Risk of stillbirth in United States patients with diagnosed intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy is associated with a 4- to 10-fold increase in the risk of stillbirth in the absence of intervention, leading to recommendations for antenatal assessment, ursodiol use, and often preterm or early term delivery. OBJECTIVE: This study aimed to determine whether current management strategies for intrahepatic cholestasis of pregnancy mitigate the elevated risk of stillbirth at a population level. STUDY DESIGN: This was a retrospective cohort study using the 2015-2020 National Readmissions Database, an administrative database developed by the United States Agency for Healthcare Research and Quality. Our study identified delivery hospitalizations, gestational age at delivery, occurrence of intrahepatic cholestasis of pregnancy and stillbirth, and comorbid conditions using the International Classification of Diseases diagnosis and procedure codes. Moreover, this study compared the timing of delivery and stillbirth rates of pregnant patients with intrahepatic cholestasis of pregnancy vs those without intrahepatic cholestasis of pregnancy at the time of delivery hospitalization. RESULTS: This study identified a cohort of 9,987,705 delivery hospitalizations in the National Readmissions Database, corresponding to a weighted national estimate of 18,609,207 births. Of these births, 152,040 (0.8%) were noted to have an intrahepatic cholestasis of pregnancy diagnosis. Patients with an intrahepatic cholestasis of pregnancy diagnosis were older, with small differences in comorbidities, such as a higher rate of gestational diabetes mellitus, than patients without an intrahepatic cholestasis of pregnancy diagnosis at delivery hospitalization. The overall rates of stillbirth were lower among those with intrahepatic cholestasis of pregnancy than among those without intrahepatic cholestasis of pregnancy (252 vs 386 per 100,000 deliveries; risk difference, 133 fewer per 100,000 deliveries; 95% confidence interval, 98-170), a finding that persisted after adjustment for insurance status, socioeconomic factors, and comorbid conditions (risk difference, 160 fewer stillbirths per 100,000 deliveries; 95% confidence interval, 127-194). Furthermore, although patients with intrahepatic cholestasis of pregnancy were more likely to deliver before term than those without intrahepatic cholestasis of pregnancy (30.1% vs 9.3%; P<.001), increased rates of stillbirth were not noted at any point after stratification of the cohort by gestational age at delivery. CONCLUSION: Patients with intrahepatic cholestasis of pregnancy diagnosis codes delivered earlier than those without intrahepatic cholestasis of pregnancy diagnosis codes, but the percentage of births affected by stillbirth was lower, even when stratifying for gestational age at birth. These results may provide reassurance to patients receiving an intrahepatic cholestasis of pregnancy diagnosis that current management does mitigate stillbirth risk in intrahepatic cholestasis of pregnancy.

Obstetric anal sphincter injuries and other delivery trauma: a US national survey of obstetrician-gynecologists.

INTRODUCTION AND HYPOTHESIS: Obstetric lacerations complicate the majority of deliveries. The application of standardized guidelines for assessing delivery trauma has not been assessed thoroughly in the United States. We recently identified gaps in US midwives' clinical assessment of delivery trauma. We conducted a cross-sectional national survey of practicing obstetricians in the USA to characterize their classification of obstetric lacerations. We hypothesized that attending obstetricians' identification and diagnosis of delivery trauma would be similar to our findings for midwives with frequent inaccuracy. METHODS: We recruited clinically active obstetricians through the Pregnancy-Related Care Research Network. We asked participants to classify (from written definitions) and diagnose (from standard illustrations) common forms of vaginal delivery trauma using the widely employed perineal laceration degree system. We performed bivariate analysis of high- and low-scoring respondents and logistic regression to model characteristics associated with higher diagnostic accuracy. RESULTS: Of the 162 respondents who started the survey, 76% (123) were included for analysis (22% of solicited emails). Overall, we found wide variation in response accuracy with as few as 62% of respondents correctly classifying certain types of lacerations. Only 49 out of 123 (40%) use the Sultan third-degree subclassification system and 67 out of 123 (52%) continue to use the midline/median approach for episiotomies. Providers reporting fewer deliveries per month and fewer publicly insured patients earned higher scores. CONCLUSIONS: Obstetricians in a nationally representative US perinatal provider network inconsistently identify perineal and nonperineal lacerations. We found important clinical knowledge gaps, suggesting that vaginal delivery diagnoses in obstetric quality studies and pelvic floor research might be inaccurate.

