Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Associations Between Program Doximity Reputation Rank and Well-Being in General Surgery Residents.

INTRODUCTION: Burnout and mistreatment are prevalent among surgical residents with considerable program-level variation. Applicants consider "program reputation," among other factors, when ranking programs. Although highly subjective, the only available measure of program reputation is from a physician survey by Doximity. It is unknown how program reputation is associated with resident well-being and mistreatment. METHODS: Resident burnout and personal accomplishment were assessed via the 2019 post-American Board of Surgery In-Training Examination survey. Additional outcomes included mistreatment, thoughts of attrition, and suicidality. Residents were stratified into quartiles based on their program's Doximity reputation rank. Multivariable logistic regression models examined the relationship between each outcome with Doximity rank quartile. RESULTS: 6956 residents (85.6% response rate) completed the survey. Higher-ranked programs had significantly higher burnout rates (top-quartile 41.3% versus bottom-quartile 33.2%; odds ratio [OR] 1.35, 95% confidence interval [CI] 1.04-1.76). There was no significant difference in personal accomplishment by program rank (OR 1.26, 95% CI 0.86-1.85). There also was no significant association between program rank and sexual harassment (OR 0.90, 95% CI 0.70-1.17), gender discrimination (OR 1.14, 95% CI 0.86-1.52), racial discrimination (OR 1.18, 95% CI 0.91-1.54), or bullying (OR 1.03, 95% CI 0.76-1.40). Suicidality (P = 0.97) and thoughts of attrition (P = 0.80) were also not associated with program rank. CONCLUSIONS: Surgical residents at higher-ranked programs report higher rates of burnout but have similar rates of mistreatment and personal accomplishment. Higher-ranked programs should be particularly vigilant to trainee burnout, and all programs should employ targeted interventions to improve resident well-being. This study highlights the need for greater transparency in reporting objective program-level quality measures pertaining to resident well-being.

Randomized controlled trial of a positive emotion regulation intervention to reduce stress in family caregivers of individuals with Alzheimer's disease: protocol and design for the LEAF 2.0 study.

BACKGROUND: Caring for a loved one with Alzheimer's disease can be stressful, resulting in poorer emotional and physical health among family caregivers. Although supportive resources for caregivers are available, distance, caregiver health, and the daily demands of caregiving are barriers to access. Based on research demonstrating the importance of positive emotions in coping with stress, our previous trial showed that dementia caregivers who participated in facilitated, web-based delivery of a positive emotion regulation intervention called LEAF (Life Enhancing Activities for Family caregivers) experienced increased positive emotion and decreased depression and anxiety. Building on this evidence, the LEAF 2.0 study aims to test whether web-based, self-guided delivery can confer similar benefits for caregivers of individuals with Alzheimer's disease. METHODS: This paper presents the design and methods for LEAF 2.0, a 3-arm web-based randomized controlled trial (N = 500) in which family caregivers of patients with Alzheimer's disease (AD) are randomized to (1) the LEAF intervention facilitated remotely via the web (N = 200), (2) the LEAF intervention self-guided online (N = 200), or (3) an emotion reporting control (N = 100), which then crosses over to the intervention after approximately 6 months, half to the facilitated arm and half to the self-guided arm. We aim to (1) compare the effect of the facilitated and self-guided LEAF positive emotion interventions to an emotion reporting control condition on AD caregiver well-being (positive emotion, depression, anxiety, and perceived stress) and secondary outcomes (caregiving burden, caregiving self-efficacy, positive aspects of caregiving, quality of care, and AD patient quality of life); (2) assess whether effects are mediated by improvements in positive emotion or other aspects of caregiver well-being; and (3) test whether caregiver age or gender or the care recipient's dementia severity moderates the effects of the intervention. DISCUSSION: If demonstrated to be effective, LEAF can be widely disseminated and ultimately have a significant impact on the stress experienced by AD caregivers and the well-being of people living with Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03610698.

Host Respiratory Transcriptome Signature Associated with Poor Outcome in Children with Influenza-Staphylococcus aureus Pneumonia.

