Topological entropy and blocking cost for geodesics in riemannian manifolds

For a pair of points $x,y$ in a compact, riemannian manifold $M$ let $n_t(x,y)$ (resp. $s_t(x,y)$) be the number of geodesic segments with length $\leq t$ joining these points (resp. the minimal number of point obstacles needed to block them). We study relationships between the growth rates of $n_t(x,y)$ and $s_t(x,y)$ as $t\to\infty$. We derive lower bounds on $s_t(x,y)$ in terms of the topological entropy $h(M)$ and its fundamental group. This strengthens the results of Burns-Gutkin \cite{BG06} and Lafont-Schmidt \cite{LS}. For instance, by \cite{BG06,LS}, $h(M)>0$ implies that $s$ is unbounded; we show that $s$ grows exponentially, with the rate at least $h(M)/2$.Comment: 13 page

Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders

The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors’ combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism–funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol

Disordered Structural Ensembles of Vasopressin and Oxytocin and Their Mutants

Vasopressin and oxytocin are intrinsically disordered cyclic nonapeptides belonging to a family of neurohypophysial hormones. Although unique in their functions, these peptides differ only by two residues and both feature a tocin ring formed by the disulfide bridge between first and sixth cysteine residues. This sequence and structural similarity are experimentally linked to oxytocin agonism at vasopressin receptors and vasopressin antagonism at oxytocin receptors. Yet single- or double-residue mutations in both peptides have been shown to have drastic impacts on their activities at either receptor, and possibly the ability to bind to their neurophysin carrier protein. In this study we perform molecular dynamics simulations of the unbound native and mutant sequences of the oxytocin and vasopressin hormones to characterize their structural ensembles. We classify the subpopulations of these structural ensembles on the basis of the distributions of radius of gyration and secondary structure and hydrogen-bonding features of the canonical tocin ring and disordered tail region. We then relate the structural changes observed in the unbound form of the different hormone sequences to experimental information about peptide receptor binding, and more indirectly, carrier protein binding affinity, receptor activity, and protease degradation. This study supports the hypothesis that the structural characteristics of the unbound form of an IDP can be used to predict structural or functional preferences of its functional bound form

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Progress towards a public chemogenomic set for protein kinases and a call for contributions

Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A longitudinal study of hospitalization rates for patients with chronic disease: results from the Medical Outcomes Study

OBJECTIVE: To prospectively compare inpatient and outpatient utilization rates between prepaid (PPD) and fee-for-service (FFS) insurance coverage for patients with chronic disease. DATA SOURCE/STUDY SETTING: Data from the Medical Outcomes Study, a longitudinal observational study of chronic disease patients conducted in Boston, Chicago, and Los Angeles. STUDY DESIGN: A four-year prospective study of resource utilization among 1,681 patients under treatment for hypertension, diabetes, myocardial infarction, or congestive heart failure in the practices of 367 clinicians. DATA COLLECTION/EXTRACTION METHODS: Insurance payment system (PPD or FFS), hospitalizations, and office visits were obtained from patient reports. Disease and severity indicators, sociodemographics, and self-reported functional status were used to adjust for patient mix and to compute expected utilization rates. PRINCIPAL FINDINGS: Compared to FFS, PPD patients had 31 percent fewer observed hospitalizations before adjustment for patient differences (p = .005) and 15 percent fewer hospitalizations than expected after adjustment (p = .078). The observed rate of FFS hospitalizations exceeded the expected rate by 9 percent. These results are not explained by system differences in patient mix or trends in hospital use over four years. Half of the PPD/FFS difference in hospitalization rate is due to intrinsic characteristics of the payment system itself. CONCLUSIONS: PPD patients with chronic medical conditions followed prospectively over four years, after extensive patient-mix adjustment, had 15 percent fewer hospitalizations than their FFS counterparts owing to differences intrinsic to the insurance reimbursement system

Differences in the mix of patients among medical specialties and systems of care. Results from the medical outcomes study

OBJECTIVE: To determine differences in the mix of patients among medical specialties and among organizational systems of care. STUDY DESIGN: Cross-sectional analysis of 20,158 adults (greater than or equal to 18 years of age) who visited providers\u27 offices during 9-day screening periods in 1986. Patient and physician information was obtained by self-administered, standardized questionnaires. SETTING: Offices of 349 physicians practicing family medicine, internal medicine, endocrinology, and cardiology within health maintenance organizations, large multispecialty groups, and solo or small single-specialty group practices in three major US cities. OUTCOME MEASURES: Demographic characteristics, prevalence of chronic disease, disease-specific severity of illness, and functional status and well-being. RESULTS: Among patients with selected physician-reported chronic illnesses (diabetes, hypertension, recent myocardial infarction, or congestive heart failure), increasing levels of severity were associated with decreasing levels of functional status and well-being and with increased hospitalizations, more physician visits, and higher numbers of prescription drugs. Compared with patients of general internists, patients of cardiologists were older (56 vs 47 years, P less than .01), had worse functional status and well-being scores (P less than .01), and carried more chronic diagnoses (mean 1.32 vs 1.02, P less than .01); patients of family practitioners were younger (40 vs 47 years, P less than .01) and more functional (P less than .01), carried fewer chronic diagnoses (0.70 vs 1.02, P less than .01), and (among diabetic patients only) had lower disease-specific severity scores (2.06 vs 2.30 on a five-point scale, P less than .01). Compared with patients in health maintenance organizations, patients visiting solo practitioners under fee-for-service payment were older (50 vs 45 years, P less than .01) and sicker (had worse physical functioning) and had a higher mean number of chronic diagnoses (1.10 vs 0.93, P less than .01). CONCLUSION: Patient mix is related to utilization and differs significantly across medical specialties and systems of care. These differences must be taken into account when interpreting variations in utilization and outcomes across specialties and systems, and when considering alternative policies for payment