Betamethasone treatment-to-delivery interval, retreatment, and severe intraventricular hemorrhage in infants <28 weeks' gestation.

BACKGROUND: Antenatal corticosteroids decrease the incidence of severe intraventricular hemorrhages (grades 3,4) in preterm infants. It is unclear whether their beneficial effects on intraventricular hemorrhage wane with time (as occurs in neonatal respiratory distress) and if repeat courses can restore this effect. Prior randomized controlled trials of betamethasone retreatment found no benefit on severe intraventricular hemorrhage rates. However, the trials may have included an insufficient number of infants at risk for intraventricular hemorrhage to be able to adequately address this question. Severe intraventricular hemorrhages occur almost exclusively in infants born <28 weeks, whereas only 7% (0%-16%) of the retreatment trials' populations were <28 weeks. OBJECTIVE: To determine if the risk of severe intraventricular hemorrhage in infants delivered <28 weeks increases when the betamethasone treatment-to-delivery interval increases beyond 9 days and to determine if betamethasone retreatment prior to delivery decreases the rate of hemorrhage. STUDY DESIGN: Observational study examining the incidence of intraventricular hemorrhage before (epoch 1) and after (epoch 2) a practice change that encouraged obstetricians to retreat pregnant women still at high risk of delivery before 28 weeks' gestation when >9 days elapsed from the first dose of betamethasone. Multivariable analyses with logistic regression using generalized estimating equations techniques were conducted to examine the rates of intraventricular hemorrhage among 410 infants <28 weeks' gestation who either delivered between 1-9 days (n=290) after the first 2-dose betamethasone course or delivered ≥10 days (and eligible for retreatment) (n=120). RESULTS: After adjusting for potential confounding variables, infants who delivered ≥10 days after a single betamethasone course had an increased risk of either severe intraventricular hemorrhage alone or the combined outcome severe intraventricular hemorrhage or death before 4 days (OR (95%CI): 2.8 (1.2, 6.6)) compared with infants who delivered between 1-9 days after betamethasone. Among the 120 infants who delivered ≥10 days after the first dose of betamethasone, 64 (53%) received a second/retreatment course of antenatal betamethasone. The severe intraventricular hemorrhage rate in infants whose mothers received a second/retreatment course of betamethasone was similar to the rate in infants who delivered within 1-9 days and significantly lower than in those who delivered ≥10 days without retreatment (OR (95%CI): 0.10 (0.02, 0.65). Following the change in guidelines, the rate of retreatment in infants who delivered ≥10 days after the first betamethasone course (and before 28 weeks) increased from epoch 1 to epoch 2 (25% to 87%, p<0.001) and the rate of severe intraventricular hemorrhage decreased from 22% to 0% (p<0.001). In contrast, the rate of severe intraventricular hemorrhage in infants who delivered 1-9 days after the initial betamethasone dose (who were not eligible for retreatment) did not change between epochs 1 and 2 (12% and 11%, respectively). CONCLUSIONS: Although betamethasone's benefits on severe intraventricular hemorrhage appear to wane after the first dose, retreatment with a second course appears to restore its beneficial effects. Encouraging earlier retreatment of women at high risk of delivery before 28 weeks was associated with a lower rate of severe intraventricular hemorrhages among infants delivering <28 weeks.

Evidence-based prescribing of opioids after laparotomy: A quality-improvement initiative in gynecologic oncology.

Introduction: Across specialties, surgeons over-prescribe opioids to patients after surgery. We aimed to develop and implement an evidence-based calculator to inform post-discharge opioid prescription size for gynecologic oncology patients after laparotomy. Methods: In 2021, open surgical gynecologic oncology patients were called 2-4 weeks after surgery to ask about their home opioid use. This data was used to develop a calculator for post-discharge opioid prescription size using two factors: 1) age of the patient, 2) oral morphine equivalents (OME) used by patients the day before hospital discharge. The calculator was implemented on the inpatient service from 8/21/22 and patients were contacted 2-4 weeks after surgery to again assess their opioid use at home. Results: Data from 95 surveys were used to develop the opioid prescription size calculator and are compared to 95 post-intervention surveys. There was no difference pre- to post-intervention in demographic data, surgical procedure, or immediate postoperative recovery. The median opioid prescription size decreased from 150 to 37.5 OME (p < 0.01) and self-reported use of opioids at home decreased from 22.5 to 7.5 OME (p = 0.05). The refill rate did not differ (12.6 % pre- and 11.6 % post-intervention, p = 0.82). The surplus of opioids our patients reported having at home decreased from 1264 doses of 5 mg oxycodone tabs in the pre-intervention cohort, to 490 doses in the post-intervention cohort, a 61 % reduction. Conclusions: An evidence-based approach for prescribing opioids to patients after laparotomy decreased the surplus of opioids we introduced into our patients' communities without impacting refill rates.

