Constraint on a varying proton-electron mass ratio 1.5 billion years after the big bang.

A molecular hydrogen absorber at a lookback time of 12.4 billion years, corresponding to 10% of the age of the Universe today, is analyzed to put a constraint on a varying proton-electron mass ratio, µ. A high resolution spectrum of the J1443+2724 quasar, which was observed with the Very Large Telescope, is used to create an accurate model of 89 Lyman and Werner band transitions whose relative frequencies are sensitive to µ, yielding a limit on the relative deviation from the current laboratory value of Δµ/µ=(-9.5 ± 5.4(stat)± 5.3(syst))×10(-6).

Thermal damage to the skin from 8.2 and 95 GHz microwave exposures in swine.

A study of burn thresholds from superficially penetrating radio-frequency (RF) energy at 8.2 and 95 GHz for swine skin was conducted. The study determined the thresholds for superficial, partial-thickness, and full-thickness burn severities after 5 seconds of exposure at power densities of 4-30 W/cm2and 2-15 W/cm2at 8.2 and 95 GHz, respectively. There were significant differences in he burn thresholds at the different severities between the two frequencies due to the large difference in energy penetration depths. Biopsies were collected from each burn site at 1, 24, 72, and 168 hr post exposure. Each sample was assessed by a burn pathologist against 20 histological factors to characterize the damage resulting from these RF overexposures. A one-dimensional, layered digital phantom that utilized realistic values for dielectric and thermal properties was used to explain some observed thresholds. The results of the heating and cooling response of the animal model and histology scores of each exposure are provided to enhance future efforts at simulation of RF overexposures and to establish damage thresholds.

Search for the rare decays K(L)→π0π0µ+µ- and K(L)→π0π0X0→π0π0µ+µ-.

The KTeV E799 experiment has conducted a search for the rare decays, K(L)→π(0)π(0)µ(+)µ(-) and K(L)→π(0)π(0)X(0)→π(0)π(0)µ(+)µ(-), where the X(0) is a possible new neutral boson that was reported by the HyperCP experiment with a mass of (214.3 ± 0.5) MeV/c(2). We find no evidence for either decay. We obtain upper limits of Br(K(L)→π(0)π(0)X(0)→π(0)π(0)µ(+)µ(-)) < 1.0 × 10(-10) and Br(K(L)→π(0)π(0)µ(+)µ(-)) < 9.2 × 10(-11) at the 90% confidence level. This result rules out the pseudoscalar X(0) as an explanation of the HyperCP result under the scenario that the dsX(0) coupling is completely real.

Flt3 ligand induces tumor regression and antitumor immune responses in vivo.

Daily treatment of mice with recombinant human Flt3 ligand (huFlt3L) results in a dramatic numerical increase in the number of dendritic cells (DCs) in vivo. Since DCs are pivotal in the induction of immune responses, we tested whether Flt3L treatment of mice challenged with a syngeneic methylcholanthrene (MCA)-induced fibrosarcoma would augment the generation of effective antitumor immune responses in vivo. Flt3L treatment not only induced complete tumor regression in a significant proportion of mice, but also decreased tumor growth rate in the remaining mice. A preliminary characterization of the cellular mechanisms involved suggests that Flt3L may be important in the treatment of cancer in situ through the generation of specific antitumor immune responses.

Molecular detection of carbapenem resistance genes in rectal swabs from patients in Gulf Cooperation Council hospitals.

BACKGROUND: Gram-negative organisms harbouring carbapenem resistance genes (CRGs) are spreading globally, including in Gulf Cooperation Council (GCC) countries. However, relatively few data are available about carriage of CRGs in hospitalized patients in this region. AIM: To determine prevalence of CRG carriage and risk factors for colonization among patients in GCC hospitals. METHODS: Rectal swabs were obtained from ∼50 intensive care unit (ICU) patients from each of 11 hospitals in five GCC countries between March and November 2019. The swabs were tested for the presence of blaKPC, blaNDM, blaVIM, blaIMP, and blaOXA-48 CRG using a commercial polymerase chain reaction test. Data on risk factors for colonization were collected and analysed. FINDINGS: Of 529 specimens screened, 138 (26.1%) were positive for one or more CRGs. The positivity rates among the hospitals ranged from 8.0% to 67.3%; ∼20% of the positive specimens harboured ≥2 CRGs. The most common CRG detected was blaOXA-48, which was present in 82 specimens (15.5%). Additional CRGs included blaNDM, blaVIM, blaKPC, and blaIMP either alone or in combination. Overall, 31.1% of patients on antibiotics on admission to the ICU were positive for CRGs compared to 16.5% not on antibiotic therapy (P < 0.001). CRG detection was also more common among patients aged >65 years (P = 0.027) and increased with hospital length of stay (P = 0.025). CONCLUSION: The rate of CRGs detected in hospitalized patients in GCC countries varied considerably. Prior antibiotic exposure, increasing age, and prolonged length of stay were associated with CRG detection.

