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INTRODUCTION: The American Joint Committee on Cancer (AJCC) staging system undergoes periodic revisions to maintain contemporary survival outcomes related to stage. Recently, the AJCC has developed a novel, systematic approach incorporating survival data to refine stage groupings. The objective of this study was to demonstrate data‐driven optimization of the version 9 AJCC staging system for anal cancer assessed through a defined validation approach. METHODS: The National Cancer Database was queried for patients diagnosed with anal cancer in 2012 through 2017. Kaplan–Meier methods analyzed 5‐year survival by individual clinical T category, N category, M category, and overall stage. Cox proportional hazards models validated overall survival of the revised TNM stage groupings. RESULTS: Overall, 24,328 cases of anal cancer were included. Evaluation of the 8th edition AJCC stage groups demonstrated a lack of hierarchical prognostic order. Survival at 5 years for stage I was 84.4%, 77.4% for stage IIA, and 63.7% for stage IIB; however, stage IIIA disease demonstrated a 73.0% survival, followed by 58.4% for stage IIIB, 59.9% for stage IIIC, and 22.5% for stage IV (p <.001). Thus, stage IIB was redefined as T1‐2N1M0, whereas Stage IIIA was redefined as T3N0‐1M0. Reevaluation of 5‐year survival based on data‐informed stage groupings now demonstrates hierarchical prognostic order and validated via Cox proportional hazards models. CONCLUSION: The 8th edition AJCC survival data demonstrated a lack of hierarchical prognostic order and informed revised stage groupings in the version 9 AJCC staging system for anal cancer. Thus, a validated data‐driven optimization approach can be implemented for staging revisions across all disease sites moving forward. Evaluation of the 8th edition American Joint Committee on Cancer staging system demonstrated a lack of hierarchical prognostic order for anal cancer. Thus, the version 9 American Joint Committee on Cancer staging system for anal cancer was revised through a validated and data‐driven approach and should similarly be applied across all disease sites moving forward. [ABSTRACT FROM AUTHOR]

The standard for cancer staging in the United States for all cancer sites, including primary carcinomas of the appendix, is the American Joint Committee on Cancer (AJCC) staging system. AJCC staging criteria undergo periodic revisions, led by a panel of site‐specific experts, to maintain contemporary staging definitions through the evaluation of new evidence. Since its last revision, the AJCC has restructured its processes to include prospectively collected data because large data sets have become increasingly robust and available over time. Thus survival analyses using AJCC eighth edition staging criteria were used to inform stage group revisions in the version 9 AJCC staging system, including appendiceal cancer. Although the current AJCC staging definitions were maintained for appendiceal cancer, incorporating survival analysis into the version 9 staging system provided unique insight into the clinical challenges in staging rare malignancies. This article highlights the critical clinical components of the now published version 9 AJCC staging system for appendix cancer, which (1) justified the separation of three different histologies (non‐mucinous, mucinous, signet‐ring cell) in terms of prognostic variance, (2) demonstrated the clinical implications and challenges in staging heterogeneous and rare tumors, and (3) emphasized the influence of data limitations on survival analysis for low‐grade appendiceal mucinous neoplasms. [ABSTRACT FROM AUTHOR]

Background: Red cell distribution width (RDW), an index for variation of red blood cell (RBC) size, has been proposed as a potential marker for poorer outcomes in several aging‐related diseases and conditions. We tested whether greater variability of RBC size, presented as a higher RDW value, predicts poor prognoses among hospitalized patients over 60 years old. Methods: We retrospectively collected data from older hospitalized patients aged ≥60 years between January 2013 to December 2017 at Sutter Health, a large integrated health system in Northern California. The RDW was measured during hospital admission and categorized with 1% intervals (≤13.9, 14.0–14.9, 15.0–15.9, 16.0–16.9, 17.0–17.9 and ≥18.0%). The primary outcome was the rate of in‐hospital mortality and secondary outcomes included 30‐day re‐admission rate and length of hospital stay (in days). Results: A total of 167,292 admissions from 94,617 patients were included. The overall in‐hospital mortality rate was 6.3%. As the RDW value increased, the rate of in‐hospital mortality gradually increased from 2.7% for the lowest RDW category to 12.2% in the highest category (p‐trend <0.001). The overall 30‐day re‐admission rate after discharge was 12.5% and the rate of 30‐day re‐admission also increased with increasing RDW categories (7.4% in the lowest group vs. 15.8% in the highest group, p‐trend <0.001). Patients with the highest RDW values at admission stayed 1.5–2.0 times longer in the hospital than patients with lower RDW values who were admitted for the same causes. Conclusions: Greater variability of RBC size is significantly associated with worse prognosis in hospitalized elderly patients, indicating higher mortality, greater risk of early re‐admission, and longer hospital stay days. Risk stratification strategies for hospitalized elderly should include RDW value. [ABSTRACT FROM AUTHOR]

