Transcriptome analysis and molecular mechanism of linseed (Linum usitatissimum L.) drought tolerance under repeated drought using single-molecule long-read sequencing.

BACKGROUND: Oil flax (linseed, Linum usitatissimum L.) is one of the most important oil crops., However, the increases in drought resulting from climate change have dramatically reduces linseed yield and quality, but very little is known about how linseed coordinates the expression of drought resistance gene in response to different level of drought stress (DS) on the genome-wide level. RESULTS: To explore the linseed transcriptional response of DS and repeated drought (RD) stress, we determined the drought tolerance of different linseed varieties. Then we performed full-length transcriptome sequencing of drought-resistant variety (Z141) and drought-sensitive variety (NY-17) under DS and RD stress at the seedling stage using single-molecule real-time sequencing and RNA-sequencing. Gene Ontology (GO) and reduce and visualize GO (REVIGO) enrichment analysis showed that upregulated genes of Z141 were enriched in more functional pathways related to plant drought tolerance than those of NY-17 were under DS. In addition, 4436 linseed transcription factors were identified, and 1190 were responsive to stress treatments. Moreover, protein-protein interaction (PPI) network analysis showed that the proline biosynthesis pathway interacts with stress response genes through RAD50 (DNA repair protein 50) interacting protein 1 (RIN-1). Finally, proline biosynthesis and DNA repair structural gene expression patterns were verified by RT- PCR. CONCLUSIONS: The drought tolerance of Z141 may be related to its upregulation of drought tolerance genes under DS. Proline may play an important role in linseed drought tolerance by maintaining cell osmotic and protecting DNA from ROS damage. In summary, this study provides a new perspective to understand the drought adaptability of linseed.

Impact of Auricular Neurostimulation in Patients Undergoing Colorectal Surgery with an Enhanced Recovery Protocol: A Pilot Randomized, Controlled Trial.