Respiratory coinfection of influenza with Staphylococcus aureus often causes severe disease; methicillin-resistant S. aureus (MRSA) coinfection is frequently fatal. Understanding disease pathogenesis may inform therapies. We aimed to identify host and pathogen transcriptomic (messenger RNA) signatures from the respiratory compartment of pediatric patients critically ill with influenza-S. aureus coinfection (ISAC), signatures that predict worse outcomes. Messenger RNA extracted from endotracheal aspirate samples was evaluated for S. aureus and host transcriptomic biosignatures. Influenza-MRSA outcomes were worse, but of 190 S. aureus virulence-associated genes, 6 were differentially expressed between MRSA-coinfected versus methicillin-susceptible S. aureus-coinfected patients, and none discriminated outcome. Host gene expression in patients with ISAC was compared with that in patients with influenza infection alone. Patients with poor clinical outcomes (death or prolonged multiorgan dysfunction) had relatively reduced expression of interferons and down-regulation of interferon γ-induced immune cell chemoattractants CXCL10 and CXCL11. In ISAC, airway host but not pathogen gene expression profiles predicted worse clinical outcomes.

Discrimination, Abuse, Harassment, and Burnout in Surgical Residency Training.

BACKGROUND: Physicians, particularly trainees and those in surgical subspecialties, are at risk for burnout. Mistreatment (i.e., discrimination, verbal or physical abuse, and sexual harassment) may contribute to burnout and suicidal thoughts. METHODS: A cross-sectional national survey of general surgery residents administered with the 2018 American Board of Surgery In-Training Examination assessed mistreatment, burnout (evaluated with the use of the modified Maslach Burnout Inventory), and suicidal thoughts during the past year. We used multivariable logistic-regression models to assess the association of mistreatment with burnout and suicidal thoughts. The survey asked residents to report their gender. RESULTS: Among 7409 residents (99.3% of the eligible residents) from all 262 surgical residency programs, 31.9% reported discrimination based on their self-identified gender, 16.6% reported racial discrimination, 30.3% reported verbal or physical abuse (or both), and 10.3% reported sexual harassment. Rates of all mistreatment measures were higher among women; 65.1% of the women reported gender discrimination and 19.9% reported sexual harassment. Patients and patients' families were the most frequent sources of gender discrimination (as reported by 43.6% of residents) and racial discrimination (47.4%), whereas attending surgeons were the most frequent sources of sexual harassment (27.2%) and abuse (51.9%). Proportion of residents reporting mistreatment varied considerably among residency programs (e.g., ranging from 0 to 66.7% for verbal abuse). Weekly burnout symptoms were reported by 38.5% of residents, and 4.5% reported having had suicidal thoughts during the past year. Residents who reported exposure to discrimination, abuse, or harassment at least a few times per month were more likely than residents with no reported mistreatment exposures to have symptoms of burnout (odds ratio, 2.94; 95% confidence interval [CI], 2.58 to 3.36) and suicidal thoughts (odds ratio, 3.07; 95% CI, 2.25 to 4.19). Although models that were not adjusted for mistreatment showed that women were more likely than men to report burnout symptoms (42.4% vs. 35.9%; odds ratio, 1.33; 95% CI, 1.20 to 1.48), the difference was no longer evident after the models were adjusted for mistreatment (odds ratio, 0.90; 95% CI, 0.80 to 1.00). CONCLUSIONS: Mistreatment occurs frequently among general surgery residents, especially women, and is associated with burnout and suicidal thoughts.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank.

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

Prevalence and risk factors for burnout in U.S. vascular surgery trainees.

