Editing TINF2 as a potential therapeutic approach to restore telomere length in dyskeratosis congenita.

Mutations in the TINF2 gene, encoding the shelterin protein TIN2, cause telomere shortening and the inherited bone marrow (BM) failure syndrome dyskeratosis congenita (DC). A lack of suitable model systems limits the mechanistic understanding of telomere shortening in the stem cells and thus hinders the development of treatment options for BM failure. Here, we endogenously introduced TIN2-DC mutations in human embryonic stem cells (hESCs) and human hematopoietic stem and progenitor cells (HSPCs) to dissect the disease mechanism and identify a gene-editing strategy that rescued the disease phenotypes. The hESCs with the T284R disease mutation exhibited the short telomere phenotype observed in DC patients. Yet, telomeres in mutant hESCs did not trigger DNA damage responses at telomeres or show exacerbated telomere shortening when differentiated into telomerase-negative cells. Disruption of the mutant TINF2 allele by introducing a frameshift mutation in exon 2 restored telomere length in stem cells and the replicative potential of differentiated cells. Similarly, we introduced TIN2-DC disease variants in human HSPCs to assess the changes in telomere length and proliferative capacity. Lastly, we showed that editing at exon 2 of TINF2 that restored telomere length in hESCs could be generated in TINF2-DC patient HSPCs. Our study demonstrates a simple genetic intervention that rescues the TIN2-DC disease phenotype in stem cells and provides a versatile platform to assess the efficacy of potential therapeutic approaches in vivo.

Intelligence quotient testing in children with hearing loss: A systematic review.

OBJECTIVE: The objective of the current study is to perform a systematic review of the research literature to evaluate the impact of hearing loss on intelligence quotient (IQ) scores in pediatric patients. DATA SOURCES: Ovid MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from their inception up to December 21st, 2021. REVIEW METHODS: Studies evaluating neurocognitive testing and hearing loss in children aged 21 years old or younger who had not undergone auditory rehabilitation were included in the study. Two independent reviewers evaluated titles, abstracts, and full texts for all included studies. RESULTS: The literature search yielded 3199 studies of which 431 studies underwent full-text screening. 21 studies were ultimately selected for inclusion and contained a total of 1716 pediatric patients assessed through 13 different validated tests of intelligence. Six studies included both hearing impaired (HI) and normal hearing (NH) patients, and IQ testing results. CONCLUSION: The results of this large systematic review demonstrate that hearing impaired children may perform lower than their age-matched normal hearing peers on IQ testing across a battery of IQ testing modalities.

Adverse events associated with anastomotic coupling devices in microvascular reconstruction.

OBJECTIVE: In light of the recent US Food and Drug Administration (FDA) Class 2 safety recall notice for anastomotic coupling devices, it is important to understand related adverse events. The aim of this study was to characterize adverse events in anastomotic coupling devices for microvascular reconstruction. METHODS: A retrospective cross-sectional analysis using the 2011 to 2021 US FDA Manufacturer and User Facility Device Experience (MAUDE) database. All reports of adverse events involving anastomotic coupling devices were retrieved from the MAUDE database. Descriptive statistics were used to analyze categorized events. RESULTS: There were a total of 293 documented adverse events related to anastomotic coupling devices. These adverse events resulted in 91 (31.1 %) patient injuries and 239 (81.6 %) device malfunctions. The most frequent patient problems were thrombosis/hematoma (n = 38; 41.8 %), unspecified injury (n = 31; 34.1 %), and failure to anastomose (n = 13; 14.3 %). Free flap necrosis was reported in 42 % of thrombosis/hematoma cases (n = 16). The most common malfunctions were devices operating differently than expected (n = 74; 31.0 %), connection problems (n = 41; 17.2 %), and twisted/bent material (n = 19; 7.9 %). There was no significant trend in the number of adverse events over the study period (p > 0.05). CONCLUSIONS: Adverse events from anastomotic coupling devices represent an important and modifiable factor in free tissue failure. Adverse events are predominately related to devices operating differently than expected and may result in vascular compromise of the free flap. Reconstructive surgeons should be cognizant of defective anastomotic coupling devices and be prepared to utilize traditional hand-sewn anastomosis.

Survival Outcomes of Advanced Thyroid Cancer Enriched in Brain Metastases Following Treatment With Small Molecule Inhibitors.

