Outcomes during delivery hospitalisations with inflammatory bowel disease.

OBJECTIVE: To characterise inflammatory bowel disease (IBD) trends and associated risk during delivery hospitalisations. DESIGN: Cross-sectional. SETTING: US delivery hospitalisations. POPULATION: Delivery hospitalisations in the 2000-2018 National Inpatient Sample. METHODS: This study analysed a nationally representative hospital discharge database based on the presence of IBD. Temporal trends in IBD were analysed using joinpoint regression to estimate the average annual percent change (AAPC). IBD severity was characterised by the presence of diagnoses such as penetrating and stricturing disease and history of bowel resection. Risks for adverse outcomes were analysed based on presence of IBD. Poisson regression models were performed with unadjusted and adjusted risk ratios (aRR) as measures of effect. MAIN OUTCOME MEASURE: Prevalence of IBD and associated adverse outcomes. RESULTS: Of 73 109 790 delivery hospitalisations, 89 965 had a diagnosis of IBD. IBD rose from 0.06% in 2000 to 0.21% in 2018 (AAPC 7.3%, 95% CI 6.7-7.9%). Among deliveries with IBD, IBD severity diagnoses increased from 4.1% to 8.1% from 2000 to 2018. In adjusted analysis, IBD was associated with increased risk for preterm delivery (aRR 1.50, 95% CI 1.47-1.53), severe maternal morbidity (aRR 1.93, 95% CI 1.83-2.04), venous thrombo-embolism (aRR 2.76, 95% CI 2.39-3.18) and surgical injury during caesarean delivery hospitalisation (aRR 5.03, 95% CI 4.76-5.31). In the presence of a severe IBD diagnosis, risk was further increased for all adverse outcomes. CONCLUSION: IBD is increasing in the obstetric population and is associated with adverse outcomes. Risk is increased in the presence of a severe IBD diagnosis. TWEETABLE ABSTRACT: Deliveries among women with inflammatory bowel disease are increasing. Disease severity is associated with adverse outcomes.

Population risk factors for nulliparous, term, singleton, vertex caesarean birth: a national cross-sectional study.

OBJECTIVE: To characterise medical, obstetric and demographic risk factors associated with nulliparous, term, singleton, vertex (NTSV) caesarean birth. STUDY DESIGN: Cross-sectional study. SETTING: United States delivery hospitalisations. POPULATION: NTSV births in 2016-18 US natality data. METHODS: This study analysed a national sample of natality data generated by the United States National Vital Statistics System. NTSV deliveries were identified. The primary outcome was caesarean birth. Risk factors including maternal age, body mass index (BMI) and pregestational diabetes were analysed. Multivariable log-linear regression models analysed factors associated with NTSV caesarean with adjusted risk ratios (aRR) as measures of effect. RESULTS: Of 11 622 400 deliveries, 3 764 707 met NTSV criteria, and their caesarean section rate was 25.9%. Maternal age 35-39 years (aRR 1.51, 95% CI 1.50-1.52) and 40-54 years (aRR 2.03, 95% 2.00-2.05) compared with age 19-34 years; BMI 25 to <30 kg/m2 (aRR 1.32, 95% CI 1.31-1.33), 30 to <35 kg/m2 (aRR 1.57 95% CI 1.56-1.58), 35 to <40 kg/m2 (aRR 1.82, 95% CI 1.80-1.83) and ≥40 kg/m2 (aRR 2.17, 95% CI 2.15-2.19) compared with BMI 18.5-24.9 kg/m2; and pregestational diabetes (aRR 1.54, 95% CI 1.51-1.57) were all associated with increased risk. Risk factors allowed stratification of patients into high-risk versus low-risk groups. The NTSV caesarean rate was 37.9% in women who had one or more of the following characteristics: age ≥35 years, BMI ≥30 kg/m2 or pregestational diabetes. In comparison, the NTSV caesarean rate was 20.8% among women without any of these three risk factors (P < 0.01). CONCLUSION: Among NTSV births, BMI, maternal age and medical conditions are important risk factors for caesarean delivery.

Impact of timing of delivery on maternal and neonatal outcomes for women after three previous caesarean deliveries; a secondary analysis of the caesarean section registry.