OBJECTIVE: Burnout and suicidality are known risks for vascular surgeons above other surgical subspecialties, with surgical trainees at risk for exposure to factors that increase burnout. This study aimed to inform initiatives to improve wellness by assessing the prevalence of hazards in vascular training (mistreatment, duty-hour violations) and the rates of wellness outcomes (burnout, thoughts of attrition/specialty change/suicide). We hypothesized that mistreatment and duty-hour violations would predispose trainees to increased burnout. METHODS: We performed a cross-sectional study of residents and fellows enrolled in accredited United States vascular surgery training programs using a voluntary, confidential survey administered during the 2020 Vascular Surgery In-Training Examination. The primary outcome assessed was burnout symptoms reported on a weekly basis or more frequently. The rates of wellness outcomes were measured. The association of mistreatment and duty hours with the primary outcome was modeled with multivariable logistic regression. RESULTS: A total of 475 residents and fellows who were enrolled in one of 120 vascular surgery training programs completed the survey (84.2% response rate). Of 408 trainees completing burnout survey items, 182 (44.6%) reported symptoms of burnout. Fewer trainees reported thoughts of attrition (n = 42 [10.0%], specialty change (n = 35 [8.4%]), or suicide (n = 22 [4.9%]). Mistreatment was reported by 191 vascular trainees (47.3%) and was more common in female trainees (n = 63 [48.5%] reporting monthly or more frequently) compared with male trainees (n = 51 [18.6%]; P < .001). Duty-hour violations were also more commonly reported by female trainees (n = 31 [21.4%] reporting 3+ months in violation) compared with male trainees (n = 50 [16.2%]; P = .002). After controlling for race/ethnicity, postgraduate year, program type, and geography, female trainees were less likely to report burnout (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.28-0.86). Trainees experiencing mistreatment monthly or more were three times more likely to report burnout (OR, 3.09; 95% CI, 1.78-5.39). Frequency of duty-hour violations also increased the odds of reporting burnout (1-2 months in violation: OR, 2.09; 95% CI, 1.17-3.73; 3+ months in violation: OR, 3.95; 95% CI, 2.24-6.97). CONCLUSIONS: Nearly one-half of vascular surgery trainees reported symptoms of burnout, which was associated with frequency of mistreatment and duty-hour violations. Interventions to improve well-being in vascular surgery must be tailored to the local training environment to address trainee experiences that contribute to burnout.

RSK2-inactivating mutations potentiate MAPK signaling and support cholesterol metabolism in hepatocellular carcinoma.

BACKGROUND & AIMS: Mutational profiling of patient tumors has suggested that hepatocellular carcinoma (HCC) development is mainly driven by loss-of-function mutations in tumor suppressor genes. p90 ribosomal S6 kinase 2 (RSK2) functions as a direct downstream kinase of ERK1/2 and elevated RSK2 expression has been reported to support oncogenic functions in some cancers. We investigated if RSK2 was also dysregulated by inactivating mutations in cancers including HCC. METHODS: We performed exome sequencing and targeted DNA sequencing on HBV-associated HCCs to examine recurrent RSK2 mutations. The functional significance and mechanistic consequences of RSK2 mutations were examined in natural RSK2-null HCC cells, and RSK2-knockout HCC cells. The potential downstream pathways underlying RSK2 mutations were investigated by RNA sequencing, qRT-PCR and mass spectrometry. RESULTS: We detected recurrent somatic RSK2 mutations at a rate of 6.3% in our HCC cohorts and revealed that, among many cancer types, HCC was the cancer most commonly harboring RSK2 mutations. The RSK2 mutations were inactivating and associated with a more aggressive tumor phenotype. We found that, functionally, restoring RSK2 expression in natural RSK2-null HBV-positive Hep3B cells suppressed proliferation and migration in vitro and tumorigenicity in vivo. Mechanistically, RSK2-inactivating mutations attenuated a SOS1/2-dependent negative feedback loop, leading to the activation of MAPK signaling. Of note, this RSK2 mutation-mediated MAPK upregulation rendered HCC cells more sensitive to sorafenib, a first-line multi-kinase inhibitor for advanced HCC. Furthermore, such activation of MAPK signaling enhanced cholesterol biosynthesis-related gene expression in HCC cells. CONCLUSIONS: Our findings reveal the mechanistic and functional significance of RSK2-inactivating mutations in HCC. These inactivating mutations may serve as an alternative route to activate MAPK signaling and cholesterol metabolism in HCC. LAY SUMMARY: In this study, we identified and functionally characterized RSK2-inactivating mutations in human hepatocellular carcinoma and demonstrated their association with aggressive tumor behavior. Mutations in RSK2 drive signaling pathways with known oncogenic potential, leading to enhanced cholesterol biosynthesis and potentially sensitizing tumors to sorafenib treatment.

