject pain and acceptability.

Fetal Intraventricular Hemorrhage in Open Neural Tube Defects: Prenatal Imaging Evaluation and Perinatal Outcomes.

BACKGROUND AND PURPOSE: Fetal imaging is crucial in the evaluation of open neural tube defects. The identification of intraventricular hemorrhage prenatally has unclear clinical implications. We aimed to explore fetal imaging findings in open neural tube defects and evaluate associations between intraventricular hemorrhage with prenatal and postnatal hindbrain herniation, postnatal intraventricular hemorrhage, and ventricular shunt placement. MATERIALS AND METHODS: After institutional review board approval, open neural tube defect cases evaluated by prenatal sonography between January 1, 2013 and April 24, 2018 were enrolled (n = 504). The presence of intraventricular hemorrhage and gray matter heterotopia by both prenatal sonography and MR imaging studies was used for classification. Cases of intraventricular hemorrhage had intraventricular hemorrhage without gray matter heterotopia (n = 33) and controls had neither intraventricular hemorrhage nor gray matter heterotopia (n = 229). A total of 135 subjects with findings of gray matter heterotopia were excluded. Outcomes were compared with regression analyses. RESULTS: Prenatal and postnatal hindbrain herniation and postnatal intraventricular hemorrhage were more frequent in cases of prenatal intraventricular hemorrhage compared with controls (97% versus 79%, 50% versus 25%, and 63% versus 12%, respectively). Increased third ventricular diameter, specifically >1 mm, predicted hindbrain herniation (OR = 3.7 [95% CI, 1.5-11]) independent of lateral ventricular size and prenatal intraventricular hemorrhage. Fetal closure (n = 86) was independently protective against postnatal hindbrain herniation (OR = 0.04 [95% CI, 0.01-0.15]) and postnatal intraventricular hemorrhage (OR = 0.2 [95% CI, 0.02-0.98]). Prenatal intraventricular hemorrhage was not associated with ventricular shunt placement. CONCLUSIONS: Intraventricular hemorrhage is relatively common in the prenatal evaluation of open neural tube defects. Hindbrain herniation is more common in cases of intraventricular hemorrhage, but in association with increased third ventricular size. Fetal closure reverses hindbrain herniation and decreases the rate of intraventricular hemorrhage postnatally, regardless of the presence of prenatal intraventricular hemorrhage.

Mechanical properties of amorphous and semi-crystalline semi-aromatic polyamides.

We investigate the mechanical properties of amorphous and semi-crystalline semi-aromatic polyamides, polyphthalamides (PPA). Three relaxation processes have been identified by DMTA which is consistent with literature for polyamide. PPA exhibit a brittle-to-ductile transition from a low impact strength to a high impact strength. At room temperature, all the studied PPA are brittle. During both tensile and compression experiments, a strain hardening behavior is observed for all the studied samples and is more pronounced in compression. The testing temperature has an influence on the strain hardening modulus, contrary to the crystallinity. Strain hardening gives properties of stability and resistance to damage.

Diffusio-osmosis and wetting on solid surfaces: a unified description based on a virtual work principle.

In order to account for diffusio-osmosis, Derjaguin proposed long ago that there is an excess pressure confined within a layer of typically a few nanometers in the vicinity of a solid surface immersed in a liquid and resulting from the interaction between the liquid and the surface. In the presence of a composition gradient in the liquid a confined pressure gradient parallel to the surface is therefore responsible for the diffusio-osmotic flow. This picture appears in contradiction with the contact theorem of colloidal science according to which such excess pressure does not exist. We propose a theoretical description for calculating hydrodynamic flows in inhomogeneous liquids in the vicinity of solid interfaces which is consistent with the contact theorem. This approach is based on a Gibbs free energy and a virtual work principle for calculating the driving forces in the liquid due to inhomogeneous composition along a capillary and to the interaction with the solid interfaces. Our approach allows us to show that the physics at play is the same in wetting or in diffusio-osmosis experiments, as one can go continuously from the latter to the former by making composition gradients sharper. We obtain an explicit expression for the diffusio-osmotic mobility which depends on the Gibbs free energy density in the vicinity of the interface and its dependance on the solute concentration in the liquid beyond the interfacial region, and which is inversely proportional to the liquid viscosity.

