Degree for weakly upper semicontinuous perturbations of quasi-m-accretive operators.

In the paper, we provide the construction of a coincidence degree being a homotopy invariant detecting the existence of solutions of equations or inclusions of the form Ax ∈ F(x), x ∈ U, where [Formula: see text] is an m-accretive operator in a Banach space E, [Formula: see text] is a weakly upper semicontinuous set-valued map constrained to an open subset U of a closed set K ⊂ E. Two different approaches are presented. The theory is applied to show the existence of non-trivial positive solutions of some nonlinear second-order partial differential equations with discontinuities. This article is part of the theme issue 'Topological degree and fixed point theories in differential and difference equations'.

The OPTIMIZE patient- and family-centered, primary care-based deprescribing intervention for older adults with dementia or mild cognitive impairment and multiple chronic conditions: study protocol for a pragmatic cluster randomized controlled trial.

BACKGROUND: Most individuals with dementia or mild cognitive impairment (MCI) have multiple chronic conditions (MCC). The combination leads to multiple medications and complex medication regimens and is associated with increased risk for significant treatment burden, adverse drug events, cognitive changes, hospitalization, and mortality. Optimizing medications through deprescribing (the process of reducing or stopping the use of inappropriate medications or medications unlikely to be beneficial) may improve outcomes for MCC patients with dementia or MCI. METHODS: With input from patients, family members, and clinicians, we developed and piloted a patient-centered, pragmatic intervention (OPTIMIZE) to educate and activate patients, family members, and primary care clinicians about deprescribing as part of optimal medication management for older adults with dementia or MCI and MCC. The clinic-based intervention targets patients on 5 or more medications, their family members, and their primary care clinicians using a pragmatic, cluster-randomized design at Kaiser Permanente Colorado. The intervention has two components: a patient/ family component focused on education and activation about the potential value of deprescribing, and a clinician component focused on increasing clinician awareness about options and processes for deprescribing. Primary outcomes are total number of chronic medications and total number of potentially inappropriate medications (PIMs). We estimate that approximately 2400 patients across 9 clinics will receive the intervention. A comparable number of patients from 9 other clinics will serve as wait-list controls. We have > 80% power to detect an average decrease of - 0.70 (< 1 medication). Secondary outcomes include the number of PIM starts, dose reductions for selected PIMs (benzodiazepines, opiates, and antipsychotics), rates of adverse drug events (falls, hemorrhagic events, and hypoglycemic events), ability to perform activities of daily living, and skilled nursing facility, hospital, and emergency department admissions. DISCUSSION: The OPTIMIZE trial will examine whether a primary care-based, patient- and family-centered intervention educating patients, family members, and clinicians about deprescribing reduces numbers of chronic medications and PIMs for older adults with dementia or MCI and MCC. TRIAL REGISTRATION: NCT03984396. Registered on 13 June 2019.

Expression III: patients' expectations and preferences regarding physician-patient relationship and clinical management-results of the international NOGGO/ENGOT-ov4-GCIG study in 1830 ovarian cancer patients from European countries.

Backround: The primary aim of this study was to investigate information needs and treatment preferences of patients with ovarian cancer, focusing especially on physician-patient relationship and treatment. Patients and methods: A questionnaire was developed based on the experiences of the national German survey 'Expression II', and was provided to patients with ovarian cancer either at initial diagnosis or with recurrent disease via Internet (online-version) or as print-out-version. Results: From December 2009 to October 2012, a total of 1830 patients with ovarian cancer from eight European countries (Austria, Belgium, France, Germany, Italy, Poland, Romania, Spain) participated, 902 (49.3%) after initial diagnosis and 731 (39.9%) with recurrent ovarian cancer. The median age was 58 years (range 17-89). Nearly all patients (96.2%) had experienced upfront surgery followed by first-line chemotherapy (91.8%). The majority of patients were satisfied with the completeness and comprehensibility of the explanation about the diagnosis and treatment options. The three most important aspects, identified by patients to improve the treatment for ovarian cancer included: 'the therapy should not induce alopecia' (42%), 'there must be more done to counter fatigue' (34.5%) and 'the therapy should be more effective' (29.7%). Out of 659 (36%) patients, who were offered participation in a clinical trial, 476 (26%) were included. Conclusion: This study underlines the high need of patients with ovarian cancer for all details concerning treatment options irrespective of their cultural background, the stage of disease and the patient's age. Increased information requirements regarding potential side effects and treatment alternatives were recorded. Besides the need for more effective therapy, alopecia and fatigue are the most important side effects of concern to patients.