Pediatric Pharmacists' Participation in Cardiopulmonary Resuscitation Events.

The Pediatric Pharmacy Advocacy Group (PPAG) understands the dilemma and varying factors that many institutions face concerning the routine participation of pharmacists in emergency resuscitation events. Acknowledging these obstacles, the PPAG encourages all institutions to strongly consider creating, adopting, and upholding policies to address pharmacists' participation in cardiopulmonary resuscitation (CPR) as evidenced by the impact pharmacist participation has shown on the reduction of hospital medication error and mortality rates in children. The PPAG advocates that pharmacists be actively involved in the institution's CPR, medical emergency team committees, and preparation of emergency drug kits and resuscitation trays. The PPAG advocates that all institutions requiring a pharmacist's participation in CPR events consider adoption of preparatory training programs. Although the PPAG does not advocate any one specific program, consideration should be taken to ensure that pharmacists are educated on the pharmacotherapy of drugs used in the CPR process, including but not limited to basic life support, Advanced Cardiac Life Support, and Pediatric Advanced Life Support algorithms; medication preparation and administration guidelines; medication compatibility; recommended dosing for emergency medications; and familiarity with the institutional emergency cart.

Measurements of the decay KL-->e+ e- gamma.

The E799-II (KTeV) experiment at Fermilab has collected 83 262 K(L)-->e+ e- gamma(gamma) events above a background of 79 events. We measure a decay width, normalized to the K(L)-->pi0pi0pi(D)0 (pi0-->gammagamma, pi0-->gammagamma, pi(D0-->e+ e- gamma(gamma)) decay width, of Gamma(K(L)-->e+e-gamma(gamma))/Gamma(K(L)-->pi0pi0pi(D)0)=(1.3302+/-0.0046(stat)+/-0.0102(syst)) x 10(-3). We also measure parameters of two K(L)gamma*gamma form factor models. In the Bergström-Massó-Singer parametrization, we find Calpha(K*)= -0.517 +/- 0.030(stat) +/- 0.022(syst). We separately fit for the first parameter of the D'Ambrosio-Isidori-Portolés model and find alpha(DIP)= -1.729 +/- 0.043(stat) +/- 0.028(syst).

Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure.

BACKGROUND: Previously, we showed that tumor necrosis factor (TNF) antagonism with etanercept, a soluble TNF receptor, was well tolerated and that it suppressed circulating levels of biologically active TNF for 14 days in patients with moderate heart failure. However, the effects of sustained TNF antagonism in heart failure are not known. METHODS AND RESULTS: We conducted a randomized, double-blind, placebo-controlled, multidose trial of etanercept in 47 patients with NYHA class III to IV heart failure. Patients were treated with biweekly subcutaneous injections of etanercept 5 mg/m(2) (n=16) or 12 mg/m(2) (n=15) or with placebo (n=16) for 3 months. Doses of 5 and 12 mg/m(2) etanercept were safe and well tolerated for 3 months. Treatment with etanercept led to a significant dose-dependent improvement in left ventricular (LV) ejection fraction and LV remodeling, and there was a trend toward an improvement in patient functional status, as determined by clinical composite score. CONCLUSION: Treatment with etanercept for 3 months was safe and well-tolerated in patients with advanced heart failure, and it resulted in a significant dose-dependent improvement in LV structure and function and a trend toward improvement in patient functional status.

Randomized, placebo-controlled, multicenter trial of granulocyte-macrophage colony-stimulating factor as infection prophylaxis in oncologic surgery. Leukine Surgical Prophylaxis Research Group.