Exploring the relationship between language, postoperative pain, and opioid use.

BACKGROUND: Racial and ethnic disparities in pain management are well documented. Differences in pain assessment and management by language have not been studied in the postoperative setting in gynecologic surgery. OBJECTIVE: This study aimed to investigate the association between language and immediate postoperative pain management by comparing pain assessments and perioperative opioid use in non-English speakers and English speakers. STUDY DESIGN: This was a retrospective cohort study comparing perioperative outcomes between non-English-speaking patients and English-speaking patients who had undergone a gynecologic oncology open surgery between July 2012 and December 2020. The primary language was extracted from the electronic medical record. Opioid use is expressed in oral morphine equivalents. Proportions are compared using chi-square tests, and mean values are compared using 2-sample t tests. Although interpreter services are widely available in our institution, the use of interpreters for any given inpatient-provider interaction is not documented. RESULTS: Between 2012 and 2020, 1203 gynecologic oncology patients underwent open surgery, of whom 181 (15.1%) were non-English speakers and 1018 (84.9%) were English speakers. There was no difference between the 2 cohorts concerning body mass index, surgical risk score, or preoperative opioid use. Compared with the English-speaking group, the non-English-speaking group was younger (57 vs 54 years old, respectively; P<.01) and had lower rates of depression (26% vs 14%, respectively; P<.01) and chronic pain (13% vs 6%, respectively; P<.01). Although non-English-speaking patients had higher rates of hysterectomy than English-speaking patients (80% vs 72%, respectively; P=.03), there was no difference in the rates of bowel resections, adnexal surgeries, lengths of surgery, intraoperative oral morphine equivalents administered, blood loss, use of opioid-sparing modalities, lengths of hospital stay, or intensive care unit admissions. In the postoperative period, compared with English-speaking patients, non-English-speaking patients received fewer oral morphine equivalents per day (31.7 vs 43.9 oral morphine equivalents, respectively; P<.01) and had their pain assessed less frequently (7.7 vs 8.8 checks per day, respectively; P<.01) postoperatively. English-speaking patients received a median of 19.5 more units of oral morphine equivalents daily in the hospital and 205.1 more units of oral morphine equivalents at the time of discharge (P=.02 and P=.04, respectively) than non-English-speaking patients. When controlling for differences between groups and several factors that may influence oral morphine equivalent use, English-speaking patients received a median of 15.9 more units of oral morphine equivalents daily in the hospital cohort and similar oral morphine equivalents at the time of discharge compared with non-English-speaking patients. CONCLUSION: Patients who do not speak English may be at risk of undertreated pain in the immediate postoperative setting. Language barrier, frequency of pain assessments, and provider bias may perpetuate disparity in pain management. Based on this study's findings, we advocate for the use of regular verbal pain assessments with language-concordant staff or medical interpreters for all postoperative patients.

Patent ductus arteriosus (PDA) and pulmonary morbidity: can early targeted pharmacologic PDA treatment decrease the risk of bronchopulmonary dysplasia?

A persistent left-to-right shunt through a patent ductus arteriosus (PDA) increases the rate of pulmonary hydrostatic fluid filtration, impairs pulmonary mechanics, and prolongs the need for respiratory support. Infants with a moderate/large PDA shunt that persists for more than 7-14 days are at increased risk for developing bronchopulmonary dysplasia (BPD) if they also require invasive ventilation for more than 10 days. In contrast, infants who require invasive ventilation for less than 10 days have similar rates of BPD no matter how long they are exposed to a moderate/large PDA shunt. Although pharmacologic PDA closure decreases the risk of abnormal early alveolar development in preterm baboons that are ventilated for 2 weeks, the findings from recent randomized controlled trials, as well as a quality improvement project, suggest that routine early targeted pharmacologic treatments, as currently employed, do not appear to alter the incidence of BPD in human infants.

Patent ductus arteriosus and the risk of bronchopulmonary dysplasia-associated pulmonary hypertension.