[Metameric macular and papular skin mastocytosis]. / Mastocytose cutanée maculopapuleuse métamérique.

BACKGROUND: Mastocytosis is characterised by the presence of abnormal quantities of mastocytes in one or more organs. Although it occurs in systemic forms of mastocytosis, isolated skin involvement is the predominant presentation, particularly in children, in the form of more or less extensive though non-systematic lesions. Herein, we report a case of maculopapular cutaneous mastocytosis that is unusual in terms of its metameric topography. PATIENTS AND METHODS: A 16-year-old youth presented with an erythematous maculopapular rash of 18 months' duration and involving pruritic inflammatory episodes strictly localised in segment T8 to the left. The skin biopsy showed a significant increase in the number of dermal mastocytes (CD117+). No KIT mutations were found in the skin lesions nor in the unimpaired skin of the opposite side. Further investigations ruled out systemic mastocytis. DISCUSSION: Herein, we report a case of cutaneous mastocytosis that is unusual in terms of its metameric disposition. There have been only two previous reports of segmental cutaneous mastocytis. The two pathological hypotheses involved precessional dermatitis that renders the skin surface susceptible to homing, and somatic mosaicism (type 1) with local mastocyte proliferation.

Recruitment and Retention for a Weight Loss Maintenance Trial Involving Weight Loss Prior to Randomization.

OBJECTIVE: A weight loss maintenance trial involving weight loss prior to randomization is challenging to implement due to the potential for dropout and insufficient weight loss. We examined rates and correlates of non-initiation, dropout, and insufficient weight loss during a weight loss maintenance trial. METHODS: The MAINTAIN trial involved a 16-week weight loss program followed by randomization among participants losing at least 4 kg. Psychosocial measures were administered during a screening visit. Weight was obtained at the first group session and 16 weeks later to determine eligibility for randomization. RESULTS: Of 573 patients who screened as eligible, 69 failed to initiate the weight loss program. In adjusted analyses, failure to initiate was associated with lower age, lack of a support person, and less encouragement for making dietary changes. Among participants who initiated, 200 dropped out, 82 lost insufficient weight, and 222 lost sufficient weight for randomization. Compared to losing sufficient weight, dropping out was associated with younger age and tobacco use, whereas losing insufficient weight was associated with non-White race and controlled motivation for physical activity. CONCLUSIONS: Studies should be conducted to evaluate strategies to maximize recruitment and retention of subgroups that are less likely to initiate and be retained in weight loss maintenance trials.

The role of peroxisome-proliferator-activating receptor gamma agonists: rosiglitazone and 15-deoxy-delta12,14-prostaglandin J2 in chronic experimental cyclosporine A-induced nephrotoxicity.

Cyclosporine A(CsA) is an immunosuppressor frequently used in the transplant surgery and in the treatment of autoimmune diseases. The therapeutic benefits of CsA are often limited by it's main side effect-nephrotoxicity. Mechanisms of chronic CsA- induced renal damage include: activation of renin-angiotensin-aldosterone system, upregulation of transforming growth factor beta (TGF-ß), oxidative stress. This study was undertaken to investigate the protective effect of the peroxisome-proliferator-activated receptors gamma (PPARs-γ) agonists: rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (PGDJ2), against CsA-induced kidney injury in male Wistar rats. CsA was administered subcutaneously at a dose of 15 mg/kg/day for 28 days. Both PPAR-γ agonists were given for 28 days 0.5 hour before the administration of CsA. Rosiglitazone was administered orally at a dose of 8 mg/kg/day and PGDJ2 was given intraperitoneally at a dose of 30 µg/kg/day. CsA induced renal failure was evidenced by increased serum levels of urea, uric acid and creatinine. Serum concentrations of GSH and GSSG, lipid peroxidation products as well as NAD+/NADH, NADP+/NADPH and ADP/ATP ratios showed, that CsA induced oxidative stress and evoked an imbalanced red-ox state in the kidney. Light and electron microscope studies showed degenerative changes within renal tubules with damage to their mitochondria, interstitial fibrosis and arteriolopathy. Immunohistochemical expression of profibrotic TGF-ß was assessed. The biochemical and morphological changes induced by CsA were limited by administration of both rosiglitazone and PGDJ2. Ultrastructural examination of renal tubular epithelial cells showed marked improvement within mitochondria. Our results indicate that both PPAR-γ agonists used in the experiment may play an important role in protecting against CsA-induced damage in the kidney.

