Identifying neonatal intensive care (NICU) admissions using administrative claims data.

BACKGROUND: To define a method for identifying neonatal intensive care unit (NICU) admissions using administrative claims data. METHODS: This was a retrospective cohort study using claims from Optum's de-identified Clinformatics® Data Mart Database (CDM) from 2016 -2020. We developed a definition to identify NICU admissions using a list of codes from the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), Current Procedural Terminology (CPT), and revenue codes frequently associated with NICU admissions. We compared agreement between codes using Kappa statistics and calculated positive predictive values (PPV) and 95% confidence intervals (CI). RESULTS: On average, revenue codes (3.3%) alone identified more NICU hospitalizations compared to CPT codes alone (1.5%), whereas the use of CPT and revenue (8.9%) and CPT or revenue codes (13.7%) captured the most NICU hospitalizations, which aligns with rates of preterm birth. Gestational age alone (4.2%) and birthweight codes alone (2.0%) identified the least number of potential NICU hospitalizations. Setting CPT codes as the standard and revenue codes as the "test,", revenue codes resulted in identifying 86% of NICU admissions (sensitivity) and 97% of non-NICU admissions (specificity). CONCLUSIONS: Using administrative data, we developed a robust definition for identifying neonatal admissions. The identified definition of NICU codes is easily adaptable, repeatable, and flexible for use in other datasets.

Testing of putative antiseizure drugs in a preclinical Dravet syndrome zebrafish model.

Dravet syndrome (DS) is a severe genetic epilepsy primarily caused by de novo mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications (ASM). Preclinical DS animal models are a valuable tool to identify candidate ASMs for these patients. Among these, scn1lab mutant zebrafish exhibiting spontaneous seizure-like activity are particularly amenable to large-scale drug screening. Prior screening in a scn1lab mutant zebrafish line generated using N-ethyl-Nnitrosourea (ENU) identified valproate, stiripentol, and fenfluramine e.g., Federal Drug Administration (FDA) approved drugs with clinical application in the DS population. Successful phenotypic screening in scn1lab mutant zebrafish consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behavior and (ii) an electrophysiology-based assay, using in vivo local field potential (LFP) recordings, to quantify electrographic seizure-like events. Using this strategy more than 3000 drug candidates have been screened in scn1lab zebrafish mutants. Here, we curated a list of nine additional anti-seizure drug candidates recently identified in preclinical models: 1-EBIO, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in scn1lab mutant zebrafish identified only 1-EBIO, chlorzoxazone and lisuride. However, second-stage LFP recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of ASMs.

High-Sensitivity Mutation Analysis of Cell-Free DNA for Disease Monitoring in Endometrial Cancer.

PURPOSE: We sought to determine whether sequencing analysis of circulating cell-free DNA (cfDNA) in patients with prospectively accrued endometrial cancer captures the mutational repertoire of the primary lesion and allows for disease monitoring. EXPERIMENTAL DESIGN: Peripheral blood was prospectively collected from 44 newly diagnosed patients with endometrial cancer over a 24-month period (i.e., baseline, postsurgery, every 6 months after). DNA from the primary endometrial cancers was subjected to targeted next-generation sequencing (NGS) of 468 cancer-related genes, and cfDNA to a high-depth NGS assay of 129 genes with molecular barcoding. Sequencing data were analyzed using validated bioinformatics methods. RESULTS: cfDNA levels correlated with surgical stage in endometrial cancers, with higher levels of cfDNA being present in advanced-stage disease. Mutations in cfDNA at baseline were detected preoperatively in 8 of 36 (22%) patients with sequencing data, all of whom were diagnosed with advanced-stage disease, high tumor volume, and/or aggressive histologic type. Of the 38 somatic mutations identified in the primary tumors also present in the cfDNA assay, 35 (92%) and 38 (100%) were detected at baseline and follow-up, respectively. In 6 patients with recurrent disease, changes in circulating tumor DNA (ctDNA) fraction/variant allele fractions in cfDNA during follow-up closely mirrored disease progression and therapy response, with a lead time over clinically detected recurrence in two cases. The presence of ctDNA at baseline (P < 0.001) or postsurgery (P = 0.014) was significantly associated with reduced progression-free survival. CONCLUSIONS: cfDNA sequencing analysis in patients with endometrial cancer at diagnosis has prognostic value, and serial postsurgery cfDNA analysis enables disease and treatment response monitoring. See related commentary by Grant et al., p. 305.