BACKGROUND: The aim of the study was to determine whether prolonged exposure to a moderate/large patent ductus arteriosus left-to-right shunt (PDA) increases the risk of late (beyond 36 weeks) pulmonary hypertension (BPD-PH) and pulmonary vascular disease (BPD-PVD) during the neonatal hospitalization in preterm infants (<28 weeks' gestation) with bronchopulmonary dysplasia (BPD). METHODS: All infants requiring respiratory support ≥36 weeks had systematic echocardiographic evaluations for BPD-PH at planned intervals. Infants were classified as having either flow-associated BPD-PH (BPD-flow-PH) or BPD-PVD. RESULTS: 256 infants survived ≥36 weeks: 105 had NO BPD (were off respiratory support by 36 weeks); 151 had BPD. 22/151 had BPD-PH (12/22 had BPD-flow-PH from a PDA that persisted beyond 36 weeks; 10/22 had BPD-PVD). Moderate/large PDA shunts that persisted beyond 36 weeks were significantly associated with an increased incidence of BPD-PH due to BPD-flow-PH. We found no association between the duration of PDA exposure and the incidence of BPD-PVD. CONCLUSIONS: Moderate/large PDA shunts increase the risk of flow-associated BPD-PH when present beyond 36 weeks. Although term infants with PDA-congenital heart disease can develop pulmonary vascular remodeling and PVD after months of PDA exposure, we found no echocardiographic evidence in preterm infants that prolonged PDA exposure increases the incidence of BPD-PVD during the neonatal hospitalization. IMPACT: In our study, preterm infants (<28 weeks' gestation) with bronchopulmonary dysplasia (BPD) had a 15% incidence of pulmonary hypertension (PH) beyond 36 weeks' postmenstrual age as a comorbidity. Moderate/large patent ductus arteriosus (PDA) shunts increased the risk of flow-associated PH when present beyond 36 weeks. Although months of prolonged PDA exposure can cause pulmonary vascular remodeling and pulmonary vascular disease (PVD) in term infants with PDA-congenital heart disease, we found no echocardiographic evidence for an association between the duration of PDA exposure and the incidence of late PVD during the neonatal hospitalization in preterm infants with BPD.

Effects of prophylactic indomethacin on morbidity and mortality in infants <25 weeks' gestation: a protocol driven intention to treat analysis.

OBJECTIVE: To determine if prophylactic indomethacin (PINDO) decreases death or bronchopulmonary dysplasia-grades 2 and 3 (death/BPD) in newborns <25 weeks. STUDY DESIGN: Intention-to-treat, cohort-controlled study of 106 infants admitted during three alternating epochs of PINDO or Expectant patent ductus arteriosus (PDA) management. RESULTS: At 7-8 days 85% of Expectant Management epoch infants had a moderate/large PDA (median exposure was 23 days). Among PINDO epoch infants only 24% still had a PDA at 7-8 days. There were no significant differences in the incidence of death/BPD or of secondary outcomes (BPD, death, necrotizing enterocolitis/spontaneous perforations, or intraventricular hemorrhage (grades 3 or 4)) in either unadjusted or adjusted comparisons between infants born in a PINDO epoch and those born in the Expectant Management epoch. CONCLUSION: Despite being at high risk for PDA-related morbidities, PINDO did not appear to alter the rates of our primary and secondary outcomes in infants <25 weeks.

Prevalence of Atherosclerotic Risk Factors Among Children and Young Adults With Arterial Ischemic Stroke.