BACKGROUND: Narcotics are the cornerstone of postoperative pain control, but the opioid epidemic and the negative physiological and psychological effects of narcotics implore physicians to utilize nonpharmacological methods of pain control. OBJECTIVE: This pilot study investigated a novel neurostimulation device for postoperative analgesia. We hypothesized that active neurostimulation would decrease postoperative narcotic requirements. DESIGN: This was a placebo-controlled, double-blinded trial. SETTINGS: This trial was conducted at an academic medical center and a Veterans Affairs hospital. PATIENTS: This trial included adult patients who underwent elective bowel resection between December 2016 and April 2018. INTERVENTIONS: Patients were randomly assigned to receive an active or inactive (sham) device, which was applied to the right ear before surgery and continued for 5 days. MAIN OUTCOME MEASURES: The primary outcome was total opioid consumption. The secondary outcomes included pain, nausea, anxiety, return of bowel function, complications, 30-day readmissions, and opioid consumption at 2 weeks and 30 days. RESULTS: A total of 57 patients participated and 5 withdrew; 52 patients were included in the analysis. Twenty-eight patients received an active device and 24 received an inactive device. There was no difference in total narcotic consumption between active and inactive devices (90.79 ± 54.93 vs 90.30 ± 43.03 oral morphine equivalents/day). Subgroup analyses demonstrated a benefit for patients after open surgery (p = 0.0278). When patients were stratified by decade, those aged 60 to 70 and >70 years derived a benefit from active devices in comparison with those aged 30 to 40, 40 to 50, and 50 to 60 years old (p = 0.01092). No serious adverse events were related to this study. LIMITATIONS: This study was limited by the small sample sizes. CONCLUSIONS: No difference in opioid use was found with auricular neurostimulation. However, this pilot study suggests that older patients and those with larger abdominal incisions may benefit from auricular neurostimulation. Further investigation in these high-risk patients is warranted. See Video Abstract at http://links.lww.com/DCR/B452.ClinicalTrials.gov identifier: NCT02892513. IMPACTO DE LA NEUROESTIMULACIN AURICULAR EN PACIENTES SOMETIDOS A CIRUGA COLORRECTAL CON UN PROTOCOLO DE RECUPERACIN MEJORADA UN ENSAYO PILOTO ALEATORIZADO Y CONTROLADO: ANTECEDENTES:Los narcóticos son la piedra angular del control del dolor postoperatorio, pero la epidemia de opioides y los efectos fisiológicos y psicológicos negativos de los narcóticos incentivan a los médicos a que utilicen métodos no farmacológicos de control del dolor.OBJETIVO:Este estudio piloto investigó un nuevo dispositivo de neuroestimulación para analgesia postoperatoria. Hipotetizamos que la neuroestimulación activa disminuiría los requerimientos narcóticos postoperatorios.DISEÑO:Este fue un ensayo doble ciego controlado con placebo.ESCENARIO:Esto se llevó a cabo en un centro médico académico y en un hospital de Asuntos de Veteranos (Veterans Affairs hospital).PACIENTES:Este ensayo incluyó pacientes adultos que se sometieron a resección intestinal electiva entre diciembre de 2016 y abril de 2018.INTERVENCIONES:Los pacientes fueron asignados al azar para recibir un dispositivo activo o inactivo (falso), que se aplicó al oído derecho antes de la cirugía y se mantuvo durante 5 días.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue el consumo total de opioides; los resultados secundarios incluyeron dolor, náusea, ansiedad, retorno de la función intestinal, complicaciones, reingresos a 30 días y consumo de opioides a 2 semanas y a 30 días.RESULTADOS:Participaron un total de 57 pacientes y 5 se retiraron; Se incluyeron 52 pacientes en el análisis. Veintiocho pacientes recibieron un dispositivo activo y 24 recibieron un dispositivo inactivo. No hubo diferencias en el consumo total de narcóticos entre los dispositivos activos e inactivos (90.79 ± 54.93 vs 90.30 ± 43.03 equivalentes de morfina oral [OME] / día). Los análisis de subgrupos demostraron un beneficio para los pacientes después de cirugía abierta (p = 0.0278). Cuando los pacientes se estratificaron por década, aquellos de 60-70 y > 70 años obtuvieron un beneficio de los dispositivos activos en comparación con los de 30-40, 40-50 y 50-60 años (p = 0.01092). No hubo eventos adversos graves relacionados con este estudio.LIMITACIONES:Este estudio estuvo limitado por los pequeños tamaños de muestra.CONCLUSIONES:No se encontró diferencia en el uso de opioides con la neuroestimulación auricular. Sin embargo, este estudio piloto sugiere que los pacientes mayores y aquellos con incisiones abdominales más grandes pueden beneficiarse de la neuroestimulación auricular. Está justificada la investigación adicional en estos pacientes de alto riesgo. Consulte Video Resumen en http://links.lww.com/DCR/B452. (Traducción-Dr. Jorge Silva Velazco).

Correction: Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

The original version of this article unfortunately contained the missing author, Caridad Martinez. The authors would like to correct the list. We apologize for any inconvenience that this may have caused. The correct author list is shown above.

Quality of Life of Patients with Wiskott Aldrich Syndrome and X-Linked Thrombocytopenia: a Study of the Primary Immune Deficiency Consortium (PIDTC), Immune Deficiency Foundation, and the Wiskott-Aldrich Foundation.

BACKGROUND: We undertook a study to determine the impact of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) and their therapies upon the health-related quality of life (HRQOL) of patients and their families. MATERIALS AND METHODS: We undertook a survey of patients and their families, who self-identified as having either WAS or XLT. We assessed the PedsQL™ 4.0, the parent proxy form, and the family impact module. These results were compared with normative data from previously published reports. RESULTS: Sixty-eight patients (29 patients completed both the PedsQL™ 4.0 and the parent proxy form; 21 completed only the PedsQL™ 4.0; and 18 completed only the parent proxy form) were included. In contrast to patient-reported outcomes, parents of patients who had a bone marrow transplant (BMT) reported that their children had better QOL scores compared with those who did not (82.6 vs. 73.3, p = 0.023). The QOL of patients vs. previously published normative data showed decreases in patient scores for psychosocial health (72.62 vs. 86.58, p = < 0.001), emotional functioning (69.91 vs. 82.64, p = < 0.001), social functioning (77.55 vs. 91.56, p = < 0.001), and school functioning (70.46 vs. 85.67, p = < 0.001). The family impact study revealed deficits in emotional, social, and cognitive functioning, communication, and worry. CONCLUSION: These results show that patients with WAS/XLT are significantly impacted with respect to QOL. BMT offered a better QOL for patients according to parents, but not as reported by the patients. Future studies should incorporate QOL to provide more data and a better understanding of outcomes for long-term survivors and decision-making regarding BMT.

Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking. METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016. RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT. CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/µL, CD8 < 50 cells/µL, CD45RA < 10%, or a restricted Vß T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913.

Brain death interval and relationship to outcomes of pediatric cardiac transplantation.

BACKGROUND: We sought to analyze brain death interval and outcomes of pediatric cardiac transplantation using national registry data. METHODS: We retrospectively evaluated a pediatric cohort from the UNOS registry from 2005 to 2014. We restricted the donor cohort to those with a primary central nervous system event as the cause of hospitalization. Brain death interval (BDI) was defined as the time between hospital admission and organ procurement. Primary outcomes were recipient and graft survival time. Logistical regression modeling was used for multivariable analysis. RESULTS: The donor cohort included 2565 cases. Multivariable analysis demonstrated no relationship between BDI and recipient or graft survival time. For patient survival time, the lowest HR was 0.94 (0.63-1.39), P = 0.531; for graft survival time, the lowest HR was 0.89 (0.53-1.49), P = 0.563. We obtained similar results using a non-restricted donor cohort. CONCLUSIONS: There was no clear relationship between BDI and recipient or graft survival after pediatric cardiac transplantation.

Self-Assessment Feedback Form Improves Quality of Out-of-Hospital CPR.

Objective: Various continuous quality improvement (CQI) approaches have been used to improve quality of cardiopulmonary resuscitation (CPR) delivered at the scene of out-of-hospital cardiac arrest. We evaluated a post-event, self-assessment, CQI feedback form to determine its impact on delivery of CPR quality metrics. Methods: This before/after retrospective review evaluated data from a CQI program in a midsized urban emergency medical services (EMS) system using CPR quality metrics captured by Zoll Medical Inc. X-series defibrillator ECG files in adult patients (≥18 years old) with non-traumatic out-of-hospital cardiac arrest. Two 9-month periods, one before and one after implementation of the feedback form on December 31, 2013 were evaluated. Metrics included the mean and percentage of goal achievement for chest compression depth (goal: >5 centimeters [cm]; >90%/episode), rate (goal: 100-120 compressions/minute [min]), chest compression fraction (goal: ≥75%), and preshock pause (goal: <10 seconds [sec]). The feedback form was distributed to all EMS providers involved in the resuscitation within 72 hours for self-review. Results: A total of 439 encounters before and 621 encounters after were evaluated including basic life support (BLS) and advanced life support (ALS) providers. The Before Group consisted of 408 patients with an average age of 61 ± 17 years, 61.8% male. The After Group consisted of 556 patients with an average age of 61 ± 17 years, 58.3% male. Overall, combining BLS and ALS encounters, the mean CPR metric values before and after were: chest compression depth (5.0 cm vs. 5.5 cm; p < 0.001), rate (109.6/min vs 114.8/min; p < 0.001), fraction (79.2% vs. 86.4%; p < 0.001), and preshock pause (18.8 sec vs. 11.8 sec; p < 0.001), respectively. Overall, the percent goal achievement before and after were: chest compression depth (48.5% vs. 66.6%; p < 0.001), rate (71.8% vs. 71.7%, p = 0.78), fraction (68.1% vs. 91.0%; p < 0.001), and preshock pause (24.1% vs. 59.5%; p < 0.001), respectively. The BLS encounters and ALS encounters had similar statistically significant improvements seen in all metrics. Conclusion: This post-event, self-assessment CQI feedback form was associated with significant improvement in delivery of out-of-hospital CPR depth, fraction and preshock pause time.

Sp1 is Involved in Vertebrate LC-PUFA Biosynthesis by Upregulating the Expression of Liver Desaturase and Elongase Genes.