PURPOSE: Postoperative infections are a frequent source of preventable morbidity and mortality in the oncologic population. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent modulator of immune effector cells in vitro and in vivo. This study was conducted to determine whether GM-CSF, when administered perioperatively, could reduce the incidence of surgical infections in cancer patients. METHODS: This was a prospective, randomized, placebo-controlled, multicenter study. Cancer patients at high risk of infectious surgical morbidity were randomized to receive GM-CSF 125 microg/m2 per day or placebo subcutaneously for 8 days beginning 3 days preoperatively. Routine antibiotic prophylaxis was administered to all patients. RESULTS: Three hundred ninety-nine patients were enrolled, with 198 randomized to receive GM-CSF. Twenty-one percent of patients experienced infections during the first 2 weeks postoperatively, and there was no difference in infection rate between the study groups. The most common sites of infection were respiratory tract (53%) and surgical wound (25%). The duration of operation and American Society of Anesthesiology (ASA) physical status classification were the most significant predictors of infection in multivariate analysis. GM-CSF was well tolerated and was not associated with fever. CONCLUSION: The eligibility criteria for this study were successful at defining a patient subgroup at high risk for postoperative infections. At an immunomodulatory dose of 125 microg/m2 per day, GM-CSF was safe and well tolerated, but did not reduce the incidence of postoperative infections in this high-risk oncologic population. Infectious morbidity in surgical oncology remains an important subject for continued clinical investigation.

Phase III study of granulocyte-macrophage colony-stimulating factor in advanced HIV disease: effect on infections, CD4 cell counts and HIV suppression. Leukine/HIV Study Group.

OBJECTIVE: To evaluate the effect of adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim, yeast-derived recombinant human GM-CSF) on incidence and time to opportunistic infection or death, plasma HIV-RNA, and CD4 cell count in patients with advanced HIV disease. METHODS: This Phase III randomized, double-blind, placebo-controlled trial enrolled subjects with CD4 cell counts < or = 50 x 10(6)/l or < or = 100 x 10(6)/l with a prior AIDS-defining illness on stable antiretroviral therapy. Subjects were stratified by baseline HIV-RNA level (> or = or < 30,000 copies/ml) and randomized to receive subcutaneous injections of GM-CSF 250 microg or placebo three times per week for 24 weeks. Subjects were permitted to continue on blinded drug for up to 20 months. Subjects were evaluated for infections, plasma HIV-RNA, lymphocyte counts, changes in antiretroviral therapy, toxicity, and survival. RESULTS: Three-hundred and nine subjects received at least one dose of study drug, 70% completed 24 weeks of therapy. Groups were well matched at baseline. Significant increases in CD4 cell and neutrophil counts were observed at 1, 3, and 6 months in the GM-CSF group. GM-CSF significantly reduced the incidence of overall infections (78% placebo versus 67% GM-CSF; P = 0.03) and delayed time to first infection (56 days placebo versus 97 days GM-CSF; P = 0.04). No statistical difference in cumulative opportunistic infections was observed between groups; however, among subjects without an opportunistic infection prior to study, the GM-CSF group demonstrated a trend towards fewer subjects with an opportunistic infection on study (26% placebo versus 8% GM-CSF; P = 0.08). Change in HIV-RNA was not significantly different between groups, but significantly fewer GM-CSF subjects with baseline viral load < 30,000 copies/ml had changes in antiretroviral therapy for increased viral load (42% placebo versus 21% GM-CSF; P = 0.01). In patients with HIV-RNA levels below the limit of detection at baseline, more GM-CSF patients maintained an undetectable viral load at 24 weeks (54% placebo versus 83% GM-CSF; P = 0.02). GM-CSF was well tolerated. CONCLUSIONS: GM-CSF significantly increased CD4 cell count and decreased virological breakthrough and overall infection rate in subjects with advanced HIV disease.

Reduction of unique noise in the psychophysics of hearing by Group Operating Characteristic analysis.

Group Operating Characteristic (GOC) analysis can be used to reduce the effects of unique noise on data from psychophysical experiments on hearing. Unique noise can come from physiological sources such as heartbeat and breathing and from other internal sources such as criterion variability, inattention, and faulty memory. The theory of GOC analysis is described and applied to the results of frequency discrimination experiments with human, pigeon, and simulated observers. The method yields relatively unattenuated measures of sensitivity, recovers Receiver Operating Characteristic curves from noisy choice data, and estimates the relative magnitudes of unique and common noise.

Pharmacological characterization of antagonists of the C5a receptor.

