PYY3-36 infused systemically or directly into the VTA attenuates fentanyl seeking in male rats.

More effective treatments for fentanyl use disorder are urgently needed. An emerging literature indicates that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate voluntary opioid taking and seeking in rodents. However, GLP-1R agonists produce adverse malaise-like effects that may limit patient compliance. Recently, we developed a dual agonist of GLP-1Rs and neuropeptide Y2 receptors (Y2Rs) that attenuates fentanyl taking and seeking at doses that do not produce malaise-like effects in opioid-experienced rats. Whether activating Y2Rs alone is sufficient to reduce opioid taking and seeking, however, is not known. Here, we investigated the efficacy of the Y2R ligand PYY3-36 to reduce fentanyl self-administration and the reinstatement of fentanyl-seeking behavior, a model of relapse in humans. Male rats were allowed to self-administer fentanyl (2.5 µg/kg, i.v.) for 21 days on a fixed-ratio 5 (FR5) schedule of reinforcement. Rats were then pretreated with vehicle or PYY3-36 (50 µg/kg s.c.; 0.1 and 1.0 µg/100 nL intra-VTA) prior to fentanyl self-administration test sessions. There were no effects of systemic or intra-VTA PYY3-36 on intravenous fentanyl self-administration. Opioid taking was then extinguished. Prior to subsequent reinstatement test sessions, rats were pretreated with vehicle or PYY3-36 (50 µg/kg s.c.; 0.1 and 1.0 µg/100 nL intra-VTA). Both systemic and intra-VTA administration of PYY3-36 attenuated fentanyl reinstatement in male rats at doses that did not affect food intake or produce adverse malaise-like effects. These findings indicate that Y2R agonism alone is sufficient to decrease fentanyl-seeking behavior during abstinence in opioid-experienced rats and further support strategies aimed at targeting Y2Rs for treating opioid use disorders.

Epigenetic effects of folate and related B vitamins on brain health throughout life: Scientific substantiation and translation of the evidence for health improvement strategies.

Suboptimal status of folate and/or interrelated B vitamins (B12 , B6 and riboflavin) can perturb one-carbon metabolism and adversely affect brain development in early life and brain function in later life. Human studies show that maternal folate status during pregnancy is associated with cognitive development in the child, whilst optimal B vitamin status may help to prevent cognitive dysfunction in later life. The biological mechanisms explaining these relationships are not clear but may involve folate-related DNA methylation of epigenetically controlled genes related to brain development and function. A better understanding of the mechanisms linking these B vitamins and the epigenome with brain health at critical stages of the lifecycle is necessary to support evidence-based health improvement strategies. The EpiBrain project, a transnational collaboration involving partners in the United Kingdom, Canada and Spain, is investigating the nutrition-epigenome-brain relationship, particularly focussing on folate-related epigenetic effects in relation to brain health outcomes. We are conducting new epigenetics analysis on bio-banked samples from existing well-characterised cohorts and randomised trials conducted in pregnancy and later life. Dietary, nutrient biomarker and epigenetic data will be linked with brain outcomes in children and older adults. In addition, we will investigate the nutrition-epigenome-brain relationship in B vitamin intervention trial participants using magnetoencephalography, a state-of-the-art neuroimaging modality to assess neuronal functioning. The project outcomes will provide an improved understanding of the role of folate and related B vitamins in brain health, and the epigenetic mechanisms involved. The results are expected to provide scientific substantiation to support nutritional strategies for better brain health across the lifecycle.

Treatment, clinical outcomes, and predictors of mortality among a national cohort of hospitalized patients with Stenotrophomonas maltophilia infection.