Ena/VASP proteins regulate activated T-cell trafficking by promoting diapedesis during transendothelial migration.

Vasodilator-stimulated phosphoprotein (VASP) and Ena-VASP-like (EVL) are cytoskeletal effector proteins implicated in regulating cell morphology, adhesion, and migration in various cell types. However, the role of these proteins in T-cell motility, adhesion, and in vivo trafficking remains poorly understood. This study identifies a specific role for EVL and VASP in T-cell diapedesis and trafficking. We demonstrate that EVL and VASP are selectively required for activated T-cell trafficking but are not required for normal T-cell development or for naïve T-cell trafficking to lymph nodes and spleen. Using a model of multiple sclerosis, we show an impairment in trafficking of EVL/VASP-deficient activated T cells to the inflamed central nervous system of mice with experimental autoimmune encephalomyelitis. Additionally, we found a defect in trafficking of EVL/VASP double-knockout (dKO) T cells to the inflamed skin and secondary lymphoid organs. Deletion of EVL and VASP resulted in the impairment in α4 integrin (CD49d) expression and function. Unexpectedly, EVL/VASP dKO T cells did not exhibit alterations in shear-resistant adhesion to, or in crawling on, primary endothelial cells under physiologic shear forces. Instead, deletion of EVL and VASP impaired T-cell diapedesis. Furthermore, T-cell diapedesis became equivalent between control and EVL/VASP dKO T cells upon α4 integrin blockade. Overall, EVL and VASP selectively mediate activated T-cell trafficking by promoting the diapedesis step of transendothelial migration in a α4 integrin-dependent manner.

A new device for assessing ankle dorsiflexion motion: reliability and validity.

STUDY DESIGN: Clinical measurement. OBJECTIVE: To determine the validity and reliability of measures obtained using a custom-made device for assessing ankle dorsiflexion motion and stiffness. BACKGROUND: Limited dorsiflexion has been implicated in the evolution of foot pain in a number of clinical populations. Assessment of ankle dorsiflexion range of motion (ROM) is, therefore, commonly performed as part of a foot and ankle examination. Conventional goniometric assessment methods have demonstrated limited intertester reliability, while alternative methods of measurements are generally more difficult to use. The Iowa ankle range of motion (IAROM) device was designed in an attempt to develop a simple, clinically relevant, and time- and cost-effective tool to measure ankle dorsiflexion range of motion and stiffness. METHODS: Validity and intertester reliability of dorsiflexion range-of-motion measures using the IAROM device were assessed at 10, 15, 20, and 25 Nm of passively applied dorsiflexion torque, with both the knee extended and flexed approximately 20°. Stiffness (change in torque/change in dorsiflexion angle) values were determined using the angular change obtained between the 15- and 25-Nm torque levels. Convergent validity (n = 12) was assessed through comparison of ankle dorsiflexion angles measured simultaneously with the IAROM device and an optoelectronic motion analysis system. Intertester reliability (n = 17) was assessed by 2 testers who took measurements within the same day. RESULTS: Validity testing demonstrated excellent agreement (intraclass correlation coefficient [ICC] values ranging from 0.95 to 0.98). Reliability testing demonstrated good to excellent intertester agreement (ICC values ranging from 0.90 to 0.95). The ICCs for ankle joint dorsiflexion stiffness were .71 and .85 for the knee in an extended and flexed position, respectively. CONCLUSION: The IAROM device provides valid and reliable measurement of ankle dorsiflexion ROM. The IAROM device also allows calculation of stiffness by measuring ROM at multiple torque levels, although the reliability of the measurement is not optimal.

A common mutation in paraoxonase-2 results in impaired lactonase activity.