Impact of morbid obesity on medical expenditures in adults.

CONTEXT: Morbid obesity (body mass index (BMI) > or =40 kg/m2) is associated with substantially increased morbidity and mortality from chronic health conditions and with poorer health-related quality of life; however, less is known about the impact of morbid obesity on healthcare expenditures. OBJECTIVE: To examine the impact of morbid obesity on healthcare expenditures using a nationally representative sample of US adults. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional analysis of 16 262 adults from the 2000 Medical Expenditure Panel Survey, a nationally representative survey of the noninstitutionalized civilian population of the United States. Per capita healthcare expenditures were calculated for National Institutes of Health BMI categories, based on self-reported height and weight, using a two-part, multivariable model adjusted for age, gender, race, income, education level, type of health insurance, marital status, and smoking status. MAIN OUTCOME MEASURES: Odds of incurring any healthcare expenditure and per capita healthcare expenditures associated with morbid obesity in 2000. RESULTS: When compared with normal-weight adults, the odds of incurring any healthcare expenditure in 2000 were two-fold greater among adults with morbid obesity. Per capita healthcare expenditures for morbidly obese adults were 81% (95% confidence interval (CI): 48-121%) greater than normal-weight adults, 65% (95% CI: 37-110%) greater than overweight adults, and 47% (95% CI: 11-96%) greater than adults with class I obesity. Excess costs among morbidly obese adults resulted from greater expenditures for office-based visits, outpatient hospital care, in-patient care, and prescription drugs. Aggregate US healthcare expenditures associated with excess body weight among morbidly obese US adults exceeded $11 billion in 2000. CONCLUSIONS: The economic burden of morbid obesity among US adults is substantial. Further research is needed to identify interventions to reduce the incidence and prevalence of morbid obesity and improve the health and economic outcomes of morbidly obese adults.

Structural studies of the putative helix 8 in the human beta(2) adrenergic receptor: an NMR study.

The recently reported crystal structure of bovine rhodopsin revealed a cytoplasmic helix (helix 8) in addition to the seven transmembrane helices. This domain is roughly perpendicular to the transmembrane bundle in the presence of an interface and may be a loop-like structure in the absence of an interface. Several studies carried out on this domain suggested that it might act as a conformational switch between the inactive and activated states of this G-protein coupled receptor (GPCR). These results raised the question whether helix 8 may be an important feature of other GPCRs as well. To explore this question, we determined the structure of a peptide representing the putative helix 8 domain in another receptor that belongs to the rhodopsin family of GPCRs, the human beta(2) adrenergic receptor (hbeta(2)AR), using two-dimensional (1)H nuclear magnetic resonance (NMR). The key results from this structural study are that the putative helix 8 domain is helical in detergent and in DMSO while in water this region is disordered; the conformation is therefore dependent upon the environment. Comparison of data from five GPCRs suggests that these observations may be generally important for GPCR structure and function.

Solution structure of a viral DNA repair polymerase.

DNA polymerase X (Pol X) from the African swine fever virus (ASFV) specifically binds intermediates in the single-nucleotide base-excision repair process, an activity indicative of repair function. In addition, Pol X catalyzes DNA polymerization with low nucleotide-insertion fidelity. The structural mechanisms by which DNA polymerases confer high or low fidelity in DNA polymerization remain to be elucidated. The three-dimensional structure of Pol X has been determined. Unlike other DNA polymerases, Pol X is formed from only a palm and a C-terminal subdomain. Pol X has a novel palm subdomain fold, containing a positively charged helix at the DNA binding surface. Purine deoxynucleoside triphosphate (dNTP) substrates bind between the palm and C-terminal subdomain, at a dNTP-binding helix, and induce a unique conformation in Pol X. The purine dNTP-bound conformation and high binding affinity for dGTP-Mg(2+) of Pol X may contribute to its low fidelity.

Solution structure of the catalytic domain of gammadelta resolvase. Implications for the mechanism of catalysis.