I Caring for the People of the Clouds: Aging and Dementia in Oaxaca i beautifully renders the caregiving practices of Zapotec-speaking families living with a relative afflicted with Alzheimer's disease, dementia or stroke. Set in Teotitlán del Valle, a world-renowned textile-weaving community twenty miles from Oaxaca City, Yahalom's field site selection was astute: Teotitlán is at once strongly indigenous yet closely linked to the globalized world. [Extracted from the article]

Background: Fatigue is prevalent and distressing among cancer survivors, but its subjective nature makes it difficult to identify. Fatigability, defined as task-specific fatigue, and endurance performance may be useful supplemental measures of functional status in cancer survivors.Methods: Fatigability, endurance performance, and cancer history were assessed every 2 years in Baltimore Longitudinal Study of Aging participants between 2007 and 2015. Fatigability was defined according to the Borg rating of perceived exertion scale after a 5-minute, slow treadmill walk; and endurance performance was calculated according to the ability and time to complete a fast-paced, 400-meter walk. The association between cancer history, fatigability, and endurance performance was evaluated using longitudinal analyses adjusted for age, sex, body mass index, and comorbidities.Results: Of 1665 participants, 334 (20%) reported a history of cancer. A combination of older age (>65 years) and a history of cancer was associated with 3.8 and 8.6 greater odds of high perceived fatigability and poor endurance, respectively (P < .01). Older adults with and without a history of cancer walked 42 and 23 seconds slower than younger adults without a history of cancer, respectively (P < .01). The median times to the development of high fatigability and poor endurance were shorter among those who had a history of cancer compared with those who had no history of cancer (P < .01).Conclusions: The current findings suggest that a history of cancer is associated with fatigability and poor endurance and that this effect is significantly greater in older adults. Evaluating the effects of cancer and age on fatigability may illuminate potential pathways and targets for future interventions. Cancer 2018;124:1279-87. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase (BTK) plays a key role in B cell receptor signaling and is considered a promising drug target for lymphoma and inflammatory diseases. We have determined the X-ray crystal structures of BTK kinase domain in complex with six inhibitors from distinct chemical classes. Five different BTK protein conformations are stabilized by the bound inhibitors, providing insights into the structural flexibility of the Gly-rich loop, helix C, the DFG sequence, and activation loop. The conformational changes occur independent of activation loop phosphorylation and do not correlate with the structurally unchanged WEI motif in the Src homology 2-kinase domain linker. Two novel activation loop conformations and an atypical DFG conformation are observed representing unique inactive states of BTK. Two regions within the activation loop are shown to structurally transform between 3- and α-helices, one of which collapses into the adenosine-5′-triphosphate binding pocket. The first crystal structure of a Tec kinase family member in the pharmacologically important DFG-out conformation and bound to a type II kinase inhibitor is described. The different protein conformations observed provide insights into the structural flexibility of BTK, the molecular basis of its regulation, and the structure-based design of specific inhibitors. PDB Code(s): , , , , , [ABSTRACT FROM AUTHOR]

OBJECTIVES: To investigate the effects of testosterone supplementation on bone, body composition, muscle, physical function, and safety in older men. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: A major medical institution. PARTICIPANTS: One hundred thirty-one men (mean age 77.1 ± 7.6) with low testosterone, history of fracture, or bone mineral density (BMD) T-score less than −2.0 and frailty. INTERVENTION: Participants received 5 mg/d of testosterone or placebo for 12 to 24 months; all received calcium (1500 mg/d diet and supplement) and cholecalciferol (1,000 IU/d). MEASUREMENTS: BMD of hip, lumbar spine, and mid-radius; body composition; sex hormones, calcium-regulating hormones; bone turnover markers; strength; physical performance; and safety parameters. RESULTS: Ninety-nine men (75.6%) completed 12 months, and 62 (47.3%) completed end therapy (mean 23 months; range 16–24 months for 62 who completed therapy). Study adherence was 54%, with 40% of subjects maintaining 70% or greater adherence. Testosterone and bioavailable testosterone levels at 12 months were 583 ng/dL and 157 ng/dL, respectively, in the treatment group. BMD on testosterone increased 1.4% at the femoral neck and 3.2% at the lumbar spine ( P=.005) and decreased 1.3% at the mid-radius ( P<.001). There was an increase in lean mass and a decrease in fat mass in the testosterone group but no differences in strength or physical performance. There were no differences in safety parameters. CONCLUSION: Older, frail men receiving testosterone replacement increased testosterone levels and had favorable changes in body composition, modest changes in axial BMD, and no substantial changes in physical function. [ABSTRACT FROM AUTHOR]

