Alcohol consumption and cancer incidence in women: interaction with smoking, body mass index and menopausal hormone therapy.

BACKGROUND: Alcohol consumption has been associated with increased risks of certain site-specific cancers and decreased risks of some other cancers. There is, however, little reliable evidence as to whether the alcohol-associated risks for specific cancers are modified by smoking, body mass index (BMI) and menopausal hormone therapy (MHT) use. METHODS: In the prospective UK Million Women Study, 1,233,177 postmenopausal women without prior cancer, mean age 56 (SD 5) years, reported their alcohol consumption in median year 1998 (IQR 1998-1999), and were followed by record-linkage for incident cancer. 438,056 women who drank no alcohol or < 1 drink/week were excluded. Cox regression yielded adjusted relative risks (RRs) and 95% confidence intervals (CIs) for 21 cancers by alcohol amount; statistical significance of interactions with smoking, BMI and MHT use was assessed after allowing for multiple testing. RESULTS: In 795,121 participants, mean consumption was 6.7 (SD 6.4) alcoholic drinks/week. During 17 (SD 5) years of follow-up, 140,203 incident cancers were recorded. There was strong evidence for a substantial association between alcohol intake and risk of upper aero-digestive cancers (oesophageal squamous cell carcinoma, oral cavity, pharynx and larynx; RR per 1 drink/day = 1.38 [95% CI 1.31-1.46]). There was also strong evidence for more moderate positive associations with breast, colorectal and pancreatic cancer (RRs per 1 drink/day = 1.12 [1.10-1.14], 1.10 [1.07-1.13], 1.08 [1.02-1.13] respectively), and moderate negative associations with thyroid cancer, non-Hodgkin's lymphoma, renal cell carcinoma and multiple myeloma (RRs per 1 drink/day = 0.79 [0.70-0.89], 0.91 [0.86-0.95], 0.88 [0.83-0.94], 0.90 [0.84-0.97] respectively). Significant interactions between alcohol and smoking were seen for upper aero-digestive cancers (RRs per 1 drink/day = 1.66 [1.54-1.79], 1.23 [1.11-1.36], 1.12 [1.01-1.25] in current, past, and never smokers respectively). BMI and MHT did not significantly modify any alcohol-associated risks. CONCLUSIONS: These findings provide robust evidence that greater alcohol intake, even within relatively moderate ranges, increases the risk of cancers of the aerodigestive tract, breast, colorectal and pancreatic cancer, and probably decreases the risk of thyroid cancer, non-Hodgkin's lymphoma, renal cell carcinoma and multiple myeloma. Associations of alcohol intake with cancer risk were not modified by MHT use, adiposity or smoking, except in the case of upper aero-digestive cancers, where the alcohol-associated risk was largely confined to smokers.

Serial EUS-Guided FNA for the Surveillance of Pancreatic Cysts: A Study of Long-Term Performance of Tumor Markers.

BACKGROUND AND AIM: The natural history of KRAS mutations in mucinous pancreatic cysts (MPCs) over time remains to be fully understood. The aim of this study was to examine the performance of DNA markers and assess changes of KRAS mutations over time. METHODS: Patients who underwent EUS-FNA of pancreatic cysts with at least two separate molecular analysis results were included in the study. We assessed the baseline patient and cyst characteristics, and DNA fluid analysis. The presence of either a KRAS mutation, or a CEA > 192 ng/ml was used as the diagnostic standard for mucinous cysts when surgical pathology was not available. RESULTS: A total of 933 pancreatic cyst fluid samples were collected, including 117 with ≥ 2 FNAs. Examinations were performed over a median of 30 months (range 1-115 months). Forty-three (36%) had a mutant KRAS on the index analysis out of which 26 had a change in their KRAS status to the wild-type. Eighty-one (64%) had a wild-type KRAS on the index analysis out of which 18 had change in their KRAS status to mutant type. There was no significant difference in the index cyst characteristics, presence of symptoms, or main duct involvement based on KRAS status change. Increasing age was associated with a changing KRAS mutation status (p = 0.023). CONCLUSION: KRAS mutations gain and loss in pancreatic cyst fluid appears to occur frequently during long-term surveillance of MPCs. Age appears to be the only predictor for KRAS change over time.

Is resident assistance equivalent to fellows during hepatectomy?