Myelomeningocele sac associated with worse lower-extremity neurological sequelae: evidence for prenatal neural stretch injury?

OBJECTIVE: To determine whether the presence of a myelomeningocele (MMC) sac and sac size correlate with compromised lower-extremity function in fetuses with open spinal dysraphism. METHODS: A radiology database search was performed to identify cases of MMC and myeloschisis (MS) diagnosed prenatally in a single center from 2013 to 2017. All cases were evaluated between 18 and 25 weeks. Ultrasound reports were reviewed for talipes and impaired lower-extremity motion. In MMC cases, sac volume was calculated from ultrasound measurements. Magnetic resonance imaging reports were reviewed for hindbrain herniation. The association of presence of a MMC sac and sac size with talipes and impaired lower-extremity motion was assessed. Post-hoc analysis of data from the multicenter Management of Myelomeningocele Study (MOMS) randomized controlled trial was performed to confirm the study findings. RESULTS: In total, 283 MMC and 121 MS cases were identified. MMC was associated with a lower incidence of hindbrain herniation than was MS (80.9% vs 100%; P < 0.001). Compared with MS cases, MMC cases with hindbrain herniation had a higher rate of talipes (28.4% vs 16.5%, P = 0.02) and of talipes or lower-extremity impairment (34.9% vs 19.0%, P = 0.002). Although there was a higher rate of impaired lower-extremity motion alone in MMC cases with hindbrain herniation than in MS cases, the difference was not statistically significant (6.6% vs 2.5%; P = 0.13). Among MMC cases with hindbrain herniation, mean sac volume was higher in those associated with talipes compared with those without talipes (4.7 ± 4.2 vs 3.0 ± 2.6 mL; P = 0.002). Review of the MOMS data demonstrated similar findings; cases with a sac on baseline imaging had a higher incidence of talipes than did those without a sac (28.2% vs 7.5%; P = 0.007). CONCLUSIONS: In fetuses with open spinal dysraphism, the presence of a MMC sac was associated with fetal talipes, and this effect was correlated with sac size. The presence of a larger sac in fetuses with open spinal dysraphism may result in additional injury through mechanical stretching of the nerves, suggesting another acquired mechanism of injury to the exposed spinal tissue. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Reaching the unreached: Performance of an enhanced peer outreach approach to identify new HIV cases among female sex workers and men who have sex with men in HIV programs in West and Central Africa.

Finding new HIV-positive cases remains a priority to achieve the UNAIDS goals. An enhanced peer outreach approach (EPOA) was implemented to expand the delivery of HIV services to female sex workers (FSWs) and men who have sex with men (MSM) in three countries in West and Central Africa. The aim of EPOA is to identify new HIV-positive cases. EPOA was implemented in Burundi among FSWs, and in Cote d'Ivoire and Democratic Republic of the Congo (DRC) among both FSWs and MSM. Implementation ranged from five to nine weeks and was nested within a three-month reporting period. Standard outreach was suspended for the duration of EPOA implementation but was resumed thereafter. Summary service statistics were used to compare HIV seropositivity during standard outreach and EPOA. Trends were analyzed during the quarter in which EPOA was implemented, and these were compared with the two preceding quarters. Differences in proportions of HIV seropositivity were tested using Pearson's chi-square test; p-values of less than 0.05 were considered statistically significant. Overall, EPOA resulted in a higher proportion of new HIV-positive cases being found, both within and between quarters. In Burundi, HIV seropositivity among FSWs was significantly higher during EPOA than during standard outreach (10.8% vs. 4.1%, p<0.001). In Cote d'Ivoire, HIV seropositivity was significantly higher during EPOA among both populations (FSWs: 5.6% vs. 1.81%, p<0.01; MSM: 15.4% vs. 5.9%; p<0.01). In DRC, HIV seropositivity was significantly higher during EPOA among MSM (6.9% vs. 1.6%; p<0.001), but not among FSWs (5.2% vs. 4.3%; p = 0.08). Trends in HIV seropositivity during routine outreach for both populations were constant during three successive quarters but increased with the introduction of EPOA. EPOA is a public health approach with great potential for reaching new populations and ensuring that they are aware of their HIV status.