Glacial cycles promote greater dispersal, which can help explain larger clutch sizes, in north temperate birds

Earth’s glacial history and patterns in the life history traits of the planet’s avifauna suggest the following interpretations of how recent geological history has affected these key characteristics of the biota: 1) Increased colonizing ability has been an important advantage of increased dispersal, and life history strategies are better categorized by dispersive colonizing ability than by their intrinsic growth rates; 2) Birds of the North Temperate Zone show a greater tendency to disperse, and they disperse farther, than tropical or south temperate birds; 3) Habitat changes associated with glacial advance and retreat selected for high dispersal ability, particularly in the North; and 4) Selection for greater dispersal throughout the unstable Pleistocene has also resulted in other well-recognized life history contrasts, especially larger clutch sizes in birds of North Temperate areas

Medicaid spending burden among beneficiaries with treatment-resistant depression.

AIM: To evaluate Medicaid spending and healthcare resource utilization (HRU) in treatment-resistant depression (TRD). MATERIALS & METHODS: TRD beneficiaries were identified from Medicaid claims databases (January 2010-March 2017) and matched 1:1 with major depressive disorder (MDD) beneficiaries without TRD (non-TRD-MDD) and randomly selected patients without MDD (non-MDD). Differences in HRU and per-patient-per-year costs were reported in incidence rate ratios (IRRs) and cost differences (CDs), respectively. RESULTS: TRD beneficiaries had higher HRU than 1:1 matched non-TRD-MDD (e.g., inpatient visits: IRR = 1.41) and non-MDD beneficiaries (N = 14,710 per cohort; e.g., inpatient visits: IRR = 3.42, p \u3c 0.01). TRD beneficiaries incurred greater costs versus non-TRD-MDD (CD = US$4382) and non-MDD beneficiaries (CD = US$8294; p \u3c 0.05). CONCLUSION: TRD is associated with higher HRU and costs versus non-TRD-MDD and non-MDD. TRD poses a significant burden to Medicaid

Missing data and chance variation in public reporting of cancer stage at diagnosis: Cross-sectional analysis of population-based data in England.

BACKGROUND: The percentage of cancer patients diagnosed at an early stage is reported publicly for geographically-defined populations corresponding to healthcare commissioning organisations in England, and linked to pay-for-performance targets. Given that stage is incompletely recorded, we investigated the extent to which this indicator reflects underlying organisational differences rather than differences in stage completeness and chance variation. METHODS: We used population-based data on patients diagnosed with one of ten cancer sites in 2013 (bladder, breast, colorectal, endometrial, lung, ovarian, prostate, renal, NHL, and melanoma). We assessed the degree of bias in CCG (Clinical Commissioning Group) indicators introduced by missing-is-late and complete-case specifications compared with an imputed 'gold standard'. We estimated the Spearman-Brown (organisation-level) reliability of the complete-case specification. We assessed probable misclassification rates against current pay-for-performance targets. RESULTS: Under the missing-is-late approach, bias in estimated CCG percentage of tumours diagnosed at an early stage ranged from -2 to -30 percentage points, while bias under the complete-case approach ranged from -2 to +7 percentage points. Using an annual reporting period, indicators based on the least biased complete-case approach would have poor reliability, misclassifying 27/209 (13%) CCGs against a pay-for-performance target in current use; only half (53%) of CCGs apparently exceeding the target would be correctly classified in terms of their underlying performance. CONCLUSIONS: Current public reporting schemes for cancer stage at diagnosis in England should use a complete-case specification (i.e. the number of staged cases forming the denominator) and be based on three-year reporting periods. Early stage indicators for the studied geographies should not be used in pay-for-performance schemes

Population based time trends and socioeconomic variation in use of radiotherapy and radical surgery for prostate cancer in a UK region: continuous survey

Objective To examine variation in the management of prostate cancer in patients with different socioeconomic status

Prospective role of cefiderocol in the management of carbapenem-resistant Acinetobacter baumannii infections: Review of the evidence