OBJECTIVE: Small molecule inhibitors (SMIs) are targeted therapies increasingly used in advanced thyroid carcinomas. This study aimed to evaluate the survival outcomes of thyroid cancer on SMI treatment, including in patients with brain metastases. METHODS: This retrospective study included patients with thyroid carcinomas who received at least one SMI between 2008 and 2022 at a tertiary level, academic institution. SMI included lenvatinib, sorafenib, dabrafenib-trametinib, selpercatinib, and cabozantinib. Patients were grouped by the presence of brain metastasis. Kaplan-Meier and log-rank tests modeled the overall survival (OS), defined from detection of first metastasis. RESULTS: In total, 116 patients (49.1% female, median age 61.1 years [IQR, 51.1-71.0]) were included. Thyroid cancer subtypes were: 57 (49.6%) papillary, 23 (19.8%) anaplastic, 23 (19.8%) medullary, and 13 (11.2%) follicular. There were 18 (15.5%) patients with brain metastases, and 98 (84.5%) with visceral metastases. Age, sex, thyroid subtype, SMI, and time to recurrence were not different between cohorts. OS was shorter in the brain metastasis cohort (31.7 vs 42.2 months, P =.44) and was not different after excluding anaplastic thyroid cancer (29.1 vs 62.3 months, P =.21). In the case of papillary thyroid cancer, patients with brain metastases trended toward worse OS (22.0 vs 59.9 months, P =.13). Nonanaplastic histology, total thyroidectomy (OR, 40.0; P <.001), number of unique therapies (OR, 10.9; P =.047), and mutation-directed therapy (OR, 24.7; P =.003) were associated with improved OS. CONCLUSION: This single-institutional analysis reports survival outcomes of 116 patients with advanced thyroid cancer on targeted therapies, including 18 patients with brain metastases. Mutation-directed therapy for BRAFV600E mutations, RET mutations, RET fusions, and NTRK fusions had superior survival.

Olfactory dysfunction incidence and resolution amongst 608 patients with COVID-19 infection.

PURPOSE: Olfactory dysfunction (OD) is a common presenting sign of coronavirus-19 (COVID-19) infection and remains persistent in up to 7 % of patients one year after diagnosis. However, demographic, socioeconomic, and medical risk factors for persistent OD are not well understood. This study aims to determine risk factors for development and persistence of OD amongst patients with COVID-19 infection. MATERIALS AND METHODS: This prospective, observational questionnaire study was performed at a tertiary-level, academic center. Patients with history of a positive COVID-19 diagnosis were sent an online questionnaire. Patients' self-reported survey responses for OD and resolution were assessed for associations with demographic variables, socioeconomic factors, and clinical data. RESULTS: In total, 608 of 26,094 patients (77.6 % women, mean age 42.7 ± 17.4 years, range 9 months-92 years) completed the survey. OD was reported by 220 (36.2 %) patients, and 139 (63.2 %) patients achieved resolution. Patients with OD were more likely to have other sinonasal and flu-like symptoms, and had a hospitalization rate of 2.7 %. There were no significant differences in age, gender, occupational or residential factors, or medical comorbidities incidence of OD development. Women reported higher rates of persistent OD (88.9 % vs 77.0 %, p = 0.045). The OD recovery rates amongst active and resolved COVID-19 infections was 27.0 % and 70.0 %, respectively (p < 0.001). CONCLUSIONS: There was a low hospitalization rate amongst patients reporting OD. One-third of patients with COVID-19 self-reported OD, and two-thirds of patients achieve OD resolution. Survey respondents with active COVID-19 infection and female gender were more likely to report persistent OD.

Development of a Risk Prediction Model for Complications Following Forehead Flaps for Nasal and Periorbital Reconstruction.