Sentinel lymph node mapping in patients with endometrial hyperplasia: A practice to preserve or abandon?

OBJECTIVES: To compare outcomes of patients with premalignant endometrial pathology undergoing hysterectomy with or without sentinel lymph node (SLN) removal. Outcomes of interest included surgical adverse events (AEs), cancer status on final pathology, postoperative treatment, and The Cancer Genome Atlas (TCGA) molecular risk profiles. METHODS: We retrospectively identified patients with premalignant pathology on preoperative endometrial biopsy who underwent hysterectomy with or without SLN mapping/excision at our institution from 01/01/2017-12/31/2021. Clinical, pathologic, surgical, and TCGA profiling data were abstracted. Appropriate statistical tests were used. RESULTS: Of 221 patients identified, 161 (73%) underwent hysterectomy with SLN excision and 60 (27%) underwent hysterectomy without SLN excision. Median age and body mass index were similar between groups. Median operative time was 130 min for those who underwent SLN mapping/excision versus 136 min for those who did not (p = 0.6). Thirty-day postoperative AE rates were 9% (n = 15/161) and 13% (n = 8/60), respectively (p = 0.9). Ninety-eight (44%) of 221 patients had grade 1-2 endometrioid endometrial cancer on final pathology (4 [4%] were stage IB or higher). Ten (10%) of 98 patients, all within the SLN group, received adjuvant treatment. Among all patients, of 33 (15%) with TCGA molecular classification data, 27 (82%) had copy number-low, 3 (9%) microsatellite instability-high, 2 (6%) POLE-ultramutated, and 1 (3%) copy number-high disease. CONCLUSIONS: SLN assessment appears safe, detects a small number of occult nodal metastases for those upstaged, and provides additional staging information that can guide adjuvant treatment. SLN mapping should be discussed in preoperative counseling and offered using a shared decision-making approach.

Impact of obesity and white adipose tissue inflammation on the omental microenvironment in endometrial cancer.

BACKGROUND: A complex relationship between adipose tissue and malignancy, involving an inflammatory response, has been reported. The goal of this work was to assess the prevalence of white adipose tissue (WAT) inflammation in patients with endometrial cancer (EC), and the association with circulating inflammation markers. Furthermore, the aim was to characterize the pathways activated in and the cell type composition of adipose tissue in patients with EC. METHODS: Adipose tissue and blood samples were prospectively collected from 101 patients with EC at initial surgery. WAT inflammation was determined based on adipocytes surrounded by macrophages forming crown-like structures. Circulating levels of metabolic syndrome-associated and inflammatory markers were quantified. RNA-sequencing was performed on adipose samples (n = 55); differential gene expression, pathway, and cellular decomposition analyses were performed using state-of-the-art bioinformatics methods. RESULTS: WAT inflammation was identified in 46 (45.5%) of 101 EC patients. Dyslipidemia, hypertension, and diabetes mellitus were significantly associated with WAT inflammation (p < .05). WAT inflammation was associated with greater body mass index (p < .001) and higher circulating levels of leptin, high-sensitivity C-reactive protein, and interleukin-6, as well as lower levels of adiponectin and sex hormone-binding globulin (p < .05). Transcriptomic analysis demonstrated increased levels of proinflammatory and pro-neoplastic-related gene expression in inflamed omental adipose tissue. CONCLUSIONS: WAT inflammation is associated with metabolic syndrome, obesity, and inflammatory markers, as well as increased expression of proinflammatory and proneoplastic genes.

Pelvic exenteration for recurrent or persistent gynecologic malignancies: Clinical and histopathologic factors predicting recurrence and survival in a modern cohort.