The site-specific DNA recombinase, gammadelta resolvase, from Escherichia coli catalyzes recombination of res site-containing plasmid DNA to two catenated circular DNA products. The catalytic domain (residues 1-105), lacking a C-terminal dimerization interface, has been constructed and the NMR solution structure of the monomer determined. The RMSD of the NMR conformers for residues 2-92 excluding residues 37-45 and 64-73 is 0.41 A for backbone atoms and 0.88 A for all heavy atoms. The NMR solution structure of the monomeric catalytic domain (residues 1-105) was found to be formed by a four-stranded parallel beta-sheet surrounded by three helices. The catalytic domain (residues 1-105), deficient in the C-terminal dimerization domain, was monomeric at high salt concentration, but displayed unexpected dimerization at lower ionic strength. The unique solution dimerization interface at low ionic strength was mapped by NMR. With respect to previous crystal structures of the dimeric catalytic domain (residues 1-140), differences in the average conformation of active-site residues were found at loop 1 containing the catalytic S10 nucleophile, the beta1 strand containing R8, and at loop 3 containing D67, R68 and R71, which are required for catalysis. The active-site loops display high-frequency and conformational backbone dynamics and are less well defined than the secondary structures. In the solution structure, the D67 side-chain is proximal to the S10 side-chain making the D67 carboxylate group a candidate for activation of S10 through general base catalysis. Four conserved Arg residues can function in the activation of the phosphodiester for nucleophilic attack by the S10 hydroxyl group. A mechanism for covalent catalysis by this class of recombinases is proposed that may be related to dimer interface dissociation.

Disenrollment from Medicare HMOs.

BACKGROUND: Since the program's inception, there has been great interest in determining whether beneficiaries who enter and subsequently leave Medicare health maintenance organizations (HMOs) are more or less costly than those remaining in fee-for-service (FFS) Medicare. OBJECTIVES: To examine whether relatively high-cost beneficiaries disenroll from Medicare HMOs (disenrollment bias) and whether disenrollment bias varies by Medicare HMO market characteristics. In addition, we compare rates of surgical procedures and hospitalizations for ambulatory care-sensitive conditions for disenrollees and continuing FFS beneficiaries. DESIGN: Cross-sectional analysis of 1994 Medicare data. PARTICIPANTS AND METHODS: Medicare beneficiaries were first sampled from the 124 counties with at least 1000 Medicare HMO enrollees. From this pool, HMO disenrollees and a sample of continuing FFS beneficiaries were drawn. The FFS beneficiaries were assigned dates of "pseudodisenrollment." Expenditures and inpatient service use were compared for 6 months after disenrollment or pseudodisenrollment. RESULTS: The HMO disenrollees were no more likely than the continuing FFS beneficiaries to have positive total expenditures (Part A plus Part B) or Part B expenditures in the first 6 months after disenrollment. However, disenrollees were more likely to have Part A expenditures. Among beneficiaries with spending, disenrollees had higher total and Part B expenditures than continuing FFS beneficiaries. Moreover, the disparity in total and Part B spending between disenrollees and continuing FFS beneficiaries increased with HMO market penetration. Although Part A spending was higher for disenrollees with spending, it was not sensitive to changes in market share. The HMO disenrollees received more surgical procedures and were hospitalized for more of the ambulatory care-sensitive conditions than the FFS beneficiaries. CONCLUSIONS: On several measures, Medicare HMOs experienced favorable disenrollment relative to continuing FFS beneficiaries as recently as 1994, which increased as HMO market share increased.

Comparing mortality and time until death for medicare HMO and FFS beneficiaries.

OBJECTIVE: To compare adjusted mortality rates of TEFRA-risk HMO enrollees and disenrollees with rates of beneficiaries enrolled in the Medicare fee-for-service sector (FFS), and to compare the time until death for decedents in these three groups. DATA SOURCE: Data are from the 124 counties with the largest TEFRA-risk HMO enrollment using 1993-1994 Medicare Denominator files for beneficiaries enrolled in the FFS and TEFRA-risk HMO sectors. STUDY DESIGN: A retrospective study that tracks the mortality rates and time until death of a random sample of 1,240,120 Medicare beneficiaries in the FFS sector and 1,526,502 enrollees in HMOs between April 1, 1993 and April 1, 1994. A total of 58,201 beneficiaries switched from an HMO to the FFS sector and were analyzed separately. PRINCIPAL FINDINGS: HMO enrollees have lower relative odds of mortality than a comparable group of FFS beneficiaries. Conversely, HMO disenrollees have higher relative odds of mortality than comparable FFS beneficiaries. Among decedents in the three groups, HMO enrollees lived longer than FFS beneficiaries, who in turn lived longer than HMO disenrollees. CONCLUSIONS: Medicare TEFRA-risk HMO enrollees appear to be, on average, healthier than beneficiaries enrolled in the FFS sector, who appear to be in turn healthier than HMO disenrollees. These health status differences persist, even after controlling for beneficiary demographics and county-level variables that might confound the relationship between mortality and the insurance sector.