BACKGROUND: Forehead flaps are a workhorse for nasal reconstruction, but complications occur in up to 30% of patients and risk factors are not well characterized. This study aimed to identify risk factors for complications, and provide clinicians a method to stratify patient risk to facilitate shared decision-making. MATERIALS AND METHODS: This retrospective study included patients who underwent forehead flaps between 2007 and 2020. Demographic and treatment characteristics were abstracted, in addition to clinical outcomes data. Multivariable regression was conducted, with step-wise variable elimination to determine inclusion in the final model. From the final regression, a risk-stratification scheme was developed. RESULTS: One hundred ninety-seven patients underwent forehead flap reconstruction, with a mean age of 68.5 years. Mean follow-up time was 42 months. There were 50 (25.4%) patients who developed a complication, including impaired nasal function (18.8%), flap congestion (5.1%), infection (2.5%), poor donor site healing (2.5%) wound dehiscence (2.0%), and flap congestion (1.5%). On univariate analysis, female sex, immunosuppression, prior radiotherapy, and larger resection area were associated with complications ( P <0.05). On multivariable analysis, female sex [odds ratio (OR): 3.89, P <0.001], hypoalbuminemia (OR: 3.70, P =0.01), and prior wide local excision (OR: 3.62, P =0.04) were predictors of complications. A clinical calculator was developed incorporating these risk factors, with a C-statistic of 0.85, indicating strong predictive value. CONCLUSIONS: We conducted the most comprehensive review of risk factors for the development of complications after forehead flap reconstruction. From this analysis, a novel, implementable, risk-stratification scheme was developed to equip surgeons with the ability to provide individualized risk assessment to patients and address preoperative comorbidities to optimize outcomes.

Incidence of Venous Thromboembolism Based on Caprini Score in Deep Inferior Epigastric Perforator Flap Breast Reconstruction.

BACKGROUND: Deep inferior epigastric perforator (DIEP) flaps are commonly used for autologous breast reconstruction, but reported rates of venous thromboembolism (VTE) are up to 6.8%. This study aimed to determine the incidence of VTE based on preoperative Caprini score following DIEP breast reconstruction. METHODS: This retrospective study included patients who underwent DIEP flaps for breast reconstruction between January 1, 2016 and December 31, 2020 at a tertiary-level, academic institution. Demographics, operative characteristics, and VTE events were recorded. Receiver operating characteristic analysis was performed to determine the area under the curve (AUC) of the Caprini score for VTE. Univariate and multivariate analyses assessed risk factors associated with VTE. RESULTS: This study included 524 patients (mean age 51.2 ± 9.6 years). There were 123 (23.5%) patients with the Caprini score of 0 to 4, 366 (69.8%) with scores 5 to 6, 27 (5.2%) with scores 7 to 8, and 8 (1.5%) patients with scores >8. Postoperative VTE occurred in 11 (2.1%) patients, at a median time of 9 days (range 1-30) after surgery. VTE incidence by the Caprini score was 1.9% for scores 3 to 4, 0.8% for scores 5 to 6, 3.3% for scores 7 to 8, and 13% for scores >8. The Caprini score achieved an AUC of 0.70. A Caprini score >8 was significantly predictive of VTE on multivariable analysis relative to scores 5 to 6 (odds ratio = 43.41, 95% confidence interval = 7.46-252.76, p < 0.001). CONCLUSION: In patients undergoing DIEP breast reconstruction, VTE incidence was highest (13%) in Caprini scores greater than eight despite chemoprophylaxis. Future studies are needed to assess the role of extended chemoprophylaxis in patients with high Caprini scores.

Utility of the finance-electronic medical record digital dashboard in pediatric otolaryngology.

BACKGROUND: The time and cost of data collection via chart review of the electronic medical record (EMR) is a research barrier. This study describes the development of a digital dashboard conjoining EMR and finance data and its application in a pediatric otolaryngology practice. METHODS: The dashboard creates a common language crosswalk between surgeries via the EMR, financial data, and national Vizient database. First, all Otolaryngology procedures billed via ICD-10 or CPT codes were categorized into Procedure Groups, which constitute the common language that links all data sources. The joined dataset was inputted into a Tableau workbook supporting dynamic filtering and custom real-time analysis. RESULTS: The dashboard includes 84 Procedure Groups within Otolaryngology. Examples for pediatrics include Sistrunk procedure and supraglottoplasty. User-friendly dynamic filtering by Procedure Group, surgery date range, age, insurance, hospital, surgeon, and discharge status were developed. Outcomes include length of stay, telephone callbacks, postoperative hemorrhage, reoperations, return to Emergency Department, readmissions, and mortality. National comparisons can be analyzed via embedded Vizient data. The usability of the dashboard was tested by evaluating pediatric tonsillectomy outcomes, which revealed a significantly higher rate of postoperative hemorrhages and reoperations during the COVID-19 pandemic. CONCLUSION: The hybrid finance/EMR dashboard creates a crosswalk between data sources and shows utility for use in evaluating patient outcomes via real-time data analysis and dynamic filtering. This innovative dashboard expedites data extraction, promoting efficient implementation of quality improvement initiatives and surgical outcomes research.

