Stage based recipient and donor outcome in twin-to-twin transfusion syndrome treated by fetoscopic laser surgery using Solomon technique.

OBJECTIVE: To evaluate twin survival stratified by Quintero stage in patients with twin-to-twin transfusion syndrome (TTTS) after Solomon laser treatment. METHODS: Single center cohort of consecutive twin pregnancies treated with Solomon laser for TTTS. Preoperative Quintero stage, perioperative characteristics and obstetric factors were related to neonatal survival of the recipient and donor at discharge. Determinants of twin survival were evaluated using univariate, logistic regression and cumulative survival probability analyses. RESULTS: Of 402 twins with TTTS, 80 (19.9%) had stage I, 126 (31.3%) stage II, 169 (42%) stage III and 27 (6.7%) stage IV. Post laser TAPS or recurrent TTTS occurred in 19 (4.7%) patients and 11 (2.7%) required repeat laser. Preterm premature rupture of membranes occurred in 150 (37.3%) patients and median gestational age of delivery 32+1 weeks. In 303 (75.4%) both twins were alive at discharge; [66 (82.5%) in stage I, 101 (80.2%) in stage II, 114 (67.5%) in stage III and 22 (81.5%) in stage IV, p=0.062]. Compared to recipients, donor survival was only lower in stage III (155 (91.7%) recipients vs 118 (69.8%) donors, Chi square 24.685, p<0.0001). Larger intertwin size discordance and umbilical artery (UA) end-diastolic velocity (EDV) determined donor demise (Nagelkerke R2 0.38, P<0.001). Overall, spontaneous post laser donor demise accounted for the majority (39.5%) of all losses. Cumulative donor survival decreased from 92% to 65% with size discordance >30% and 48% when UA EDV was absent (p<0.001). CONCLUSION: Solomon laser achieves TTTS resolution and double survival in a high proportion of cases. Recipient and donor survival is comparable unless there is significant size discordance and placental dysfunction. This degree of unequal placental sharing, typically found in stage III, is the primary factor preventing double survival due to a higher rate of donor demise. This article is protected by copyright. All rights reserved.

Recent trends and risk factors associated with Clostridioides difficile infections in hospitalized patients with inflammatory bowel disease.

BACKGROUND: Clostridioides difficile infections (CDIs) are common among patients with inflammatory bowel disease (IBD) and can mimic and exacerbate IBD flares, thus warranting appropriate testing during flares. AIMS: To examine recent trends in rates of CDI and associated risk factors in hospitalized IBD patients, which may better inform targeted interventions to mitigate the risk of infection. METHODS: This is a retrospective analysis using the Nationwide Readmissions Database from 2010 to 2020 of hospitalized individuals with Crohn's disease (CD) or ulcerative colitis (UC). Longitudinal changes in rates of CDI were evaluated using International Classification of Diseases codes. Multivariable logistic regression evaluated the association between patient- and hospital-related factors and CDI. RESULTS: There were 2,521,935 individuals with IBD who were hospitalized at least once during the study period. Rates of CDI in IBD-related hospitalizations increased from 2010 to 2015 (CD: 1.64%-3.32%, p < 0.001; UC: 4.15%-5.81%, p < 0.001), followed by a steady decline from 2016 to 2020 (CD: 3.15%-2.27%, p < 0.001; UC: 5.04%-4.27%, p < 0.001). In multivariable models, CDI was associated with the Charlson-Deyo comorbidity index, public insurance, and hospital size. CDI was associated with increased mortality. CONCLUSIONS: Rates of CDI among hospitalized patients with IBD had initially increased, but have declined since 2015. Increased comorbidity, large hospital size, public insurance, and urban teaching hospitals were associated with higher rates of CDI. CDI was associated with increased mortality in hospitalized patients with IBD. Continued vigilance, infection control, and treatment of CDI can help continue the trend of declining infection rates.

A rise in social media utilization by U.S. neurology residency programs in the era of COVID-19.

OBJECTIVE: To determine how neurology departments and residency programs in the United States used virtual communication to adapt to the COVID-19 pandemic, we investigated the presence and use of social media pages, virtual outreach events, and virtual internship opportunities. METHODS: Twitter, Instagram, and Facebook accounts were identified (or noted as nonexistent) for 159 accredited neurology departments and residency programs. Google searches and social media site specific searches were performed. For existing pages, the date of creation was determined and all posts on and after March 1st, 2020, were assessed to investigate the presence of virtual open house advertisements. Each program was also assessed for virtual sub-internship and elective opportunities on the Visiting Student Application Service (VSAS). RESULTS: A majority of neurology residency programs (110) had a social media presence, particularly on Twitter and Instagram. Most residency program Twitter and Instagram accounts were created after March 1st, 2020, and this was not the case on Facebook. Twitter and Instagram were used most to advertise virtual opportunities. A correlation was observed between presence and number of social media accounts and program prestige. Few programs offered virtual opportunities on VSAS for the 2020-2021 year. CONCLUSION: Neurology residency programs adapted to the COVID-19 pandemic by creating residency social media accounts, primarily on Instagram and Twitter, and hosting virtual informational events. We recommend that neurology residency applicants create professional Instagram and Twitter accounts to network with programs and receive updates about virtual events. Similarly, going forward, we recommend continued social media use by neurology residency programs for applicant outreach.

FAIR data sharing: The roles of common data elements and harmonization.

The value of robust and responsible data sharing in clinical research and healthcare is recognized by patients, patient advocacy groups, researchers, journal editors, and the healthcare industry globally. Privacy and security concerns acknowledged, the act of exchanging data (interoperability) along with its meaning (semantic interoperability) across studies and between partners has been difficult, if not elusive. For shared data to retain its value, a recommendation has been made to follow the Findable, Accessible, Interoperable, Reusable (FAIR) principles. Without applying appropriate data exchange standards with domain-relevant content standards and accessible rich metadata that uses applicable terminologies, interoperability is burdened by the need for transformation and/or mapping. These obstacles to interoperability limit the findability, accessibility and reusability of data, thus diminishing its value and making it impossible to adhere to FAIR principles. One effort to standardize data collection has been through common data elements (CDEs). CDEs are data collection units comprising one or more questions together with a set of valid values. Some CDEs contain standardized terminology concepts that define the meaning of the data, and others include links to unique terminology concept identifiers and unique identifiers for each CDE; however, usually CDEs are defined for specific projects or collaborations and lack traceable or machine readable semantics. While the name implies that these are 'common', this has not necessarily been a requirement, and many CDEs have not been commonly used. The National Institutes of Health (NIH) CDEs are, in fact, a conglomerate of CDEs developed in silos by various NIH institutes. Therefore, CDEs have not brought the anticipated benefit to the industry through widescale interoperability, nor is there widespread reuse of CDEs. Certain institutes in the NIH recommend, albeit do not enforce, institute-specific preferred CDEs; however, at the NIH level a preponderance of choice and a lack of any overarching harmonization of CDEs or consistency in linking them to controlled terminology or common identifiers create confusion for researchers in their efforts to identify the best CDEs for their protocol. The problem of comparing data among studies is exacerbated when researchers select different CDEs for the same variable or data collection field. This manuscript explores reasons for the disappointingly low adoption of CDEs and the inability of CDEs or other clinical research standards to broadly solve the interoperability and data sharing problems. Recommendations are offered for rectifying this situation to enable responsible data sharing that will help in adherence to FAIR principles and the realization of Learning Health Systems for the sake of all of us as patients.

Hematologic profile of neonates with growth restriction is associated with rate and degree of prenatal Doppler deterioration.

OBJECTIVE: To examine the relationship between hematologic parameters at birth and prenatal progression of Doppler abnormalities in fetal growth restriction (FGR). METHODS: The study was a secondary analysis of FGR patients (abdominal circumference < 5th percentile and umbilical artery pulsatility index (UA-PI) elevation) with at least three examinations prior to delivery. Prenatal progression was classified as rapid, moderate or slow based on the interval between diagnosis and delivery and the extent of UA, middle cerebral artery and ductus venosus Doppler abnormalities. Associations between diagnosis-to-delivery interval, Doppler Z-scores, progression and hematologic parameters at birth were examined. RESULTS: Of 130 patients, 54 (41.5%) had rapid, 51 (39.2%) moderate and 25 (19.2%) slow deterioration, delivering within 4, 6 and 9 weeks of diagnosis, respectively. The strongest association of moderate and rapid deterioration was with a low platelet count (r2 = 0.37 and 0.70, respectively; P < 0.0001). In patients with moderate deterioration, platelet count correlated inversely with UA-PI (ρ = -0.44, P = 0.001) and was lowest when end-diastolic velocity was absent. With rapid progression, platelet count correlated inversely with nucleated red blood cell count (ρ = -0.51, P < 0.001) but no longer with UA-PI. CONCLUSION: Our observations suggest a relationship between prenatal clinical progression of FGR and hematologic abnormalities at birth. Accelerating cardiovascular deterioration is associated with decreased platelet count, which can be explained by placental consumption or dysfunctional erythropoiesis and thrombopoiesis.

Doppler and biophysical assessment in growth restricted fetuses: distribution of test results.

OBJECTIVE: Multi-vessel Doppler ultrasonography and biophysical profile scoring (BPS) are used in the surveillance of growth restricted fetuses (IUGR). The interpretation of both tests performed concurrently may be complex. This study examines the relationship between Doppler ultrasonography and biophysical test results in IUGR fetuses. METHODS: Three hundred and twenty-eight IUGR fetuses (abdominal circumference < 5th percentile, elevated umbilical artery (UA) pulsatility index (PI)) had concurrent surveillance with UA, middle cerebral artery (MCA) and ductus venosus (DV) Doppler ultrasonography and BPS (fetal tone, movement, breathing, maximal amniotic fluid pocket and fetal heart rate). Patients were stratified into three groups according to their Doppler examination: (1) abnormal UA alone; (2) brain sparing (MCA-PI > 2 SD below mean for gestational age); and (3) abnormal DV (PI > 2 SD above the mean for gestational age) and BPS groups: (1) normal (> 6/10); (2) equivocal (6/10); and (3) abnormal (< 6/10). Predictions of short-term perinatal outcomes by both modalities were compared for stratification. The distribution and concordance of Doppler and BPS test results were examined for the whole patient group and based on delivery prior to 32 weeks' gestation. RESULTS: Abnormal UA Doppler results alone were observed in 109 fetuses (33.2%), brain sparing in 87 (26.5%) and an abnormal DV in 132 (40.2%). The BPS was normal in 158 (48.2%), equivocal in 68 (20.7%) and abnormal in 102 (31.1%). Both testing modalities stratified patients into groups with comparable acid-base disturbance and perinatal outcome. Of the nine possible test combinations the largest subgroups were: abnormal UA alone/normal BPS (n = 69; 21%) and abnormal DV Doppler/abnormal BPS (n = 62; 18.9%). Assessment of compromise by both testing modalities was concordant in 146 (44.5%) cases. In 182 fetuses with discordant results the BPS grade was better in 115 (63.2%, P < 0.0001). Marked disagreement of test abnormality was present in 57 (17.4%) fetuses. Of these, abnormal venous Doppler in the presence of a normal BPS constituted the largest group (Chi-square P < 0.002). Stratification was not significantly different in patients delivered prior to 32 weeks' gestation. CONCLUSION: Doppler ultrasonography and BPS effectively stratify IUGR fetuses into risk categories, but Doppler and BPS results do not show a consistent relationship with each other. Since fetal deterioration appears to be independently reflected in these two testing modalities further research is warranted to investigate how they are best combined.

Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2.

In the face of systemic risk factors, certain regions of the arterial vasculature remain relatively resistant to the development of atherosclerotic lesions. The biomechanically distinct environments in these arterial geometries exert a protective influence via certain key functions of the endothelial lining; however, the mechanisms underlying the coordinated regulation of specific mechano-activated transcriptional programs leading to distinct endothelial functional phenotypes have remained elusive. Here, we show that the transcription factor Kruppel-like factor 2 (KLF2) is selectively induced in endothelial cells exposed to a biomechanical stimulus characteristic of atheroprotected regions of the human carotid and that this flow-mediated increase in expression occurs via a MEK5/ERK5/MEF2 signaling pathway. Overexpression and silencing of KLF2 in the context of flow, combined with findings from genome-wide analyses of gene expression, demonstrate that the induction of KLF2 results in the orchestrated regulation of endothelial transcriptional programs controlling inflammation, thrombosis/hemostasis, vascular tone, and blood vessel development. Our data also indicate that KLF2 expression globally modulates IL-1beta-mediated endothelial activation. KLF2 therefore serves as a mechano-activated transcription factor important in the integration of multiple endothelial functions associated with regions of the arterial vasculature that are relatively resistant to atherogenesis.

folded gastrulation, cell shape change and the control of myosin localization.