The Role of Personal Accomplishment in General Surgery Resident Well-being.

OBJECTIVE: To investigate the association of personal accomplishment (PA) with the other subscales, assess its association with well-being outcomes, and evaluate drivers of PA by resident level. BACKGROUND: Most studies investigating physician burnout focus on the emotional exhaustion (EE) and depersonalization (DP) subscales, neglecting PA. Therefore, the role of PA is not well understood. METHODS: General surgery residents were surveyed following the 2019 American Board of Surgery In-Training Examination regarding their learning environment. Pearson correlations of PA with EE and DP were assessed. Multivariable logistic regression models assessed the association of PA with attrition, job satisfaction, and suicidality and identified factors associated with PA by PGY. RESULTS: Residents from 301 programs were surveyed (85.6% response rate, N = 6956). Overall, 89.4% reported high PA, which varied by PGY-level (PGY1: 91.0%, PGY2/3: 87.7%, PGY4/5: 90.2%; P = 0.02). PA was not significantly correlated with EE (r = -0.01) or DP (r = -0.08). After adjusting for EE and DP, PA was associated with attrition (OR 0.60, 95%CI 0.46-0.78) and job satisfaction (OR 3.04, 95%CI 2.45-3.76) but not suicidality (OR 0.72, 95%CI 0.48-1.09). Although the only factor significantly associated with PA for interns was resident cooperation, time in operating room and clinical autonomy were significantly associated with PA for PGY2/3. For PGY4/5s, PA was associated with time for patient care, resident cooperation, and mentorship. CONCLUSION: PA is a distinct metric of resident well-being, associated with job satisfaction and attrition. Drivers of PA differ by PGY level and may be targets for intervention to promote resident wellness and engagement.

Comprehensive Characterization of the General Surgery Residency Learning Environment and the Association With Resident Burnout.

OBJECTIVES: To characterize the learning environment (ie, workload, program efficiency, social support, organizational culture, meaning in work, and mistreatment) and evaluate associations with burnout in general surgery residents. BACKGROUND SUMMARY DATA: Burnout remains high among general surgery residents and has been linked to workplace exposures such as workload, discrimination, abuse, and harassment. Associations between other measures of the learning environment are poorly understood. METHODS: Following the 2019 American Board of Surgery In-Training Examination, a cross-sectional survey was administered to all US general surgery residents. The learning environment was characterized using an adapted Areas of Worklife survey instrument, and burnout was measured using an abbreviated Maslach Burnout Inventory. Associations between burnout and measures of the learning environment were assessed using multivariable logistic regression. RESULTS: Analysis included 5277 general surgery residents at 301 programs (85.6% response rate). Residents reported dissatisfaction with workload (n = 784, 14.9%), program efficiency and resources (n = 1392, 26.4%), social support and community (n = 1250, 23.7%), organizational culture and values (n = 853, 16.2%), meaning in work (n = 1253, 23.7%), and workplace mistreatment (n = 2661, 50.4%). The overall burnout rate was 43.0%, and residents were more likely to report burnout if they also identified problems with residency workload [adjusted odds ratio (aOR) 1.60, 95% confidence interval (CI) 1.31-1.94], efficiency (aOR 1.74; 95% CI 1.49-2.03), social support (aOR 1.37, 95% CI 1.15-1.64), organizational culture (aOR 1.64; 95% CI 1.39-1.93), meaning in work (aOR 1.87; 95% CI 1.56-2.25), or experienced workplace mistreatment (aOR 2.49; 95% CI 2.13-2.90). Substantial program-level variation was observed for all measures of the learning environment. CONCLUSIONS: Resident burnout is independently associated with multiple aspects of the learning environment, including workload, social support, meaning in work, and mistreatment. Efforts to help programs identify and address weaknesses in a targeted fashion may improve trainee burnout.

Association of Surgical Resident Wellness With Medical Errors and Patient Outcomes.