Impact of body mass index in patulous Eustachian tube: Does rapid weight loss influence symptom improvement?

OBJECTIVES: Weight loss has been proposed as risk factor for patulous Eustachian tube (PET), however, it has not been well-characterized how this subpopulation responds to standard treatments. This study aimed to evaluate PET symptom improvement in the setting of and absence of rapid weight loss. METHODS: This retrospective case series included patients diagnosed with PET at an academic institution. Demographic characteristics, medical comorbidities, presenting symptoms, treatment, and outcomes of symptom improvement were reviewed. Univariate analysis modeled the likelihood of symptom improvement between rapid weight loss and non-rapid weight loss patients. RESULTS: A total of 124 patients (median age 55 years, 61 % female) were included. At diagnosis, 7 (5.6 %) patients were underweight, 40 (32.3 %) were normal weight, 32 (25.8 %) were overweight, and 45 (36/3 %) were obese. There were 39 (31.5 %) patients who had history of weight loss prior to presentation; of these, 22 (17.7 %) noted rapid weight loss and 17 (13.7 %) had non-rapid weight loss. There were 62 (50.0 %) patients who were recommended conservative treatment, and 62 (50.0 %) who underwent medical and/or surgical treatment. Symptom resolution was achieved in 49 (39.5 %) patients. On univariate analysis, patients with rapid weight loss were significantly more likely to experience improvement (p = 0.006) than non-rapid weight loss. Rapid weight loss patients had a four-fold increased likelihood of symptom improvement compared to non-rapid weight loss patients (OR = 4.8, p = 0.053). CONCLUSIONS: While rapid weight loss and bariatric surgery are reported risk factors for the development of PET, our findings suggest that patients with rapid weight loss are significantly more likely to achieve symptom improvement than non-rapid weight loss.

Breast Implant-Related Outcomes After Cardiothoracic Surgeries and Electrophysiologic Procedures.

BACKGROUND: Outcomes related to preexisting breast implants after cardiothoracic procedures are poorly characterized. This study evaluated complications after minimally invasive cardiac surgery (MICS), median sternotomy (MS), and electrophysiologic procedures (EP) in patients with preexisting breast implants. METHODS: A retrospective review of patients with prior breast implants who underwent MICS, MS, or EP from 1994 to 2019 was performed. Demographic, treatment, and outcome characteristics were recorded. χ 2 Test and analysis of variance were used to perform statistical comparisons. RESULTS: In total, 78 patients (37 MICS, 21 MS, and 20 EP) were identified. Mean breast implant age was 13.3, 11.7, and 10.2 years, respectively ( P = 0.235). Intraoperative plastic surgeon involvement was present in 26 (70.3%) MICS cases, compared with 2 (9.5%) MS and 0% EP ( P < 0.001). Intraoperative rupture occurred in 5 (13.5%) MICS cases and no MS or EP cases ( P < 0.001). Postoperative implant complications occurred in 6 (16.2%) MICS, 8 (38.1%) MS, and 5 (25.0%) EP ( P = 0.350) cases, with median time to complication of 5.9, 5.4, and 38.9 months, respectively ( P = 0.596). Revision surgery was performed in 5 (13.5%) MICS, 7 (33.3%) MS, and 5 (25.0%) EP ( P = 0.246) cases. On multivariate analysis, lack of intraoperative plastic surgeon involvement ( P = 0.034) and breast implant age ( P = 0.001) were significant predictors of postoperative complications. CONCLUSIONS: Long-term complication rates are highest among patients with breast implants undergoing MS. Plastic surgeon involvement was significantly associated with fewer postoperative complications. Our results support a multidisciplinary approach to managing breast implants during cardiothoracic procedures.

Ten-Year Institutional Experience to Predict Risk of Calvarial Bone Flap Loss Using Long-Term Outcome Data.