Carbapenem-resistant Acinetobacter baumannii (CRAB) has been classified by the World Health Organization as being in the critical category of pathogens requiring urgent new antibiotic treatment options. Cefiderocol, the first approved siderophore cephalosporin, was designed for the treatment of carbapenem-resistant Gram-negative pathogens, particularly the non-fermenting species A. baumannii and Pseudomonas aeruginosa. Cefiderocol is mostly stable against hydrolysis by serine β-lactamases and metallo-β-lactamases, which are leading causes of carbapenem resistance. This review collates the available evidence on the in vitro activity, pharmacokinetics/pharmacodynamics, and efficacy and safety of cefiderocol, and outlines its current role in the management of CRAB infections. In vitro surveillance data show susceptibility rates of \u3e90% for cefiderocol against CRAB isolates as well as in vitro synergism with a variety of antibiotics recommended in guidelines. Clinical efficacy of cefiderocol monotherapy against CRAB infections has been demonstrated in the descriptive, open-label CREDIBLE-CR and the non-inferiority, double-blind APEKS-NP randomised clinical trials as well as in real-world cases in patients with underlying health problems. To date, the frequency of on-therapy development of cefiderocol resistance in A. baumannii appears to be low, but monitoring is highly recommended. Within current treatment guidelines for moderate-to-severe CRAB infections, cefiderocol is recommended for infections in which other antibiotics failed and in combination with other active antibiotics. In vivo pre-clinical data support the combination of sulbactam or avibactam with cefiderocol to enhance efficacy and to suppress the emergence of cefiderocol resistance. The benefit of combination therapy in the clinical setting is yet to be determined in prospective studies

Markers of Inflammation in Bacterial Diarrhea among Travelers, with a Focus on Enteroaggregative Escherichia coli Pathogenicity

The intestinal inflammatory response of traveler's diarrhea acquired in Goa, India, and Guadalajara, Mexico, was studied. Fecal lactoferrin was found in stool samples in which enteroaggregative Escherichia coli (EAEC), enterotoxigenic E. coli, or Salmonella or Shigella species were isolated, with Shigella-positive cases showing the highest level. Samples from cases of Shigella-associated diarrhea had the highest concentrations of fecal cytokines. Travelers to India who had EAEC-associated diarrhea showed elevated levels of interleukin (IL)-8 (median, 341.15 pg/mL) and IL-1β (median, 749.90 pg/mL). Although 15 travelers to Mexico who had EAEC-associated diarrhea had a median concentration of 0 pg/mL for both IL-8 and IL-1β, 2 had high levels of IL-8 (1853 and 11,786 pg/mL), and 5 showed elevated levels of IL-1β (1-1240 pg/mL). Samples from patients in India who had pathogen-negative diarrhea or from patients in Mexico who had asymptomatic EAEC infection were negative for cytokines. Bacterial pathogens causing traveler's diarrhea commonly produce intestinal inflammation, although a subset of patients with EAEC-associated diarrhea fail to develop an inflammatory respons

Brain-Derived Neurotrophic Factor Expression and Respiratory Function Improve after Ampakine Treatment in a Mouse Model of Rett Syndrome

Rett syndrome (RTT) is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is thought to act as a transcriptional repressor of brain-derived neurotrophic factor (BDNF), Mecp2 null mice, which develop an RTT-like phenotype, exhibit progressive deficits in BDNF expression. These deficits are particularly significant in the brainstem and nodose cranial sensory ganglia (NGs), structures critical for cardiorespiratory homeostasis, and may be linked to the severe respiratory abnormalities characteristic of RTT. Therefore, the present study used Mecp2 null mice to further define the role of MeCP2 in regulation of BDNF expression and neural function, focusing on NG neurons and respiratory control. We find that mutant neurons express significantly lower levels of BDNF than wild-type cells in vitro, as in vivo, under both depolarizing and nondepolarizing conditions. However, BDNF levels in mutant NG cells can be increased by chronic depolarization in vitro or by treatment of Mecp2 null mice with CX546, an ampakine drug that facilitates activation of glutamatergic AMPA receptors. Ampakine-treated Mecp2 null mice also exhibit marked functional improvement, characterized by restoration of normal breathing frequency and minute volume. These data demonstrate that BDNF expression remains plastic in Mecp2 null mice and raise the possibility that ampakine compounds could be of therapeutic value in the treatment of RTT

Efficient massively parallel simulation of dynamic channel assignment schemes for wireless cellular communications