Paraoxonases (PONs) are a family of lactonases with promiscuous enzyme activity that has been implicated in multiple diseases. PON2 is intracellularly located, is the most ubiquitously expressed PON, and has the highest lactonase activity of the PON family members. Whereas some single-nucleotide polymorphisms (SNPs) in PON1 have resulted in altered enzymatic activity in serum, to date the functional consequences of SNPs on PON2 function remain unknown. We hypothesized that a common PON2 SNP would result in impaired lactonase activity. Substitution of cysteine for serine at codon 311 in recombinant PON2 resulted in normal protein production and localization but altered glycosylation and decreased lactonase activity. Moreover, we screened 200 human lung samples for the PON2 Cys(311) variant and found that in vivo this mutation impaired lactonase activity. These data suggest that impaired lactonase activity may play a role in innate immunity, atherosclerosis, and other diseases associated with the PON2 311 SNP.

Formin-like 1 mediates effector T cell trafficking to inflammatory sites to enable T cell-mediated autoimmunity.

Lymphocyte migration is essential for the function of the adaptive immune system, and regulation of T cell entry into tissues is an effective therapy in autoimmune diseases. Little is known about the specific role of cytoskeletal effectors that mediate mechanical forces and morphological changes essential for migration in complex environments. We developed a new Formin-like-1 (FMNL1) knock-out mouse model and determined that the cytoskeletal effector FMNL1 is selectively required for effector T cell trafficking to inflamed tissues, without affecting naïve T cell entry into secondary lymphoid organs. Here, we identify a FMNL1-dependent mechanism of actin polymerization at the back of the cell that enables migration of the rigid lymphocyte nucleus through restrictive barriers. Furthermore, FMNL1-deficiency impairs the ability of self-reactive effector T cells to induce autoimmune disease. Overall, our data suggest that FMNL1 may be a potential therapeutic target to specifically modulate T cell trafficking to inflammatory sites.

The Agility total ankle arthroplasty. Seven to sixteen-year follow-up.

BACKGROUND: We previously reported the intermediate-term results with the early version of the Agility total ankle replacement, a unique design that takes advantage of arthrodesis of the tibiofibular syndesmosis for tibial component support. The purpose of this study was to report longer-term results of this procedure in the treatment of disabling ankle arthritis. METHODS: We conducted an independent review of all Agility total ankle replacements performed by a single surgeon between 1984 and 1994. Follow-up evaluation consisted of completion of a validated ankle osteoarthritis scale and a short questionnaire and a review of the radiographs. All radiographs were evaluated for evidence of the development of progressive hindfoot arthritis, nonunion of the tibiofibular syndesmosis, progressive radiolucent lines, osteolysis, and component subsidence. RESULTS: One hundred and thirty-two arthroplasties were performed in 126 patients. After a mean follow-up period of nine years, thirty-three patients (thirty-six implants) had died, fourteen patients (11%) had a revision of the implant or an ankle arthrodesis, and one had the leg amputated because of an unrelated cause. Of the remaining seventy-eight patients (eighty-one ankles), sixty-seven (sixty-nine ankles) were followed clinically. More than 90% of them reported that they had decreased pain and were satisfied with the outcome of the surgery. We found modest differences in a comparison of the pain and disability scores with those of age-matched controls. Of the 117 ankles that had been followed radiographically for a minimum of two years, twenty-two (19%) had progressive subtalar arthritis, seventeen (15%) had progressive talonavicular arthritis, and nine (8%) had a syndesmosis nonunion. Eighty-nine (76%) of the 117 ankles had some evidence of peri-implant radiolucency. CONCLUSIONS: Arthrodesis of the tibiofibular syndesmosis impacts the radiographic and clinical outcomes with the Agility total ankle replacement. The relatively low rates of radiographic hindfoot arthritis and revision procedures at an average of nine years after the arthroplasty are encouraging. Agility total ankle replacement is a viable and durable option for the treatment of ankle arthritis in selected patients.