OBJECTIVES: The aims of this study were to: (1) measure the prevalence of self-reported medical error among general surgery trainees, (2) assess the association between general surgery resident wellness (ie, burnout and poor psychiatric well-being) and self-reported medical error, and (3) examine the association between program-level wellness and objectively measured patient outcomes. SUMMARY OF BACKGROUND DATA: Poor wellness is prevalent among surgical trainees but the impact on medical error and objective patient outcomes (eg, morbidity or mortality) is unclear as existing studies are limited to physician and patient self-report of events and errors, small cohorts, or examine few outcomes. METHODS: A cross-sectional survey was administered immediately following the January 2017 American Board of Surgery In-training Examination to clinically active general surgery residents to assess resident wellness and self-reported error. Postoperative patient outcomes were ascertained using a validated national clinical data registry. Associations were examined using multivariable logistic regression models. RESULTS: Over a 6-month period, 22.5% of residents reported committing a near miss medical error, and 6.9% reported committing a harmful medical error. Residents were more likely to report a harmful medical error if they reported frequent burnout symptoms [odds ratio 2.71 (95% confidence interval 2.16-3.41)] or poor psychiatric well-being [odds ratio 2.36 (95% confidence interval 1.92-2.90)]. However, there were no significant associations between program-level resident wellness and any of the independently, objectively measured postoperative American College of Surgeons National Surgical Quality improvement Program outcomes examined. CONCLUSIONS: Although surgical residents with poor wellness were more likely to self-report a harmful medical error, there was not a higher rate of objectively reported outcomes for surgical patients treated at hospitals with higher rates of burnout or poor psychiatric well-being.

Facilitator Contact, Discussion Boards, and Virtual Badges as Adherence Enhancements to a Web-Based, Self-guided, Positive Psychological Intervention for Depression: Randomized Controlled Trial.

BACKGROUND: Adherence to self-guided interventions tends to be very low, especially in people with depression. Prior studies have demonstrated that enhancements may increase adherence, but little is known about the efficacy of various enhancements in comparison to, or in combination with, one another. OBJECTIVE: The aim of our study is to test whether 3 enhancements-facilitator contact (FC), an online discussion board, and virtual badges (VB)-alone, or in combination, improve adherence to a self-guided, web-based intervention for depression. We also examined whether age, gender, race, ethnicity, comfort with technology, or baseline depression predicted adherence or moderated the effects that each enhancement had on adherence. METHODS: Participants were recruited through web-based sources and, after completing at least 4 out of 7 daily emotion reports, were sequentially assigned to 1 of 9 conditions-the intervention alone; the intervention plus 1, 2, or all 3 enhancements; or an emotion reporting control condition. The intervention was a positive psychological program consisting of 8 skills that specifically targeted positive emotions, and it was delivered over 5 weeks in a self-guided, web-based format. We operationalized adherence as the number of skills accessed. RESULTS: A total of 602 participants were enrolled in this study. Participants accessed, on average, 5.61 (SD 2.76) of 8 skills. The total number of enhancements participants received (0-3) did not predict the number of skills accessed. Participants who were assigned to the VB+FC condition accessed significantly more skills than those in the intervention only conditions. Furthermore, participants in arms that received the combination of both the VB and FC enhancements (VB+FC and VB+FC+online discussion board) accessed a greater number of skills relative to the number of skills accessed by participants who received either VB or FC without the other. Moderation analyses revealed that the receipt of VB (vs no VB) predicted higher adherence among participants with moderately severe depression at baseline. CONCLUSIONS: The results suggested that the VB+FC combination significantly increased the number of skills accessed in a self-guided, web-based intervention for elevated depression. We have provided suggestions for refinements to these enhancements, which may further improve adherence. TRIAL REGISTRATION: ClinicalTrials.gov NCT02861755; http://clinicaltrials.gov/ct2/show/NCT02861755.

Predictive biomarkers and tumor microenvironment in female genital melanomas: a multi-institutional study of 55 cases.