OBJECTIVES: To analyze treatment, clinical outcomes, and predictors of inpatient mortality in hospitalized patients with Stenotrophomonas maltophilia infection. STUDY DESIGN: Retrospective cohort study. METHODS: We included patients admitted to Veterans Affairs hospitals nationally with S. maltophilia cultures and treatment from 2010 to 2019. We described patient and clinical characteristics, antibiotic treatment, and clinical outcomes. Univariate and multivariable logistic regression were used to evaluate predictors of inpatient mortality. RESULTS: We identified 3891 hospitalized patients treated for an S. maltophilia infection, of which 13.7% died during admission. The most common antibiotic agents were piperacillin/tazobactam (39.7%), sulfamethoxazole/trimethoprim (23.3%), and levofloxacin (23.2%). Combination therapy was used in 16.6% of patients. Independent predictors of inpatient mortality identified in multivariable analysis included the following: presence of current acute respiratory failure (adjusted odds ratio [aOR] 4.74, 95% confidence interval [CI] 3.63-6.19), shock (aOR 3.00, 95% CI 2.31-3.90), acute renal failure (aOR 2.06, 95% CI 1.64-2.60), and septicemia (aOR 1.90, 95% CI 1.49-2.42), age 65 years and older (aOR 2.05, 95% CI 1.07-3.94, reference age 18-49 years), hospital-acquired infection (aOR 1.87, 95% CI 1.48-2.37), Black (aOR 1.58, 95% CI 1.21-2.06) and other races (aOR 1.65, 95% CI 1.41-2.41, reference White), liver disease (aOR 1.51, 95% CI 1.02-2.22), and median Charlson comorbidity score or higher (aOR 1.36, 95% CI 1.08-1.71, reference less than median). Clinical outcomes were similar between patients infected with sulfamethoxazole/trimethoprim-resistant, levofloxacin-resistant, and multidrug-resistant S. maltophilia strains compared to non-resistant strains. CONCLUSIONS: In our national cohort of hospitalized patients with S. maltophilia infection, 13.7% of patients died during admission and several predictors of inpatient mortality were identified. Predictors related to the severity of infection were among the strongest identified. It is important that in severely ill patients presenting to the hospital, S. maltophilia be considered as a cause.

Predictors of potentially suboptimal treatment of urinary tract infections in long-term care facilities.

BACKGROUND: Suboptimal antibiotic treatment of urinary tract infection (UTI) is high in long-term care facilities (LTCFs) and likely varies between facilities. Large-scale evaluations have not been conducted. AIM: To identify facility-level predictors of potentially suboptimal treatment of UTI in Veterans Affairs (VA) LTCFs and to quantify variation across facilities. METHODS: This was a retrospective cohort study of 21,938 residents in 120 VA LTCFs (2013-2018) known as Community Living Centers (CLCs). Potentially suboptimal treatment was assessed from drug choice, dose frequency, and/or treatment duration. To identify facility characteristics predictive of suboptimal UTI treatment, LTCFs with higher and lower rates of suboptimal treatment (≥median, < median) were compared using unconditional logistic regression models. Joinpoint regression models were used to quantify average percentage difference across facilities. Multilevel logistic regression models were used to quantify variation across facilities. FINDINGS: The rate of potentially suboptimal antibiotic treatment varied from 1.7 to 34.2 per 10,000 bed-days across LTCFs. The average percentage difference in rates across facilities was 2.5% (95% confidence interval (CI): 2.4-2.7). The only facility characteristic predictive of suboptimal treatment was the incident rate of UTI per 10,000 bed-days (odds ratio: 4.9; 95% CI: 2.3-10.3). Multilevel models demonstrated that 94% of the variation between facilities was unexplained after controlling for resident and CLC characteristics. The median odds ratio for the full multilevel model was 1.37. CONCLUSION: Potentially suboptimal UTI treatment was variable across VA LTCFs. However, most of the variation across LTCFs was unexplained. Future research should continue to investigate factors that are driving suboptimal antibiotic treatment in LTCFs.

Liaison psychiatry professionals' views of general hospital care for patients with mental illness: The care of patients with mental illness in the general hospital setting.

OBJECTIVE: Explore the experiences of liaison psychiatry professionals, to gain a greater understanding of the quality of care patients with mental illness receive in the general hospital setting; the factors that affect the quality of care; and their insights on interventions that could improve care. METHODS: A survey questionnaire and qualitative in depth interviews were used to collect data. Data collection took place at the Royal College of Psychiatrists Faculty of Liaison Psychiatry Annual conference. Qualitative analysis was done using thematic analysis. RESULTS: Areas of concern in the quality of care of patients with co-morbid mental illness included 'diagnostic overshadowing', 'poor communication with patient', 'patient dignity not respected' and 'delay in investigation or treatment'. Eleven contributing factors were identified, the two most frequently mentioned were 'stigmatising attitudes of staff towards patients with co-morbid mental illness' and 'complex diagnosis'. The general overview of care was positive with areas for improvement highlighted. Interventions suggested included 'formal education' and 'changing the liaison psychiatry team'. CONCLUSION: The cases discussed highlighted several areas where the quality of care received by patients with co-morbid mental illness is lacking, the consequences of which could be contributing to physical health disparities. It was acknowledged that it is the dual responsibility of both the general hospital staff and liaison staff in improving care.