OBJECTIVE: Hepatectomy is a complex operative procedure frequently performed at academic institutions with trainee participation. The aim of this study was to determine the effect of assistant's training level on outcomes following hepatectomy. METHODS: A retrospective review of a prospective, single-institution ACS-NSQIP database was performed for patients that underwent hepatectomy (2013-2016). Patients were divided by trainee assistant level: hepatopancreatobiliary (HPB) fellow versus general surgery resident (PGY 4-5). Demographic, perioperative, and 30-day outcome variables were compared using Chi-Square/Fisher's exact, Mann-Whitney U test, and multivariable regression. Cases involving a senior-level general surgery resident or HPB fellow as first assistant were included (n = 352). Those with a second attending, junior-level resident, or no documented assistant were excluded (n = 39). RESULTS: Patients undergoing hepatectomy with an HPB fellow as primary assistant had more frequent preoperative biliary stenting, longer operative time, and more concomitant procedures including biliary reconstruction, resulting in a higher rate of post-hepatectomy liver failure (PHLF) (15% vs. 8%, P = 0.044). However, trainee level did not impact PHLF on multivariable analysis (OR 0.60, 95% CI [0.29-1.25], P = 0.173). Fellows assisted with proportionally more major hepatectomies (45% vs. 31%; P = 0.010) and resections for hepatobiliary cancers (31% vs. 19%, P = 0.014). On stratified analysis of major and minor hepatectomies, outcomes were similar between trainee groups. CONCLUSION: Fellows performed higher complexity cases with longer operative time. Despite these differences, outcomes were similar regardless of assistant training level. Resident and HPB fellow participation in operations requiring liver resection provide comparable quality of care.

Intrinsic and regulated properties of minimally edited trypanosome mRNAs.

Most mitochondrial mRNAs in kinetoplastids require extensive uridine insertion/deletion editing to generate translatable open reading frames. Editing is specified by trans-acting gRNAs and involves a complex machinery including basal and accessory factors. Here, we utilize high-throughput sequencing to analyze editing progression in two minimally edited mRNAs that provide a simplified system due their requiring only two gRNAs each for complete editing. We show that CYb and MURF2 mRNAs exhibit barriers to editing progression that differ from those previously identified for pan-edited mRNAs, primarily at initial gRNA usage and gRNA exchange. We demonstrate that mis-edited junctions arise through multiple pathways including mis-alignment of cognate gRNA, incorrect and sometimes promiscuous gRNA utilization and inefficient gRNA anchoring. We then examined the roles of accessory factors RBP16 and MRP1/2 in maintaining edited CYb and MURF2 populations. RBP16 is essential for initiation of CYb and MURF2 editing, as well as MURF2 editing progression. In contrast, MRP1/2 stabilizes both edited mRNA populations, while further promoting progression of MURF2 mRNA editing. We also analyzed the effects of RNA Editing Substrate Binding Complex components, TbRGG2 and GAP1, and show that both proteins modestly impact progression of editing on minimally edited mRNAs, suggesting a novel function for GAP1.

MRB7260 is essential for productive protein-RNA interactions within the RNA editing substrate binding complex during trypanosome RNA editing.

The trypanosome RNA editing substrate binding complex (RESC) acts as the platform for mitochondrial uridine insertion/deletion RNA editing and facilitates the protein-protein and protein-RNA interactions required for the editing process. RESC is broadly comprised of two subcomplexes: GRBC (guide RNA binding complex) and REMC (RNA editing mediator complex). Here, we characterize the function and position in RESC organization of a previously unstudied RESC protein, MRB7260. We show that MRB7260 forms numerous RESC-related complexes, including a novel, small complex with the guide RNA binding protein, GAP1, which is a canonical GRBC component, and REMC components MRB8170 and TbRGG2. RNA immunoprecipitations in MRB7260-depleted cells show that MRB7260 is critical for normal RNA trafficking between REMC and GRBC. Analysis of protein-protein interactions also reveals an important role for MRB7260 in promoting stable association of the two subcomplexes. High-throughput sequencing analysis of RPS12 mRNAs from MRB7260 replete and depleted cells demonstrates that MRB7260 is critical for gRNA exchange and early gRNA utilization, with the exception of the initiating gRNA. Together, these data demonstrate that MRB7260 is essential for productive protein-RNA interactions with RESC during RNA editing.

Alcohol intake and Parkinson's disease risk in the million women study.