A demand-side view of risk adjustment.

This paper analyzes the efficient allocation of consumers to health plans. Specifically, we address the question of why employers that offer multiple health plans often make larger contributions to the premiums of the high-cost plans. Our perspective is that the subsidy for high-cost plans represents a form of demand-side risk adjustment that improves efficiency. Without such subsidies (and in the absence of formal risk adjustment), too few employees would choose the high-cost plans preferred by high-risk workers. We test the theory by estimating a model of the employer premium subsidy, using data from a survey of large public employers in 1994. Our empirical analysis shows that employers are more likely to subsidize high-cost plans when the benefits of risk adjustment are greater. The findings suggest that the premium subsidy can accomplish some of the benefits of formal risk adjustment.

[Side effects during dobutamine stress echocardiography in patients with aortic stenosis]. / Bezpieczenstwo echokardiograficznego testu obciazeniowego z dobutamina zastosowanego u chorych ze zwezeniem zastawki aortalnej.

The purpose of the study was to assess the safety of the dobutamine stress echocardiography (DASE) in patients with aortic stenosis (AS). 161 patients (mean age 59 +/- 13 years) with AS were prospectively studied with DASE. There were 58 female and 103 male. Dobutamine was given in stepwise increasing doses from 5 to 40 ug/kg/min. Mean maximal dose achieved was 31.4 ug/kg/min. The test was positive in 40 (24.8%) patients. Significant coronary artery disease was present in 60 (37.3%) patients. DASE resulted in significant increase in transvalvular mean gradient from 29.3 +/- 12.5 mmHg at rest to 46.3 +/- 19.3 mmHg at peak dose. There was no significant increase in valve area. There were no death, myocardial infarction or episodes of sustained ventricular tachycardia as a result of DASE. The test was terminated when following conditions were revealed: target heart rate (39.1%), left ventricular asynergy (25.5%), maximal established dose achieved (8.1%), side effects (27.3%). The most common side effects with the need of test cessation were arrhythmias (9.9%) and hypotension (9.9%). The most side effects were usually well tolerated without need of medical treatment. We conclude that DASE may be safely performed in patients with AS. Side effects are more common than in patients with coronary disease, but are usually well tolerated without need of medical treatment.

Structural basis for the topological specificity function of MinE.

Correct positioning of the division septum in Escherichia coli depends on the coordinated action of the MinC, MinD and MinE proteins. Topological specificity is conferred on the MinCD division inhibitor by MinE, which counters MinCD activity only in the vicinity of the preferred midcell division site. Here we report the structure of the homodimeric topological specificity domain of Escherichia coli MinE and show that it forms a novel alphabeta sandwich. Structure-directed mutagenesis of conserved surface residues has enabled us to identify a spatially restricted site on the surface of the protein that is critical for the topological specificity function of MinE.

Discovery and characterization of a family of insecticidal neurotoxins with a rare vicinal disulfide bridge.

We have isolated a family of insect-selective neurotoxins from the venom of the Australian funnel-web spider that appear to be good candidates for biopesticide engineering. These peptides, which we have named the Janus-faced atracotoxins (J-ACTXs), each contain 36 or 37 residues, with four disulfide bridges, and they show no homology to any sequences in the protein/DNA databases. The three-dimensional structure of one of these toxins reveals an extremely rare vicinal disulfide bridge that we demonstrate to be critical for insecticidal activity. We propose that J-ACTX comprises an ancestral protein fold that we refer to as the disulfide-directed beta-hairpin.

Solution structure of a dynein motor domain associated light chain.

Dyneins are molecular motors that translocate towards the minus ends of microtubules. In Chlamydomonas flagellar outer arm dynein, light chain 1 (LC1) associates with the nucleotide binding region within the gamma heavy chain motor domain and consists of a central leucine-rich repeat section that folds as a cylindrical right handed spiral formed from six beta-beta-alpha motifs. This central cylinder is flanked by terminal helical subdomains. The C-terminal helical domain juts out from the cylinder and is adjacent to a hydrophobic surface within the repeat region that is proposed to interact with the dynein heavy chain. The position of the C-terminal domain on LC1 and the unexpected structural similarity between LC1 and U2A' from the human spliceosome suggest that this domain interacts with the dynein motor domain.