The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan ≥ 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (lifespan ≤ 79y, mean = 75.7 ± 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68–0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15–1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan. [ABSTRACT FROM AUTHOR]

Spleen tyrosine kinase is considered an attractive drug target for the treatment of allergic and antibody mediated autoimmune diseases. We have determined the co-crystal structures of spleen tyrosine kinase complexed with three known inhibitors: YM193306, a 7-azaindole derivative and R406. The cis-cyclohexyldiamino moiety of YM193306 is forming four hydrophobically shielded polar interactions with the spleen tyrosine kinase protein and is therefore crucial for the high potency of this inhibitor. Its primary amino group is inducing a conformational change of the spleen tyrosine kinase DFG Asp side chain. The crystal structure of the 7-azaindole derivative bound to spleen tyrosine kinase is the first demonstration of a 2-substituted 7-azaindole bound to a protein kinase. Its indole-amide substituent is tightly packed between the N- and C-terminal kinase lobes. The co-crystal structure of the spleen tyrosine kinase–R406 complex shows two main differences to the previously reported structure of spleen tyrosine kinase soaked with R406: (i) the side chain of the highly conserved Lys is disordered and not forming a hydrogen bond to R406 and (ii) the DFG Asp side chain is pointing away from and not towards R406. The novel protein–ligand interactions and protein conformational changes revealed in these structures guide the rational design and structure-based optimization of second-generation spleen tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Objectives. To determine whether older women with abdominal aortic calcification had a greater cardiovascular and all-cause mortality, as such data are limited in older adults. Design. Prospective cohort study with a mean follow-up of 13 years Setting. Community-based sample with four US clinical centres. Subjects. A total of 2056 women aged ≥65 years with abdominal aortic calcification assessed on baseline radiographs. Main outcome measure. Mortality rate (all, cardiovascular, cancer or other cause) adjudicated from death certificates and hospital records. Results. The prevalence of abdominal aortic calcification increased with age, ranging from 60% at age 65–69 years to 96% at 85 years and older. Participants with aortic calcification were more likely to die during follow-up of any cause (47% vs. 27%) or a cardiovascular-specific cause (18% vs. 11%, both P < 0.001) than those without aortic calcification. In age-adjusted analyses, aortic calcification was associated with a greater rate of all-cause and cause-specific mortality (cardiovascular, cancer, and other, all P ≤ 0.01). In analyses adjusted for age and cardiovascular risk factors, aortic calcification was associated with an increased rate of all-cause mortality (HR: 1.37, 95% CI: 1.15–1.64), and noncardiovascular noncancer mortality (HR: 1.57, 95% CI: 1.17–2.11). The associations between aortic calcification and cancer mortality (HR: 1.44, 95% CI: 1.00–2.08) or cardiovascular mortality (HR: 1.18, 95% CI: 0.88–1.57) showed a similar pattern without reaching statistical significance, but was slightly stronger for mortality from coronary heart disease (HR: 1.53, 95% CI: 0.91–2.56). Conclusions. Abdominal aortic calcification in older women is associated with increased mortality. Future research should examine potential mechanisms for this association. [ABSTRACT FROM AUTHOR]

Presents a study which identified perceived deterrents to contraceptive use among chronically homeless women. Most common deterrents to contraceptive use; Results; Discussion.