BACKGROUND: Alcohol intake may be associated with a lower risk of Parkinson's disease (PD), but findings from previous studies have been inconclusive. OBJECTIVE: To determine the association between alcohol intake and PD risk in the Million Women Study, a large, prospective study of women in the UK. METHODS: Between 1996 and 2001, approximately 1.3 million women in the UK, mean age 56 (standard deviation, 5) years, were recruited into the Million Women Study. Information on alcohol intake, lifestyle factors, and medical history was collected at recruitment by questionnaire. Information on incident cases of PD was ascertained by record linkage to national hospital admission records and death registrations. We estimated multivariable-adjusted relative risks and corresponding 95% confidence intervals using Cox proportional hazards models according to categories of alcohol intake. RESULTS: During an average of 17.9 years of follow-up, 11,009 women had a new record of PD among 1,309,267 women. In drinkers, the multivariable-adjusted relative risk comparing women who drank more than 14 drinks of alcohol per week with women who drank 1 to 2 drinks of alcohol per week was 0.99 (95% confidence interval: 0.90, 1.10). Results did not materially change after excluding the first 10 years of follow-up (relative riskadjusted = 1.01; 95% confidence interval: 0.90, 1.13). There were no significant trends in alcohol-related PD risk among never smokers. Additionally, examining this association by type of alcohol intake also yielded null findings. CONCLUSION: These results do not support an association between alcohol intake and PD risk in women. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Optometry Compensation Study: Narrowing Down the Unexplained Gender Wage Gap in Optometry.

SIGNIFICANCE: Men earn at least 6.5% more than women in their first full-time jobs as optometrists. For current salaries, the gender wage gap is more than 13%. This study details the gender wage gap that remains after controlling for practice ownership, residency training, and employer-defined full-time work. PURPOSE: The purpose of this study was to measure the gender wage gap by region and practice type for full-time optometrists who did not complete a residency and do not own their practice. METHODS: Participants completed an online survey, providing data for their first and current optometry positions and demographic information. Respondents who reported full-time employment in the United States, not completing a residency, and not owning their practice were selected for further analysis by census region and practice type. In each category, the gender wage gap was calculated. RESULTS: In all regions and practice types, men were paid higher starting salaries than women. For current salaries, men were paid higher in almost all regions and practice types. The wage gap increased from starting salary to current salary, although not in all regions and practice types. CONCLUSIONS: When practice ownership, residency completion, and full-time work are controlled for, there remains a difference in the pay received by men and women in optometry. The salary data presented in this study may help optometrists narrow the wage gap.

Trypanosome RNA Editing Mediator Complex proteins have distinct functions in gRNA utilization.

Uridine insertion/deletion RNA editing is an essential process in kinetoplastid parasites whereby mitochondrial mRNAs are modified through the specific insertion and deletion of uridines to generate functional open reading frames, many of which encode components of the mitochondrial respiratory chain. The roles of numerous non-enzymatic editing factors have remained opaque given the limitations of conventional methods to interrogate the order and mechanism by which editing progresses and thus roles of individual proteins. Here, we examined whole populations of partially edited sequences using high throughput sequencing and a novel bioinformatic platform, the Trypanosome RNA Editing Alignment Tool (TREAT), to elucidate the roles of three proteins in the RNA Editing Mediator Complex (REMC). We determined that the factors examined function in the progression of editing through a gRNA; however, they have distinct roles and REMC is likely heterogeneous in composition. We provide the first evidence that editing can proceed through numerous paths within a single gRNA and that non-linear modifications are essential, generating commonly observed junction regions. Our data support a model in which RNA editing is executed via multiple paths that necessitate successive re-modification of junction regions facilitated, in part, by the REMC variant containing TbRGG2 and MRB8180.

Travel distance affects rates and reasons for inpatient visits after pancreatectomy.

BACKGROUND: Centralization of complex surgical care leads to increased travel distances for patients. We sought to determine if increased travel distance to the index hospital altered inpatient Visit rates following pancreatectomy. METHODS: Pancreatectomies from 2013-2016 were reviewed retrospectively from a single high-volume institution. Travel distance for 936 patients was determined, and patients were grouped by 50-mile increments. Visits (Observations or Readmissions) and corresponding reasons were gathered. RESULTS: 222 patients (23.7%) had a Visit to any hospital (AH) within 90 days postoperative; 195 (87.8%) were to the index hospital (IH). The <50 miles group had the highest Visit rate to AH (28.6% vs. 17.8% vs. 24.6%; P = 0.008) and the IH (26.9% vs. 15.2% vs. 20.6%; P = 0.002) compared to 50-100 and > 100 miles. This trend was statistically significant for Observations, but not Readmissions. Gastrointestinal (GI) complaints alone led to 20.7% patients requiring Visits to AH at 90-days, mostly in <50miles group for Visits and Observations at AH and IH. CONCLUSIONS: Patients closest to the IH had the highest Visit and Observation rate following pancreatectomy without affecting Readmission rate, with GI complaints as a driving factor. Inpatient education and outpatient symptom management may reduce repeat hospitalization.

