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BACKGROUND AND OBJECTIVES: Congenital syphilis (CS) is increasing in the United States and is associated with intersecting social and structural determinants of health. This study aimed to delineate birthing parent characteristics associated with CS in an adjusted model. METHODS (N = 720): People diagnosed with syphilis during pregnancy from 2017 to 2018 who were interviewed and linked to infants in the California state surveillance system were included (herein, “birthing parents”). Sociodemographic and clinical CS risk factors informed a stepwise multivariable logistic regression model in which the outcome of interest was infants born with CS. CS prevention continuums delineated the proportion of pregnant people with syphilis who completed steps (e.g., prenatal care entry, syphilis testing, treatment) needed to prevent CS; the outcome was delivering an infant without CS. We stratified continuums by homelessness and methamphetamine use to explore differences in CS outcomes. RESULTS: Of 720 birthing parents, 245 (34%) delivered an infant with CS. Although CS was initially associated with homelessness (odds ratio [OR] = 2.5, 95% confidence interval [CI]: 1.6, 4.0) and methamphetamine use (OR = 2.1, 95% CI: 1.4, 3.1), the addition of prenatal care into a final adjusted model attenuated these associations to not significant. In CS prevention continuums, delivering an infant without CS was less likely for people who reported methamphetamine use (p < .001) and/or homelessness (p < .001). However, when examining only those who received prenatal care, statistical differences for these predictors no longer existed. In the final adjusted model the following were associated with CS: no prenatal care (OR = 16.7, 95% CI: 9.2, 30.3) or late prenatal care (OR = 2.9, 95% CI: 1.9, 4.2); early stage of syphilis (OR = 2.6, 95% CI: 1.8, 3.7); living in Central California (OR = 2.1, 95% CI: 1.1, 4.2). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This is the first analysis to explore birthing parent characteristics associated with delivering an infant with CS in an adjusted model. We demonstrate that prenatal care, when accessed, can result in effective CS prevention among people who are unhoused and/or using methamphetamine equally well compared to counterparts without these risk factors.

OBJECTIVE: To explore the normal distribution of cervical sagittal alignment and the relationship between cervical alignment and global spine balance in asymptomatic young adults. METHODS: A cohort of 272 asymptomatic Chinese adults (including 161 males and 111 females, with an average age of (23.2±4.4) years, ranging from 18 to 45 years) were prospectively recruited from November 2011 to December 2014. The C(0)-C(2) angle, disk angles from C(2)-C(3) to C(6)-C(7), vertebral angles from C(3) to C(7), T(1) slope, thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), sacral slope (SS), C(2)-C(7) sagittal vertical axis (C(2)-C(7)SVA), center of gravity of head to C(7)SVA (CGH-C(7)SVA), C(7)-S(1)SVA were measured and statistically analyzed. All the subjects were categorized with the Roussouly classification and the cervical morphologies were evaluated as lordotic, straight, sigmoid or kyphotic. Spinal sagittal alignment parameters were compared between different sexes and Roussouly classifications with independent student t test, analysis of variance (ANOVA) or Chi-square test. Correlations between cervical sagittal alignment and global spine sagittal alignment were calculated using the Pearson and Spearman correlation coefficient. Linear regression analysis was performed. RESULTS: Sixty-seven males and 59 females aged from 18 to 30 years old were included in the study. The mean value of C(0)-C(7) was 26.0°±12.8°, composed of 15.2°±6.7° for C(0)-C(2), 9.1°±12.1° for sum of disk angles from C(2)-C(3) to C(6)-C(7), and 1.4°±10.2° for sum of vertebral angles from C(3) to C(7). C(2)-C(7)SVA [(18.6±7.9) mm] and CGH-C(7)SVA [(22.9±12.3) mm]were offset ideally by C(7)-S(1)SVA [(-21.6±31.0) mm]. Males had a larger T(1) slope (P < 0.05) and accordingly, a larger cervical lordosis C(2)-C(7) (P < 0.01) and C(0)-C(7) angle (P < 0.01) than females. Males had a smaller C(7)-S(1)SVA (P < 0.01) and accordingly, a smaller CGH-C(7)SVA (P=0.165) than females. Significant difference was found between cervical alignment of different Roussouly types (P < 0.01). In general, a larger LL was consistent with a set of larger TK, C(2)-C(7)angle, C(0)-C(7) angle, and vice versa. There was no significant correlation between cervical morphology and the Roussouly classification (Chi-square=10.548, P=0.308). There was significant correlation between cervical alignment and T(1) slope (P < 0.01), TK (P < 0.01). There was significant correlation between adjacent segmental angles from T(1) slope up to C(0)-C(2) angle (P < 0.05). CONCLUSION: Normative values of each vertebral angle and disk angle were established. The cervical lordosis occurred mainly at C(0)-C(2) and disk levels, which was influenced by parameters of other parts of the spine, such as T(1) slope, TK and the Roussouly classification. There was significant correlation between adjacent disk angles.

Women with a history of ductal carcinoma in situ (DCIS) have an elevated risk of a subsequent invasive breast cancer, but there are few established potentially modifiable factors known to lower this risk. Bisphosphonates are a commonly used treatment for patients with osteoporosis and have been shown to lower risks of recurrence and mortality in patients with invasive breast cancer; however, their use has not previously been investigated within the context of DCIS. Utilizing a population-based nested case–control design, we compared 301 cases of women diagnosed with DCIS and a subsequent breast cancer and 587 individually matched controls (on age, DCIS diagnosis year, primary treatment, histology, grade, and disease-free survival time) who were diagnosed with DCIS but never a subsequent breast cancer. Information on recency and duration of bisphosphonate use was ascertained from patient interviews and medical record reviews. Current users of bisphosphonates had a reduced risk of developing an invasive breast cancer compared with never users [OR = 0.50; 95% confidence interval (CI): 0.26–0.99]. Users of bisphosphonates for ≥48 months had a similar reduction in risk (OR = 0.45; 95% CI, 0.24–1.06). This is the first study to document that bisphosphonate use is associated with a lower risk of subsequent invasive breast cancer among women with a history of DCIS. This finding is consistent with the protective effect of bisphosphonates observed in other breast cancer settings. If validated by others, bisphosphonates may be an effective risk-reducing approach with the potential added benefits of its positive impacts on bone health and fracture risk. Significance: This study finds that bisphosphonate use among women with a history of DCIS is associated with lower risk of subsequent invasive breast cancer, providing a potential preventative approach for this high-risk population.

Background: Parkinson’s disease (PD) is characterized by brain metabolic networks, specifically associated with motor and cognitive manifestations. Few studies have investigated network changes in cerebral hemispheres ipsilateral and contralateral to the clinically more affected body side. Objective: We examined hemispheric network abnormalities and their relationship to striatal dopaminergic deficits in PD patients at different stages. Methods: 45 PD patients underwent dual-tracer positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and 18F-fluorodopa (FDOPA) in a high-resolution PET scanner. In all patients, we computed expression levels for the PD-related motor/cognition metabolic patterns (PDRP/PDCP) as well as putamen/caudate FDOPA uptake values in both hemispheres. Resulting hemispheric measures in the PD group were compared with corresponding healthy control values and assessed across disease stages. Results: Hemispheric PDRP and PDCP expression was significantly elevated contralateral and ipsilateral to the more affected body side in patients with unilateral symptoms (H&Y 1: p