Importance: Arterial ischemic stroke (AIS) incidence has decreased overall in recent decades yet has increased in young adults. The potential associations with atherosclerotic risk factors (ARFs) remain unknown. Objective: To assess the ages at which ARFs may be risk factors associated with AIS. Design, Setting, and Participants: A nested case-control study was conducted within Kaiser Permanente Northern California (KPNC) from January 1, 2000, through December 31, 2014. Data were analyzed from 2019 to 2022. Cases were identified using diagnostic codes and radiology reports. A total of 2 to 3 controls per case, matched on age and enrollment dates, were randomly identified and confirmed as stroke-free by medical record review. Only ARFs documented prior to stroke diagnosis (or the same date in controls) were considered to ensure the same period of observation. Comparisons were stratified by decade of life. Cases and controls were selected from the KPNC population (4.7 million children and 7.5 million young adults). Medical record review was conducted of all children (aged 29 days to 19 years) and a sample of young adults (aged 20-49 years) with International Classification of Diseases, Ninth Revision code or radiology text string search suggestive of AIS. Stroke-free controls were randomly selected. Exposures: Hypertension, hyperlipidemia, diabetes, obesity, and smoking history. Main Outcomes and Measures: Odds of AIS. In all analyses, cases and controls were compared using logistic regression. Results: A total of 141 pediatric cases (69 [48.9%] aged 29 days to 9 years; 72 [51.1%] aged 10-19 years) and 364 pediatric controls (168 [46.2%] aged 0-9 years; 196 [53.8%] aged 10-19 years) and 455 young adult cases (71 [15.6%] aged 20-29 years; 144 [31.6%] aged 30-39 years; and 240 [52.7%] aged 40-49 years) and 1018 young adult controls (121 [11.9%] aged 20-29 years; 298 [29.3%] aged 30-39 years; and 599 [58.8%] aged 40-49 years) were identified. The percent of the cases that were male or female did not differ from the percent in the control group. The odds ratio (OR) of having any ARFs on AIS was 1.87 (95% CI, 0.72-4.88) for age range 0 to 9 years; OR, 1.00 (95% CI, 0.51-1.99) for age range 10 to 19 years; OR, 2.3 (95% CI, 1.17- 4.51) for age range 20 to 29 years; OR, 3.57 (95% CI, 2.34-5.45) for age range 30 to 39 years; and OR, 4.91 (95% CI, 3.52-6.86) for age range 40 to 49 years. The risk associated with multiple ARFs was OR, 5.29 (95% CI, 0.47-59.4) for age range 0 to 9 years; OR, 2.75 (95% CI, 0.77-9.87) for age range 10 to 19 years; OR, 7.33 (95% CI, 1.92-27.9) for age range 20 to 29 years; OR, 9.86 (95% CI, 4.96-19.6) for age range 30 to 39 years; and OR, 9.35 (95% CI, 6.31-13.8) for age range 40 to 49 years. The ARF findings by both definitions were significant in all young adult groups. Atherosclerosis was the presumed etiology in 0% of cases in the age group 0 to 9 years, 1.4% in the age group 10 to 19 years, 8.5% in the age group 20 to 29 years, 21.5% in the age group 30 to 39 years, and 42.5% in the age group 40 to 49 years. Conclusions and Relevance: Although atherosclerosis may not be a common cause of AIS in children or in early young adulthood, findings of this study suggest that ARFs associated with stroke in older adults are present in childhood and increase with age. Efforts to reduce these risk factors should begin as early as possible.

Patent ductus arteriosus, tracheal ventilation, and the risk of bronchopulmonary dysplasia.

BACKGROUND: An increased risk for bronchopulmonary dysplasia (BPD) exists when moderate-to-large patent ductus arteriosus shunts (hsPDA) persist beyond 14 days. GOAL: To examine the interaction between prolonged exposures to tracheal ventilation (≥10 days) and hsPDA on the incidence of BPD in infants <28 weeks gestation. STUDY DESIGN: Predefined definitions of prolonged ventilation (≥10 days), hsPDA (≥14 days), and BPD (room air challenge test at 36 weeks) were used to analyze deidentified data from the multicenter TRIOCAPI RCT in a secondary analysis of the trial. RESULTS: Among 307 infants who survived >14 days, 41 died before 36 weeks. Among survivors, 93/266 had BPD. The association between BPD and hsPDA depended on the length of intubation. In multivariable analyses, prolonged hsPDA shunts were associated with increased BPD (odds ratio (OR) (95% confidence interval (CI)) = 3.00 (1.58-5.71)) when infants required intubation for ≥10 days. In contrast, there was no significant association between hsPDA exposure and BPD when infants were intubated <10 days (OR (95% CI) = 1.49 (0.98-2.26)). A similar relationship between prolonged hsPDA and length of intubation was found for BPD/death (n = 307): infants intubated ≥10 days: OR (95% CI) = 2.41 (1.47-3.95)); infants intubated <10 days: OR (95% CI) = 1.37 (0.86-2.19)). CONCLUSIONS: Moderate-to-large PDAs were associated with increased risks of BPD and BPD/death-but only when infants required intubation ≥10 days. IMPACT: Infants with a moderate-to-large hsPDA that persist beyond 14 days are only at risk for developing BPD if they also receive prolonged tracheal ventilation for ≥10 days. Infants who receive less ventilatory support (intubation for <10 days) have the same incidence of BPD whether the ductus closes shortly after birth or whether it persists as a moderate-to-large shunt for several weeks. Early PDA closure may be unnecessary in infants who require short durations of intubation since the PDA does not seem to alter the incidence of BPD in infants who require intubation for <10 days.

Clinical characteristics and outcomes of infants compared with children diagnosed with rhabdomyosarcoma: Analysis of surveillance, epidemiology and end results data from 2000 to 2016.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, but occurs infrequently in infants (<1 year). Historically, infants with RMS have worse overall survival compared to other pediatric age groups. AIM: This study aims to assess the clinical features and treatment factors associated with survival comparing infants to children aged 1-9 years diagnosed with RMS. METHODS: Children aged <10 years diagnosed with RMS between 2000 and 2016 were identified using the SEER database. Descriptive statistics were used to assess demographic, clinical, and treatment characteristics of infants and children with RMS. Kaplan-Meier estimates and Cox proportional hazards regression were performed to assess for factors associated with survival. RESULTS: Age <1 year was independently associated with an increased risk of mortality. Compared to children aged 1-9 years, fewer infants received standard of care therapy, that is, chemotherapy combined with local control (surgery and/or radiation; 86.8 vs. 75.7%; p = .009). In comparing the frequency of specific treatment modalities (used alone or in combination with other modalities), infants were less likely to receive radiation therapy (34.0 vs. 66.4%; p < .001) and more likely to receive surgery (68.9 vs. 57.5%; p = .02) than children aged 1-9 years. Across age groups, chemotherapy combined with local control was significantly associated with reduced mortality. Alveolar histology, metastatic disease, and Hispanic ethnicity were negatively associated with survival. CONCLUSIONS: Age of <1 year was an independent risk factor for increased mortality from RMS compared to ages 1-9 years. Fewer infants were treated with chemotherapy combined with local control, the therapy associated with best survival in all age groups. Other factors contributing to differences in survival should be further explored.

A Large Thyroid Fine Needle Aspiration Biopsy Cohort with Long-Term Population-Based Follow-Up.

Background: Prior studies evaluating thyroid fine needle aspiration biopsies (FNABs) have limited the calculation of risk of malignancy (ROM) to cytologic specimens with corresponding histologic specimens, and clinical follow-up for those patients who do not undergo immediate surgery has been largely disregarded. Moreover, there is marked variability in how researchers have approached thyroid FNAB statistical analyses. This study addresses the urgent need for information from a large cohort of patients with long-term clinical follow-up to more accurately determine the performance of thyroid FNAB and ROM for each diagnostic category. Methods: A retrospective review of the University of California, San Francisco (UCSF), pathology database for thyroid FNABs from January 1, 1997, to December 31, 2004, was performed. Diagnoses were coded using the 2017 The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), and patients were matched to both the UCSF cancer registry and California Cancer Registry. Data were analyzed using the Kaplan-Meier method, and stratified by TBSRTC diagnostic category. Kaplan-Meier curves were used to estimate incidence rates of malignancy, stratified by FNAB category. Cox proportional hazards models were used to determine the instantaneous ROM. Results: Initial FNABs from 2207 patients were included. Median follow-up period after the first thyroid FNAB was 13.9 years (range: 10.5-18.4 years). During follow-up, there were 279 confirmed diagnoses of thyroid malignancy. Estimates derived from Kaplan-Meier curves demonstrated that the risk of having a thyroid malignancy was low for nondiagnostic and benign categories, intermediate for atypia of undetermined significance (AUS), follicular lesion of undetermined significance (FLUS), AUS/FLUS combined, and follicular neoplasm, and high for suspicious and malignant categories. A total of 52/1575 false-negative cases (3.2%) were identified. Excluding papillary microcarcinomas, the false-negative rate was 1.5% (23/1575). No patients with a false-negative diagnosis died of thyroid cancer during the follow-up period. Conclusions: Asymptomatic patients with low-risk clinical and radiologic features and initially benign or unsatisfactory biopsy are unlikely to develop thyroid malignancy and highly unlikely to die of thyroid cancer. FNAB is highly accurate in detecting malignancy. Additional studies evaluating similar large data sets after the adoption of TBSRTC and the integration of molecular testing are needed.

Molecularly Classified Uterine FIGO Grade 3 Endometrioid Carcinomas Show Distinctive Clinical Outcomes But Overlapping Morphologic Features.

FIGO grade 3 endometrioid endometrial carcinoma (EEC) is a heterogenous group of tumors with variable molecular and clinicopathologic characteristics but is treated clinically as a single entity. There is a need for additional objective markers to help guide management. The aim of this study was to evaluate a cohort of FIGO grade 3 EEC to validate the prognostic impact of molecular classification using POLE mutation (POLE-mut) analysis and immunohistochemistry for p53 and mismatch repair proteins. A secondary aim was to assess for any morphologic or immunophenotypic correlates among the molecular groups. Ninety-five cases of FIGO grade 3 EEC who underwent a hysterectomy at our institution were identified. Ten tumors (11%) harbored POLE-mut, 35 tumors (37%) showed mismatch repair deficiency, 18 tumors (19%) showed aberrant p53 staining (p53-ab), and 26 cases (27%) lacked all of these findings and were classified as no specific molecular profile. Six separate cases harbored >1 abnormality (multiple classifier), 5 of which had POLE-mut. The POLE-mut group and multiple classifier group showed excellent clinical outcomes, the p53-ab group showed the worst clinical outcomes and the 2 remaining groups showed intermediate prognosis. While the POLE-mut tumors showed a statistically significant enrichment for morphologic features including serous-like atypia and lymphocytic infiltrates, these findings were seen across all 4 molecular groups. There was no correlation between molecular grouping and tumor immunophenotypic findings, but overall 18% and 24% of tumors were completely negative for PAX-8 and estrogen receptor, respectively. Five CTNNB1 mutations were identified, 3 of which occurred in the context of a POLE-mut (including 1 multiple classifier case with MLH1/PMS2 loss). Thus our study corroborates the prognostic impact of molecular classification of high-grade endometrioid carcinoma of the uterus, achieved by readily available immunohistochemical stains in addition to POLE-mut analysis.