BACKGROUND: Calvarial bone flap (CBF) loss is a common complication following craniotomy and subsequent skull reconstruction can be challenging. Defining predictors of CBF failure not only improves patient outcomes but reduces the need for complex reconstruction often requiring plastic surgery consultation. As CBF failure can occur many years following craniotomy, this study aimed to determine risk factors of CBF loss using long-term follow-up. MATERIALS AND METHODS: This retrospective study included patients who underwent craniotomy with CBF reinsertion between 2003 and 2013 at a tertiary academic institution. Patients were included if demographics, comorbidities, and long-term outcomes were available. Multivariable logistic regression modeled the odds of CBF failure, defined as permanent removal for bone flap-related issues. The median follow-up was 6.9 years (interquartile range: 1.8-10.8 y). RESULTS: There were 222 patients who met inclusion criteria and underwent craniotomy with CBF reinsertion, primarily for tumor resection or intracranial pressure relief. CBF failure occurred in 76 (34.2%) patients. Up to 4 CBF reinsertions were performed in both failure and nonfailure groups. The risks of CBF loss increased with each additional CBF elevation by 17-fold ( P <0.001), male sex by 3-fold ( P =0.005), and tumor etiology by 3-fold ( P =0.033) ( C -index=0.942). CONCLUSIONS: Each CBF reinsertion dramatically increases the risk of CBF loss. This finding may optimize patient selection and surgical planning. Early multidisciplinary discussions between plastic surgeons and neurosurgeons may avoid multiple CBF elevations and prevent the adverse sequela of high-risk calvarial reconstruction efforts.

The Effect of Preoperative Gender-Affirming Hormone Therapy Use on Perioperative Adverse Events in Transmasculine Individuals Undergoing Masculinizing Chest Surgery for Gender Affirmation.

BACKGROUND: Many providers require cessation of gender-affirming hormone therapy (GAHT) for transgender patients prior to undergoing masculinizing chest surgery (MCS) due to concerns about increased adverse events in the presence of exogenous hormones. Evidence has suggested that continuation of GAHT for certain patients may be safe for gender-affirming procedures. OBJECTIVES: The aim of this study was to compare adverse event rates for GAHT cessation vs GAHT continuation in patients undergoing MCS. METHODS: This multicenter, retrospective study included patients at the Cleveland Clinic and MetroHealth System who underwent MCS between 2016 and 2020. RESULTS: There were 236 patients who met the inclusion criteria. Of these, 172 (72.9%) discontinued testosterone GAHT prior to surgery and 64 (27.1%) continued the therapy. Mean [standard deviation] age at surgery was 25 [8] years, and mean BMI was 29.5 [6.6] kg/m.2 The median duration of testosterone therapy was 18 months (range, 0-300 months). There was no significant difference in tobacco use (P = 0.73), diabetes (P = 0.54), thrombophilia (P = 0.97), or history of thromboembolism (P = 0.39). Most patients underwent the double-incision free nipple graft technique (77.9%). There was no significant difference in surgical time (P = 0.12), intraoperative complications (P = 0.54), or postoperative complications (P = 0.34). The most common complication was postoperative bleeding/hematoma (7.2%). Other complications included seroma (2.1%), infection (1.3%), and nipple graft failure (0.4%). There were no thromboembolic complications. CONCLUSIONS: There is no significant difference in the incidence of perioperative adverse events for patients who continue GAHT preoperatively vs patients who stop GAHT prior to MCS.