PurposeThe αvβ6-BP peptide selectively targets the integrin αvβ6, a cell surface receptor recognized as a prognostic indicator for several challenging malignancies. Given that the 4-[18F]fluorobenzoyl (FBA)-labeled peptide is a promising PET imaging agent, radiolabeling via aluminum [18F]fluoride chelation and introduction of an albumin binding moiety (ABM) have the potential to considerably simplify radiochemistry and improve the pharmacokinetics by increasing biological half-life.ProceduresThe peptides NOTA-αvβ6-BP (1) and NOTA-K(ABM)-αvβ6-BP (2) were synthesized on solid phase, radiolabeled with aluminum [18F]fluoride, and evaluated in vitro (integrin ELISA, albumin binding, cell studies) and in vivo in mouse models bearing paired DX3puroβ6 [αvβ6(+)]/DX3puro [αvβ6(-)], and for [18F]AlF 2, BxPC-3 [αvβ6(+)] cell xenografts (PET imaging, biodistribution).ResultsThe peptides were radiolabeled in 23.0 ± 5.7% and 22.1 ± 4.4% decay-corrected radiochemical yield, respectively, for [18F]AlF 1 and [18F]AlF 2. Both demonstrated excellent affinity and selectivity for integrin αvβ6 by ELISA (IC50(αvβ6) = 3-7nM vs IC50(αvβ3) > 10μM) and in cell binding studies (51.0 ± 0.7% and 47.2 ± 0.7% of total radioactivity bound to DX3puroβ6 cells at 1h, respectively, vs. ≤ 1.2% to DX3puro for both compounds). The radiotracer [18F]AlF 1 bound to human serum at 16.3 ± 1.9%, compared to 67.5 ± 1.0% for the ABM-containing [18F]AlF 2. In vivo studies confirmed the effect of the ABM on blood circulation (≤ 0.1% ID/g remaining in blood for [18F]AlF 1 as soon as 1h p.i. vs. > 2% ID/g for [18F]AlF 2 at 6h p.i.) and higher αvβ6(+) tumor uptake (4h: DX3puroβ6; [18F]AlF 1: 3.0 ± 0.7% ID/g, [18F]AlF 2: 7.2 ± 0.7% ID/g; BxPC-3; [18F]AlF 2: 10.2 ± 0.1% ID/g).ConclusionBoth compounds were prepared using standard chemistries; affinity and selectivity for integrin αvβ6 in vitro remained unaffected by the albumin binding moiety. In vivo, the albumin binding moiety resulted in prolonged circulation and higher αvβ6-targeted uptake.

IntroductionMelasma is a pigmentation disorder of the skin. Characterised by brown to gray-brown patches on the face and neck, the condition predominantly affects women and has been associated with pregnancy, hormonal variation and sun exposure. Melasma can be disfiguring and anxiety-provoking, and quality of life is often adversely impacted. Management includes sun protection, laser and energy device therapy, topical and oral skin-bleaching agents and chemical peels. While clinical trials of melasma exist, there is a lack of consistency in reported outcomes, which has been a barrier to the aggregation of data in systematic reviews and meta-analyses. This protocol describes a planned process for development of a minimum set of outcomes (ie, ‘core outcome set’) that should be measured in all clinical trials of melasma.Methods and analysisAn exhaustive list of potential outcomes will be extracted from four sources: (1) systematic literature review of outcomes in clinical trials; (2) semistructured patient interviews; (3) brochures, pamphlets, clinical trial registries, and other published and unpublished sources and documentation; and (4) interviews with non-patient, non-physician stakeholders, including federal regulators, industry scientists and non-physician providers. An international two-round Delphi process will then be performed to identify the outcomes deemed most important to patients and physicians. Subsequently, a consensus meeting will be convened to review and process the results, and to vote on a final set of core outcomes.Ethics and disseminationEthics approval was provided by the Northwestern University Institutional Review Board (protocol ID: STU00201637). This study is registered with both the Core Outcome Measures in Effectiveness Trials and Cochrane Skin-Core Outcome Set Initiative initiatives, and this protocol is in accordance with the guidelines for protocol development of both groups. All findings from the study described in this protocol will be disseminated to all stakeholders involved in the development process and will be submitted for publication in peer-reviewed journals.PROSPERO registration numberCRD42020214189.

Background In the United States, liver cancer is the fifth and seventh most common cause of cancer-related death among men and women, respectively. Compared with other racial or ethnic groups in the United States, Asian and Pacific Islander populations experience the highest incidence rates of liver cancer, but little is known about disparities in risk of advanced-stage disease or risk of liver cancer mortality across these heterogenous populations. Methods In a population-based cohort of 60 146 patients aged 20-79 years diagnosed with liver cancer from 2004 to 2018 identified through the Surveillance, Epidemiology, and End Results Program, we examined associations between race or ethnicity, including specific Asian and Pacific Islander subgroups, and risk of advanced-stage liver cancer and liver cancer–specific mortality. Results Compared with non-Hispanic White patients, non-Hispanic Black, Filipino, and Laotian patients had 30%-85% elevated odds of being diagnosed with stage IV liver cancer, whereas Hispanic, Vietnamese, and Chinese patients had 7%-33% lower odds of being diagnosed with stage IV liver cancer (all P Conclusions Substantial variations in risk of advanced-stage liver cancer and risk of liver cancer mortality were observed by race and ethnicity, including considerable heterogeneity across individuals broadly defined as Asians and Pacific Islanders. Further efforts to understand the contributors to these disparities are needed to inform potential targeted screening and treatment interventions.

Alcohol is an established risk factor for invasive breast cancer, and women with a prior ductal carcinoma in situ diagnosis are at higher risk of invasive breast cancer than the general population. However, for women with a prior ductal carcinoma in situ diagnosis, few studies have evaluated the association between alcohol and smoking and risk of subsequent invasive breast cancer.Utilizing a population-based case-control design nested among women diagnosed with a ductal carcinoma in situ between 1995 and 2013, we compared 243 cases diagnosed with a subsequent invasive breast cancer and 423 individually matched controls never diagnosed with a subsequent breast cancer.Compared with never to occasional drinkers, drinkers consuming at least 7 alcoholic drinks per week on average at ductal carcinoma in situ diagnosis had a higher risk of invasive breast cancer that was borderline significant (OR 1.79, 95% CI 1.01-3.17, P value = 0.04). Smoking was not significantly associated with risk of developing an invasive breast cancer after adjustment for alcohol consumption.These findings suggest that consuming at least one alcoholic drink per day on average is positively associated with invasive breast cancer for women with a prior ductal carcinoma in situ diagnosis. If confirmed, modulating alcohol consumption could be one strategy for women with a history of ductal carcinoma in situ to impact their risk of invasive breast cancer.

Background Dysfunction and inflammation of hearts subjected to cold ischemic preservation may differ between left and right ventricles, suggesting distinct strategies for amelioration. Methods and Results Explanted murine hearts subjected to cold ischemia for 0, 4, or 8 h in preservation solution were assessed for function during 60 min of warm perfusion and then analyzed for cell death and inflammation by immunohistochemistry and western blotting and total RNA sequencing. Increased cold ischemic times led to greater left ventricle (LV) dysfunction compared to right ventricle (RV). The LV experienced greater cell death assessed by TUNEL+ cells and cleaved caspase‐3 expression (n = 4). While IL‐6 protein levels were upregulated in both LV and RV, IL‐1β, TNFα, IL‐10, and MyD88 were disproportionately increased in the LV. Inflammasome components (NOD‐, LRR‐, and pyrin domain‐containing protein 3 (NLRP3), adaptor molecule apoptosis‐associated speck‐like protein containing a CARD (ASC), cleaved caspase‐1) and products (cleaved IL‐1β and gasdermin D) were also more upregulated in the LV. Pathway analysis of RNA sequencing showed increased signaling related to tumor necrosis factor, interferon, and innate immunity with ex‐vivo ischemia, but no significant differences were found between the LV and RV. Human donor hearts showed comparable inflammatory responses to cold ischemia with greater LV increases of TNFα, IL‐10, and inflammasomes (n = 3). Conclusions Mouse hearts subjected to cold ischemia showed time‐dependent contractile dysfunction and increased cell death, inflammatory cytokine expression and inflammasome expression that are greater in the LV than RV. However, IL‐6 protein elevations and altered transcriptional profiles were similar in both ventricles. Similar changes are observed in human hearts., Increasing duration of murine donor heart storage with subsequent ex‐vivo perfusion using clinically utilized histidine‐tryptophan‐ketoglutarate preservation solution induced progressively higher expression of IL‐1β, MyD88, TNFα, IL‐6, MCP1, and inflammasome components. This inflammatory response was disproportionately greater in the left ventricle compared to the right ventricle. We confirm that LV contractility and relaxation were also degraded to a greater degree in the left ventricle compared to the right ventricle following progressively longer periods of preservation. Murine findings corroborated with results from human preserved donor hearts where we also observed selective upregulation of TNFα, MCP1, and inflammasome components (Nlrp3, cleaved IL‐1β‐p17) in the left ventricle compared to the right ventricle during cold preservation.

The natural history of idiopathic Parkinson’s disease (PD) varies considerably across patients. While PD is generally sporadic, there are known genetic influences: the two most common, mutations in the LRRK2 or GBA1 gene, are associated with slower and more aggressive progression, respectively. Here, we applied graph theory to metabolic brain imaging to understand the effects of genotype on the organization of previously established PD-specific networks. We found that closely matched PD patient groups with the LRRK2-G2019S mutation (PD-LRRK2) or GBA1 variants (PD-GBA) expressed the same disease networks as sporadic disease (sPD), but PD-LRRK2 and PD-GBA patients exhibited abnormal increases in network connectivity that were not present in sPD. Using a community detection strategy, we found that the location and modular distribution of these connections differed strikingly across genotypes. In PD-LRRK2, connections were gained within the network core, with the formation of distinct functional pathways linking the cerebellum and putamen. In PD-GBA, by contrast, the majority of functional connections were formed outside the core, involving corticocortical pathways at the network periphery. Strategically localized connections within the core in PD-LRRK2 may maintain PD network activity at lower levels than in PD-GBA, resulting in a less aggressive clinical course.

Background: Type II diabetes and certain diabetes treatments have been observed to impact breast cancer risk. However, their associations with different breast cancer molecular subtype defined by estrogen receptor (ER)/progesterone receptor (PR)/HER2 status are unclear. Methods: We conducted a retrospective multi-center population-based case–case study consisting of 4,557 breast cancer cases to evaluate the impact of type II diabetes and diabetes medications on the risk of different breast cancer molecular subtypes [ER+/HER2−, ER+/HER2+, triple negative (ER−/PR−/HER2−), and HER2 overexpressing (H2E, ER−/PR−/HER2+)]. Using ER+/HER2− cases as the reference group, we estimated ORs and corresponding 95% confidence intervals (CI) for each subtype using polytomous logistic regression. Results: Compared with those without a diabetes history, women with type II diabetes had a 38% (95% CI, 1.01–1.89) increased odds of triple-negative breast cancer (TNBC). Current and longer term recent metformin use (13–24 months of treatment within the 24-month period prior to breast cancer diagnosis) was associated with elevated odds of TNBC (OR = 1.54; 95% CI, 1.07–2.22 and OR = 1.80; 95% CI, 1.13–2.85, respectively). Conclusions: The odds of having a triple-negative rather than ER+/HER2− breast cancer is greater for women with type II diabetes, and particularly for those who were users of metformin. This finding is supported by some preclinical data suggesting that diabetes may be more strongly associated with risk of triple-negative disease. Impact: Our study provides novel evidence regarding potential differential effects of type II diabetes and metformin use on risk of different molecular subtypes of breast cancer.

INTRODUCTION: Oral contraceptive use is a well-established risk factor for breast cancer and is common among reproductive-aged women in the United States. Its relationship with less common, more aggressive, molecular subtypes is less clear. METHODS: A population-based case-case analysis was conducted comparing three less common molecular subtypes to luminal A breast cancer among 1701 premenopausal cases aged 21–49 diagnosed with a first primary invasive breast cancer between 2004 and 2015. Medical record reviews and structured interviewer administered questionnaires were used to collect data on oral contraceptive use. Multinomial logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for recency of oral contraceptive use for each subtype of breast cancer. RESULTS: Current use of oral contraceptives and use within five years before diagnosis was associated with lower odds of H2E tumors compared to luminal A tumors [odds ratio (OR)=0.5, 95% confidence interval (CI): 0.3, 0.9 and OR=0.5, 95% CI: 0.4, 0.8, respectively] with increasing duration associated with decreasing odds (p for trend

Background HIV-associated neurocognitive disorder (HAND) remains prevalent in the era of combination antiretroviral therapy (cART). The prevalence of HAND in Hong Kong is not known. Methods Between 2013 and 2015, 98 treatment-naïve HIV-1-infected individuals were referred to and screened by the AIDS Clinical Service, Queen Elizabeth Hospital with (1) the International HIV Dementia Scale (IHDS), a screening tool that targets moderate to severe HAND, (2) the Montreal Cognitive Assessment (MoCA), a frequently used cognitive screening test and (3) the Patient Health Questionnare-9 (PHQ-9), a 9-item questionnaire that evaluates depression symptoms. Within the study period, 57 of them completed the second set of IHDS and MoCA at 6 months after baseline assessment. Results Most participants were male (94%), with a median age of 31 years. At baseline, 38 (39%) and 25 (26%) of them scored below the IHDS (≤10) and MoCA (25/26) cut-offs respectively. Poor IHDS performers also scored lower on MoCA (p = 0.039) but the correlation between IHDS and MoCA performance was weak (r = 0.29, p = 0.004). Up to a third of poor IHDS performers (13/38) showed moderate depression (PHQ-9 > 9). In the multivariable analysis, a lower education level (p = 0.088), a history of prior psychiatric illness (p = 0.091) and the presence of moderate depression (p = 0.079) tended to be significantly associated with poor IHDS performance. At follow-up, 54 out of 57 were on cART, of which 46 (85%) had achieved viral suppression. Their blood CD4+ T-lymphocytes and IHDS scores were higher at follow-up compared to baseline values (both p

Aim Direct kidney involvement in B-cell lymphoproliferative disease is a rare disorder with only a few studies reported in Caucasian patients. The clinicopathological characteristics and outcome of this entity remain poorly described. Methods We retrospectively studied all adult Chinese patients who had histology-proven renal parenchymal infiltration by malignant B-cells between 1/1/2000 and 31/12/2018 at 2 tertiary hospitals in Hong Kong. Clinical, pathological and radiological data were collected from 20 patients. Follow-up data were analyzed until 31/12/2019. Results Median follow-up duration was 22 (1-171) months. Only 7 patients (35%) had established diagnosis of hematological cancer before kidney biopsy. Diffuse large B-cell lymphoma (DLBCL) was the most common subtype in our cohort (n=5, 25%). Others included low-grade B-cell lymphoma (n=11), intravascular large B-cell lymphoma (n=1), mantle cell lymphoma (n=1) and multiple myeloma (n=2). Fourteen patients (70%) presented with AKI while 12 patients (60%) had proteinuria. Seven patients (35%) had unilateral renal mass, 1 had bilateral renal masses and 1 had bilateral diffuse nephromegaly in computed tomography. Lymphomatous tubulointerstitial infiltration was the prevalent histological finding. Nine patients (45%) had coexisting renal lesions other than direct tumor infiltration. All but 1 patient received chemotherapy. Ten patients died and renal responders had a significantly better survival than non-renal responders (P=0.03). Conclusion Direct tumor infiltration can occur in a wide variety of B-cell lymphoproliferative disorders. Coexisting immunoglobulin-related nephropathy is frequently found. Renal biopsy is required for early diagnosis which allows timely and appropriate treatment. This article is protected by copyright. All rights reserved.

Background The opioid epidemic has seen a drastic increase in the incidence of drug-associated infective endocarditis (IE). No clinical tool exists to predict operative morbidity and mortality in patients undergoing surgery. Methods A multi-institutional database was reviewed between 2011 and 2018. Multivariate logistic regression was fitted in an automated stepwise fashion. The STratification risk analysis in OPerative management of drug-associated IE (STOP) score was constructed. Morbidity was defined as reintubation, prolonged ventilation, pneumonia, renal failure, dialysis, stroke, reoperation for bleeding, and a permanent pacemaker. Cross-validation provided an unbiased estimate of out-of-sample performance. Results A total of 1181 patients underwent surgery for drug-associated IE (median age, 39; interquartile range [IQR], 30-54, 386 women [32.7%], 341 reoperations for prosthetic valve endocarditis [28.9%], 316 patients with multivalve disease [26.8%]). Operative morbidity and mortality were 41.1% and 5.9%, respectively. Predictors of morbidity were dialysis (95% confidence interval [CI], 1.16-2.82), emergent intervention (1.83-4.73), multivalve procedure (1.01-1.98), causative organisms other than Streptococcus (1.09-2.02), and type of valve procedure performed [aortic valve procedure (1.07-2.15), mitral valve replacement (1.03-2.05), tricuspid valve replacement (1.21-2.60)]. Predictors of mortality were dialysis (1.29-5.74), active endocarditis (1.32-83), lung disease (1.25-5.43), emergent intervention (1.69-6.60), prosthetic valve endocarditis (1.24-3.69), aortic valve procedure (1.49-5.92) and multivalve disease (1.00-2.95). Variables maximizing explanatory power were translated into a scoring system. Each point increased odds of morbidity and mortality by 22.0% and 22.4% with an accuracy of 94.0% and 94.1%, respectively. Conclusion Drug-related IE is associated with significant morbidity and mortality. An easily-applied risk stratification score may aid in clinical decision-making.

Purpose To document the epidemiology, presentation, clinical interventions, and outcomes of paediatric glaucoma in Hong Kong. Methods This multicentre territory-wide retrospective study was performed by reviewing charts of patients with paediatric glaucoma in six clusters of the Hong Kong Hospital Authority and The Chinese University of Hong Kong from 2006 to 2015. Results This study included 150 eyes of 98 patients with paediatric glaucoma (presenting age: 5.2±5.7 years). Of them, 35 eyes (23.3%) had primary congenital glaucoma, 22 eyes (14.7%) had juvenile open-angle glaucoma, and 93 eyes (62.0%) had secondary glaucoma. The most prevalent types of secondary glaucoma were lens-related after cataract extraction (18.0%), Axenfeld-Rieger anomaly (5.3%), uveitis (5.3%), Sturge-Weber syndrome (4.7%), and traumatic (3.3%). The most common clinical presentations were parental concerns (20.7%) including cloudy cornea (12.7%) and tearing/photophobia (8.0%), followed by poor visual acuity (18.0%), high intraocular pressure (13.3%), and strabismus (6.0%). The follow-up duration was 8.46±6.51 years. Furthermore, 63.2% of eyes with primary glaucoma and 45.2% of eyes with secondary glaucoma were treated surgically. The final visual acuity was 0.90±0.98 LogMAR; intraocular pressure was 18.4±6.6 mm Hg; and number of glaucoma medications was 2.22±1.61. Conclusion Primary congenital glaucoma was most prevalent, followed by juvenile open-angle glaucoma and aphakic glaucoma. Most eyes with primary glaucoma required surgical treatment. Parental concerns were important clinical presentations. Basic assessments by healthcare providers to identify glaucoma signs (eg, poor visual acuity, high intraocular pressure, and strabismus) warranted prompt referral to an ophthalmologist.

Summary Rabbit embryos develop as bilaminar discs at gastrulation as in humans and most other mammals, whereas rodents develop as egg cylinders. Primordial germ cells (PGCs) appear to originate during gastrulation according to many systematic studies on mammalian embryos. Here, we show that rabbit PGC (rbPGC) specification occurs at the posterior epiblast at the onset of gastrulation. Using newly derived rabbit pluripotent stem cells, we show robust and rapid induction of rbPGC-like cells in vitro with WNT and BMP morphogens, which reveals SOX17 as the critical regulator of rbPGC fate as in several non-rodent mammals. We posit that development as a bilaminar disc is a crucial determinant of the PGC regulators, regardless of the highly diverse development of extraembryonic tissues, including the amnion. We propose that investigations on rabbits with short gestation, large litters, and where gastrulation precedes implantation can contribute significantly to advances in early mammalian development.

Background: Evidence-based breast cancer treatment guidelines recommend the most appropriate course of therapy based on tumor characteristics and extent of disease. Evaluating the multilevel factors associated with guideline discordance is critical to identifying strategies to eliminate breast cancer survival disparities. Methods: We identified females diagnosed with a first primary, stage I–III breast cancer between the ages of 20–69 years of age from the population-based Seattle-Puget Sound Surveillance, Epidemiology, and End Results registry. Participants completed a survey about social support, utilization of patient support services, hypothesized barriers to care, and initiation of breast cancer treatment. We used logistic regression to estimate odds ratios and 95% confidence intervals (CI). Results: Among 1,390 participants, 10% reported guideline-discordant care. In analyses adjusted for patient-level sociodemographic factors, individuals who did not have someone to go with them to appointments or drive them home (OR 1.96; 95% CI, 1.09–3.59) and those who had problems talking to their doctors or their staff (OR 2.03; 95% CI, 1.13–3.64) were more likely to be guideline discordant than those with social support or without such problems, respectively. Use of patient support services was associated with a 43% lower odds of guideline discordance (OR 0.57; 95% CI, 0.36–0.88). Conclusions: Although guideline discordance in this cohort of early-stage breast cancer survivors diagnosed Impact: This study supports extending the reach of interventions designed to improve guideline concordance.

Basal-like breast cancer (BLBC) is a particularly aggressive intrinsic molecular subtype of breast cancer that lacks targeted therapies. There is also no clinically useful test to risk stratify patients with BLBC. We hypothesized that a transcriptome-based phenotypic characterization of BLBC tumors and their microenvironments may overcome these challenges.We conducted a retrospective correlative genomic sequencing study using a matched pairs design with validation in five independent cohorts. The study was conducted on a large population-based prospective cohort of the major molecular subtypes of breast cancer conducted in the greater Seattle-Puget Sound metropolitan area. Cases consisted of women 20-69 years of age first diagnosed with invasive breast cancer identified through the population-based Surveillance Epidemiology and End Results program. Patients for this analysis (We found that cancer cell intrinsic and immunologic phenotypes are independent predictors of recurrence. By simultaneously interrogating the tumor and its microenvironment, we developed a compound risk model that stratified patients into low-, medium-, and high-risk groups, with a 14%/56%/74% chance of recurrence, respectively. Biologically, the primary tumors of patients who developed a recurrence had increased growth factor signaling and stem-like features, while nonrecurrent tumors showed high lymphocyte infiltration with clonal expansion of T and B cells, as well as antitumor polarization of macrophages. We validated our model in five independent cohorts, including three large cohorts, where BRAVO-DX was highly informative in identifying patients with disease recurrence [HR, 6.79 (95% confidence interval (CI), 1.89-24.37); HR, 3.45 (95% CI, 2.41-4.93); and HR, 1.69 (95% CI, 1.17-2.46)]. A smaller gene set focused on the tumor immunophenotype, BRAVO-IMMUNE, was highly prognostic in all five cohorts.Together, these results indicate that phenotypic characteristics of BLBCs and their microenvironment are associated with recurrence-free survival and demonstrate the utility of intrinsic and extrinsic phenotypes as independent prognostic biomarkers in BLBC. Pending further evaluation and validation, our prognostic model has the potential to inform clinical decision-making for patients with BLBC as it identifies those at high risk of rapidly progressing on standard chemotherapy, as well as those who may benefit from alternative first-line therapies.