The rabbitfish Siganus canaliculatus was the first marine teleost demonstrated to have the ability for the biosynthesis of long-chain (≥C20) polyunsaturated fatty acids (LC-PUFA) from C18 PUFA precursors, and all the catalytic enzymes including two fatty acyl desaturase 2 (Δ4 Fads2 and Δ6/Δ5 Fads2) and two elongases (Elovl4 and Elovl5) have been identified, providing a good model for studying the regulatory mechanisms of LC-PUFA biosynthesis in fish. Stimulatory protein 1 (Sp1) has been speculated to be a vital transcription factor in determining the promoter activity of Fads-like genes in fish, however its regulatory effects on gene expression and LC-PUFA biosynthesis have not been demonstrated. Bioinformatic analysis predicted potential Sp1 binding sites in the promoters of the rabbitfish Δ6/Δ5 fads2 and elovl5, but not in Δ4 fads2 promoter. Here we cloned full-length cDNA of the rabbitfish sp1 gene, which encoded a putative protein of 701 amino acids, and was expressed in all tissues studied with highest levels in gill and eyes. The dual luciferase reporter assay in HepG2 line cells demonstrated the importance of the Sp1 binding site for the promoter activities of both Δ6/Δ5 fads2 and elovl5. Moreover, the electrophoretic mobility shift assay confirmed the direct interaction of Sp1 with the two promoters. Insertion of the Sp1 binding site of Δ6/Δ5 fads2 promoter into the corresponding region of the Δ4 fads2 promoter significantly increased activity of the latter. In the Siganus canaliculatus hepatocyte line (SCHL) cells, mRNA levels of Δ6/Δ5 fads2 and elovl5 were positively correlated with the expression of sp1 when sp1 was overexpressed or knocked-down by RNAi or antagonist (mithramycin) treatment. Moreover, overexpression of sp1 also led to a higher conversion of 18:2n-6 to 18:3n-6, 18:2n-6 to 20:2n-6, and 18:3n-3 to 20:3n-3, which related to the functions of Δ6/Δ5 Fads2 and Elovl5, respectively. These results indicated that Sp1 is involved in the transcriptional regulation of LC-PUFA biosynthesis by directly targeting Δ6/Δ5 fads2 and elovl5 in rabbitfish, which is the first report of Sp1 involvement in the regulation of LC-PUFA biosynthesis in vertebrates.

Long-term Quality of Life in Neonatal Surgical Disease.

OBJECTIVE: This prospective observational study was designed to assess Pediatric Quality of Life (PedsQL) after surgical treatment for congenital diaphragmatic hernia (CDH), esophageal atresia/tracheoesophageal fistula (EA/TEF), Hirschsprung disease (HD), gastroschisis (GAS), omphalocele (OMP), and necrotizing enterocolitis (NEC). SUMMARY OF BACKGROUND DATA: Improvements in neonatal and surgical care have led to increased survival for many newborn conditions. Quality of life in these patients is seldom explored in a longitudinal manner. We hypothesized that age-adjusted physical and psychosocial scores would improve over time, but with diagnosis-dependent variation. METHODS: Data were collected from 241 patients (CDH = 52; EA/TEF = 62; HD = 46; GAS = 32; OMP = 26; NEC = 23) in an institutional Clinical Outcomes Registry (COR) from 2012 to 2017. Aggregate physical, psychosocial, and overall PedsQL scores were determined for each diagnosis. Spline regression models were created to model scores as a function of age. RESULTS: Physical scores trended up for all diagnoses except CDH and NEC beyond age 10. Psychosocial scores trended up for all diagnoses except NEC and EA/TEF beyond age 10. Beyond age 12, CDH, GAS, and HD patients had overall scores within the normal range, while NEC, OMP, and EA/TEF patients had scores similar to children with chronic medical illness. CONCLUSION: Variation exists in long-term PedsQL scores after neonatal surgery for selected, complex disease. Beyond age 12, quality of life is significantly impaired in NEC, moderately impaired in OMP and EA/TEF, and within normal range for CDH, HD, and GAS patients at the population level. These data are relevant to prenatal and perioperative discussions with patients and families.

A Multi-institutional Comparison of Adrenal Venous Sampling in Patients with Primary Aldosteronism: Caution Advised if Successful Bilateral Adrenal Vein Sampling is Not Achieved.