Evaluating the Effects of Enhanced Recovery Pathways in Craniosynostosis: National Trends in Hospitalization Charges and Length of Stay in Craniosynostosis Surgery.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) pathways are multimodal approaches aimed at minimizing postoperative surgical stress, reducing hospitalization time, and lowering hospitalization charges. Enhanced Recovery After Surgery is broadly and increasingly implemented in hospitals across the country. Early reports have shown ERAS to reduce length of stay (LOS) after commonly performed pediatric surgeries. However, LOS and hospital charges after craniosynostosis have not been studied. We hypothesized that extended hospital LOS is correlated with increased hospitalization charges associated with open cranial vault surgery (CVS) and that over a multiyear timeframe, LOS and cost would decrease because of the increased adoption of ERAS in pediatric surgery. METHODS: The Healthcare Cost and Utilization Project's National Inpatient Sample database was analyzed from January 2007 to December 2014. All patients who were diagnosed with craniosynostosis who underwent CVS were included. Variables of interest included demographic data, hospital characteristics, hospitalization data, and total hospital charges. Univariate and generalized linear regression models were used to examine associations between selected variables and the hospitalization charges. RESULTS: There were 54,583 patients diagnosed with craniosynostosis between 2007 and 2014. Of these patients, 22,916 (41.9%) received CVS. The median total hospital charge was $66,605.77 (interquartile range, $44,095.60-$101,071.17). The median LOS was 3 days (interquartile range, 2-4 days), and there was no significant change in LOS by year (P = 0.979). However, despite a stable LOS, mean hospitalization charge increased significantly by year (P < 0.01). Regression analysis demonstrated the proportion of eligible patients who underwent CVS substantially increased over the selected timeframe (P < 0.01). Most procedures were performed in urban teaching hospitals and high-volume hospitals. There was no significant association between hospital volume and hospitalization charge (P = 0.331). CONCLUSIONS: Increasing hospital charges despite constant LOS for craniosynostosis CVS procedures was observed between 2007 and 2014. Although ERAS has reduced LOS for common pediatric surgical procedures, no decrease in LOS for CVS has been observed. The charges significantly increased over the same period including high-volume centers. Further study to safely lower LOS and hospitalization charges for this procedure may reduce the overall health care burden.

Diagnostic Accuracy of Prostate Biopsy for Detecting Cribriform Gleason Pattern 4 Carcinoma and Intraductal Carcinoma in Paired Radical Prostatectomy Specimens: Implications for Active Surveillance.

PURPOSE: Prostatic adenocarcinoma with cribriform morphology and/or intraductal carcinoma has higher recurrence and mortality rates after radiation and surgery. While the prognostic impact of these features is well studied, concordance with cribriform morphology and/or intraductal carcinoma on biopsy and prostatectomy has only recently gained attention. Our primary objective was to evaluate the diagnostic performance of biopsy to detect cribriform morphology and/or intraductal carcinoma in paired biopsy and prostatectomy specimens in a large contemporary cohort. MATERIALS AND METHODS: Patients who underwent prostate biopsy or had biopsies reviewed prior to prostatectomy at a tertiary hospital between November 2017 and November 2018 were included in study. Sensitivity and specificity were calculated to assess concordance with cribriform morphology and/or intraductal carcinoma on biopsy and prostatectomy. The association of biopsy diagnosed with cribriform morphology and/or intraductal carcinoma with adverse pathology was assessed by multivariable regression. RESULTS: Of the 455 men who underwent prostatectomy 216 (47.5%) had biopsy identified with cribriform morphology and/or intraductal carcinoma. For cribriform morphology and/or intraductal carcinoma the sensitivity and specificity of biopsy was 56.5% and 87.2%, respectively. In men eligible for active surveillance sensitivity was 34.1% and specificity was 88.1%. Magnetic resonance imaging targeted biopsies did not improve sensitivity (53.5%). Cribriform morphology and/or intraductal carcinoma identified on prostatectomy correlated with adverse pathological findings. However, compared to cribriform morphology and/or intraductal carcinoma negative biopsies, biopsies identified with cribriform morphology and/or intraductal carcinoma were not independently associated with adverse pathology. This was likely due to biopsy low sensitivity. CONCLUSIONS: In this cohort biopsy was not sensitive for detecting cribriform morphology and/or intraductal carcinoma and this was not improved by magnetic resonance imaging fusion. However, specificity was high, suggesting that when present on biopsy, cribriform morphology and/or intraductal carcinoma may be considered in treatment planning algorithms.

Defining and Assessing Geriatric Risk Factors and Associated Health Care Utilization Among Older Adults Using Claims and Electronic Health Records.