The effect of prolonged tracheal intubation on the association between patent ductus arteriosus and bronchopulmonary dysplasia (grades 2 and 3).

OBJECTIVE: To determine if the need for mechanical ventilation alters the association between prolonged patent ductus arteriosus (PDA) exposure and bronchopulmonary dysplasia (grades 2 and 3) (BPD). STUDY DESIGN: Observational study of 407 infants (<28 weeks' gestation) with echocardiograms performed at planned intervals. RESULTS: Twelve percent (48/407) of study infants had BPD (grades 2 and 3). In a multivariable regression model, exposure to a moderate-to-large PDA shunt for ≥7 days was associated with an increased risk of BPD (grades 2 and 3) (from 16 to 35%: aRD = 19% (6, 32%), p < 0.005) when infants required ≥10 days of intubation (n = 170). In contrast, there was no significant association between prolonged PDA exposure and BPD when infants required ≤9 days of intubation (aRD = 4%) (-1, 10%) (n = 237). CONCLUSIONS: Moderate-to-large PDAs are associated with an increased risk of BPD-but only when infants require intubation ≥10 days.

Association of comorbid depression with inpatient outcomes in critical limb ischemia.

There is a growing body of evidence that peripheral artery disease (PAD) may be impacted by depression. The objective of this study is to determine whether outcomes, primarily major amputation, differ between patients with depression and those without who presented to hospitals with critical limb ischemia (CLI), the end-stage of PAD. A retrospective cohort of patients hospitalized for CLI during 2012 and 2013 was identified from the National Inpatient Sample (NIS) using ICD-9 codes. The primary outcome was major amputation and secondary outcomes were length of stay and other complications. The sample included 116,008 patients hospitalized for CLI, of whom 10,512 (9.1%) had comorbid depression. Patients with depression were younger (64 ± 14 vs 67 ± 14 years, p < 0.001) and more likely to be female (55% vs 41%, p < 0.001), white (73% vs 66%, p < 0.001), and tobacco users (46% vs 41%, p < 0.001). They were also more likely to have prior amputations (9.8% vs 7.9%, p < 0.001). During the hospitalization, the rate of major amputation was higher in patients with comorbid depression (11.5% vs 9.1%, p < 0.001). In multivariable analysis, excluding patients who died prior to/without receiving an amputation (n = 2621), comorbid depression was associated with a 39% increased odds of major amputation (adjusted OR 1.39, 95% CI 1.30, 1.49; p < 0.001). Across the entire sample, comorbid depression was also independently associated with a slightly longer length of stay (ß = 0.199, 95% CI 0.155, 0.244; p < 0.001). These results provide further evidence that depression is a variable of interest in PAD and surgical quality databases should include mental health variables to enable further study.

Relationship between Duration of Infant Exposure to a Moderate-to-Large Patent Ductus Arteriosus Shunt and the Risk of Developing Bronchopulmonary Dysplasia or Death Before 36 Weeks.

OBJECTIVE: This study was aimed to examine the relationship between duration of infant exposure to a moderate-to-large patent ductus arteriosus (PDA) shunt and the risk of developing bronchopulmonary dysplasia (BPD) or death before 36 weeks (BPD/death). STUDY DESIGN: Infants <28 weeks' gestation who survived ≥7 days (n = 423) had echocardiograms performed on day 7 and at planned intervals. RESULTS: In multivariable regression models, BPD/death did not appear to be increased until infants had been exposed to a moderate-to-large PDA for at least 7-13 days: OR (95%CI) (referent = closed or small PDA): moderate-to-large PDA exposure for <7 days: 0.38 (range, 0.10-1.46); for 7 to 13 days = 2.12 (range, 1.04-4.32); for ≥14 days = 3.86 (range, 2.15-6.96). Once the threshold of 7 to 13 days had been reached, additional exposure (≥14 days) did not significantly add to the increased incidence of BPD/death: (referent exposure = 7-13 days) exposure for 14 to 27 days = 1.34 (range, 0.52-3.45); for 28 to 48 days = 2.34 (range, 0.88-6.19); for ≥49 days = 1.80 (range. 0.59-5.47). A similar relationship was found for the outcome of BPD-alone. CONCLUSION: Infants < 28 weeks' gestation required at least 7 to 13 days of exposure to a moderate-to-large PDA before a significant increase in the incidence of BPD/death was apparent. Once this threshold was reached additional exposure to a moderate-to-large PDA did not significantly add to the increased incidence of BPD/death.

Peripheral Artery Disease Is Associated with a Deficiency of Erythrocyte Membrane n-3 Polyunsaturated Fatty Acids.

Population-based data suggest that individuals who consume large dietary amounts of n-3 polyunsaturated fatty acids (PUFA) have lower odds of peripheral artery disease (PAD); however, clinical studies examining n-3 PUFA levels in patients with PAD are sparse. The objective of this study is to compare erythrocyte membrane fatty acid (FA) content between patients with PAD and controls. We conducted a cross-sectional study of 179 vascular surgery outpatients (controls, 34; PAD, 145). A blood sample was drawn and the erythrocyte FA content was assayed using capillary gas chromatography. We calculated the ratio of the n-3 PUFA eicosapentaenoic acid (EPA) to the n-6 PUFA arachidonic acid (ARA) as well as the omega-3 index (O3I), a measure of erythrocyte content of the n-3 PUFA, EPA, and docosahexaenoic acid (DHA), expressed as a percentage of total erythrocyte FA. Compared with controls, patients with PAD smoked more and were more likely to have hypertension and hyperlipidemia (p < 0.05). Patients with PAD had a lower mean O3I (5.0 ± 1.7% vs 6.0 ± 1.6%, p < 0.001) and EPA:ARA ratio (0.04 ± 0.02 vs 0.05 ± 0.05, p < 0.001), but greater mean total saturated fats (39.5 ± 2.5% vs 38.5 ± 2.6%, p = 0.01). After adjusting for several patient characteristics, comorbidities, and medications, an absolute decrease of 1% in the O3I was associated with 39% greater odds of PAD (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.03-1.86, and p = 0.03). PAD was associated with a deficiency of erythrocyte n-3 PUFA, a lower EPA:ARA ratio, and greater mean total saturated fats. These alterations in FA content may be involved in the pathogenesis or development of poor outcomes in PAD.

Leptinemia is Associated With Peripheral Artery Disease.

BACKGROUND: Leptin, adiponectin, and resistin are in a class of hormones called adipokines that are produced by adipocytes and have been implicated in the causal pathway of atherosclerosis. We examined the association between adipokine levels and peripheral artery disease (PAD), hypothesizing that after adjusting for fat mass, leptin and resistin would be higher, whereas adiponectin would be lower, in patients with PAD. METHODS: A cross-sectional sample of 179 predominately male (97%) vascular surgery outpatients was recruited from the San Francisco Veterans Affairs Medical Center (SFVAMC). PAD was defined as either an ankle-brachial index < 0.9 plus symptoms of claudication or prior revascularization for symptomatic PAD (n = 141). Controls had an ankle-brachial index ≥0.9 and no history of atherosclerotic disease (n = 38). Adipokines were assayed using commercially available ELISA kits and values were log-transformed. Fat mass was measured using bioelectrical impedance. RESULTS: In an analysis adjusting for body mass index (BMI) and atherosclerotic risk factors, higher serum leptin was associated with PAD (OR 2.54, 95% CI 1.07-6.01, P = 0.03), whereas high molecular weight adiponectin was inversely associated, though not significantly (OR 0.60, 95% CI 0.33-1.08, P = 0.09). Resistin was not associated with PAD. Sensitivity analyses using fat mass/height2 rather than BMI yielded similar results. CONCLUSIONS: These results indicate that after adjusting for BMI or fat mass, serum leptin levels are positively and independently associated with PAD, whereas high molecular weight adiponectin might be inversely associated. Using a more representative, nonveteran sample, further investigations should focus on the potential role of adipokines in the pathophysiology of PAD as well as determine whether leptin levels have clinical utility in predicting PAD outcomes.

Fish Oil Increases Specialized Pro-resolving Lipid Mediators in PAD (The OMEGA-PAD II Trial).