The global cell movements that shape an embryo are driven by intricate changes to the cytoarchitecture of individual cells. In a developing embryo, these changes are controlled by patterning genes that confer cell identity. However, little is known about how patterning genes influence cytoarchitecture to drive changes in cell shape. In this paper, we analyze the function of the folded gastrulation gene (fog), a known target of the patterning gene twist. Our analysis of fog function therefore illuminates a molecular pathway spanning all the way from patterning gene to physical change in cell shape. We show that secretion of Fog protein is apically polarized, making this the earliest polarized component of a pathway that ultimately drives myosin to the apical side of the cell. We demonstrate that fog is both necessary and sufficient to drive apical myosin localization through a mechanism involving activation of myosin contractility with actin. We determine that this contractility driven form of localization involves RhoGEF2 and the downstream effector Rho kinase. This distinguishes apical myosin localization from basal myosin localization, which we find not to require actinomyosin contractility or FOG/RhoGEF2/Rho-kinase signaling. Furthermore, we demonstrate that once localized apically, myosin continues to contract. The force generated by continued myosin contraction is translated into a flattening and constriction of the cell surface through a tethering of the actinomyosin cytoskeleton to the apical adherens junctions. Our analysis of fog function therefore provides a direct link from patterning to cell shape change.

Statins exert endothelial atheroprotective effects via the KLF2 transcription factor.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, have been shown to positively impact vascular function independent of their plasma lipid-lowering action. Several of these beneficial effects involve modulation of gene expression. Here we explored whether the transcription factor Kruppel-like factor 2 (KLF2), a biomechanically activated gene we recently identified as part of the endothelial "atheroprotective phenotype," is regulated by statins and whether this mechanism is important for the non-lipid lowering beneficial effects mediated by these drugs in endothelium. The mRNA levels of KLF2 in human umbilical vein endothelial cells increased in the presence of various statins. KLF2 induction was observed within 8 h after drug treatment and remained elevated for at least 24 h. This statin effect on KLF2 expression was reversed by addition of mevalonate and its downstream metabolite geranygeranyl pyrophosphate. Furthermore, inhibition of protein geranylgeranylation with GGTI-298 significantly induced KLF2 levels, whereas inhibition of farnesylation did not. Statin-mediated KLF2 expression was followed by the up-regulation of several of its downstream transcriptional targets. Using small interfering RNA to block KLF2 expression, we demonstrated that this transcription factor is necessary for the statin-mediated regulation of several pathophysiologically relevant genes. These results strongly implicate KLF2 as a transcriptional regulator of the statin-mediated effects in vascular endothelium and provide a novel mechanism for the well established non-lipid lowering beneficial cardiovascular effects of statins.

Preterm premature rupture of membranes without labor is not associated with increased levels of matrix metalloproteinase-9 protein.

OBJECTIVES: Preterm premature rupture of membranes (PROM) accounts for 30-40% of all preterm births. The objectives of this study were to determine whether matrix metalloproteinase-9 (MMP-9) is increased in preterm PROM fetal membranes, whether labor or gestational age affects expression, and whether the increase is localized to the rupture site or is membrane-wide. METHODS: Fetal membranes were collected from 15 pregnancies complicated by preterm PROM and 26 control cases, which delivered at term or preterm without PROM. The preterm PROM cases represented both patients who labored and those who did not. Membrane samples at the rupture site and a remote site (approximately > 5 cm) were analyzed for MMP-9 protein and enzymatic activity by Western blot and gelatin zymography, respectively. RESULTS: MMP-9 levels in fetal membranes were similar at both the rupture and the remote sites. The highest levels of total MMP-9 protein were found in preterm PROM patients with labor (p < 0.05) and were increased four-fold over protein levels in non-laboring preterm PROM patients delivered by Cesarean section (p < 0.001). In preterm PROM patients without labor, levels of MMP-9 protein were similar to those of non-laboring patients at term and preterm. Zymography correlated with protein results in all membranes. CONCLUSIONS: Preterm PROM without labor is not associated with increased membrane levels of MMP-9 protein, suggesting that its local elevation does not play a role in early membrane rupture.