OBJECTIVES: To explore pre-operative factors and their impact on overall survival (OS) in a modern cohort of patients who underwent pelvic exenteration (PE) for gynecologic malignancies. METHODS: A retrospective review was performed for all patients who underwent a PE from 1/1/2010 through 12/31/2018 at our institution. Inclusion criteria were exenteration due to recurrent or progressive carcinoma of the uterus, cervix, vagina or vulva, with histologically confirmed complete surgical resection of the malignancy. Exclusion criteria included PE for palliation of symptoms without recurrence, and for ovarian or rare histologic malignancies. Univariable and multivariable analysis were performed to identify factors predicting prolonged survival. RESULTS: Overall, 71 patients met the inclusion criteria. Median age at time of exenteration was 62 years (range, 28-86 years). Vulvar cancer was the most common primary diagnosis (32%); 30% had cervical cancer; 23%, uterine cancer; 15%, vaginal cancer. Median OS was 55.1 months (95% confidence interval (CI): 36-not estimable) with a median follow-up time of 40.8 months (95% CI: 1-116.1). On univariable analysis, age > 62 years (hazard ratio (HR) 2.71, 95% CI 1.27-5.79), American Society of Anesthesia (ASA) 3-4 (HR: 3.41 (95% CI 1.03-11.29), and vulvar cancer (HR 4.19 (95% CI 1.17-14.96) predicted worse OS. Tumor size and prior progression-free interval (PFI) did not meet statistical significance in OS analyses. On multivariable analysis, there were no significant factors associated with worse OS. CONCLUSIONS: PE performed with curative intent may be considered a treatment option in well-counseled, carefully selected patients, irrespective of tumor size and PFI before exenteration.

Toward a rational and ethical sociotechnical system of autonomous vehicles: A novel application of multi-criteria decision analysis.

The impacts of autonomous vehicles (AV) are widely anticipated to be socially, economically, and ethically significant. A reliable assessment of the harms and benefits of their large-scale deployment requires a multi-disciplinary approach. To that end, we employed Multi-Criteria Decision Analysis to make such an assessment. We obtained opinions from 19 disciplinary experts to assess the significance of 13 potential harms and eight potential benefits that might arise under four deployments schemes. Specifically, we considered: (1) the status quo, i.e., no AVs are deployed; (2) unfettered assimilation, i.e., no regulatory control would be exercised and commercial entities would "push" the development and deployment; (3) regulated introduction, i.e., regulatory control would be applied and either private individuals or commercial fleet operators could own the AVs; and (4) fleets only, i.e., regulatory control would be applied and only commercial fleet operators could own the AVs. Our results suggest that two of these scenarios, (3) and (4), namely regulated privately-owned introduction or fleet ownership or autonomous vehicles would be less likely to cause harm than either the status quo or the unfettered options.

Comparison of minimally invasive versus open surgery in the treatment of endometrial carcinosarcoma.

OBJECTIVE: The aim of this study was to compare perioperative and oncologic outcomes between minimally invasive and open surgery in the treatment of endometrial carcinosarcoma. METHODS: We retrospectively identified all patients with newly diagnosed endometrial carcinosarcoma who underwent primary surgery via any approach at our institution from January 2009 to January 2018. Patients with known bulky disease identified on preoperative imaging were excluded. The χ2 and Mann-Whitney U tests were used to compare categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival, and compared using the log rank test. RESULTS: We identified 147 eligible patients, of whom 37 (25%) underwent an open approach and 110 (75%) underwent minimally invasive surgery. Within the minimally invasive group, 92 (84%) of 110 patients underwent a robotic procedure and 14 (13%) underwent a laparoscopic procedure. Four minimally invasive cases (4%) were converted to open procedures. Median age, body mass index, operative time, stage, complication grade, and use of adjuvant treatment were clinically and statistically similar between groups. Median length of hospital stay in the open group was 4 days (range 3-21) compared with 1 day (range 0-6) in the minimally invasive group (p<0.001). The rates of any 30-day complication were 46% in the open and 8% in the minimally invasive group (p<0.001). The rates of grade 3 or higher complications were 5.4% and 1.8%, respectively (p=0.53). Median follow-up for the entire cohort was 30 months (range 0.4-121). Two-year progression-free survival rates were 52.8% (SE±8.4) in the open group and 58.5% (SE±5.1) in the minimally invasive group (p=0.7). Two-year disease-specific survival rates were 66.1% (SE±8.0) and 81.4% (SE±4.1), respectively (p=0.8). CONCLUSIONS: In patients with clinical stage I endometrial carcinosarcoma, minimally invasive compared with open surgery was not associated with poor oncologic outcomes, but with a shorter length of hospital stay and a lower rate of overall complications.

The impact of near-infrared angiography and proctoscopy after rectosigmoid resection and anastomosis performed during surgeries for gynecologic malignancies.