1. Potent and highly selective small molecule antagonists have recently been developed by us for C5a receptors (C5aR) on human polymorphonuclear leukocytes (PMN). In this study we compared a new cyclic antagonist, F-[OPdChaWR], with an acyclic derivative, MeFKPdChaWr, for their capacities to bind to C5aR on human PMN and human umbilical artery membranes. We also compared their inhibition of myeloperoxidase (MPO) secretion from human PMNs and their inhibition of human umbilical artery contraction induced by human recombinant C5a. 2. In both PMNs and umbilical artery, the cyclic and acyclic C5a antagonists displayed insurmountable antagonism against C5a. There were differences in selectivities for the C5aR with F-[OPdChaWR] (pKb 8.64+/-0.21) being 30 times more potent than MeFKPdChaWr (pKb 7.16+/-0.11, P<0.05) in PMNs, but of similar potency (pKb 8.19+/-0.38 vs pKb 8.28+/-0.29, respectively) in umbilical artery. This trend was also reflected in their relative binding affinities, both antagonists having similar affinities (-logIC50 values) for C5aR in umbilical artery membranes (F-[OPdChaWR], 7.00+/-0.46; MeFKPdChaWr, 7.23+/-0.17), whereas in PMN membranes the C5aR affinity of the cycle F-[OPdChaWR] (7.05+/-0. 06) was four times higher than that of acyclic MeFKPdChaWr (6.43+/-0. 24, P<0.05). 3. In summary, the results reveal that these antagonists are insurmountable in nature against C5a for C5aR on at least two human cell types, and the differences in relative receptor binding affinities and antagonistic potencies against C5a are consistent with differences in receptors within these cell types. The nature of these differences is yet to be elucidated.

Differential activities of decapeptide agonists of human C5a: the conformational effects of backbone N-methylation.

Analogues of the potent, conformationally biased, decapeptide agonist of human C5a anaphylatoxin, C5a(65-74)Y65,F67,P69,P71,D-Ala73 (YSFKPMPLaR, peptide 54), were synthesized with methyl groups occupying specific amide nitrogen atoms along the peptide backbone. This N-methylation induced crucial extended backbone conformations in a manner similar to the two Pro residues, but without eliminating the contributions made by the side-chain of the residue for which Pro was substituted. The presence of backbone N-methyl groups on peptide 54 analogues had pronounced detrimental effects on the ability to bind and activate C5aRs expressed on human PMNs, but not on the ability to contract smooth muscle of human umbilical artery. Several N-methylated analogues of peptide 54 (peptides 56, 67, 124, 125, and 137) were significantly more selective for smooth muscle contraction, which is mediated by tissue resident macrophages, than for enzyme release from PMNs. Indeed, peptide 67, YSFKDMP(MeL)aR was almost 3000-fold more selective for smooth muscle contraction than for PMN enzyme release. Consistent with these differential activities was the observation that peptide 67 expressed a significantly greater binding affinity to C5aRs expressed on rat macrophages than on rat PMNs. This differential activity was also observed in vivo in the rat where peptide 67 induced a hypotensive response similar to peptide 54 and rhuC5a, but without accompanying neutropenia.

Single-dose, placebo-controlled, phase I study of oral dolasetron.

STUDY OBJECTIVES: To evaluate the safety, tolerability, and pharmacokinetics of single, escalating doses of oral dolasetron mesylate, a new 5-HT3 receptor antagonist. DESIGN: Double-blind, placebo-controlled, dose-escalating phase I study. SETTING: A clinical research center. PATIENTS: One hundred twenty healthy male volunteers. INTERVENTIONS: Subjects received either placebo or oral dolasetron mesylate 50, 100, 150, 200, 250, 300, or 400 mg. MEASUREMENTS AND MAIN RESULTS: Compared with placebo, subjects receiving dolasetron mesylate reported a greater frequency of headache, light-headedness, dizziness, increased appetite, and nausea. There were no clinically significant changes in mean laboratory values from before to after treatment. Adverse events were transient, mild or moderate, and similar to those after single intravenous doses of the drug. No clinically significant electrocardiographic changes occurred, but lengthening of the QRS complex duration and dose-dependent lengthening of PR and QTc intervals were observed 1-2 hours after dosing. These effects were asymptomatic and were mainly associated with higher doses (< or = 300 mg). CONCLUSION: Dolasetron mesylate is well tolerated when administered in single oral doses up to 400 mg to healthy volunteers. Clinical trials are under way to evaluate the agent's efficacy in preventing chemotherapy-induced and postoperative nausea and vomiting with doses up to 200 mg.

Contamination of potable roof-collected rainwater in Auckland, New Zealand.