INTRODUCTION: In patients with primary aldosteronism (PA), adrenal venous sampling (AVS) is recommended to differentiate between unilateral (UNI) or bilateral (BIL) adrenal disease. A recent study suggested that lateralization could be predicted, based on the ratio of aldosterone/cortisol levels (A/C) between the left adrenal vein (LAV) and inferior vena cava (IVC), with a 100% positive predictive value (PPV). This study aimed to validate those findings utilizing a larger, multi-institutional cohort. METHODS: A retrospective review was performed of patients with PA who underwent AVS from 2 tertiary-care institutions. Laterality was predicted by an A/C ratio of >3:1 between the dominant and non-dominant adrenal. AVS results were compared to LAV/IVC ratios utilizing the published criteria (Lt ≥ 5.5; Rt ≤ 0.5). RESULTS: Of 222 patients, 124 (57%) had UNI and 98 (43%) had BIL disease based on AVS. AVS and LAV/IVC findings were concordant for laterality in 141 (64%) patients (69 UNI, 72 BIL). Using only the LAV/IVC ratio, 54 (24%) patients with UNI disease on AVS who underwent successful surgery would have been assumed to have BAH unless AVS was repeated, and 24 (11%) patients with BIL disease on AVS may have been incorrectly offered surgery (PPV 70%). Based on median LAV/IVC ratios (left 5.26; right 0.31; BIL 2.84), no LAV/IVC ratio accurately predicted laterality. DISCUSSION: This multi-institutional study of patients with both UNI and BIL PA failed to validate the previously reported PPV of LAV/IVC ratio for lateralization. Caution should be used in interpreting incomplete AVS data to differentiate between UNI versus BIL disease and strong consideration given to repeat AVS prior to adrenalectomy.

Minimally invasive hepatectomy conversions: an analysis of risk factors and outcomes.

BACKGROUND: Surgical approach may influence morbidity following hepatectomy. This study sought to compare outcomes in minimally invasive surgery (MIS), conversion from MIS to open, and planned open hepatectomy patients and analyze factors leading to conversion. METHODS: The 2014 National Surgical Quality Improvement Program dataset was queried for patients undergoing hepatectomy. Patients were divided into three cohorts: MIS, open, or conversion. Propensity matching was performed to compare MIS vs. conversion (3:1) and open vs. conversion (8:1). The logistic regression model was used to identify odds ratios for conversion. RESULTS: Patients undergoing conversion had a higher transfusion rate (26% vs. 9%, p < 0.001), longer length of stay (5 vs. 3 days, p < 0.001), and higher morbidity (38% vs. 18%, p < 0.001) than MIS patients. Patients who underwent conversion had similar short-term outcomes to those who had planned open procedures. Independent predictors of conversion included hypertension (OR 1.91; 95% CI 1.12-3.26) and right lobectomy (OR 20.23; 95% CI 3.74-109.35). CONCLUSION: Patients with hypertension and those undergoing right lobectomy had a higher risk of conversion to open procedure. Conversion resulted in higher morbidity and longer length of stay compared to MIS patients, but outcomes were similar to planned open procedures.

Etanercept and Corticosteroid Therapy for the Treatment of Late-Onset Idiopathic Pneumonia Syndrome.

Idiopathic pneumonia syndrome (IPS) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) that typically occurs within the first 100 days after transplantation. Tumor necrosis factor α (TNF-α) has been shown to be a key mediator of IPS, and the TNF-α binding protein etanercept appeared to improve IPS outcomes in small retrospective and prospective studies. IPS also has been observed to occur later (>100 days) after HSCT; however, little is known about the disease course and whether a TNF-α-based therapeutic strategy is efficacious in these patients. To address this question, we performed a retrospective analysis of 23 patients who underwent HSCT between 2004 and 2016 at our institution who developed late-onset IPS and received treatment with etanercept and high-dose corticosteroids (CS). Ten of the 23 patients (43%) attained a complete clinical response to etanercept and CS. Responses were significantly more likely to occur in patients who did not require positive pressure ventilation at the time of diagnosis. Those who responded experienced a durable survival benefit, with a 2-year overall survival of 67%. In the 13 patients (57%) who did not respond to etanercept and CS, the median overall survival was only 13 days (range, 1 to 60 days). The difference in 2-year overall survival between responders and nonresponders was statistically significant (67% versus 0%; P < .001). These results indicate that late-onset IPS carries high mortality, but that treatment with etanercept and CS has activity and can result in long-term survival in some patients. Prompt diagnosis and early institution of therapy before the need for advanced respiratory support is critical for maximizing responses.