The BiPo-3 detector.

The BiPo-3 detector is a low radioactive detector dedicated to measuring ultra-low natural contaminations of 208Tl and 214Bi in thin materials, initially developed to measure the radiopurity of the double ß decay source foils of the SuperNEMO experiment at the µBq/kg level. The BiPo-3 technique consists in installing the foil of interest between two thin ultra-radiopure scintillators coupled to low radioactive photomultipliers. The design and performances of the detector are presented. In this paper, the final results of the 208Tl and 214Bi activity measurements of the first enriched 82Se foils are reported for the first time, showing the capability of the detector to reach sensitivities in the range of some µBq/kg.

Genotype and phenotype in 12 additional individuals with SATB2-associated syndrome.

SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible.

Search for Neutrinoless Quadruple-ß Decay of

We report the results of a first experimental search for lepton number violation by four units in the neutrinoless quadruple-ß decay of ^{150}Nd using a total exposure of 0.19 kg yr recorded with the NEMO-3 detector at the Modane Underground Laboratory. We find no evidence of this decay and set lower limits on the half-life in the range T_{1/2}>(1.1-3.2)×10^{21} yr at the 90% C.L., depending on the model used for the kinematic distributions of the emitted electrons.

Orthopaedic triage at a physiotherapist-led 'Musculoskeletal Assessment Clinic': a seven-month service evaluation of outcomes.

BACKGROUND: A number of clinical specialist physiotherapist (CSP)-led musculoskeletal triage clinics have been established in the Republic of Ireland as a means of managing patients referred for an outpatient orthopaedic consultation. AIMS: The purpose of this study was to evaluate the outcomes of a recently established 'Musculoskeletal Assessment Clinic' (MAC) in St Vincent's University Hospital (SVUH) Dublin. We identified the (a) number of patients independently managed by the CSPs and (b) conversion rate to orthopaedic intervention as a useful measure of this. METHODS: University College Dublin Research Ethics Committee granted ethical exemption and the Clinical Audit Department of SVUH approved the study. A retrospective service evaluation was carried out on all orthopaedic patients who attended the MAC between January and July 2012. Data were analysed using SPSS v20 using descriptive statistics. RESULTS: Seven-hundred and fourteen patients attended the MAC, 54 % of whom were female; mean age 50 years (range 12-89). The majority of patients were diagnosed with low back pain (35 %) and knee osteoarthritis (16 %). The majority of patients who attended the MAC (76 %) were independently managed by the CSPs without need for orthopaedic consultation; from a valid sample (n = 110), 80 patients required orthopaedic intervention, a conversion rate of 73 %. The most common interventions were arthroplasty (22 %) and arthroscopy (16 %). CONCLUSIONS: The findings of this service evaluation indicate that a significant number of patients referred for an orthopaedic consultation may be managed independently by a CSP and that onward referrals for orthopaedic consultation were highly appropriate.

Changing epidemiology of methicillin-resistant Staphylococcus aureus in the Veterans Affairs Healthcare System, 2002-2009.