This study aimed to investigate the impact of tumor mutational burden (TMB) and DNA damage repair (DDR) gene alteration on overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients.A DNA library of cancer cells from 67 NSCLC patients in stages III-IV was constructed for next-generation sequencing (NGS). Geneseeq422 probes were used for hybridization enrichment. The target-enriched library was sequenced on HiSeqNGS platforms, and we analyzed the relevant signaling pathways. Then, we correlated the OS of the patients with TMB and DDR mutations.Many significant alterations were found, including in the EGFR, p53, KRAS, RB1, ERBB2, NF1, DNMT3A, ALK, MYC, PIK3CA, ROS1, BRAF, ARID1A, PTEN, CDKN2A, and FGF19 genes. We also identified many mutations in the genes relevant to the DDR pathway. Interestingly, we found that the TMB of patients with DDR gene mutations was dramatically higher than that in the DDR wild-type (WT). Univariable analysis showed that DNMT3A, RB1, DDR pathway-related gene mutations, and TMB were critical factors for the effects on OS. Multivariable analysis confirmed that DNMT3A and mutations in the DDR pathway-related genes were important for predicting OS.Multiple mutations in the genes of the DDR pathway caused higher TMB levels, which resulted in longer OS. By contrast, OS was significantly longer in patients with non-DNMT3A mutations than in those with DNMT3A variants. DNMT3A alteration in NSCLC patients led to poor outcomes.

PURPOSE: The α(v)β(6)-BP peptide selectively targets the integrin α(v)β(6), a cell surface receptor recognized as a prognostic indicator for several challenging malignancies. Given that the 4-[(18)F] fluorobenzoyl (FBA)-labeled peptide is a promising PET imaging agent, radiolabeling via aluminum [(18)F]fluoride chelation and introduction of an albumin binding moiety (ABM) have the potential to considerably simplify radiochemistry and improve the pharmacokinetics by increasing biological half-life. PROCEDURES: The peptides NOTA-α(v)β(6)-BP (1) and NOTA-K(ABM)-α(v)β(6)-BP (2) were synthesized on solid phase, radiolabeled with aluminum [(18)F]fluoride, and evaluated in vitro (integrin ELISA, albumin binding, cell studies) and In vivo in mouse models bearing paired DX3puroβ6 [α(v)β(6)(+)]/DX3puro [α(v)β(6)(−)], and for [(18)F]AlF 2, BxPC-3 [α(v)β(6)(+)] cell xenografts (PET imaging, biodistribution). RESULTS: The peptides were radiolabeled in 23.0 ± 5.7 % and 22.1 ± 4.4 % decay-corrected radiochemical yield, respectively, for [(18)F]AlF 1 and [(18)F]AlF 2. Both demonstrated excellent affinity and selectivity for integrin α(v)β(6) by ELISA (IC(50)(α(v)β(6)) = 3–7 nM vs IC(50)(α(v)β(3)) > 10 μM) and in cell binding studies (51.0 ± 0.7 % and 47.2 ± 0.7 % of total radioactivity bound to DX3puroβ6 cells at 1 h, respectively, vs. ≤ 1.2 % to DX3puro for both compounds). The radiotracer [(18)F]AlF 1 bound to human serum at 16.3 ± 1.9 %, compared to 67.5 ± 1.0 % for the ABM-containing [(18)F]AlF 2. In vivo studies confirmed the effect of the ABM on blood circulation (≤ 0.1 % ID/g remaining in blood for [(18)F]AlF 1 as soon as 1 h p.i. vs. > 2 % ID/g for [(18)F]AlF 2 at 6 h p.i.) and higher α(v)β(6)(+) tumor uptake (4 h: DX3puroβ6; [(18)F]AlF 1: 3.0 ± 0.7 % ID/g, [(18)F]AlF 2: 7.2 ± 0.7 % ID/g; BxPC-3; [(18)F]AlF 2: 10.2 ± 0.1 % ID/g). CONCLUSION: Both compounds were prepared using standard chemistries; affinity and selectivity for integrin α(v)β(6) in vitro remained unaffected by the albumin binding moiety. In vivo, the albumin binding moiety resulted in prolonged circulation and higher α(v)β(6)-targeted uptake.

The optimal screening frequency of sexually transmitted infections (STIs) for MSM and transgender women (TGW) on HIV pre-exposure prophylaxis (PrEP) is unclear, with present guidelines recommending screening every 3-6 months. We aimed to determine the number of STIs for which treatment would have been delayed without quarterly screening.The US PrEP Demonstration Project was a prospective, open-label cohort study that evaluated PrEP delivery in STI clinics in San Francisco and Miami, and a community health center in Washington, DC. In all, 557 HIV-uninfected MSM and TGW were offered up to 48 weeks of PrEP and screened quarterly for STIs.The proportion of gonorrhea, chlamydia, and syphilis infections for which treatment would have been delayed had screening been conducted every 6 versus every 3 months was determined by taking the number of asymptomatic STIs at weeks 12 and 36 divided by the total number of infections during the study follow-up period for each STI.Among the participants, 50.9% had an STI during follow-up. If screening had been conducted only semiannually or based on symptoms, identification of 34.3% of gonorrhea, 40.0% of chlamydia, and 20.4% of syphilis infections would have been delayed by up to 3 months. The vast majority of participants (89.2%) with asymptomatic STIs reported condomless anal sex and had a mean of 8.1 partners between quarterly visits.Quarterly STI screening among MSM on PrEP could prevent a substantial number of partners from being exposed to asymptomatic STIs, and decrease transmission.

Objective: This survey followed the birth population-based study conducted in 2010 in Huai’an, Jiangsu Province, with the aim to estimate perinatal-neonatal mortality and preterm birth rate in emer...

Here we present an optimized workflow for global proteome and phosphoproteome analysis of tissues or cell lines that uses isobaric tags (TMT (tandem mass tags)-10) for multiplexed analysis and relative quantification, and provides 3× higher throughput than iTRAQ (isobaric tags for absolute and relative quantification)-4-based methods with high intra- and inter-laboratory reproducibility. The workflow was systematically characterized and benchmarked across three independent laboratories using two distinct breast cancer subtypes from patient-derived xenograft models to enable assessment of proteome and phosphoproteome depth and quantitative reproducibility. Each plex consisted of ten samples, each being 300 μg of peptide derived from 0.88. The maximum deviation for the phosphoproteome coverage was 37,000 quantified phosphosites per sample and differential quantification correlations of r > 0.72. The full procedure, including sample processing and data generation, can be completed within 10 d for ten tissue samples, and 100 samples can be analyzed in −4 months using a single LC-MS/MS instrument. The high quality, depth, and reproducibility of the data obtained both within and across laboratories should enable new biological insights to be obtained from mass spectrometry-based proteomics analyses of cells and tissues together with proteogenomic data integration.

Background Tong-Xie-Yao-Fang (TXYF) is a Chinese herbal formula for treating chronic diarrhoea accompanied by abdominal pain. The results were inconsistent in previous trials examining its effect. Aim To study the efficacy of TXYF granules for treating diarrhoea-predominant irritable bowel syndrome (IBS-D). Methods We performed a double-blind, placebo-controlled randomised trial and enrolled 160 participants with IBS-D. The participants had VAS scores ≥3 cm in IBS-D global symptoms and ≥2 days in a week with abdominal pain and loose stools (Bristol score 5, 6 or 7). They were randomly assigned to received TXYF or placebo during a treatment period of 4 weeks, and they were followed up for 8 weeks after treatment. The primary outcome was adequate relief of IBS-D global symptoms for at least 2 of 4 weeks during weeks 1-4. Secondary outcomes included mean weekly VAS scores of IBS-D major symptoms, mean weekly stool frequency, mean weekly Bristol score, and adverse events. Results 155 of 160 patients completed the trial. We found a significantly higher rate of adequate relief of global symptoms in TXFY group during weeks 1 to 4 (57.5% vs 37.5%, χ2 = 5.6391, P = 0.017); logistic regression analysis showed a similar result (OR 2.2, 95% CI 1.2-4.4, P = 0.016). Most of the secondary outcomes showed superiority of TXYF over placebo in weekly assessment from week 3 to week 7. The adverse event rate was low in both groups (3.8% vs 3.8%, P = 1.000). Conclusion During a 4 week trial, TXFY granules were superior to placebo in controlling symptoms of IBS-D.

Blood-circulating microRNAs (miRNAs) have been reported to be used as potential biomarkers in various cancers. MiR-101 has been found to act as a tumor suppressor in many tumor types, but little is known for osteosarcoma. The purpose of this study was to investigate miR-101 expression in osteosarcoma patients and assess its correlation with clinical features and prognosis. Serum samples from 152 osteosarcoma patients and 70 healthy controls were detected using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The data showed that miR-101 expression levels were remarkably underexpressed in serum samples from osteosarcoma patients compared to controls, and the post-treatment serum miR-101 expression was significantly higher than that in the pre-treatment expression. Low serum miR-101 expression was positively associated with advanced clinical stage and distant metastasis. Receiver operating characteristic (ROC) curve analysis showed that serum miR-101 could serve as a useful marker for osteosarcoma diagnosis, with a high sensitivity and specificity. Moreover, patients with high miR-101 expression had longer overall survival and recurrence free survival than those with low miR-101 expression. In addition, both univariate and multivariate analyses showed that serum miR-101 downregulation was associated with shorter overall survival and recurrence free survival. Our present results implicated serum miR-101 might be a useful biomarker for the clinical diagnosis and prognosis of osteosarcoma.

BackgroundHIV preexposure prophylaxis (PrEP) using daily oral tenofovir-disoproxil-fumarate/emtricitabine (TDF/FTC) is effective for preventing HIV acquisition, but concerns remain about its potential kidney toxicity. This study examined kidney function in individuals using PrEP in real-world clinical settings.SettingDemonstration project in 2 sexually transmitted infection clinics and a community health center.MethodsWe evaluated kidney function among men who have sex with men and transgender women taking tenofovir-disoproxil-fumarate/emtricitabine PrEP for up to 48 weeks. Serum creatinine and urine dipstick for protein were obtained at 12-week intervals. Kidney function was estimated using creatinine clearance (CrCl) (Cockcroft-Gault) and estimated glomerular filtration rate (eGFR) (CKD-EPI).ResultsFrom October 2012 to January 2014, we enrolled 557 participants (median age 33). Mean creatinine increased from baseline to week 12 by 0.03 mg/dL (4.6%) (P < 0.0001); mean CrCl decreased by 4.8 mL/min (3.0%) (P < 0.0001). These changes remained stable through week 48 (P = 0.81, P = 0.71 respectively). There were 75/478 (15.7%) participants who developed worsening proteinuria at week 12 compared with baseline (P < 0.0001), and this percent remained stable through week 48 (P = 0.73). Twenty-five participants (5.1%) developed new-onset eGFR

Background We aimed to examine the efficacy of surgical revascularization with respect to improvement in ventricular function and survival in patients with ischemic cardiomyopathy and poor left ventricular function. Methods We retrospectively analyzed the data of 429 patients (median age 64.6 years, 81.1% male) with ejection fractions Results Postoperatively, ejection fraction increased by 10.1% ± 13.1% (from 31.4% ± 7.1% to 41.6% ± 13.6%; p 5 (8.8% ± 14.2%) years ( p = 0.442). Following propensity matching, there was no significant difference between the combined off-pump/beating heart and cardioplegic arrest groups with respect to survival or postoperative complications. Conclusions Patients with moderate to severe left ventricular dysfunction experience long-term improvement in left ventricular ejection fraction after coronary artery bypass. However, right ventricular function often continues to decline, contributing to persistent or worsening heart failure symptoms and late mortality. No difference in survival was seen between the 2 techniques.

Background: This study compares the morphology and outcomes of acute retrograde type A dissections (RTADs) with acute antegrade type A dissections (ATADs), and acute type B dissections. Materials and methods: From 2000 to 2016, there were 12 acute RTADs, 96 ATADs, and 92 type B dissections with available imaging. Dissections were characterized using computerized tomography angiography images. We examined clinical features, tear characteristics, and various morphologic measurements. Results: Compared with acute type B dissections, RTAD primary tears were more common in the distal arch (75% versus 43%, P = 0.04), and the false-to-true lumen contrast intensity ratio at the mid-descending thoracic aorta was lower (0.46 versus 0.71, P = 0.020). RTAD had less false lumen decompression because there were fewer aortic branch vessels distal to the subclavian that were perfused through the false lumen (0.40 versus 2.19, P < 0.001). Compared with ATAD, RTAD had less root involvement where root true-to-total lumen area ratio was higher (0.88 versus 0.76, P = 0.081). Furthermore, RTAD had a lower false-to-true lumen contrast intensity ratio at the root (0.25 versus 0.57, P < 0.05), ascending aorta (0.25 versus 0.72, P < 0.001), and proximal arch (0.39 versus 0.67, P < 0.05). RTAD were more likely to undergo aortic valve resuspension (100% versus 74%, P = 0.044). Conclusions: RTAD tends to occur when primary tears occur in close proximity to the aortic arch and when false lumen decompression through the distal aortic branches are less effective. Compared with ATAD, RTAD has less root involvement, and successful aortic valve resuspension is more likely.

Previous studies suggest that alcohol consumption and risk of breast cancer may differ by histologic subtype and hormone receptor status, though results are not entirely consistent. In this population-based case-control study, we evaluated the association between alcohol consumption and risk of invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and invasive ductal-lobular carcinoma (IDLC) overall and by estrogen receptor (ER) status, among women aged 55–74 years of age. Using polytomous regression, associations between current alcohol consumption, overall and by type of alcohol, and breast cancer risk were evaluated in 891 controls and 905 IDC, 567 ILC, and 489 IDLC cases. Current alcohol use was moderately associated with risk of ILC (odds ratio = 1.25, 95% confidence interval 0.99, 1.58) with a positive dose-response relationship based on average number of drinks per week consumed (P trend = 0.0005). When further stratified by ER status, alcohol use was positively associated with risk of ER+ ILC (P trend = 0.002) and ER+ IDC (P trend = 0.02), but inversely associated with risk of ER−IDC (P trend = 0.01). No association between alcohol and risk of IDLC tumors was observed. While the link between alcohol consumption and breast cancer risk is well established, our results suggest that the increased risk associated with alcohol is largely limited to ER+ ILC and ER+ IDC. Thus, avoiding or moderating alcohol consumption may be one way that women can lower their risks of these forms of breast cancer.

Background This study investigates the efficacy of aortic valve (AV) resuspension with preservation of the native aortic root in maintaining AV competence during type A dissection repair. Methods A total of 154 acute type A dissection repairs were performed from January 2000 to July 2015. AV resuspension was performed in 120 patients to address AV insufficiency (AI). Survival data were derived from 120 patients who had AV resuspensions and all 154 acute type A dissection repairs. Results Of the 70 patients who presented initially with moderate-to-severe AI, 43 underwent AV resuspension. Echocardiographic data for analysis were available in 40 of these 43 patients. In the group with moderate-to-severe AI at presentation, AV resuspension was able to achieve mild or less AI in 38 of 40 patients (95%) and trivial or no AI in 29 of 40 patients (73%) after weaning from cardiopulmonary bypass. The presence of moderate-to-severe preoperative AI did not predict the ability to achieve trivial or no AI with resuspension immediately after coming off cardiopulmonary bypass ( p = 0.3) or on subsequent follow-up ( p = 0.8). Mean echocardiographic follow-up for AV resuspension was 1.21 ± 2.57 years. Three patients who underwent AV resuspension required AV reoperation at follow-up. There was no survival difference between patients who did or did not have AV resuspension ( p = 0.3). Conclusions AV resuspension is able to improve valve competency with good outcomes even in patients with moderate or severe AI at presentation. Overall long-term survival is unchanged compared with other operative strategies for the AV.

Human sparganosis is a foodborne zoonosis endemic in Asia. We report a series of 9 histologically confirmed human sparganosis cases in Hong Kong, China. All parasites were retrospectively identified as Spirometra erinaceieuropaei. Skin and soft tissue swelling was the most common symptom, followed by central nervous system lesions.

Patients with chronic renal failure (CRF) who are undergoing hemodialysis are at increased risk for infective endocarditis (IE). However, outcomes of surgical treatment for IE in these patients have not been well studied.Between 1997 and 2017, 539 patients underwent surgical treatment for IE. Of these patients, 125 were undergoing hemodialysis for end-stage renal disease (ESRD), and 414 had no history of CRF. Primary end points compared in this study were short-term survival and long-term survival.Preoperatively, dialysis-treated patients had higher incidences of diabetes (43% vs 18%), hypertension (79% vs 49%), congestive heart failure (63% vs 48%), cardiogenic shock (13% vs 5.3), and sepsis (29% vs 18%) (all P.05). Postoperatively, they experienced higher rates of prolonged mechanical ventilation (54% vs 22%), pneumonia (17% vs 5.6%), sepsis (6.4% vs 1.0%), cardiac arrest (7.2% vs 1.7%), gastrointestinal events (14% vs 5.1%), and operative mortality (14% vs 5.8%) (all P.05). The 5- and 10-year survival rates were significantly worse in the dialysis-treated group at 29% and 16%, respectively, compared with 72% and 53% in the patients who did not have CRF (P.001). ESRD was a risk factor for both short-term mortality (odds ratio, 2.0) and long-term mortality (hazard ratio, 2.7). Rates of reoperation in dialysis-treated patients were very low: 5- and 10-year incidences were 0% and 2.0%, respectively.In patients with ESRD and IE, poor postoperative outcomes emphasized the importance of prevention and raised the question whether indications for surgical treatment in the general population are appropriate for patients who are dialysis dependent. Additionally, low rates of reoperation supported the use of bioprosthetic valves in these patients.

Aortic valve (AV) repair (AVr) using a central coaptation stitch or bioprosthetic AV replacement (AVR) are most commonly performed at the time of durable left ventricular assist device implant to address AV insufficiency (AI).Prospective data collection on 46 patients undergoing left ventricular assist device implant from 2007 through 2018 who received concomitant AVr (n = 40) or AVR (n = 6) was retrospectively analyzed to assess freedom from recurrent aortic insufficiency. Paired Wilcoxon rank-sum test was used to compare echocardiographic findings. Mantel-Cox statistics were used to analyze survival.For AVr, central coaptation led to a mean decrease in AI severity by 2.1 ± 1.0 grades (P.001). Three patients (7.5%) had recurrence of at least moderate AI by 3 years. In comparison, all patients in the AVR group had mild or less AI on subsequent follow-up. Success of AVr in downgrading AI severity was associated with a smaller aortic root diameter (P = .011) and sinotubular junction diameter (P = .003). An aortic root diameter greater than 3.5 cm was predictive of less improvement in AI severity compared with 3.5 cm or less (1.83 ± 1.03 versus 2.47 ± 0.80 grades of improvement; P = .038). Duration of cardiopulmonary bypass was 32 minutes longer and duration of aortic cross-clamp was 38 minutes longer for AVR versus AVr cohorts. No difference in 30-day (P = .418) or overall survival (P = .572) between the AVr and AVR groups was seen.Aortic valve repair for addressing AI has a recurrence rate of 7.5% at 3 years. Success in downgrading AI is more likely with a smaller aortic root. No difference in survival was observed between AVr and AVR.

SUMMARY A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have “mirror” effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes., Graphical Abstract, In Brief Using 3D morphometric imaging, Qiu et al. demonstrate that large copy-number variants (CNVs) of 16p11.2 have significant effects on craniofacial structure that are conserved in humans and model organisms, and they demonstrate that these craniofacial phenotypes are attributable to the dosage effects of multiple genes within the CNV region.

We aimed to quantify incidence and operative risks associated with reoperative valve surgeries (RVS) in patients with drug-associated infective endocarditis in a multi-center setting.We formed a registry of patients with drug-associated infective endocarditis who underwent valve surgeries at 8 US centers between 2011 and 2017. Outcomes of first-time valve surgery (FVS) and RVS were compared. Multivariable logistic regression models related RVS to 30-day mortality. Poisson regression models were fitted to evaluate temporal trends in overall case volume and proportions of patients undergoing RVS.The cohort consisted of 925 patients with drug-associated infective endocarditis who underwent a valve surgery, of which 652 were FVS and 273 were RVS. Patients undergoing FVS had fewer comorbidities than those undergoing RVS. Overall case volume increased from 108 in 2012 to 229 cases in 2017 (P .001). The proportion of redo valve cases increased from 19% in 2012 to 28% in 2017 (P .001). The 30-day mortality in RVS was higher compared with FVS (8.1% vs 4.8%; P = .049). An increase in unadjusted mortality rates were observed as the number of prior cardiac surgeries increased, from 4.8% in FVS to 11.8% in ≥3 RVS. Multivariable model demonstrated that RVS was associated with an increased risk of 30-day mortality (odds ratio, 2.22; 95% confidence interval, 1.22-4.06; P = .010).An increasing proportion of valve surgery for drug-associated infective endocarditis is for RVS. Despite being young and harboring few comorbidities, the RVS cohort is still susceptible to increased risk of 30-day mortality compared with those undergoing FVS.

A direct measure of spoken lexical processing based on neuroimaging technology would provide us useful information to understand the neural mechanisms underlying speech or auditory language processing. The neural mechanisms of spoken word segmentation for English as a second language (ESL) learners remain elusive. The present study, using functional near-infrared spectroscopy (fNIRS), addresses this issue by measuring hemodynamic responses in the temporo-parietal junction (TPJ) and the prefrontal cortex (PFC) in a word-spotting task, designed with two task conditions (easy vs. difficult). Thirty participants, divided into a high listening proficiency group (HLG) and a low listening proficiency group (LLG), were tested. Results revealed significantly less TPJ activation in the HLG than in the LLG. Further analyses supported this result by showing that activation in the TPJ was in a negative correlation with listening proficiency. This association appears to be related to the more efficient use of processing resources in a bottom-up fashion for accurate and efficient sensory representations in high proficient language learners. In contrast, cortical activation in the PFC increased with listening proficiency and was stronger in the difficult task condition than in the easy task condition, implying that recruitment of top-down cognitive control functions might play a role in word segmentation. Our results suggest that the combination of the functions mediated via bottom-up sensory input processing (demonstrated in the TPJ activation) and top-down cognitive processing (demonstrated in the PFC activation) are crucial for ESL listeners' spoken word segmentation.

Background Systemic inflammation during implant of a durable left ventricular assist device (LVAD) may contribute to adverse outcomes. We investigated the association of the preoperative inflammatory markers with subsequent right ventricular failure (RVF). Materials and methods Prospective data was collected on 489 patients from 2003 through 2017 who underwent implantation of a durable LVAD. Uni- and multivariable correlation with leukocytosis was determined using linear and binary logistic regression. The population was also separated into low ( 10.5 K/ul, n = 127) white blood cell count (WBC) groups. Mantel-Cox statistics was used to analyze survival data. Results Postop RVF was associated with a higher preop WBC (11.3 + 5.7 vs 8.7 + 3.1) and C-reactive protein (CRP, 5.6 + 4.4 vs 3.3 + 4.7) levels. Multivariable analysis identified an independent association between increased WBC preoperatively with increased lactate dehydrogenase (LDH, P

Objective: To determine whether cognitive impairment in Parkinson disease (PD) and Alzheimer disease (AD) derives from the same network pathology. Methods: We analyzed 18 F-fluorodeoxyglucose PET scans from 40 patients with AD and 40 age-matched healthy controls from the Alzheimer’s Disease Neuroimaging Initiative and scanned an additional 10 patients with AD and 10 healthy controls at The Feinstein Institute for Medical Research to derive an AD-related metabolic pattern (ADRP) analogous to our previously established PD cognition-related pattern (PDCP) and PD motor-related pattern (PDRP). We computed individual subject expression values for ADRP and PDCP in 89 patients with PD and correlated summary scores for cognitive functioning with network expression. We also evaluated changes in ADRP and PDCP expression in a separate group of 15 patients with PD scanned serially over a 4-year period. Results: Analysis revealed a significant AD-related metabolic topography characterized by covarying metabolic reductions in the hippocampus, parahippocampal gyrus, and parietal and temporal association regions. Expression of ADRP, but not PDCP, was elevated in both AD groups and correlated with worse cognitive summary scores. Patients with PD showed slight ADRP expression, due to topographic overlap with the network underlying PD motor-related pattern degeneration, but only their PDCP expression values increased as cognitive function and executive performance declined. Longitudinal data in PD disclosed an analogous dissociation of network expression. Conclusions: Cognitive dysfunction in PD is associated with a specific brain network that is largely spatially and functionally distinct from that seen in relation to AD.

Introduction Anosognosia or impaired self-awareness of motor symptoms (ISAm) has been rarely investigated in Parkinson's disease (PD). We here studied the relationship between ISAm during periods with and without dopaminergic medication (ON- and OFF-state), and clinical, neuropsychological, and neuroimaging data to further elucidate behavioural aspects and the neurobiological underpinnings of ISAm. Methods Thirty-one right-handed, non-demented, non-depressed PD patients were included. ISAm was evaluated using a recently developed scale that assesses awareness of dyskinesia, resting tremor, and bradykinesia. The test was applied during both ON- and OFF-states. Multiple correlation analyses between ISAm and behavioural data were conducted. In addition, imaging of glucose metabolism using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was performed to investigate the neural basis of ISAm. A multiple regression approach was applied to investigate metabolism alterations related to ISAm. Results In the OFF-state, higher ISAm was associated with left-sided disease onset, older age, and shorter disease duration. Concerning FDG-PET data, there was a significant negative correlation between higher OFF-state ISAm and decreased glucose metabolism in the right inferior frontal gyrus (IFG). In the ON-state, ISAm was not significantly correlated with clinical or behavioural data. However, there was a significant correlation between higher ISAm and an increased metabolism in the bilateral medial frontal gyrus, left IFG, right superior frontal gyrus and right precentral gyrus. Conclusion The results support the role of the right hemisphere in awareness of motor symptoms in the OFF-state. In the ON-state, dopaminergic medication and dyskinesia influence ISAm and relate to metabolism changes in bilateral frontal regions.

Background: Reproductive factors are among the most well-established risk factors for breast cancer. However, their associations with different breast cancer subtypes defined by joint estrogen receptor (ER)/progesterone receptor (PR)/HER2 status remain unclear. Methods: We assessed relationships between reproductive factors and risks of luminal A (ER+/HER2−), luminal B (ER+/HER2+), triple-negative (TN; ER−/PR−/HER2−), and HER2-overexpressing (H2E; ER−/HER2+) breast cancers in a population-based case–case study consisting of 2,710 women ages 20–69 years diagnosed between 2004 and 2012. ORs and 95% confidence intervals (CI) were estimated with luminal A cases serving as the reference group using polytomous logistic regression. Results: Earlier age at first full-term pregnancy and age at menopause were positively associated with odds of TN breast cancer (Ptrend: 0.003 and 0.024, respectively). Parity was associated with a 43% (95% CI, 1.08–1.89) elevated odds of H2E breast cancer, and women who had ≥3 full-term pregnancies had a 63% (95% CI, 1.16–2.29, Ptrend = 0.013) increased odds of this subtype compared with nulliparous women. Breast feeding for ≥36 months was associated with a 49% (OR 0.51; 95% CI, 0.27–0.99) lower odds of TN breast cancer. Conclusion: Our results suggest that reproductive factors contribute differently to risks of the major molecular subtypes of breast cancer. Impact: African American and Hispanic women have higher incidence rates of the more aggressive TN and H2E breast cancers and their younger average age at first pregnancy, higher parity, and less frequent breast feeding could in part contribute to this disparity. Cancer Epidemiol Biomarkers Prev; 25(9); 1297–304. ©2016 AACR.

Triple negative (TN, tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2)) and HER2-overexpressing (H2E, ER-/HER2+) tumors are two particularly aggressive subtypes of breast cancer. There is a lack of knowledge regarding the etiologies of these cancers and in particular how anthropometric factors are related to risk. We conducted a population-based case-case study consisting of 2659 women aged 20-69 years diagnosed with invasive breast cancer from 2004 to 2012. Four case groups defined based on joint ER/PR/HER2 status were included: TN, H2E, luminal A (ER+/HER2-), and luminal B (ER+/HER2+). Polytomous logistic regression was used to estimate odds ratios (ORs) and associated 95 % confidence intervals (CIs) where luminal A patients served as the reference group. Obese premenopausal women [body mass index (BMI) ≥30 kg/m(2)] had an 82 % (95 % CI 1.32-2.51) increased risk of TN breast cancer compared to women whose BMI25 kg/m(2), and those in the highest weight quartile (quartiles were categorized based on the distribution among luminal A patients) had a 79 % (95 % CI 1.23-2.64) increased risk of TN disease compared to those in the lowest quartile. Among postmenopausal women obesity was associated with reduced risks of both TN (OR = 0.74, 95 % CI 0.54-1.00) and H2E (OR = 0.47, 95 % CI 0.32-0.69) cancers. Our results suggest obesity has divergent impacts on risk of aggressive subtypes of breast cancer in premenopausal versus postmenopausal women, which may contribute to the higher incidence rates of TN cancers observed among younger African American and Hispanic women.

SUMMARY The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this “proteogenomics” approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases.Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy., In Brief Breast cancer is a highly heterogeneous disease with variable outcomes and subtype-driven treatment approaches, making precision medicine a considerable challenge. Proteogenomic analyses of 122 primary breast cancers provide insights into clinically relevant biology, including cell cycle dysregulation, tumor immunogenicity, aberrant metabolism, and heterogeneity in therapeutic target expression., Graphical Abstract