A cost-effective chart review sampling design to account for phenotyping error in electronic health records (EHR) data.

OBJECTIVES: Electronic health records (EHR) are commonly used for the identification of novel risk factors for disease, often referred to as an association study. A major challenge to EHR-based association studies is phenotyping error in EHR-derived outcomes. A manual chart review of phenotypes is necessary for unbiased evaluation of risk factor associations. However, this process is time-consuming and expensive. The objective of this paper is to develop an outcome-dependent sampling approach for designing manual chart review, where EHR-derived phenotypes can be used to guide the selection of charts to be reviewed in order to maximize statistical efficiency in the subsequent estimation of risk factor associations. MATERIALS AND METHODS: After applying outcome-dependent sampling, an augmented estimator can be constructed by optimally combining the chart-reviewed phenotypes from the selected patients with the error-prone EHR-derived phenotype. We conducted simulation studies to evaluate the proposed method and applied our method to data on colon cancer recurrence in a cohort of patients treated for a primary colon cancer in the Kaiser Permanente Washington (KPW) healthcare system. RESULTS: Simulations verify the coverage probability of the proposed method and show that, when disease prevalence is less than 30%, the proposed method has smaller variance than an existing method where the validation set for chart review is uniformly sampled. In addition, from design perspective, the proposed method is able to achieve the same statistical power with 50% fewer charts to be validated than the uniform sampling method, thus, leading to a substantial efficiency gain in chart review. These findings were also confirmed by the application of the competing methods to the KPW colon cancer data. DISCUSSION: Our simulation studies and analysis of data from KPW demonstrate that, compared to an existing uniform sampling method, the proposed outcome-dependent method can lead to a more efficient chart review sampling design and unbiased association estimates with higher statistical efficiency. CONCLUSION: The proposed method not only optimally combines phenotypes from chart review with EHR-derived phenotypes but also suggests an efficient design for conducting chart review, with the goal of improving the efficiency of estimated risk factor associations using EHR data.

An integrative healthcare model with heartfulness meditation and care coordination improves outcomes in cyclic vomiting syndrome.

BACKGROUND: Cyclic vomiting syndrome (CVS) is associated with psychosocial comorbidity and often triggered by stress. Since the current disease-centered care model does not address psychosocial factors, we hypothesized that holistic, patient-centered care integrating meditation and addressing psychosocial needs through a care coordinator will improve healthcare outcomes in CVS. METHODS: We conducted a prospective randomized controlled trial: 49 patients with CVS (mean age: 34 ± 14 years; 81% female) were randomized to conventional health care (controls) or Integrative Health care (IHC) (27: controls, 22: IHC). The IHC group was assigned a care coordinator and received meditation with a certified instructor. Outcomes including psychological distress, coping strategies to manage chronic stress, cognitive symptom management, and Health-Related Quality of Life (HRQoL) were measured. KEY RESULTS: In intention-to-treat analyses, patients receiving IHC showed significant improvement in multiple domains of coping including positive reframing, planning, and reduction in self-blame (p values ≤0.05), and physical HRQoL (p = 0.03) at 6 months. They also leaned toward spirituality/religion as a coping measure (p ≤ 0.02 at 3 and 6 months). Subgroup analysis of compliant patients showed additional benefit with significant reduction in psychological distress (p = 0.04), improvement in sleep quality (p = 0.03), reduction in stress levels (0.02), improvement in physical HRQoL (0.04), and further improvement in other domains of coping (p < 0.05). CONCLUSIONS AND INFERENCES: An IHC model incorporating meditation and care coordination improves patient outcomes in CVS and is a useful adjunct to standard treatment. Studies to determine the independent effects of meditation and care coordination are warranted.

The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill.