BACKGROUND: As more women are presenting with three previous caesarean deliveries (CD), providers may suggest early term delivery as a means to avoid the risk of spontaneous labour and associated maternal morbidity. OBJECTIVE: To determine whether early term delivery is associated with lower maternal and neonatal morbidity for women with three previous CD. STUDY DESIGN: Secondary analysis of a prospective registry of CD at 19 US academic centres from 1999 to 2002. POPULATION: Women with three previous CD undergoing scheduled or emergent delivery with live, singleton gestations 37-41+ weeks of gestation were included. Women with non-low transverse incisions, antepartum stillbirth, previous myomectomy, fetal anomalies, more or fewer than three previous CD or attempting trial of labour after caesarean section were excluded. METHODS: Gestational age was categorised by week. We fitted logistic regression models to adjust for clinically relevant or statistically significant confounders. MAIN OUTCOME MEASURES: The primary and secondary outcomes were composites, respectively, of maternal and neonatal morbidity. RESULTS: In all, 821 women met the inclusion criteria; maternal morbidity composite occurred in 9.86% and neonatal morbidity occurred in 10.5%. After adjusting for confounding variables, maternal and neonatal morbidity occurred least frequently at 39 weeks. CONCLUSIONS: In women with three previous CDs, adverse maternal outcomes do not increase with increasing gestational age beyond 37 weeks but early term elective repeat CDs are associated with higher neonatal morbidity. Elective delivery of women with three previous CD at 39 weeks of gestation is safe in the absence of maternal or fetal indications for early term delivery. TWEETABLE ABSTRACT: Delivery of women with three previous caesarean deliveries at 39 weeks, in the absence of maternal or fetal indications for early term delivery, is associated with decreased maternal morbidity.

Trends in operative vaginal delivery, 2005-2013: a population-based study.

OBJECTIVE: The objectives of this study were to determine temporal trends in forceps and vacuum delivery and factors associated with operative vaginal delivery. DESIGN: Retrospective cohort. SETTING: Population-based study of US birth records. POPULATION: US births from 2005 to 2013. METHODS: This study evaluated forceps and vacuum extraction during vaginal delivery in live-born, non-anomalous singleton gestations from ≥ 36 to < 42 weeks of gestation. The primary outcomes were vacuum, forceps and overall operative delivery. Obstetric, medical and demographic characteristics associated with operative vaginal delivery were analysed. Multivariable logistic regression models were developed to determine factors associated with forceps/vacuum use. RESULTS: A total of 22 598 971 vaginal deliveries between 2005 and 2013 were included in the analysis. In all, 1 083 318 (4.8%) were vacuum-assisted and 237 792 (1.1%) were by forceps. Both vacuum and forceps deliveries decreased over the study period; vacuum deliveries decreased from 5.8% in 2005 to 4.1% in 2013, and forceps deliveries decreased from 1.4% to 0.9% during the same period. The adjusted odds ratio for forceps delivery was 0.70 (95% CI 0.69-0.72) in 2013 with 2005 as a reference. For vacuum delivery the odds ratio was 0.68 (95% CI 0.67-0.69) comparing the same years. CONCLUSION: Forceps and vacuum deliveries decreased during the study period. Low rates of operative delivery pose a challenge for resident education and may limit the degree to which women have access to alternatives to caesarean delivery. Initiatives that allow future generations of obstetricians to develop expertise in performing operative deliveries in the setting of decreased volume are an urgent resident education priority. TWEETABLE ABSTRACT: Forceps and vacuum delivery decreased significantly in the USA from 2005 to 2013.

Gestational diabetes in the United States: temporal changes in prevalence rates between 1979 and 2010.

OBJECTIVE: To examine age-period-cohort effects on trends in gestational diabetes mellitus (GDM) prevalence in the US, and to evaluate how these trends have affected the rates of stillbirth and large for gestational age (LGA)/macrosomia. DESIGN: Retrospective cohort study. SETTING: USA, 1979-2010. POPULATION: Over 125 million pregnancies (3 337 284 GDM cases) associated with hospitalisations. METHODS: Trends in GDM prevalence were examined via weighted Poisson models to parse out the extent to which GDM trends can be attributed to maternal age, period of delivery, and maternal birth cohort. Multilevel models were used to assess the contribution of population effects to the rate of GDM. Log-linear Poisson regression models were used to estimate the contributions of the increasing GDM rates to changes in the rates of LGA and stillbirth between 1979-81 and 2008-10. MAIN OUTCOME MEASURES: Rates and rate ratios (RRs). RESULTS: Compared with 1979-1980 (0.3%), the rate of GDM has increased to 5.8% in 2008-10, indicating a strong period effect. Substantial age and modest cohort effects were evident. The period effect is partly explained by period trends in body mass index (BMI), race, and maternal smoking. The increasing prevalence of GDM is associated with a 184% (95% CI 180-188%) decline in the rate of LGA/macrosomia and a 0.75% (95% CI 0.74-0.76) increase in the rate of stillbirths for 2008-10, compared with 1979-81. CONCLUSIONS: The temporal increase in GDM can be attributed to period of pregnancy and age. Increasing BMI appears to partially contribute to the GDM increase in the US. TWEETABLE ABSTRACT: The increasing prevalence of GDM can be attributed to period of delivery and increasing maternal age.