BACKGROUND: N-3 polyunsaturated fatty acid (PUFA) supplementation has been associated with reduced mortality and inflammation in patients with cardiovascular disease. There are limited data on the effects of n-3 PUFA supplementation in patients with peripheral artery disease (PAD). MATERIALS AND METHODS: The OMEGA-PAD II trial was a double-blinded, randomized, placebo-controlled trial to assess the effect of 3 mo of high-dose oral n-3 PUFA supplementation on inflammation, endothelial function, and walking ability in patients with PAD. RESULTS: Twenty-four patients with claudication received 4.4 g/d of fish oil or placebo for 3 mo. Outcomes measured included high-sensitivity C-reactive protein levels, the omega-3 index, endothelial function as measured via flow-mediated vasodilation, walking impairment questionnaire, and a 6-min walk test. Plasma levels of specialized pro-resolving lipid mediators (SPMs) were measured by liquid-chromatography-tandem mass spectrometry. In patients treated with fish oil, the absolute mean omega-3 index significantly increased from baseline (fish oil: 7.2 ± 1.2%, P < 0.001; placebo: -0.4 ± 0.9%, P = 0.31; between-group P < 0.001). Furthermore, there were significant increases in several pathway markers of SPM biosynthesis, including several mono-hydroxyeicosapentaenoic acids and mono-hydroxydocosahexaenoic acids. We also observed significant increases in the SPM lipoxin A5 (fish oil: 0.57 ± 0.70 pg/mL, P = 0.05; placebo: 0.01 ± 0.38 pg/mL, P = 0.93; between-group P = 0.04) and resolvin E3 (fish oil: 154 ± 171 pg/mL, P = 0.04; placebo: 32 ± 54 pg/mL, P = 0.08; between-group P = 0.04). There were no significant changes in high-sensitivity C-reactive protein, flow-mediated vasodilation, walking impairment questionnaire, or 6-min walk test in the fish oil group. CONCLUSIONS: Fish oil increases SPMs in plasma of patients with PAD. Further studies are required to determine whether these early changes translate to clinical improvements in patients with PAD.

Serum resistin is associated with impaired endothelial function and a higher rate of adverse cardiac events in patients with peripheral artery disease.

OBJECTIVE: Resistin is a hormone that has been associated with metabolic syndrome and cardiovascular disease. The role of resistin in patients with peripheral artery disease (PAD) has not been fully explored. This study seeks to understand the relationship between serum resistin, vascular function, and cardiovascular outcomes in patients with PAD. METHODS: There were 106 patients with PAD who were recruited between 2011 and 2016. Patients attended a baseline visit during which a comprehensive vascular physiology assessment including medical and surgical history, radial artery tonometry, and flow mediated-vasodilation (FMD) was completed. A blood sample was drawn, and serum resistin was assayed using enzyme-linked immunosorbent assay kits. Using the time of study enrollment as the time of origin, incident major adverse cardiac events (MACEs) were identified by subsequent chart review and defined as a composite end point of myocardial infarction, coronary revascularization, transient ischemic attack, stroke, or death from a cardiac cause. RESULTS: Patients had a mean age of 68 ± 8 years, were largely white (75%), and had comorbidities commonly associated with PAD including hypertension (92%), hyperlipidemia (87%), coronary artery disease (37%), and diabetes mellitus (38%). After stratification by resistin quartile, higher resistin quartiles were significantly associated with an older age, a greater number of pack-years smoked, and a lower estimated glomerular filtration rate. Despite similar comorbidities and medication use, endothelial function, as measured by FMD, was significantly lower with increasing resistin quartile (I, 9.1% ± 3.3%; II, 7.1% ± 3.5%; III, 5.8% ± 4.0%; IV, 5.6% ± 3.5%; P = .002). In multivariable linear regression, higher resistin quartiles (III and IV) were associated with lower FMD relative to quartile I after adjusting for several patient characteristics, medications, and comorbidities (III, -2.26 [95% confidence interval (CI), -4.51 to -0.01; P = .05]; IV, -2.53 [95% CI, -4.87 to -0.20; P = .03]). During a median follow-up period of 36 months (interquartile range, 29-45 months), 21 patients experienced the primary end point. In a Cox proportional hazards model adjusted for smoking status, coronary artery disease, and age, each 1 ng/mL increase in resistin was associated with a 10% increased risk of MACEs (hazard ratio, 1.10; 95% CI, 1.00-1.20; P = .04). CONCLUSIONS: In patients with PAD, higher levels of resistin were associated with impaired endothelial function and an increased rate of MACEs. These results suggest that resistin may be a marker or effector of impaired vascular physiology and adverse cardiac outcomes in patients with PAD. Further research is needed to determine the potential mechanisms by which resistin may impair endothelial function and increase MACEs in this population.