Clinical criteria for integrated molecular pathology in intraductal papillary mucinous neoplasm: less is more.

BACKGROUND: For pancreatic cysts with negative cytology, Integrated Molecular Pathology (IMP) is a malignancy risk score integrating clinical criteria with pancreatic cyst fluid DNA profiling. Aside from main pancreatic duct (MPD) diameter, integrated clinical criteria are not International Consensus Guidelines High-Risk Stigmata. We predicted exclusion of clinical criteria except MPD diameter could simplify the IMP and better distinguish invasive/malignant disease. METHODS: Records of >1100 patients with IPMN were reviewed retrospectively. Sensitivity, specificity, and accuracy of conventional IMP for invasive/malignant disease was compared to DNA profile including only MPD ≥10mm (IMP-10.) Invasive outcomes were invasive-IPMN/adenocarcinoma on surgical pathology, pathologic or radiographic evidence of invasive/metastatic disease during surveillance. Malignant outcomes included high grade dysplastic IPMN (HGD-IPMN). RESULTS: 225 patients who met study criteria underwent 283 IMP evaluations: 98 followed by surgery, 185 followed by ≥ 23 months surveillance. IMP-10 had greater specificity (90.1% vs. 73.7%) and accuracy (89.8% vs. 74.2%) for invasive disease compared to IMP in surgery + surveillance patients, but lower sensitivity (77.8% vs. 88.9%). Trends were similar in surgery patients alone and malignant outcome analyses. CONCLUSION: IMP-10 excludes less-reliable clinical factors resulting in greater accuracy in predicting invasive/malignant disease and fewer patients with benign disease being recommended for surgery.

High-throughput sequencing of partially edited trypanosome mRNAs reveals barriers to editing progression and evidence for alternative editing.

Uridine insertion/deletion RNA editing in kinetoplastids entails the addition and deletion of uridine residues throughout the length of mitochondrial transcripts to generate translatable mRNAs. This complex process requires the coordinated use of several multiprotein complexes as well as the sequential use of noncoding template RNAs called guide RNAs. The majority of steady-state mitochondrial mRNAs are partially edited and often contain regions of mis-editing, termed junctions, whose role is unclear. Here, we report a novel method for sequencing entire populations of pre-edited partially edited, and fully edited RNAs and analyzing editing characteristics across populations using a new bioinformatics tool, the Trypanosome RNA Editing Alignment Tool (TREAT). Using TREAT, we examined populations of two transcripts, RPS12 and ND7-5', in wild-typeTrypanosoma brucei We provide evidence that the majority of partially edited sequences contain junctions, that intrinsic pause sites arise during the progression of editing, and that the mechanisms that mediate pausing in the generation of canonical fully edited sequences are distinct from those that mediate the ends of junction regions. Furthermore, we identify alternatively edited sequences that constitute plausible alternative open reading frames and identify substantial variability in the 5' UTRs of both canonical and alternatively edited sequences. This work is the first to use high-throughput sequencing to examine full-length sequences of whole populations of partially edited transcripts. Our method is highly applicable to current questions in the RNA editing field, including defining mechanisms of action for editing factors and identifying potential alternatively edited sequences.

Characterization of fibromyalgia symptoms in patients 55-95 years old: a longitudinal study showing symptom persistence with suboptimal treatment.

BACKGROUND: Fibromyalgia (FM) has been understudied in the elderly population, a group with particular vulnerabilities to pain, reduced mobility, and sleep disruption. AIMS: To characterize FM symptoms and treatments in a cohort of older subjects examined over time to determine the extent to which current, community-based treatment for older FM patients is in accord with published guidelines, and effective in reducing symptoms. METHODS: A longitudinal, observational study of 51 subjects with FM (range 55-95 years) and 81 control subjects (58-95 years) performed at Banner Sun Health Research Institute in Sun City, AZ, USA. Serial history and examination data were obtained over a 6-year period. FM data included medical history, medications, physical examination, tender point examination, neuropsychological testing, sleep and pain ratings, the Physical Function Subscale of the Fibromyalgia Impact Questionnaire, and other standardized scales to evaluate depression and other psychiatric symptoms, and cognitive and functional impairment. RESULTS: Pain and stiffness that interfered with physical activity, sleep, and mood were reported by 80 % or more of subjects. Over time, pain involved an increasing number of body areas. Over half of subjects were treated with NSAIDs, one-quarter with opioids, and one-quarter with estrogen. Few were treated with dual-acting antidepressants or pregabalin. DISCUSSION: In this cohort of elders with suboptimally treated FM, substantial persistence of symptoms was seen over time. In general, recommended treatments were either not used or not tolerated. CONCLUSIONS: Age-appropriate treatments as well as education of primary care providers are needed to improve treatment of FM in the older population.