Female genital melanomas are rare. At diagnosis, most affected patients have advanced disease. Surgery remains the primary treatment, and adjuvant therapy is largely ineffective. Recently, immune checkpoints and the mitogen-activated protein kinase pathway have been explored as treatment targets. However, evaluation of these biomarkers in genital melanomas is limited. We evaluated the clinicopathological features of 20 vulvar, 32 vaginal, and three cervical melanomas and assessed programmed cell death ligand 1 (PD-L1) expression, CD8 tumor-infiltrating lymphocyte density, mismatch repair proteins, VE1 immunohistochemistry, and KIT and BRAF mutations. The median age of the patients was 66 years, and median tumor sizes were 25, 30, and 20 mm for vulvar, vaginal, and cervical tumors, respectively. Mean mitotic figures were 18, 19, and 30 per mm2. Thirty-seven patients (67%) had operable tumors. After a median follow-up of 15 months, only nine patients (16%) were alive. Eight of the nine survivors did not have lymph node metastasis. Using 5% as the threshold, PD-L1 expression was observed in 55%, 50%, and 33% of vulvar, vaginal, and cervical tumors, respectively, when the Roche SP263 antibody was used and 20%, 53%, and 0%, respectively, when the Dako 28-8 antibody was used. The median CD8 tumor-infiltrating lymphocyte density was significantly higher in vulvar/vaginal than cervical melanomas and correlated with PD-L1 expression. No cases exhibited loss of mismatch repair proteins. Five cases harbored KIT mutations, three of which were hotspots. BRAF V600E mutation was not detected. Univariable analysis showed that tumor size greater than or equal to 33 mm, mitotic figures of greater than or equal to 10 per mm2, lymph node metastasis, and low CD8+ tumor-infiltrating lymphocyte density were adverse prognostic factors. Thus, patients with genital melanomas have a poor prognosis, and evaluation of multiple biomarkers is necessary to identify patients who may benefit from immunotherapy or targeted therapy.

Evaluation of the Role of stat3 in Antibody and TH17-Mediated Responses to Pneumococcal Immunization and Infection by Use of a Mouse Model of Autosomal Dominant Hyper-IgE Syndrome.

Loss-of-function mutations in the signal transducer and activator of transcription 3 gene (stat3) result in autosomal dominant hyper-IgE syndrome (AD-HIES), a condition in which patients have recurrent debilitating infections, including frequent pneumococcal and staphylococcal pneumonias. stat3 mutations cause defective adaptive TH17 cellular responses, an immune mechanism believed to be critical for clearance of pneumococcal colonization and diminished antibody responses. Here we wished to evaluate the role of stat3 in the clearance of pneumococcal carriage and immunity using mice with a stat3 mutation recapitulating AD-HIES. We show here that naive AD-HIES mice have prolonged nasal carriage of pneumococcus compared to WT mice. Mutant and wild-type mice were then immunized with a pneumococcal whole-cell vaccine (WCV) that provides TH17-mediated protection against pneumococcal colonization and antibody-mediated protection against pneumonia and sepsis. WCV-immunized AD-HIES mice made significantly less pneumococcus-specific interleukin-17A (IL-17A) and antibody than WT mice. The WCV-elicited protection against colonization was abrogated in AD-HIES mice, but immunization with WCV still protected AD-HIES mice against aspiration pneumonia/sepsis. Taken together, our results suggest that impaired clearance of nasopharyngeal carriage due to poor adaptive IL-17A responses may contribute to the increased rates of pneumococcal respiratory infection in AD-HIES patients.

A randomized pilot trial of a positive affect skill intervention (lessons in linking affect and coping) for women with metastatic breast cancer.