Because medical illness is associated with increased inflammation and an increased risk for treatment-resistant major depressive disorder, anti-cytokine therapy may represent a novel, and especially efficacious, treatment for depression. We hypothesized that blockade of the interleukin (IL)-6 signaling pathway with tocilizumab would decrease depression and related symptomatology in a longitudinal cohort of allogeneic hematopoietic stem cell transplantation (HCT) patients, a medically ill population with a significant inflammation and psychopathology. Patients undergoing allogeneic HCT received either a single dose of tocilizumab one day prior to HCT (n = 25), or HCT alone (n = 62). The primary outcome included depressive symptoms at 28 days post HCT; anxiety, fatigue, sleep, and pain were assessed at pretreatment baseline and days +28, +100, and +180 post HCT as secondary outcomes. Multivariate regression demonstrated that preemptive treatment with tocilizumab was associated with significantly higher depression scores at D28 vs. the comparison group (ß = 5.74; 95% CI 0.75, 10.73; P = 0.03). Even after adjustment for baseline depressive symptoms, propensity score, and presence of acute graft-versus-host disease (grades II-IV) and other baseline covariates, the tocilizumab-exposed group continued to have significantly higher depression scores compared to the nonexposed group at D28 (ß = 4.73; 95% CI 0.64, 8.81; P = 0.02). Despite evidence that IL-6 antagonism would be beneficial, blockade of the IL-6 receptor with tocilizumab among medically ill patients resulted in significantly more-not less-depressive symptoms.

Mitral Valve Surgery in Neonates, Infants, and Children: Surgical Approach, Outcomes, and Predictors.

The surgical treatment of mitral disease in pediatrics is challenging. Managing diversity in patient anatomy, growth, and the need for long-term anticoagulation requires trade-offs between imperfect solutions. We sought to assess our approach to pediatric mitral valve surgery and identify predictors associated with mortality and recurrent mitral disease. The medical records, echocardiograms, and operative reports of all patients who underwent surgical intervention on the mitral valve from January 2000 to April 2016 were reviewed. A total of 143 patients underwent mitral valve surgery, 64 of which were neonates or infants (ages 10-355 days) and 79 of which were children (ages 1-17.8 years). Neonates and infants had a higher preoperative New York Heart Association heart failure classification in comparison to children (P < 0.001) with a less severe degree of mitral valve insufficiency (P = 0.007). Postoperative outcomes for primary repair patients (n = 133) demonstrated significant differences in recurrence of mitral valve disease, with 38% of neonates/infants and 21% of children affected (P = 0.028). Five-year rates of mortality or transplant were 22% (8%, 33%) in neonates and infants compared to 4% (0%, 10%) in children, P = 0.013. Mitral valve surgery in neonates and infants is particularly high risk and is associated with higher rate of recurrence and reintervention early. However, if successful early, mitral valve repair in neonates and infants can result in a durable freedom from reintervention that parallels freedom from reintervention in older children undergoing repair. Further understanding of mechanisms of failure and better matching of anatomic substrate to strategy is needed.

Breast Cancer in Women Aged 80 Years or Older: An Analysis of Treatment Patterns and Disease Outcomes.

No clear standard treatment guidelines exist for older women with breast cancer. In this study we aimed to examine the practice patterns and treatment outcomes of women ≥80 years old with invasive breast cancer. A retrospective chart review at a single academic institution was performed of 124 women diagnosed with stage I to III invasive breast cancer aged ≥80 years between 2005 and 2014. Median age of diagnosis was 84 years. Fifty-nine of the cancers (48%) were detected using mammography. One hundred twelve patients (90%) underwent surgery. There was no difference in comorbidities between the surgical and nonsurgical group (P = .800). In multivariate analysis, age was predictive of receiving surgery (P < .001). Overall survival probability was higher for those who received hormonal therapy (P = .002), radiation therapy (P = .041), and those with lower-stage tumors (P = .018). Surgery was not predictive of survival. It is important to consider comorbidities, complications and, longevity when determining whether elderly women diagnosed with breast cancer benefit from surgery.

Pparγ Is Involved in the Transcriptional Regulation of Liver LC-PUFA Biosynthesis by Targeting the Δ6Δ5 Fatty Acyl Desaturase Gene in the Marine Teleost Siganus canaliculatus.