Serious maternal complications in relation to severe pre-eclampsia: a retrospective cohort study of the impact of hospital volume.

OBJECTIVE: We examined rates of serious maternal complications in relation to severe pre-eclampsia based on the delivering hospital's annualised volume. DESIGN: Retrospective cohort study. POPULATION AND SETTING: Singleton deliveries (n = 25 782 235) in 439 hospitals in the USA. METHODS: Annualised hospital volume was categorised as 25-500, 501-1000, 1001-2000 and >2000. MAIN OUTCOME MEASURES: Rates of in-hospital maternal death and serious maternal complications, including puerperal cerebrovascular disorders, pulmonary oedema, disseminated intravascular coagulation, acute renal, heart and liver failure, sepsis, haemorrhage and intubation in relation to severe pre-eclampsia. We derived adjusted risk ratio (RR) and 95% confidence interval (CI), from hierarchical Poisson regression models. RESULTS: Severe pre-eclampsia was associated with an 8.7-fold (95% CI 7.6, 10.1) risk of composite maternal complications, with similar RRs across levels of hospital volumes. However, compared with hospitals with low annual volume (<2000), maternal mortality rates in relation to severe pre-eclampsia were lower in high volume hospitals. The rates of serious maternal complications were 410.7 per 10 000 to women who delivered in hospitals with a high rate of severe pre-eclampsia (≥2.12%) and 584.8 per 10 000 to women who delivered in hospitals with low severe pre-eclampsia rates (≤0.41; RR 1.75, 95% CI 1.24, 2.45). CONCLUSIONS: While the risks of serious maternal complications in relation to severe pre-eclampsia was similar across hospital delivery volume categories, deaths showed lower rates in large delivery volume hospitals than in smaller volume hospitals. The risk of complications was increased in hospitals with low compared with high severe pre-eclampsia rates. TWEETABLE ABSTRACT: Hospital volume had little impact on the association between severe pre-eclampsia and maternal complications.

Neurodevelopmental outcomes in children in relation to placental abruption.

OBJECTIVE: Placental abruption has a profound impact on perinatal mortality, but implications for neurodevelopment during childhood remain unknown. We examined the association between abruption and neurodevelopment at 8 months and 4 and 7 years and evaluated the extent to which these associations were mediated through preterm delivery. DESIGN: Secondary analysis of a multicenter prospective cohort study. SETTING: Multicenter US National Collaborative Perinatal Project (1959-76). POPULATION: Women that delivered singleton live births. METHODS: Analyses of IQ scores were based on marginal structural models (MSM) to account for losses to follow-up. We also carried out a causal mediation analysis to evaluate if the association between abruption and cognitive deficits was mediated through preterm delivery, and performed a sensitivity analysis for unobserved confounding. MAIN OUTCOME MEASURES: We evaluated cognitive development based on the Bayley scale at 8 months (Mental and Motor Scores), and intelligent quotient (IQ) based on the Stanford-Binet scale at 4 years and the Wechsler Intelligence Scale for Children at 7 years. RESULTS: The confounder and selection-bias adjusted risk ratio (RR) of abnormal 8-month Motor and Mental assessments were 2.35 (95%CI 1.39, 3.98) and 2.03 (95%CI 1.13, 3.64), respectively, in relation to abruption. The associations at 4 years were attenuated and resolved at 7 years. The proportion of children with abruption-associated neurological deficits mediated through preterm delivery ranged from 27 to 75%. Following adjustment for unobserved confounding the proportion mediated through preterm delivery was attenuated. CONCLUSION: The effect of abruption on neurodevelopmental outcomes appears restricted to an effect that is largely mediated through preterm delivery. TWEETABLE ABSTRACT: Increased risk of cognitive deficits in relation to abruption appears to be mediated through preterm delivery.

The effect of maternal haematocrit on offspring IQ at 4 and 7 years of age: a secondary analysis.