BACKGROUND: We conducted a randomized pilot trial to examine the feasibility, acceptability, and preliminary efficacy of a 5 week positive affect skills intervention (LILAC: lessons in linking affect and coping) for women with metastatic breast cancer. Additionally, we examined whether online delivery of the intervention would offer comparable benefits as in-person delivery. METHODS: Women with metastatic breast cancer (N = 39) were randomized to an in-person intervention, online intervention, or in-person attention-matched control. Psychological well-being (depression [Center for Epidemiologic Studies Depression Scale], positive and negative affect [Differential Emotions Scale], cancer-specific quality of life [Multidimensional Quality of Life Scale-Cancer Version]), and positive coping (mindfulness, positive-affect skill use, and self-compassion [Self-Compassion Scale: Short-Form]) were assessed at baseline, 1 week post-intervention, and 1 month post-intervention follow-up. RESULTS: The LILAC intervention showed good feasibility, acceptability, and retention. Although the study was not adequately powered to detect between-group differences in change on preliminary efficacy outcomes, within-group comparisons revealed that LILAC participants (in-person and online combined) showed reductions in depression and negative affect by the 1 month follow-up (d = -0.81). Notably, LILAC participants fell below the clinical threshold for depression (Center for Epidemiologic Studies Depression Scale = 16) by the 1 month follow-up (t[17] = -2.22, P = .04, d = -0.52), whereas control participants did not differ from threshold (t[9] = 0.45, P = .66, d = 0.14). CONCLUSIONS: The LILAC intervention, regardless of delivery method, shows feasibility, acceptability, and preliminary efficacy for promoting psychological well-being in women with metastatic breast cancer. This research provides support for a larger randomized trial to test more definitively the potential benefits of LILAC. A strength of the LILAC intervention includes its innovative focus on positive affect. The efficacy of the online delivery suggests the potential for widespread Internet dissemination.

Prediction of biogeographical ancestry from genotype: a comparison of classifiers.

DNA can provide forensic intelligence regarding a donor's biogeographical ancestry (BGA) and other externally visible characteristics (EVCs). A number of algorithms have been proposed to assign individual human genotypes to a BGA using ancestry informative marker (AIM) panels. This study compares the BGA assignment accuracy of the population clustering program STRUCTURE and three generic classification approaches including a Bayesian algorithm, genetic distance, and multinomial logistic regression (MLR). A selection of 142 ancestry informative single nucleotide polymorphisms (SNPs) were chosen from existing marker panels (SNPforID 34-plex, Eurasiaplex, Seldin, and Kidd's AIM panels) to assess BGA classification at the continental level for Africans, Europeans, East Asians, and Amerindians. A training set of 1093 individuals with self-declared BGA from the 1000 Genomes phase 1 database was used by each classifier to predict BGA in a test set of 516 individuals from the HGDP-CEPH (Stanford) cell line panel. Tests were repeated with 0, 10, 50, 70, and 90% of the genotypes missing. Comparison of the area under the receiver operating characteristic curves (AUROCs) showed high accuracy in STRUCTURE and the generic Bayesian approach. The latter algorithm offers a computationally simpler alternative to STRUCTURE with little loss in accuracy and is suitable for phenotype prediction while STRUCTURE is not.

Outcomes of applying the NOF, NOGG and Taiwanese guidelines to a cohort of Chinese early postmenopausal women.

OBJECTIVE: We applied the NOF (National Osteoporosis Foundation, USA), NOGG (National Osteoporosis Guideline Group, UK) and Taiwanese guidelines to a cohort of postmenopausal women and compared the effectiveness in fracture prevention according to these guidelines. DESIGN: This study is part of the Hong Kong Osteoporosis Study in which postmenopausal women underwent regular assessment and followed up for fracture outcome. SUBJECTS: We studied 2266 treatment-naïve postmenopausal women with mean age of 62·1 years and mean follow-up of 4·5 years. MEASUREMENT: The treatment recommendations based on different guidelines were compared. The women were followed up to determine the rate of fracture occurrence. RESULTS: A total of 106 new major osteoporotic fractures (MOF) were reported, of which 21 were hip fractures (HF). Application of the NOF, NOGG and Taiwanese guidelines resulted in bone mineral density (BMD) screening of 40·7%, 1·3% and 31·8% and treatment of 26·8%, 15·5% and 25·4% of the cohort, respectively. 85·7%, 52·4% and 85·7% of the subjects who sustained HFs would be offered treatment according to the NOF, NOGG and Taiwanese guidelines, respectively. Likewise, 58·5%, 34% and 59·4% of the subjects who sustained MOF would be offered treatment according to the 3 guidelines, respectively. The clinical utility indexes for the 3 guidelines based on the occurrence of MOF during follow-up were 0·0597, 0·0345 and 0·0651, respectively. The corresponding numbers for HFs were even lower. CONCLUSION: The clinical utility for these three guidelines is low for this postmenopausal cohort. Specific guidelines should be needed to guide BMD screening and treatment in our society.