OBJECTIVES: Reducing anastomotic leak rates after rectosigmoid resection and anastomosis is a priority in patients undergoing gynecologic oncology surgery. Therefore, we investigated the implications of performing near-infrared angiography (NIR) via proctoscopy to assess anastomotic perfusion at the time of rectosigmoid resection and anastomosis. METHODS: We identified all patients who underwent rectosigmoid resection and anastomosis for a gynecologic malignancy between January 1, 2013 and December 31, 2018. NIR proctoscopy was assessed via the PINPOINT Endoscopic Imaging System (Stryker). RESULTS: A total of 410 patients were identified, among whom NIR was utilized in 133 (32.4%). There were no statistically significant differences in age, race, BMI, type of malignancy, surgery, histology, FIGO stage, hypertension, diabetes, or preoperative chemotherapy between NIR and non-NIR groups. All cases of rectosigmoid resection underwent stapled anastomosis. The anastomotic leak rate was 2/133 (1.5%) in the NIR cohort compared with 13/277 (4.7%) in the non-NIR cohort (p = 0.16). Diverting ostomy was performed in 9/133 (6.8%) NIR and 53/277 (19.9%) non-NIR patients (p < 0.001). Postoperative abscesses occurred in 8/133 (6.0%) NIR and 44/277 (15.9%) non-NIR patients (p = 0.004). The NIR cohort had significantly fewer post-operative interventional procedures (12/133, 9.0% NIR vs. 55/277, 19.9% non-NIR, p = 0.006) and significantly fewer 30-day readmissions (14/133, 10.5% NIR vs. 61/277, 22% non-NIR, p = 0.004). CONCLUSIONS: NIR proctoscopy is a safe tool for assessing anastomotic rectal perfusion after rectosigmoid resection and anastomosis, with a low anastomotic leak rate of 1.5%. Its potential usefulness should be evaluated in randomized trials in patients undergoing gynecologic cancer surgery.

Effect of a Patient Decision Aid on Lung Cancer Screening Decision-Making by Persons Who Smoke: A Randomized Clinical Trial.

Importance: Lung cancer screening with low-dose computed tomography lowers lung cancer mortality but has potential harms. Current guidelines support patients receiving information about the benefits and harms of lung cancer screening during decision-making. Objective: To examine the effect of a patient decision aid (PDA) about lung cancer screening compared with a standard educational material (EDU) on decision-making outcomes among smokers. Design, Setting, and Participants: This randomized clinical trial was conducted using 13 state tobacco quitlines. Current and recent tobacco quitline clients who met age and smoking history eligibility for lung cancer screening were enrolled from March 30, 2015, to September 12, 2016, and followed up for 6 months until May 5, 2017. Data analysis was conducted between May 5, 2017, and September 30, 2018. Interventions: Participants were randomized to the PDA video Lung Cancer Screening: Is It Right for Me? (n = 259) or to EDU (n = 257). Main Outcomes and Measures: The primary outcomes were preparation for decision-making and decisional conflict measured at 1 week. Secondary outcomes included knowledge, intentions, and completion of screening within 6 months of receiving the intervention measured by patient report. Results: Of 516 quit line clients enrolled, 370 (71.7%) were younger than 65 years, 320 (62.0%) were female, 138 (26.7%) identified as black, 47 (9.1%) did not have health insurance, and 226 (43.8%) had a high school or lower educational level. Of participants using the PDA, 153 of 227 (67.4%) were well prepared to make a screening decision compared with 108 of 224 participants (48.2%) using EDU (odds ratio [OR], 2.31; 95% CI, 1.56-3.44; P < .001). Feeling informed about their screening choice was reported by 117 of 234 participants (50.0%) using a PDA compared with 66 of 233 participants (28.3%) using EDU (OR, 2.56; 95% CI, 1.72-3.79; P < .001); 159 of 234 participants (68.0%) using a PDA compared with 110 of 232 (47.4%) participants using EDU reported being clear about their values related to the harms and benefits of screening (OR, 2.37; 95% CI, 1.60-3.51; P < .001). Participants using a PDA were more knowledgeable about lung cancer screening than participants using EDU at each follow-up assessment. Intentions to be screened and screening behaviors did not differ between groups. Conclusions and Relevance: In this study, a PDA delivered to clients of tobacco quit lines improved informed decision-making about lung cancer screening. Many smokers eligible for lung cancer screening can be reached through tobacco quit lines. Trial Registration: ClinicalTrials.gov identifier: NCT02286713.