Expression of human paraoxonase 1 decreases superoxide levels and alters bacterial colonization in the gut of Drosophila melanogaster.

Paraoxonases (PON) are a family of proteins (PON1, 2 and 3) with multiple enzymatic activities. PON1 interferes with homoserine lactone-mediated quorum sensing in bacteria and with reactive oxygen species (ROS) in humans and mice. PON1 gene mutations have been linked to multiple traits, including aging, and diseases of the cardiovascular, nervous and gastrointestinal system. The overlapping enzymatic activities in the PON family members and high linkage disequilibrium rates within their polymorphisms confound animal and human studies of PON1 function. In contrast, arthropods such as Drosophila melanogaster have no PON homologs, resulting in an ideal model to study interactions between PON genotype and host phenotypes. We hypothesized that expression of PON1 in D. melanogaster would alter ROS. We found that PON1 alters expression of multiple oxidative stress genes and decreases superoxide anion levels in normal and germ-free D. melanogaster. We also found differences in the composition of the gut microbiota, with a remarkable increase in levels of Lactobacillus plantarum and associated changes in expression of antimicrobial and cuticle-related genes. PON1 expression directly decreased superoxide anion levels and altered bacterial colonization of the gut and its gene expression profile, highlighting the complex nature of the interaction between host genotype and gut microbiota. We speculate that the interaction between some genotypes and human diseases may be mediated by the presence of certain gut bacteria that can induce specific immune responses in the gut and other host tissues.

MMP9 modulates tight junction integrity and cell viability in human airway epithelia.

The family of zinc- and calcium-dependent matrix metalloproteases (MMPs) play an important role in remodeling of the airways in disease. Transcriptional regulation by proinflammatory cytokines increases lymphocyte-derived MMP9 levels in the airway lumen of asthmatics. Moreover, the levels of the MMP9 inhibitor, tissue inhibitor of metalloprotease (TIMP1), are decreased leading to increased protease activity. The mechanism by which MMP9 activity leads to asthma pathogenesis and remodeling remains unclear. Using a model of well-differentiated human airway epithelia, we found that apical MMP9 significantly increases transepithelial conductance. Moreover, apical MMP9 treatment decreased immunostaining of tight junction proteins suggesting disruption of barrier function. Consistent with this, viruses gained access to the epithelial basolateral surface after MMP9 treatment, which increased infection efficiency. All of these effects were blocked by TIMP1. In addition, loss of epithelial integrity correlated with increased epithelial cell death. Thus we hypothesized that MMP9 exerts its effects on the epithelium by cleaving one or more components of cell-cell junctions and triggering anoikis. Taken together, these data suggest that a component of airway remodeling associated with asthma may be directly regulated by MMP9.

How effective is intensive nonoperative initial treatment of patients with diabetes and Charcot arthropathy of the feet?

UNLABELLED: Diabetes mellitus and its related complications are increasing at epidemic rates in the United States. Similarly, Charcot foot and ankle deformities are becoming more prevalent. We did a retrospective review of 115 patients (127 limbs) with diabetes mellitus-associated neuroarthropathy to determine the major clinical outcomes. We hypothesized that an intensive disease-specific protocol would result in low rates of amputations. A single treatment protocol was followed for all subjects treated in a tertiary-based orthopaedic department from 1983-2003. Major outcome variables assessed included rates of below-knee amputation, long-term brace wear, reulceration, reconstructive surgeries, and bilaterality. Survivorship analyses were done during a median followup of 3.8 years. In this cohort, diabetic Charcot arthropathy treated in a structured, intensive, and nonoperative manner was associated with an approximately 2.7% annual rate of amputation, a 23% risk of requiring bracing for more than 18 months, and a 49% risk of recurrent ulceration. Limbs with open ulcers at initial presentation or chronically recurrent ulcers had increased risk for amputation. These results suggest that improved methods of care are needed for patients with diabetes who have Charcot arthropathy. LEVEL OF EVIDENCE: Therapeutic study, Level IV (case series--no, or historical control group). See the Guidelines for Authors for a complete description of levels of evidence.