A secular increase in BMD in Chinese women.

Population-based studies have revealed a decline in the incidence of age-adjusted hip fractures in southern Chinese women during the past decade. To determine whether there was a secular change in population characteristics that accounted for this decline, we compared the bone mineral density (BMD) and lifestyle habits of two cohorts of women who were more than 50 years of age and who were recruited from 1995 to 2000 and 2005 to 2010. The BMD levels in the 2005-2010 cohort were significantly higher at the spine and hip and ranged from 3.6 to 17.8% among the different age groups. Additionally, a significantly lower prevalence of subjects with osteoporosis and osteopenia was observed. Longer reproductive years, higher levels of physical activity, higher estradiol and 25(OH) vitamin D levels, and lower alkaline phosphatase levels were found in the 2005-2010 cohort. After adjusting for bone-determining factors, significant differences were detected in the BMD levels at the lumbar spine, femoral neck, and total hip (4.17, 9.02, and 9.34%, respectively) in women >50 years of age but not in women ≤50 years of age. The secular increase in BMD and healthier lifestyles most likely led to the decline in the incidence of age-adjusted fractures.

Quality of Life in Patients and Their Spouses and Cohabitating Partners in the Year Following a Cancer Biopsy (the Couples Cope Study): Protocol for a Prospective Observational Study.

BACKGROUND: Receiving a diagnosis of cancer is a profound and often very stressful experience. Few studies have prospectively recruited patients prior to receiving a new diagnosis of cancer and included spouses or partners. OBJECTIVE: The aim of the Couples Cope Study is to understand the impact of undergoing a diagnostic biopsy and receiving a new cancer diagnosis on quality of life (QoL) in both patients and their spouses or partners, as well as on the quality of their relationship. This protocol paper describes the study design and assesses the feasibility of recruitment and retention. METHODS: Study staff reviewed the schedules of collaborating physicians using specific encounter codes to identify patients scheduled for breast or prostate biopsies. Potential participants were prescreened via the electronic health record and sent a recruitment letter at least 2 to 3 weeks prior to their biopsy procedure. Patients subsequently underwent a phone screening to determine eligibility. Patients who enrolled provided study staff with contact information for their spouses or partners. All consent forms were completed online. Surveys were completed online prior to receiving the biopsy results (baseline), and at 1, 3, 6, and 9 months after the biopsy. Study staff engaged in ongoing, personalized contact with participants and sent assessment completion reminders via phone and email. RESULTS: A total of 2294 patients undergoing a breast or prostate biopsy were identified and 69% (n=1582) were eligible for phone screening following electronic health record prescreening. Of the 431 patients who underwent phone screening, 75% (n=321) were eligible to participate. Of the eligible patients, 72% (n=231) enrolled and 82% (n=190) of enrolled patients had an accompanying partner or spouse who also enrolled. A total of 77% (34/44) of patients who received a cancer diagnosis and 72% (26/36) of their spouses or partners were retained through 9 months, while 80% (53/66) of patients who received a benign diagnosis and 68% (42/62) of their partners were retained. CONCLUSIONS: Prospective recruitment of patients undergoing diagnostic biopsy and their partners is feasible and requires both strategic collaboration with providers and concerted prescreening and recruitment efforts by study staff. Importantly, this study was able to conduct all study activities online without disrupting clinical workflow and without requiring patients and their spouses or partners to come into the laboratory. Consideration should be given to the ratio of biopsies to cancer diagnoses, which can vary significantly by cancer type. Prospective studies are needed and can inform our ability to provide effective support earlier to couples facing a possible cancer diagnosis. Future studies should examine other tumor types that have received less attention in QoL studies, include behavioral and neurobiological assessments beyond self-report measures, and follow couples beyond 9 months in order to examine long-term effects on QoL. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52361.