OBJECTIVE: To determine whether maternal haematocrit during pregnancy is associated with offspring IQ. DESIGN/SETTING/POPULATION: A secondary analysis of the Collaborative Perinatal Project, which enrolled women between 1959 and 1966 at 12 university hospitals in the United States. METHODS: We evaluated the relation between maternal haematocrit and IQ at 4 and 7 years of age. Linear and log-linear regression models were used to adjust for possible confounders. Marginal structural models with stabilised weights were used to account for selection bias due to children lost to follow up. MAIN OUTCOME MEASURES: Offspring IQ at 4 and 7 years of age. RESULTS: Of 35 959 patients, 1521 (4.2%) had moderate anaemia, 13 769 (38.3%) had mild anaemia, 18 227 (50.7%) had a normal haematocrit, and 2442 (6.8%) had a high haematocrit. The mean IQ at 4 and 7 years was significantly lower in the moderate and mild anaemia groups than in the normal haematocrit group (92.3 and 94.7 versus 100.6, respectively, P < 0.01, at 4 years; and 90.2 and 93.4 versus 99.1 at 7 years, P < 0.01). The high haematocrit group had a significantly higher mean IQ (104.5 at 4 years; 103.2 at 7 years) when compared with the normal haematocrit group (P < 0.01). Women with moderate anaemia were more likely to have children with IQ of 70-84 at 4 years (RR 1.22, 95% CI 1.08-1.38) and <70 at 7 years (RR 1.59, 95% CI 1.14-2.23). Women with a high haematocrit were more likely to have children with an IQ ≥120 at 7 years (RR 1.22, 95% CI 1.08-1.39). CONCLUSIONS: Maternal haematocrit is associated with offspring IQ at 4 and 7 years of age. TWEETABLE ABSTRACT: There is a nonlinear relation between maternal haematocrit and offspring IQ at 4 and 7 years of age.

Prolonged latency of preterm prelabour rupture of membranes and neurodevelopmental outcomes: a secondary analysis.

OBJECTIVE: To determine whether prolonged latency after preterm prelabour rupture of membranes (PPROM) is associated with an increased risk for adverse neurodevelopmental outcomes. DESIGN: This is a secondary analysis of the randomised controlled trial of magnesium sulphate for the prevention of cerebral palsy. SETTING: Multicentre trial. POPULATION: A total of 1305 women with PPROM were analysed, 1056 of whom had an interval of <3 weeks between diagnosis and delivery and 249 of whom had an interval of ≥3 weeks between diagnosis and delivery. METHODS: We evaluated whether the time interval between diagnosis of PPROM and delivery was associated with an increased risk for adverse neurodevelopmental outcomes. Latency was analysed as a continuous variable and categorised by weeks of latency. MAIN OUTCOME MEASURES: The primary outcome was motor and mental Bayley scores of <70 at 2 years of age. Secondary outcomes included motor and mental Bayley scores <85 and mean Bayley scores. Logistic regression was used to control for confounding factors. RESULTS: In the univariate analysis, motor and mental Bayley scores of <70 were similar in the <3 weeks (16.8 and 14.4%) and ≥3 weeks (15.3 and 14.1%) groups. In the regression analysis adjusting for confounding factors, PPROM for ≥3 weeks was an independent risk factor for motor (adjusted odds ratio (aOR) 2.12; 95% confidence interval, 95% CI 1.29-3.49) and mental (aOR 1.83, 95% CI 1.13-3.00) Bayley scores of <70. Neonatal sepsis, gestational age at delivery, maternal education, and race were significantly associated with neurodevelopmental outcomes. CONCLUSIONS: Whereas delivery at later gestational age is associated with improved prognosis for many outcomes, prolonged exposure to an intrauterine environment of PPROM is an independent risk factor for adverse neurodevelopmental outcomes. TWEETABLE ABSTRACT: Prolonged PPROM was associated with motor and mental Bayley scores of <70.

A comparison of recommendations for pharmacologic thromboembolism prophylaxis after caesarean delivery from three major guidelines.