One-hundred and twenty-five domestic roof-collected rainwater supplies in four rural Auckland districts were investigated in a cross-sectional survey to determine water quality. Samples of cold faucet water were analysed for physico-chemical and microbiological determinands, including metals (zinc, copper and lead), bacterial indicator organisms--heterotrophic plate count (HPC), total coilforms (TC), faecal coliforms (FC), enterococci (ENT), bacterial pathogens including Salmonella spp., Legionella spp., Campylobacter spp., Aeromonas spp. and the protozoa, Cryptosporidium and Giardia. Twenty-two supplies (17.6%) exceeded one or more of the maximum acceptable values (MAV) or maximum guideline values for chemical determinands of the New Zealand Drinking Water Standards (NZDWS) and 70 (56.0%) supplies exceeded the microbiological criteria of < 1 FC/100 mL. Eighteen supplies (14.4%) exceeded the NZDWS MAV for lead of 0.01 mg/L and three (2.4%) exceeded that for copper, of 2 mg/L. Those supplies with lead or galvanised iron comprising part of the roof or collecting system were more likely to show lead contamination (p = 0.019) as were those supplies with a pH less than 7 (p = 0.013). The presence of the indicator organisms HPC, TC, FC and ENT were all significantly correlated with one another. Aeromonas spp. were identified in 20 (16.0%) supplies. There was a positive association between the presence of Aeromonas and the bacterial indicator organisms. Households reporting at least one member with gastrointestinal symptoms in the month prior to sampling, were more likely to have Aeromonas spp. identified in their water supply than those households without symptoms (odds ratio 3.22, 95% CI 1.15-9.01, p = 0.021). Salmonella typhimurium was detected in one of 115 (0.9%) supplies. Legionella spp. and Campylobacter spp. were not detected. There were 50 supplies sampled for protozoa (sampling criteria: > or = 30 FC or > or = 60 ENT). Cryptosporidium oocysts were detected in 2 (4%) of these. Giardia was not detected. This study demonstrates that roof-collected rainwater systems provide potable supplies of relatively poor physiochemical and microbiological quality in the Auckland area. Further research is required on Aeromonas spp. as potential indicators of both microbiological quality and health risk along with design and maintenance strategies to minimise contamination of potable roof-collected rainwater supplies.

Five-fingered hand associated with partial or complete tibial absence and pre-axial polydactyly. A kindred of 15 affected individuals in five generations.

A kindred of 15 affected individuals in five generations is described with autosomal dominant inheritance of bilateral five-fingered hand. Some of them had additional pre-axial polydactyly of the fingers or toes and some had partial or complete absence of the tibia. The range of expression of the gene is variable and genetic advice to these families must take account of the whole spectrum of defects. The function of both upper and lower limbs was improved by surgery. A distinction is drawn between the five-fingered hand shown in this family and the different deformity of a four-fingered hand with a triphalangeal thumb.

Uterine perforation by GyneFix frameless IUD: two case reports.

Two cases of uterine perforation are described, occurring 11 days and 4 months, respectively, after the insertion of GyneFix, a frameless intra-uterine contraceptive device (IUD). In both the cases initial ultrasound scan showed the intra-uterine position of the device. Removal of the IUD, either by laparoscopy or laparotomy, had to be carried out. Awareness of this complication, insertion of GyneFix by a trained operator, appropriateness of ultrasound scan monitoring and possible underreporting of this complication are discussed.

Serological markers of hepatitis B infection in Niue children.

Hepatitis B infection is hyperendemic in the adult population of Niue. In order to determine the age at which infection is acquired and the contribution of vertical and horizontal transmission, the sera from 1055 children were tested for markers of hepatitis B infection. Eleven percent (11.0%) were found to be carriers of hepatitis B surface antigen (HBsAg) and a further 33.6% had antibody to hepatitis B surface antigen (anti-HBs). While less than 15% of the population were infected before the age of two years, these children had the greatest risk of becoming chronic carriers. The simplest method of controlling hepatitis B infection in Niue would be to immunise all newborn babies.

Mobilizing training resources for rural foster parents, adoptive parents, and applicants in Oregon, U.S.A.

This article describes a program for legally mandated training of foster and adoptive applicants and parents across a vast rural territory. The development of this varied program and its funding sources can serve as an example for other rural areas.

Time to disease-related pain and first opioid use in patients with metastatic castration-resistant prostate cancer treated with sipuleucel-T.

BACKGROUND: Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)). METHODS: Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer-related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan-Meier method and Cox regression. RESULTS: Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR)=0.819; 95% confidence interval (CI): 0.616-1.089; P=0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR=0.755; 95% CI: 0.579-0.985; P=0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kaplan-Meier curves for both end points began to diverge at 6 months. CONCLUSIONS: Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy.