Strong Constraints on Neutrino Nonstandard Interactions from TeV-Scale ν_{µ} Disappearance at IceCube.

We report a search for nonstandard neutrino interactions (NSI) using eight years of TeV-scale atmospheric muon neutrino data from the IceCube Neutrino Observatory. By reconstructing incident energies and zenith angles for atmospheric neutrino events, this analysis presents unified confidence intervals for the NSI parameter ε_{µτ}. The best-fit value is consistent with no NSI at a p value of 25.2%. With a 90% confidence interval of -0.0041≤ε_{µτ}≤0.0031 along the real axis and similar strength in the complex plane, this result is the strongest constraint on any NSI parameter from any oscillation channel to date.

Search for Relativistic Magnetic Monopoles with Eight Years of IceCube Data.

We present an all-sky 90% confidence level upper limit on the cosmic flux of relativistic magnetic monopoles using 2886 days of IceCube data. The analysis was optimized for monopole speeds between 0.750c and 0.995c, without any explicit restriction on the monopole mass. We constrain the flux of relativistic cosmic magnetic monopoles to a level below 2.0×10^{-19} cm^{-2} s^{-1} sr^{-1} over the majority of the targeted speed range. This result constitutes the most strict upper limit to date for magnetic monopoles with ß≳0.8 and up to ß∼0.995 and fills the gap between existing limits on the cosmic flux of nonrelativistic and ultrarelativistic magnetic monopoles.

Simple, illustrated medicines information improves ARV knowledge and patient self-efficacy in limited literacy South African HIV patients.

Few studies have investigated antiretroviral (ARV) knowledge and self-efficacy in limited literacy patients. Using a randomized controlled study design, we investigated the influence of a simple pre-tested patient information leaflet (PIL) containing both text and illustrations on HIV- and ARV-related knowledge and on self-efficacy over six months in a limited literacy African population. The recruited patients were randomly allocated to either control (standard care) or intervention group (standard care plus illustrated PIL). HIV and medicines-related knowledge was evaluated with a 22-question test at baseline, one, three, and six months. Self-efficacy was assessed using a modified version of the HIV Treatment Adherence Self-Efficacy Scale. Two-thirds of the patients were female, mean age was 39.0 ± 9.6 years and mean education was 7.3 ± 2.8 years. Patients who received the PIL showed a significant knowledge increase over the six-month period (62.0-94.4%), with improvement at each subsequent interview whereas the control group showed no improvement. At baseline, side effect knowledge was the lowest (50-56%) but increased in the intervention group to 92%. Similarly, other medicine-related knowledge at baseline (57-67%) improved significantly (93%) and was sustained over six months. Cohen's d values post-baseline ranged between 1.36 and 2.18, indicating a large intervention effect. Self-efficacy improved significantly over six months in intervention but not control patients. At baseline, patients with ≤ 3 years of education had lower knowledge and self-efficacy but this was not observed post-intervention, which we attribute to the PIL mitigating the effect of limited education. Knowledge and self-efficacy were significantly correlated in the intervention group. In conclusion, a low-cost intervention of a well-designed, pre-tested, simple, illustrated PIL significantly increased both ARV knowledge and self-efficacy in HIV patients with limited education.

Evidence for neutrino emission from the nearby active galaxy NGC 1068.

A supermassive black hole, obscured by cosmic dust, powers the nearby active galaxy NGC 1068. Neutrinos, which rarely interact with matter, could provide information on the galaxy's active core. We searched for neutrino emission from astrophysical objects using data recorded with the IceCube neutrino detector between 2011 and 2020. The positions of 110 known gamma-ray sources were individually searched for neutrino detections above atmospheric and cosmic backgrounds. We found that NGC 1068 has an excess of [Formula: see text] neutrinos at tera-electron volt energies, with a global significance of 4.2σ, which we interpret as associated with the active galaxy. The flux of high-energy neutrinos that we measured from NGC 1068 is more than an order of magnitude higher than the upper limit on emissions of tera-electron volt gamma rays from this source.

Modifiable and fixed factors predicting quality of life in people with colorectal cancer.

BACKGROUND: People with colorectal cancer have impaired quality of life (QoL). We investigated what factors were most highly associated with it. METHODS: Four hundred and ninety-six people with colorectal cancer completed questionnaires about QoL, functioning, symptoms, co-morbidity, cognitions and personal and social factors. Disease, treatment and co-morbidity data were abstracted from case notes. Multiple linear regression identified modifiable and unmodifiable factors independently predictive of global quality of life (EORTC-QLQ-C30). RESULTS: Of unmodifiable factors, female sex (P<0.001), more self-reported co-morbidities (P=0.006) and metastases at diagnosis (P=0.036) significantly predicted poorer QoL, but explained little of the variability in the model (R(2)=0.064). Adding modifiable factors, poorer role (P<0.001) and social functioning (P=0.003), fatigue (P=0.001), dyspnoea (P=0.001), anorexia (P<0.001), depression (P<0.001) and worse perceived consequences (P=0.013) improved the model fit considerably (R(2)=0.574). Omitting functioning subscales resulted in recent diagnosis (P=0.002), lower perceived personal control (P=0.020) and travel difficulties (P<0.001) becoming significant predictors. CONCLUSION: Most factors affecting QoL are modifiable, especially symptoms (fatigue, anorexia, dyspnoea) and depression. Beliefs about illness are also important. Unmodifiable factors, including metastatic (or unstaged) disease at diagnosis, have less impact. There appears to be potential for interventions to improve QoL in patients with colorectal cancer.

Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes.

Individual studies indicate that kidney transplantation is associated with lower mortality and improved quality of life compared with chronic dialysis treatment. We did a systematic review to summarize the benefits of transplantation, aiming to identify characteristics associated with especially large or small relative benefit. Results were not pooled because of expected diversity inherent to observational studies. Risk of bias was assessed using the Downs and Black checklist and items related to time-to-event analysis techniques. MEDLINE and EMBASE were searched up to February 2010. Cohort studies comparing adult chronic dialysis patients with kidney transplantation recipients for clinical outcomes were selected. We identified 110 eligible studies with a total of 1 922 300 participants. Most studies found significantly lower mortality associated with transplantation, and the relative magnitude of the benefit seemed to increase over time (p < 0.001). Most studies also found that the risk of cardiovascular events was significantly reduced among transplant recipients. Quality of life was significantly and substantially better among transplant recipients. Despite increases in the age and comorbidity of contemporary transplant recipients, the relative benefits of transplantation seem to be increasing over time. These findings validate current attempts to increase the number of people worldwide that benefit from kidney transplantation.

The impact of pancreas transplantation on kidney allograft survival.

Whether pancreas after kidney transplantation (PAK) compromises kidney allograft survival, and what pre-PAK glomerular filtration rate (GFR) should be used to select patients for PAK is unclear. We analyzed all (n = 2776) PAK recipients in the United States between 1989 and 2007 and compared their risk of kidney failure to a comparator group of n = 13 635 young adult diabetic kidney only transplant recipients during the same time after accounting for selection bias by the use of a propensity score for PAK in a multivariate time to event analysis. In a secondary analysis, we determined the association of pre-PAK GFR with subsequent kidney allograft survival. Despite an increased risk of death early after pancreas transplantation, PAK recipients had a decreased long-term risk of kidney allograft failure compared to diabetic kidney only transplant recipients HR = 0.89; 95% CI: [0.78-1.00]; p = 0.05. An association of pre-PAK GFR with kidney survival was not evident until 3 years after pancreas transplantation, and patients with a pre-PAK GFR of 30-39 mL/min still attained 10-year post-PAK kidney survival of 69%. We conclude that PAK is associated with improved kidney allograft survival, and pre-PAK GFR 30-39 mL/min should not preclude PAK. Expanded use of PAK is warranted.

Anti-interferon-γ autoantibody and opportunistic infections: case series and review of the literature.

Immune defects in interleukin-12-dependent interferon-gamma (IFN-γ) pathways are associated with disseminated infections caused by non-tuberculous mycobacteria (NTM) and Salmonella. Recently, there have been an increasing number of reports of acquired autoantibodies to IFN-γ in adults, especially in Asian patients. We describe here three human immunodeficiency virus-negative Thai adults who had persistent or recurrent disseminated infections caused by NTM, Salmonella, and other opportunistic pathogens, possibly due to anti-IFN-γ autoantibodies. The antibodies were shown to exhibit very high inhibitory activity to IFN-γ. Two patients also developed Sweet's syndrome during the course of infections. In addition, we also review all previous reports of patients with anti-IFN-γ antibodies who were susceptible to NTM and Salmonella infections.

[Medical students as members of the health care team]. / Los estudiantes de medicina como parte del equipo de salud.

BACKGROUND: Teaching hospitals include both undergraduate and postgraduate students, but the role of medical students in the health care team has not been clearly established. AIM: To know the opinion of different professionals about the role of medical students and how this opinion may have an influence in medical education. MATERIAL AND METHODS: A qualitative method was used, asking open questions to focus groups of physicians, nurses and midwives, technicians and undergraduate medical students of 4th and 5th grade. RESULTS: Physicians believe that medical students have no special role in the health care team, nurses think that they may help in communication with patients, and technicians (nurses's aids) value their companionship and closeness with patients. Medical students recognize that their main function is to learn but they are aware that they do help patients. They suggest increasing their integration with other students of other health related careers. CONCLUSIONS: Although medical students are usually not seen as part of the health care team, they may fulfill a role with patients during their clinical learning practice. This would improve the quality of their training and the multidisciplinary work of the health care team.

Post-traumatic amnesia and its relationship to the functional outcome of people with severe traumatic brain injury.

OBJECTIVE: To investigate the relationship between Post-Traumatic Amnesia (PTA) duration, length of stay and functional outcomes in Australian in-patients with severe traumatic brain injury (TBI). DESIGN: Retrospective, descriptive study using prospectively collected data from the Uniform Data Set for Medical Rehabilitation (UDSMR). METHODS: Prospective collection of Westmead PTA scores and analysis of database for admissions for primary TBI rehabilitation from 1993-2003. Functional Independence Measure (FIM) was used to measure functional outcome. Statistical analysis using SPSS Version 13. RESULTS: Six hundred and thirty-eight consecutive admissions; 611 patients had PTA classified by ranges, 436 of whom had an exact number of PTA days. Mean age 37.6 years; more than 90% had a PTA duration greater than 1 week. Significant predictors of discharge FIM scores and total length of hospitalization were PTA duration, admission FIM scores and acute length of hospitalization. CONCLUSIONS: PTA duration correlates with length of hospitalization and discharge function. PTA duration affects recovery rate. Implications include use of PTA duration for prognosticating, discharge planning and funding systems.

Digitizing Medicines for Remote Capture of Oral Medication Adherence Using Co-encapsulation.

High-resolution measurement of medication adherence is essential to personalized drug therapy. A US Food and Drug Administration (FDA)-cleared device, using an edible ingestion sensor (IS), external wearable patch, and paired mobile device can detect and record ingestion events. Oral medications must be combined with an IS to generate precise "digitized-medication" ingestion records. We developed a Good Manufacturing Practice protocol to repackage oral medications with the IS within certified Capsugel capsules, termed co-encapsulation (CoE). A randomized bioequivalence study of CoE-IS-Rifamate (Isoniazid/Rifampin 150/300 mg) vs. native-Rifamate was conducted in 12 patients with active Mycobacterium tuberculosis and demonstrated bioequivalence using the population method ratio test (95% confidence interval). Subsequently, CoE-IS-medications across all biopharmaceutical classes underwent in vitro dissolution testing utilizing USP and FDA guidelines. CoE-IS medications tested met USP dissolution specifications and were equivalent to their native formulations. CoE combines oral medications with the IS without altering the quality of the native formulation, generating "digitized" medications for remote capture of dosing histories.

A prospective evaluation of adherence to medication in first episode schizophrenia.

The aim of this study was to identify the features of first episode schizophrenia that predict adherence antipsychotic medication at six-month follow-up. We used validated instruments to assess clinical and socio-demographic variables in all patients with first episode schizophrenia from a defined geographical area admitted to a Dublin psychiatric hospital over a four-year period (N=100). At six-month follow-up (N=60) we assessed adherence to medication using the Compliance Interview. One third of patients with schizophrenia were non-adherent with medication within six months of their first episode of illness. High levels of positive symptoms at baseline, lack of insight at baseline, alcohol misuse at baseline and previous drug misuse predict non-adherence. These results indicate that an identifiable subgroup of patients with first episode schizophrenia is at high risk of early non-adherence to medication. While high positive symptom scores pre-date and predict non-adherence in most patients, reduced insight is the best predictor of non-adherence in patients who do not misuse alcohol or other drugs.

Transfection and expression of mutant p53 protein does not alter the in vivo or in vitro growth characteristics of the AA/C1 human adenoma derived cell line, including sensitivity to transforming growth factor-beta 1.

Mutation of the p53 gene is thought to be a late event in human colorectal carcinogenesis, involved in the malignant conversion of the adenoma to the carcinoma. One of the questions that we hoped to address was whether, in vivo, a single mutational event in one p53 gene is sufficient to confer a significant growth advantage on a colonic epithelial cell. Such a growth advantage could result either from an increase in growth rate and/or loss of response to inhibitory growth signals naturally present in the colonic crypt. We therefore introduced the pC53-SCX3 143 (Val-Ala) p53 mutation into a non tumorigenic adenoma derived cell line, AA/C1, which contained a truncating APC mutation, activating K-ras mutation but was wild-type for the p53 protein. High levels of mutant p53 protein were detected in the pC53-SCX3 transfected AA/C1 cell lines but was found not to affect either the in vitro (colony forming efficiency, anchorage independence) or in vivo (tumorigenicity in nude mice) growth, when compared to vector control or the parental AA/C1 cell line. In addition, to test whether the cells become less sensitive to inhibitory growth factors, the response of the cell lines to the naturally occurring growth inhibitor TGF beta was also investigated. Even though TGF beta had previously been implicated in the control of growth of intestinal epithelium, expression of the mutant p53 protein did not affect the sensitivity of the parental AA/C1 cell line to TGF beta. Under the experimental conditions tested expression of the 143 (Val-Ala) p53 protein was unable to affect the in vitro or in vivo growth characteristics of the adenoma derived AA/C1 cell line. When compared to other studies, these results suggest that the genetic background of the individual recipient cell may greatly influence the effect of expression of a particular p53 mutation.

Molecular events including p53 and k-ras alterations in the in vitro progression of a human colorectal adenoma cell line to an adenocarcinoma.

The aim of the current study was to identify genetic abnormalities in human colorectal adenoma and carcinoma derived cell lines, and to determine whether the genetic changes which occur in vitro are relevant to the in vivo situation. Loss of 1p(33-35) region was shown to be the most common chromosome 1 abnormality and loss of heterozygosity (LOH) of the DCC gene and/or adjacent sequences was detected in all adenoma derived cells as well as the carcinoma cell lines. The level of p53 protein was also investigated as increased cellular p53 protein had previously been associated with mutation of the p53 gene. A further aim was to investigate genetic changes in our in vitro model of tumour progression, where the adenoma derived PC/AA cell line has previously been converted in vitro to two distinct tumorigenic phenotypes, producing either an adenocarcinoma or a mucinous carcinoma in athymic nude mice. Progression to the adenocarcinoma phenotype was shown to involve a specific chromosome 1 rearrangement, loss of both normal copies of chromosome 18 (although DCC gene sequences were retained), loss of the remaining wild type allele of k-ras resulting in homozygosity for the k-ras codon 12 mutation and increased cellular p53 protein as detected by SDS-PAGE Western blotting. The increase in p53 protein was shown not to be due to the acquisition of a mutation in the p53 gene. Interestingly, progression of the adenoma derived PC/AA cell line to the mucinous malignant phenotype did not involve any of these molecular rearrangements, suggesting that different genetically distinct pathways are involved in colorectal carcinogenesis. These studies show that the genetic changes in our in vitro model of human colorectal tumour progression are similar to those observed in in vivo studies.

The adenomatous polyposis coli protein and retinoblastoma protein are cleaved early in apoptosis and are potential substrates for caspases.

Apoptosis in human monocytic THP.1 tumour cells, induced by diverse stimuli, was accompanied by proteolytic cleavage of the adenomatous polyposis coli gene product (APC) and by sequential cleavage of the retinoblastoma susceptibility gene product (Rb). Cleavage of poly(ADP-ribose) polymerase (PARP), APC and the initial cleavage of Rb at the carboxy terminal region all occurred at a similar time, early in the apoptotic process. Subsequently, Rb underwent a secondary cleavage to 43 kDa and 30 kDa protein fragments. Two caspase inhibitors, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.FMK) and acetyl-Tyr-Val-Ala-Asp chloromethyl ketone (YVAD.CMK), had markedly different effects on the induction of apoptosis. Z-VAD.FMK inhibited the primary and secondary cleavage of Rb, cleavage of APC and PARP, and apoptosis assessed by flow cytometry. In marked contrast, YVAD.CMK inhibited cleavage of APC and the secondary cleavage of Rb to the 43 kDa and 30 kDa protein fragments but did not inhibit the primary carboxy terminal cleavage of Rb, PARP proteolysis or apoptosis assessed by flow cytometry. These results suggest that different caspases are responsible for the cleavage of different substrates at different stages during the apoptotic process and that a caspase may either cleave APC directly or may be involved in the pathway leading to APC proteolysis. This is the first report suggesting that a cytoplasmic tumour suppressor gene (APC) may be cleaved by a caspase during apoptosis.

Physiological changes during carbon dioxide inhalation in patients with panic disorder, major depression, and premenstrual dysphoric disorder: evidence for a central fear mechanism.

BACKGROUND: Inhalation of carbon dioxide (CO(2)) has been shown to produce more anxiety in patients with panic disorder (PD) than in healthy comparison subjects or patients with most other psychiatric illnesses tested, although premenstrual dysphoric disorder (PMDD) may be an exception. Several reasons have been proposed to explain CO(2) breathing effects in PD. We examined differences in respiratory response to CO(2) breathing in 4 groups to address these issues. METHODS: Patients with PD (n = 52), healthy controls (n = 32), patients with PMDD (n = 10), and patients with major depression without panic (n = 21) were asked to breathe 5% and 7% CO(2). Continuous measures of respiratory physiological indices were made. RESULTS: Carbon dioxide breathing produced the expected increases in all 4 respiratory variables measured. More patients with PD and PMDD had panic attacks than did controls or patients with major depression. Subjects who experienced panic during 5% or 7% CO(2) inhalation had the most extreme increases regardless of diagnostic group. Among patients with PD, baseline end-tidal carbon dioxide levels were significantly lower in those who subsequently had a panic attack during 5% CO(2) breathing than those who did not. CONCLUSIONS: Although CO(2) breathing causes a higher rate of panic attacks in patients with PD than other groups (except PMDD), the physiological features of a panic attack appear similar across groups. Once a panic attack is triggered, minute ventilation and respiratory rate increase regardless of whether the subject carries a PD diagnosis. These findings are compatible with preclinical fear conditioning models of anxiogenesis.

An optimised biphasic culture system for the generation of functional dendritic cells from patients with acute lymphoblastic leukaemia at presentation and in clinical remission.