OBJECTIVE: Guidelines for pharmacologic obstetric venous thromboembolism (VTE) prophylaxis from the American Congress of Obstetricians (ACOG), the Royal College of Obstetricians and Gynaecologists (RCOG), and the American College of Chest Physicians (Chest) vary significantly. The objective of this study was to determine the practical implications of these recommendations in terms of prophylaxis rates for a tertiary obstetric population. STUDY DESIGN: Cross-sectional. SETTING: Tertiary referral hospital. POPULATION: Patients post-operative day 1 after caesarean delivery. METHODS: This cross-sectional study evaluated rates of pharmacologic prophylaxis for women based on RCOG, ACOG, and Chest recommendations. Medical, obstetric, and demographic risk factors for thromboembolism were reviewed for individual patients. Rates of prophylaxis based on each of the guidelines with 95% confidence intervals were calculated. OUTCOME MEASURE: Recommended pharmacologic prophylaxis. RESULTS: About 293 patients were included in the analysis. Under RCOG guidelines, 85.0% of patients would receive post-caesarean pharmacologic prophylaxis [95% confidence interval (CI) 80.5-88.6%] compared with 1.0% of patients under ACOG guidelines (95% CI 0.3-3.0%) and 34.8% of patients under Chest guidelines (95% CI 29.6-40.4%). Caesarean during labour, obesity, advanced maternal age, pre-eclampsia, and multiple gestation were among the most commonrisk factors. CONCLUSION: Recommended prophylaxis differed significantly. Under ACOG recommendations a small minority of patients would receive prophylaxis, whereas under RCOG recommendations a large majority of patients would receive low-molecular-weight heparin. Given the large differences in prophylaxis rates for post-caesarean thromboprophylaxis based on different guidelines, further research is urgently needed to compare the risks and benefits of recommendations. TWEETABLE ABSTRACT: Recommendations from major society guidelines for post-caesarean thromboprophylaxis differ greatly.

Clinical indication and timing of antenatal corticosteroid administration at a single centre.

OBJECTIVE: To determine how well antenatal corticosteroids (ACS) were timed, based on the indication for administration for women delivering preterm. DESIGN: Retrospective cohort study. SETTING: Tertiary medical centre. POPULATION: Six hundred and thirty women who had singleton preterm births between 24 and 34 weeks' gestational age. METHODS: Charts from 2006 to 2011 were reviewed for indications for ACS administration, which included premature rupture of membranes, threatened preterm labour, risk factors for spontaneous preterm birth such as short ultrasound cervical length, positive fetal fibronectin, and hypertensive disorders of pregnancy. Charts were reviewed for timing of ACS administration in relation to delivery. MAIN OUTCOME MEASURES: The primary outcome was optimal timing, defined as administration of ACS ≥ 24 hours to ≤ 7 days prior to delivery. RESULTS: Of 630 women who delivered preterm, 589 (93%) received ACS prior to delivery. ACS timing was optimal in 40% (238 of 589) of cases. Women with hypertensive disorders were most likely to have steroids optimally timed (62%). Asymptomatic women at increased risk for preterm delivery were less likely to receive optimally timed ACS (12%). The majority of women who received steroids >2 weeks prior to delivery (57%) received a second course. CONCLUSION: A majority of women who delivered preterm did not receive optimally timed ACS. Diagnostic tools that identified women at risk for preterm birth were not able to identify patients for appropriate steroid timing. Given the range of clinical scenarios in which patients are at increased risk for preterm delivery, further research is needed to assist clinicians in optimising steroid administration. TWEETABLE ABSTRACT: Optimal timing of antenatal steroids prior to delivery does not occur in most cases.

Hospital variation in maternal complications following caesarean delivery in the United States: 2006-2012.

OBJECTIVE: To assess hospital variability in and patient and hospital factors associated with caesarean delivery (CD) complications. STUDY DESIGN: Population-based cohort. SETTING: United States delivery admissions. POPULATION: Women who underwent a CD between 2006 and 2012. METHODS: Hospital-specific random-effects log-linear regression models were developed to account for patient, obstetric, and hospital risk factors related to a composite complication outcome including infection, haemorrhage, surgical complications and prolonged hospital stay. Between-hospital variability in rates of CD complications was also estimated. MAIN OUTCOME MEASURE: Composite complication rate. RESULTS: Among 1 339 397 women who underwent CD in 457 hospitals, 6.4% (n = 85 838) experienced a complication. The most frequent complications were haemorrhage, transfusion, length of stay >7 days, and endometritis. Complications were strongly associated with the presence of obstetric factors and pre-existing medical conditions. Complication rates were 54% higher among black (8.8%) than white (5.7%) women (P < 0.001), and were more common in teaching (8.1%) than non-teaching (5.4%) hospitals (P < 0.001). In an adjusted model, the mean complication rate was 6.7%. A small proportion of hospitals (4.8%) had a complication rate greater than twice the mean (≥13.4%). Complications were strongly associated with the presence of obstetrical factors and pre-existing medical conditions. CONCLUSIONS: CD complication rates are strongly associated with patient and obstetric factors. While CD complication rates may be a quality metric of limited utility given the low rate of complications across most hospitals, a small number of hospitals demonstrate particularly high rates of complications. Review of CD complication rates may be an important aspect of quality assurance processes for these centres. TWEETABLE ABSTRACT: A small number of hospitals demonstrate particularly high rates of caesarean complications.