Minimally invasive surgery versus laparotomy for radical hysterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: To compare oncologic and perioperative outcomes in patients who underwent minimally invasive surgery (MIS) compared to laparotomy for newly diagnosed early-stage cervical carcinoma. METHODS: We retrospectively identified patients who underwent radical hysterectomy for stage IA1 with lymphovascular invasion (LVI), IA2, or IB1 cervical carcinoma at our institution from 1/2007-12/2017. Clinicopathologic characteristics and surgical and oncologic survival outcomes were compared using appropriate statistical testing. Multivariable Cox regression analysis was used to control for potential confounders. RESULTS: We identified 196 evaluable cases-117 MIS (106 robotic [90.6%]) and 79 laparotomy cases. Cohorts had similar age, BMI, substage, histologic subtype, clinical and pathologic tumor size, positive margins, and presence of LVI. The MIS group had more cases with no residual tumor in the hysterectomy (24.8% vs. 10.1%, P = 0.01). The laparotomy group had more cases with positive nodes (29.1% vs. 17.1%, P = 0.046) and more patients who received adjuvant therapy (53.2% vs. 33.3%, P = 0.006). Median follow-up was ~4 years. Five-year disease-free survival (DFS) rates were 87.0% in the MIS group and 86.6% in the laparotomy group (P = 0.92); 5-year disease-specific survival (DSS) rates were 96.5% and 93.9%, respectively (P = 0.93); and 5-year overall survival (OS) rates were 96.5% and 87.4%, respectively (P = 0.15). MIS was not associated with DFS, DSS, or OS on multivariable regression analysis. The rate of postoperative complications was significantly lower in the MIS cohort (11.1% vs. 20.3%; P = 0.04). CONCLUSIONS: MIS radical hysterectomy for cervical carcinoma did not confer worse oncologic outcomes in our single-center and concurrent series of patients with early-stage cervical carcinoma.

Sentinel lymph node mapping alone compared to more extensive lymphadenectomy in patients with uterine serous carcinoma.

OBJECTIVES: The objective of our study was to assess survival among patients with uterine serous carcinoma (USC) undergoing sentinel lymph node (SLN) mapping alone versus patients undergoing systematic lymphadenectomy (LND). METHODS: We retrospectively reviewed patients undergoing primary surgical treatment for newly diagnosed USC at our institution from 1/1/1996-12/31/2017. Patients were assigned to either SLN mapping alone (SLN cohort) or systematic LND without SLN mapping (LND cohort). Progression-free (PFS) and overall survival (OS) were estimated using Kaplan-Meier method, compared using Logrank test. RESULTS: 245 patients were available for analysis: 79 (32.2%) underwent SLN, 166 (67.7%) LND. 132 (79.5%) in the LND cohort had paraaortic LND (PALND) versus none in the SLN cohort. Median age: 66 and 68 years in the SLN and LND cohorts, respectively (p>0.05). Proportion of stage I/II disease: 67.1% (n = 53) and 64.5% (n = 107) in the SLN and LND cohorts, respectively (p>0.05). Median follow-up: 23 (range, 1-96) and 66 months (range, 4-265) in the SLN and LND cohorts, respectively (p < 0.001). Two-year OS in stage I/II disease (n = 160, 60.1%): 96.6% (SE ± 3.4) and 89.6% (SE ± 2.2) in the SLN and LND cohorts, respectively (p = 0.8). Two-year OS in stage III disease (n = 77): 73.6% (SE ± 10.2) and 77.3% (SE ± 5.8) in the SLN and LND cohorts, respectively (p = 0.8). CONCLUSIONS: SLN mapping alone and systematic LND yielded similar survival outcomes in stage I-III USC. In our practice, the SLN algorithm has replaced systematic LND as the primary staging modality in this setting.

Characteristics and survival of ovarian cancer patients treated with neoadjuvant chemotherapy but not undergoing interval debulking surgery.

OBJECTIVE: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) confers similar outcomes as primary debulking surgery and chemotherapy. Little is known about patients who receive NACT but do not undergo debulking surgery. Our aim was to characterize these patients. METHODS: We prospectively identified patients with newly diagnosed stage III/IV ovarian cancer treated with NACT from 7/1/15-12/1/17. Fisher exact and Wilcoxon rank-sum tests were used to compare clinical characteristics by surgical status. The Kaplan-Meier method was used to estimate survival outcomes. Log-rank test and Cox proportional hazards model were applied to assess the relationship of covariates to outcome, and time-dependent covariates were applied to variables collected after diagnosis. RESULTS: Of 224 women who received NACT, 162 (72%) underwent IDS and 62 (28%) did not undergo surgery. The non-surgical group was older (p<0.001), had higher Charlson comorbidity index (CCI; p<0.001), lower albumin levels (p=0.007), lower Karnofsky performance scores (p<0.001), and were more likely to have dose reductions in NACT (p<0.001). Reasons for no surgery included poor response to NACT (39%), death (15%), comorbidities (24%), patient preference (16%), and loss to follow-up (6%). The no surgery group had significantly worse overall survival (OS) than the surgery group (hazard ratio=3.34; 95% confidence interval=1.66-6.72; p<0.001), after adjustment for age, CCI, and dose reductions. CONCLUSIONS: A significant proportion of women treated with NACT do not undergo IDS, and these women are older, frailer, and have worse OS. More studies are needed to find optimal therapies to maximize outcomes in this high-risk, elderly population.

Characteristics and survival of ovarian cancer patients treated with neoadjuvant chemotherapy but not undergoing interval debulking surgery / 부인종양

Secondary surgical resection for patients with recurrent uterine leiomyosarcoma.

OBJECTIVES: To assess outcomes after secondary surgical resection in patients with recurrent uterine leiomyosarcoma (uLMS). METHODS: We retrospectively identified all patients who had no evidence of disease after initial surgery for uLMS, who underwent surgery for a first recurrence at our institution between 1/1991 and 10/2013. We excluded patients who received any therapy for recurrence prior to secondary resection, and patients who underwent surgery soon after morcellation [of presumed benign fibroids] showed widespread disease. Overall survival (OS) was determined from time of first recurrence to death or last follow-up. RESULTS: We identified 62 patients: 29 with abdominal/pelvic recurrence only, 30 with lung recurrence only, 3 with both. Median time to first recurrence was 18 months (95% CI: 13.3-23.3): 15.8 months (95% CI: 13.0-18.6) abdominal/pelvic recurrence; 24.1 months (95% CI: 14.5-33.7) lung-only recurrence (p = 0.03). Median OS was 37.7 months (95% CI: 25.9-49.6) abdominal/pelvic recurrence; 78.1 months (95% CI: 44.8-11.4) lung recurrence (p = 0.02). Complete gross resection (CGR) was achieved in 58 cases (93%), with gross residual ≤1 cm in 2 (3.5%) and >1 cm in 2 (3.5%). Median OS based on residual disease was 54.1 months (95% CI: 24.9-83.3), 38.7 months (95% CI: NE), 1.7 months (95% CI: NE), respectively (p < 0.001). In cases with CGR, neither adjuvant radiation (N = 9), chemotherapy (N = 8) nor hormonal therapy (N = 10) was associated with improved OS. CONCLUSIONS: Secondary surgical resection of recurrent uLMS is reasonable in patients with a high probability of achieving CGR. Lung-only recurrences were associated with more favorable outcome. Following CGR, additional therapy may not offer benefit.

Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.

Separating the wheat from the chaff: systematic identification of functionally relevant noncoding variants in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.

In vitro antifungal activity of fluconazole and voriconazole against non-Candida yeasts and yeast-like fungi clinical isolates.

The risk of opportunistic infections caused by non-Candida yeasts and yeast-like fungi is increasingly common, mainly in immunocompromised patients. Appropriate first-line therapy has not been defined and standardized, mainly due to the low number of cases reported. To improve empirical treatment guidelines, we describe the susceptibility profile to fluconazole and voriconazole of 176 non-Candida yeasts and yeast-like fungi collected from hospitals in Piedmont, North West Italy from January 2009 to December 2013. The results showed that most isolates are susceptible to voriconazole (94%), but less susceptible to fluconazole (78%), suggesting that voriconazole could be used as first-line therapy in infections caused by these fungi.