We have tested the hypothesis that functional dendritic cells (DC) may be generated from patients with acute lymphoblastic leukaemia (ALL). We evaluated the production of DC from blast cells taken at presentation from nine children with ALL. Blast cells were expanded in serum-free medium supplemented with Flt3L, G-CSF, GM-CSF, IL-3, IL-6 and SCF for 7 days and subsequently stimulated with Flt3L, GM-CSF and TGF-beta for a further 14 days, with the addition of TNF-alpha for the final 48 h of culture. Cultured cells had the morphological appearance of DC and expressed the DC-associated antigens CD1A (range 2-87%) and CD83 (15-44%). Expression of the co-stimulatory molecules CD80 and CD86 was increased and the majority of these cells retained their expression of CD34 (73+/-4%) and HLA-DR (79+/-5%). Seven of the nine ALL had a leukaemia-specific abnormality and DC generated from five of these seven cases were derived from the leukaemic clone. Leukaemic DC derived from four HLA-A*02-positive ALL pulsed with CMV-associated peptides could induce significant proliferation of peptide-specific CD8+ T cells. This specificity was verified using tetrameric complexes of HLA class l/antigenic peptide. DC could also be generated from cells taken at times of complete remission of ALL and from normal controls using these culture conditions. These findings show that functional DC can be generated both from ALL blasts and from patients in remission; these might be utilised in future for immunotherapeutic strategies in the treatment of ALL.

Oxidative stress in Huntington's disease.

It has been five years since the elucidation of the genetic mutation underlying the pathogenesis of Huntington's disease (HD) (97), however the precise mechanism of the selective neuronal death it propagates still remains an enigma. Several different etiological processes may play roles, and strong evidence from studies in both humans and animal models suggests the involvement of energy metabolism dysfunction, excitotoxic processes, and oxidative stress. Importantly, the recent development of transgenic mouse models of HD led to the identification of neuronal intranuclear inclusion bodies in affected brain regions in both mouse models and in HD brain, consisting of protein aggregates containing fragments of mutant huntingtin protein. These observations opened new avenues of investigation into possible huntingtin protein interactions and their putative pathogenetic sequelae. Amongst these studies, findings of elevated levels of oxidative damage products such as malondialdehyde, 8-hydroxydeoxyguanosine, 3-nitrotyrosine and heme oxygenase in areas of degeneration in HD brain, and of increased free radical production in animal models, indicate the involvement of oxidative stress either as a causative event, or as a secondary constituent of the cell death cascade in the disease. Here we review the evidence for oxidative damage and potential mechanisms of neuronal death in HD.

Instructional set does not alter outcome of respiratory challenges in panic disorder.

In an attempt to reproduce the findings of Rapee et al (1986) that instructional set could alter the anxiogenic effects of carbon dioxide inhalation, 45 patients with panic disorder received two sets of instructions and then underwent a series of respiratory challenges (room air hyperventilation, 5% and 7% CO2 inhalation). The instructions failed to alter the anxiogenic response to any of the interventions.

Effect of antipanic treatment on response to carbon dioxide.

BACKGROUND: Disordered breathing among patients with panic disorder, including hyperventilation during attacks and increased anxiogenic response to carbon dioxide (CO2) inhalation, is well established. We wished to assess whether there is a change in the physiological response to CO2 after patients have undergone antipanic therapy with either tricyclic antidepressants or cognitive behavioral therapy (CBT). METHODS: Twenty-nine patients with panic disorder underwent baseline CO2 sensitivity testing using the traditional Read rebreathing method and then received either antidepressant treatment (n = 21) or CBT (n = 8). After completing treatment, CO2 testing was repeated. A comparison sample of 14 normal volunteers also had two CO2 sensitivity tests, separated by an average of 21.6 (SD = 8.8) weeks. RESULTS: Using a liberal standard, in which all CO2 sensitivity tests whose correlations between minute ventilation and end-tidal CO2 were at least .75 were used, patients, but not controls, demonstrated a significant reduction in CO2 sensitivity between the first and second test. Using a more conservative .90 correlation standard reduced the sample size available and resulted in trend reduction in patients but no significant change in controls. There was a suggestion that the change was most pronounced in treatment responders, although the number of patient nonresponders is extremely small in this sample. CONCLUSIONS: These data indicate that treatment reduces CO2 sensitivity in patients with panic disorder. We speculate that manipulation of the serotonergic and noradrenergic neurotransmission systems, both known to play a role in the control of respiration, may have a specific effect in reducing respiratory hyperactivity in panic disorder.