Geometric analysis of cross-linkability for protein fold discrimination.

Protein structure provides insight into the evolutionary origins, functions, and mechanisms of proteins. We are pursuing a minimalist approach to protein fold identification that characterizes possible folds in terms of consistency of their geometric features with restraints derived from relatively cheap, high-throughput experiments. One such experiment is residue-specific cross-linking analyzed by mass spectrometry. This paper presents a suite of novel lower- and upper-bounding algorithms for analyzing the distance between surface cross-link sites and thereby validating predicted models against experimental cross-linking results. Through analysis and computational experiments, using simulated and published experimental data, we demonstrate that our algorithms enable effective model discrimination.

Restriction enzyme BsoBI-DNA complex: a tunnel for recognition of degenerate DNA sequences and potential histidine catalysis.

BACKGROUND: Restriction endonucleases form a diverse family of proteins with substantial variation in sequence, structure, and interaction with recognition site DNA. BsoBI is a thermophilic restriction endonuclease that exhibits both base-specific and degenerate recognition within the sequence CPyCGPuG. RESULTS: The structure of BsoBI complexed to cognate DNA has been determined to 1.7 A resolution, revealing several unprecedented features. Each BsoBI monomer is formed by inserting a helical domain into an expanded EcoRI-type catalytic domain. DNA is completely encircled by a BsoBI dimer. Recognition sequence DNA lies within a 20 A long tunnel of protein that excludes bulk solvent. Interactions with the specific bases are made in both grooves through direct and water-mediated hydrogen bonding. Interaction with the degenerate position is mediated by a purine-specific hydrogen bond to N7, ensuring specificity, and water-mediated H bonding to the purine N6/O6 and pyrimidine N4/O4, allowing degeneracy. In addition to the conserved active site residues of the DX(n)(E/D)ZK restriction enzyme motif, His253 is positioned to act as a general base. CONCLUSIONS: A catalytic mechanism employing His253 and two metal ions is proposed. If confirmed, this would be the first example of histidine-mediated catalysis in a restriction endonuclease. The structure also provides two novel examples of the role of water in protein-DNA interaction. Degenerate recognition may be mediated by employing water as a hydrogen bond donor or acceptor. The structure of DNA in the tunnel may also be influenced by the absence of bulk solvent.

Crystal structure of protein isoaspartyl methyltransferase: a catalyst for protein repair.

BACKGROUND: Formation of isoaspartyl residues is one of several processes that damage proteins as they age. Protein L-isoaspartate (D-aspartate) O-methyltransferase (PIMT) is a conserved and nearly ubiquitous enzyme that catalyzes the repair of proteins damaged by isoaspartyl formation. RESULTS: We have determined the first structure of a PIMT from crystals of the T. maritima enzyme complexed to S-adenosyl-L-homocysteine (AdoHcy) and refined it to 1.8 A resolution. Although PIMT forms one structural unit, the protein can be divided functionally into three subdomains. The central subdomain closely resembles other S-adenosyl-L-methionine-dependent methyltransferases but bears a striking alteration of topological connectivity, which is not shared by any other member of this family. Rather than arranged as a mixed beta sheet with topology 6 upward arrow7 downward arrow5 upward arrow4 upward arrow1 upward arrow2 upward arrow3 upward arrow, the central sheet of PIMT is reorganized to 7 upward arrow6 downward arrow5 upward arrow4 upward arrow1 upward arrow2 upward arrow3 upward arrow. AdoHcy is largely buried between the N-terminal and central subdomains by a conserved and largely hydrophobic loop on one rim of the binding cleft, and a conserved Ser/Thr-rich beta strand on the other. The Ser/Thr-rich strand may provide hydrogen bonds for specific interactions with isoaspartyl substrates. The side chain of Ile-206, a conserved residue, crosses the cleft, restricting access to the donor methyl group to a deep well, the putative isoaspartyl methyl acceptor site. CONCLUSIONS: The structure of PIMT reveals a unique modification of the methyltransferase fold along with a site for specific recognition of isoaspartyl substrates. The sequence conservation among PIMTs suggests that the current structure should prove a reliable model for understanding the repair of isoaspartyl damage in all organisms.