Fast, efficient parallel algorithms are presented for discrete event simulations of dynamic channel assignment schemes for wireless cellular communication networks. The driving events are call arrivals and departures, in continuous time, to cells geographically distributed across the service area. A dynamic channel assignment scheme decides which call arrivals to accept, and which channels to allocate to the accepted calls, attempting to minimize call blocking while ensuring co-channel interference is tolerably low. Specifically, the scheme ensures that the same channel is used concurrently at different cells only if the pairwise distances between those cells are sufficiently large. Much of the complexity of the system comes from ensuring this separation. The network is modeled as a system of interacting continuous time automata, each corresponding to a cell. To simulate the model, conservative methods are used; i.e., methods in which no errors occur in the course of the simulation and so no rollback or relaxation is needed. Implemented on a 16K processor MasPar MP-1, an elegant and simple technique provides speedups of about 15 times over an optimized serial simulation running on a high speed workstation. A drawback of this technique, typical of conservative methods, is that processor utilization is rather low. To overcome this, new methods were developed that exploit slackness in event dependencies over short intervals of time, thereby raising the utilization to above 50 percent and the speedup over the optimized serial code to about 120 times

17β-Estradiol dysregulates innate immune responses to Pseudomonas aeruginosa respiratory infection and is modulated by estrogen receptor antagonism

ABSTRACT Females have a more severe clinical course than males in terms of several inflammatory lung conditions. Notably, females with cystic fibrosis (CF) suffer worse outcomes, particularly in the setting of Pseudomonas aeruginosa infection. Sex hormones have been implicated in experimental and clinical studies; however, immune mechanisms responsible for this sex-based disparity are unknown and the specific sex hormone target for therapeutic manipulation has not been identified. The objective of this study was to assess mechanisms behind the impact of female sex hormones on host immune responses to P. aeruginosa . We used wild-type and CF mice, which we hormone manipulated, inoculated with P. aeruginosa , and then examined for outcomes and inflammatory responses. Neutrophils isolated from mice and human subjects were tested for responses to P. aeruginosa . We found that female mice inoculated with P. aeruginosa died earlier and showed slower bacterial clearance than males ( P &lt; 0.0001). Ovariectomized females supplemented with 17β-estradiol succumbed to P. aeruginosa challenge earlier than progesterone- or vehicle-supplemented mice ( P = 0.0003). 17β-Estradiol-treated ovariectomized female mice demonstrated increased lung levels of inflammatory cytokines, and when rendered neutropenic the mortality difference was abrogated. Neutrophils treated with 17β-estradiol demonstrated an enhanced oxidative burst but decreased P. aeruginosa killing and earlier cell necrosis. The estrogen receptor (ER) antagonist ICI 182,780 improved survival in female mice infected with P. aeruginosa and restored neutrophil function. We concluded that ER antagonism rescues estrogen-mediated neutrophil dysfunction and improves survival in response to P. aeruginosa . ER-mediated processes may explain the sex-based mortality gap in CF and other inflammatory lung illnesses, and the ER blockade represents a rational therapeutic strategy. </jats:p

Stage–specific incidence trends of renal cancers in the East of England, 1999–2016

Objectives: To determine stage-specific time-trends in renal cancer incidence. Methods: We used population-based East Anglia data 1999−2016 (population ∼2 million) on 5,456 primary renal cancer diagnoses, estimating stage-specific annual incidence using Poisson regression, allowing for changing time-trends, and adjusting for sex, age, and socioeconomic deprivation. Results: Renal cancer incidence increased from 9.8–16.4 cases per 100,000 during 1999−2016. Incidence of Stage I, II, and III cases increased over time, most steeply for Stage I, with annual Incidence Rate Ratio [IRR] for Stage I of 1.09 (95 % CI 1.07–1.12) during 1999−2010; and 1.03 (1.00–1.05) during 2011−2016. In contrast, the annual incidence of Stage IV renal cancer decreased during most years, IRR of 0.99 (0.98–1.00) during 2003−2016. Conclusion: The findings are consistent with both earlier detection of symptomatic renal cancer and increasing identification of asymptomatic lesions. However, the decreasing incidence of late-stage disease suggests genuine shifts towards earlier diagnosis