The reported data on the association of kidney and urinary tract malformations with supernumerary nipples are contradictory. We examined 200 children, ages 1 month-16 years, who were being followed because of recurrent urinary tract infection for supernumerary nipples. The patients were divided into two groups: those who were found to have urinary tract malformations on radiographic studies (n = 92) and those who were not (n = 108). All children were examined for any abnormal pigmentation along the milk line, and the entire body was examined for ectopic supernumerary nipples. Two of the children with proved urinary tract pathology and two of the children with no urinary tract pathology had supernumerary nipples. The odds ratio for having supernumerary nipples among the first group was 1.18 (95% Cl: 0.084-16.53, p = 0.627). Our results indicate no association between kidney and urinary tract malformations and supernumerary nipples. We believe the message to the practicing physician is that there is no need for radiographic or ultrasonographic investigation of the urinary tract in asymptomatic children found to have supernumerary nipples on routine physical examination. [ABSTRACT FROM AUTHOR]

Offers examples of structural contexts in which either women or men had the power to influence key aspects of women's reproductive activities. Clandestine abortion decisions in Cali, Colombia; Conjugal and reproductive dynamics in an indigenous Mexican village; Fetal diagnosis for high-risk Mexican babies in the United States.

There has been relatively little research on men's experiences with fetal diagnosis or their role in their female partners' decisions about whether to be tested. This issue may be of particular salience in the delivery of genetic services to Latino groups, where it is often assumed that lower rates of genetic service utilization are linked to men's refusal to allow their wives to be tested. Here we present data from a multimethod study on the use of amniocentesis by Mexican-origin women in Southern California. We focus on the role male partners played in the women's amniocentesis decisions. Contrary to expectation, we found that women made the majority of the decisions about amniocentesis, although their partners'presence at the genetic consultation where the amniocentesis was offered proved an important predictive factor in amniocentesis uptake. [ABSTRACT FROM AUTHOR]

This influence of prolonged isolation in an extreme environment on depressive symptoms, personality, and coping resources was examined in 121 members of the United States Antarctic Program in 1988-1989. Subjects were followed for a 1-year period in Antarctica. Winter-over personnel experienced an increase in depressive symptoms, avoidance as a coping method, and emotional discharge as a coping resource from baseline (T0) to Year-1 (T1). At T0, education, negative life events, job-related stress, low self-confidence, active cognitive and behavioral coping methods, and low satisfaction with social support were independent predictors of depressive symptoms. At T1, negative life events, low self-confidence, active behavioral and avoidance coping methods, affective regulation as a coping resource, and low satisfaction with social support were independent predictors of depressive symptoms. However, with the exception of T0 depressive symptoms, none of the social and demographic characteristics and T0 psychosocial measures predicted T1 depressive symptoms. The results of this study support the hypothesis that coping may be more strongly associated with environmental conditions that influence severity of stressor and availability of coping resources than with more remote and stable background factors. [ABSTRACT FROM AUTHOR]

Focuses on the requirement of informed consent for prenatal testing in the United States. Distinct types of prenatal tests; Alpha-fetoprotein as marker for health problems; Informed consent in theory and practice; Consent and maternal serun alpha-fetoprotein (MASFP) testing; Underlying assumption of the consumers' right and bioethical view of informed consent.

The results are reported of a replication and extension of the study by Brownell [1985], which focused on the effects of environmental complexity and dynamism on the use of accounting-based controls in the U.S. parent company of a large multi-national organization. The study reported here examines the Australian subsidiary of the company, and its results confirm previous findings, indicating that both job satisfaction and performance are enhanced in circumstances where heavy reliance on accounting-based controls is confined to situations of low environmental complexity. The results also indicate that non-accounting, "behavior" controls have a role in the foreign subsidiary but take on a form other than the placement of U.S. nationals in senior management positions in the subsidiary. Differences in the environment faced by the parent and subsidiary also produced predicted differences in reliance on accounting measures in performance evaluation. [ABSTRACT FROM AUTHOR]

Patients with Rasmussen encephalitis (RE) may develop a variety of involuntary movements. We report a 26-year-old woman who presented with a 3-year history of progressive, continuous myoclonus of the left side of the face and left arm as well as left spastic hemiparesis. Magnetic resonance imaging of the brain showed right hemisphere and basal ganglia atrophy, and 24-hour electroencephalogram demonstrated diffuse slowing with random sharp waves in both hemispheres. An 18-fluoro-deoxy-glucose positron emission tomography scan indicated hypometabolism of the right cerebral hemisphere, including basal ganglia and thalamus. We successfully treated her myoclonus with injections of botulinum toxin A into the left zygomaticus muscle. © 2006 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Presents a letter to the editor in response to the article "Conscientious Autonomy: Displacing Decisions in Health Care," by Rebecca Kukla, in the March-April 2005 issue of "Hastings Center Report."