As the first marine teleost demonstrated to have the ability of long-chain polyunsaturated fatty acids (LC-PUFA) biosynthesis from C18 PUFA precursors, the rabbitfish Siganus canaliculatus provides us a unique model for clarifying the regulatory mechanisms of LC-PUFA biosynthesis in teleosts aiming at the replacement of dietary fish oil (rich in LC-PUFA) with vegetable oils (rich in C18 PUFA precursors but devoid of LC-PUFA). In the study of transcription regulation of gene encoding the Δ6Δ5 fatty acyl desaturase (Δ6Δ5 Fads), a rate-limiting enzyme catalyzing the first step of LC-PUFA biosynthesis in rabbitfish, a binding site for the transcription factor (TF), peroxisome proliferator-activated receptor γ (Pparγ), was predicted in Δ6Δ5 fads2 promoter by bioinformatics analysis, and thus the present study focused on the regulatory roles of Pparγ on Δ6Δ5 fads2. First, the activity of the Δ6Δ5 fads2 promoter was proved to be downregulated by pparγ overexpression and upregulated by treatment of Pparγ antagonist (GW9662), respectively, in HEK 293T cells with the dual luciferase reporter assay. Pparγ was further confirmed to interact with the promoter by electrophoretic mobility shift assay. Moreover, in S. canaliculatus hepatocyte line (SCHL) cells, GW9662 decreased the expression of pparγ together with increase of Δ6Δ5 fads2 mRNA. Besides, Δ6Δ5 fads2 expression was increased by pparγ RNAi knockdown and reduced by its mRNA overexpression. Furthermore, knockdown of pparγ induced a high conversion of 18:3n-3 to 18:4n-3 and 18:2n-6 to 18:3n-6, while pparγ mRNA overexpression led to a lower conversion of that, and finally a significant decrease of 20:4n-6(ARA), 20:5n-3(EPA), and 22:6n-3(DHA) production. The results indicate that Pparγ is involved in the transcriptional regulation of liver LC-PUFA biosynthesis by targeting Δ6Δ5 fads2 in rabbitfish, which is the first report of Pparγ involvement in the regulation of LC-PUFA biosynthesis in teleosts.

Ketamine infusion for pain control in adult patients with multiple rib fractures: Results of a randomized control trial.

BACKGROUND: Rib fractures occur in up to 40% of trauma patients and are associated with increased mortality. Opiate-based pain regimens remain the cornerstone of rib fracture management; however, concerns around opioids have fostered interest in alternative analgesics. Ketamine is currently being used in lieu of opioids, but little evidence exists supporting its use within the trauma population. METHODS: A prospective, randomized, double-blind placebo-controlled trial of adult patients with three or more rib fractures admitted to a Level I trauma center was conducted. Exclusion criteria included age older than 64 years, Glasgow Coma Scale score less than 13, and chronic opiate use. The experimental arm received low-dose ketamine (LDK) at 2.5 µg·kg·min while the placebo cohort received an equivalent rate of 0.9% normal saline. All infusions were continued for 48 hours. The primary outcome was reduction in numeric pain score (NPS) during the first 24 hours. Secondary outcomes studied included oral morphine equivalent (OME) utilization, length of stay, epidural rates, pulmonary complications, and adverse events. RESULTS: Forty-five (49%) of 91 patients were randomized to the experimental arm. Both groups were similar in makeup. Overall, 74.7% were male, had a median age of 49 years, and an Injury Severity Score (ISS) of 14. Low-dose ketamine was not associated with a significant reduction in 24-hour NPS or OME totals. Subgroup analysis of 45 severely injured patients (ISS, >15) demonstrated that LDK was associated with a significant reduction in OME utilization during the first 24 hours (35.7 vs. 68, p = 0.03), 24 hours to 48 hours (64.2 vs. 96, p = 0.03), and overall (152.1 vs. 198, p = 0.048). No difference in other secondary outcomes or adverse events was noted. CONCLUSION: Low-dose ketamine failed to decrease NPS or OME within the overall cohort, but a decrease in OME was observed among patients with an ISS greater than 15. Confirmatory studies are necessary to determine if LDK is a useful adjunct among severely injured patients. LEVEL OF EVIDENCE: Therapeutic study, level II.