BACKGROUND: Using electronic health records (EHRs), in addition to claims, to systematically identify patients with factors associated with adverse outcomes (geriatric risk) among older adults can prove beneficial for population health management and clinical service delivery. OBJECTIVE: To define and compare geriatric risk factors derivable from claims, structured EHRs, and unstructured EHRs, and estimate the relationship between geriatric risk factors and health care utilization. RESEARCH DESIGN: We performed a retrospective cohort study of patients enrolled in a Medicare Advantage plan from 2011 to 2013 using both administrative claims and EHRs. We defined 10 individual geriatric risk factors and a summary geriatric risk index based on diagnosed conditions and pattern matching techniques applied to EHR free text. The prevalence of geriatric risk factors was estimated using claims, structured EHRs, and structured and unstructured EHRs combined. The association of geriatric risk index with any occurrence of hospitalizations, emergency department visits, and nursing home visits were estimated using logistic regression adjusted for demographic and comorbidity covariates. RESULTS: The prevalence of geriatric risk factors increased after adding unstructured EHR data to structured EHRs, compared with those derived from structured EHRs alone and claims alone. On the basis of claims, structured EHRs, and structured and unstructured EHRs combined, 12.9%, 15.0%, and 24.6% of the patients had 1 geriatric risk factor, respectively; 3.9%, 4.2%, and 15.8% had ≥2 geriatric risk factors, respectively. Statistically significant association between geriatric risk index and health care utilization was found independent of demographic and comorbidity covariates. For example, based on claims, estimated odds ratios for having 1 and ≥2 geriatric risk factors in year 1 were 1.49 (P<0.001) and 2.62 (P<0.001) in predicting any occurrence of hospitalizations in year 1, and 1.32 (P<0.001) and 1.34 (P=0.003) in predicting any occurrence of hospitalizations in year 2. CONCLUSIONS: The results demonstrate the feasibility and potential of using EHRs and claims for collecting new types of geriatric risk information that could augment the more commonly collected disease information to identify and move upstream the management of high-risk cases among older patients.

Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy.

In pregnancy, trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodelling has been implicated in pre-eclampsia, a major complication of pregnancy, for a long time but the underlying mechanisms remain unclear. Corin (also known as atrial natriuretic peptide-converting enzyme) is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important in regulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here we identify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodelling were markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts in invading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations in pre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia.

VALUE AND PERFORMANCE OF ACCOUNTABLE CARE ORGANIZATIONS: A COST-MINIMIZATION ANALYSIS.

OBJECTIVES: Determine the relationship between quality of an accountable care organization (ACO) and its long-term reduction in healthcare costs. METHODS: We conducted a cost minimization analysis. Using Centers for Medicare and Medicaid cost and quality data, we calculated weighted composite quality scores for each ACO and organization-level cost savings. We used Markov modeling to compute the probability that an ACO transitioned between different quality levels in successive years. Considering a health-systems perspective with costs discounted at 3 percent, we conducted 10,000 Monte Carlo simulations to project long-term cost savings by quality level over a 10-year period. We compared the change in per-member expenditures of Pioneer (early-adopters) ACOs versus Medicare Shared Savings Program (MSSP) ACOs to assess the impact of coordination of care, the main mechanism for cost savings. RESULTS: Overall, Pioneer ACOs saved USD 641.24 per beneficiary and MSSP ACOs saved USD 535.59 per beneficiary. By quality level: (a) high quality organizations saved the most money (Pioneer: USD 459; MSSP: USD 816); (b) medium quality saved some money (Pioneer: USD 222; MSSP: USD 105); and (c) low quality suffered financial losses (Pioneer: USD -40; MSSP: USD -386). CONCLUSIONS: Within the existing fee-for-service healthcare model, ACOs are a mechanism for decreasing costs by improving quality of care. Higher quality organizations incorporate greater levels of coordination of care, which is associated with greater cost savings. Pioneer ACOs have the highest level of integration of services; hence, they save the most money.

Communication between oocytes and somatic cells regulates volatile pheromone production in Caenorhabditis elegans.

Males of the androdioecious species Caenorhabditis elegans are more likely to attempt to mate with and successfully inseminate C. elegans hermaphrodites that do not concurrently harbor sperm. Although a small number of genes have been implicated in this effect, the mechanism by which it arises remains unknown. In the context of the battle of the sexes, it is also unknown whether this effect is to the benefit of the male, the hermaphrodite, or both. We report that successful contact between mature sperm and oocyte in the C. elegans gonad at the start of fertilization causes the oocyte to release a signal that is transmitted to somatic cells in its mother, with the ultimate effect of reducing her attractiveness to males. Changes in hermaphrodite attractiveness are tied to the production of a volatile pheromone, the first such pheromone described in C. elegans.