Copper-mediated synthesis of N-alkenyl-α,ß-unsaturated nitrones and their conversion to tri- and tetrasubstituted pyridines.

A Chan-Lam reaction has been used to prepare N-alkenyl-α,ß-unsaturated nitrones, which undergo a subsequent thermal rearrangement to the corresponding tri- and tetrasubstituted pyridines. The optimization and scope of these transformations is discussed. Initial mechanistic experiments suggest a reaction pathway involving oxygen transfer followed by cyclization.

Tumor necrosis factor-costimulated T lymphocytes from patients with systemic sclerosis trigger collagen production in fibroblasts.

OBJECTIVE: The role of tumor necrosis factor (TNF) in systemic sclerosis (SSc) remains controversial. The present study was undertaken to investigate the influence of TNF receptor (TNFR)-costimulated lymphocytes on collagen expression in fibroblasts. METHODS: TNFR expression on mononuclear cells from the dermis and blood of SSc patients was assessed by flow cytometry. Peripheral blood CD3+ lymphocytes were activated with CD3/CD28 beads and costimulated with TNFR-selective variants. Expression of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), IL-10, and IL-13 was detected by enzyme-linked immunosorbent assay or quantitative reverse transcription-polymerase chain reaction. Healthy fibroblasts were incubated with conditioned media from TNFR-costimulated T lymphocytes, and type I collagen expression was quantified. RESULTS: TNFRI and TNFRII were up-regulated on dermal T lymphocytes from patients with diffuse cutaneous SSc. TNFRII expression correlated with skin thickening. After CD3/CD28 activation, peripheral blood lymphocytes from SSc patients produced more IL-6, sIL-6R, and IL-13 compared to healthy lymphocytes. Costimulation with TNFRI-selective ligands and soluble TNF further increased IL-6 expression, whereas costimulation with TNFRII led to greater release of sIL-6R. IL-10 expression, which normally occurs after TNFRII costimulation, was impaired in SSc T cells. Supernatants of TNF-costimulated SSc lymphocytes induced higher type I collagen expression in fibroblasts, which was partially reversible by dual inhibition of IL-6 and IL-13. Expression of TNFR and IL-6 in the dermis was reversible in a patient who received lymphoablative therapy prior to autologous hematopoietic stem cell transplantation. CONCLUSION: TNF-costimulated T lymphocytes from SSc patients have a propensity to secrete profibrotic cytokines, while the ability to produce IL-10 is weakened. These results suggest that T lymphocytes in SSc support fibrosis, but might lack the capacity to resolve inflammation.

Sources of medical error in refractive surgery.

PURPOSE: To evaluate the causes of laser programming errors in refractive surgery and outcomes in these cases. METHODS: In this multicenter, retrospective chart review, 22 eyes of 18 patients who had incorrect data entered into the refractive laser computer system at the time of treatment were evaluated. Cases were analyzed to uncover the etiology of these errors, patient follow-up treatments, and final outcomes. The results were used to identify potential methods to avoid similar errors in the future. RESULTS: Every patient experienced compromised uncorrected visual acuity requiring additional intervention, and 7 of 22 eyes (32%) lost corrected distance visual acuity (CDVA) of at least one line. Sixteen patients were suitable candidates for additional surgical correction to address these residual visual symptoms and six were not. Thirteen of 22 eyes (59%) received surgical follow-up treatment; nine eyes were treated with contact lenses. After follow-up treatment, six patients (27%) still had a loss of one line or more of CDVA. Three significant sources of error were identified: errors of cylinder conversion, data entry, and patient identification error. CONCLUSION: Twenty-seven percent of eyes with laser programming errors ultimately lost one or more lines of CDVA. Patients who underwent surgical revision had better outcomes than those who did not. Many of the mistakes identified were likely avoidable had preventive measures been taken, such as strict adherence to patient verification protocol or rigorous rechecking of treatment parameters.