PURPOSE: The epidemiology of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) is changing. Temporal trends and differences between healthcare settings must be described in order to better predict future risk factors associated with this dangerous bacterial infection. METHODS: A national MRSA-infected cohort was identified from 2002 to 2009 in the Veterans Affairs Healthcare System of the United States: hospital (HOS), long-term care (LTC), and outpatient (OPT). We analyzed within-setting time trends using generalized linear mixed models and between-setting differences with χ(2) and Wilcoxon rank-sum tests. RESULTS: The incidence of S. aureus, methicillin-susceptible S. aureus (MSSA), and MRSA infections increased significantly over time in all three settings based on modeled annual percentage changes (P < 0.001). MRSA incidence rates rose by 14, 10, and 37% per year in the HOS, LTC, and OPT settings, respectively. Among 56,345 MRSA-infected patients, the comorbidity burden was highest among LTC inpatients (n = 4,427) and lowest among outpatients (n = 7,250), with an average absolute difference in specific comorbidities of +2 and -7%, respectively, compared to HOS inpatients (n = 44,668). Over time, there was a significant (P ≤ 0.02) decrease in previous inpatient admissions and surgeries (all settings); diabetes with complications and surgical site infections (HOS, OPT); and median length of stay and inpatient mortality (HOS, LTC). Alternatively, obesity, chronic renal disease, and depression were more common between 2002 and 2009 (P ≤ 0.02). CONCLUSIONS: Over the past 8 years, we observed significant changes in the epidemiology of MRSA infections, including decreases in traditional MRSA risk factors, improvements in clinical outcomes, and increases in other patient characteristics that may affect risk.

Measurement of the ßß decay half-life of 130Te with the NEMO-3 detector.

We report results from the NEMO-3 experiment based on an exposure of 1275 days with 661 g of (130)Te in the form of enriched and natural tellurium foils. The ßß decay rate of (130)Te is found to be greater than zero with a significance of 7.7 standard deviations and the half-life is measured to be T(½)(2ν) = [7.0 ± 0.9(stat) ± 1.1(syst)] × 10(20) yr. This represents the most precise measurement of this half-life yet published and the first real-time observation of this decay.

Risk factors associated with mupirocin resistance in meticillin-resistant Staphylococcus aureus.

Implementation of meticillin-resistant Staphylococcus aureus (MRSA) decolonisation programmes has been increasing and the emergence of mupirocin resistance has been reported. However, the patient-level risk factors associated with mupirocin resistance are not clear. In this study, independent predictors of mupirocin resistance in MRSA among Providence Veterans Affairs Medical Center patients with MRSA-positive culture dates between 1 July 2004 and 30 June 2008 were identified using a frequency-matched case-control study. Forty cases (mupirocin-resistant) were matched on culture date quarter and year to 270 controls (mupirocin-susceptible). The adjusted conditional logistic regression model identified three significant independent predictors associated with mupirocin resistance in MRSA: (1) exposure to mupirocin in the year prior to the culture date [odds ratio (OR): 9.84; 95% confidence interval (CI): 2.93-33.09]; (2) Pseudomonas aeruginosa infection in the year before the culture-related admission (4.85; 1.20-19.61); and (3) cefepime use in the year prior to culture (2.80; 1.03-7.58). In sensitivity analyses, previous mupirocin exposure was associated with low-level [minimum inhibitory concentration (MIC) 8-128mg/L; 23 cases, 202 controls; OR: 6.32; 95% CI: 1.58-25.33] and high-level (MIC ≥256mg/L; 17 cases, 151 controls; OR: 11.18; 95% CI: 1.89-66.30) mupirocin resistance. To our knowledge, this is the first case-control study to reveal a strong association between previous mupirocin exposure and subsequent mupirocin resistance in MRSA, with demonstrated robustness in low- and high-level mupirocin resistance. Mupirocin susceptibility monitoring is critical for facilities instituting decolonisation with mupirocin as increased use may reduce effectiveness through resistance.

Dose profile modeling of Idaho National Laboratory's active neutron interrogation laboratory.

A new laboratory has been commissioned at Idaho National Laboratory for performing active neutron interrogation research and development. The facility is designed to provide radiation shielding for deuterium-tritium (DT) fusion (14.1 MeV) neutron generators (2 x 10(8) n/s), deuterium-deuterium (DD) fusion (2.5 MeV) neutron generators (1 x 10(7) n/s), and (252)Cf spontaneous fission neutron sources (6.96 x 10(7) n/s, 30 microg). Shielding at the laboratory is comprised of modular concrete shield blocks 0.76 m thick with tongue-in-groove features to prevent radiation streaming, arranged into one small and one large test vault. The larger vault is designed to allow operation of the DT generator and has walls 3.8m tall, an entrance maze, and a fully integrated electrical interlock system; the smaller test vault is designed for (252)Cf and DD neutron sources and has walls 1.9 m tall and a simple entrance maze. Both analytical calculations and numerical simulations were used in the design process for the building to assess the performance of the shielding walls and to ensure external dose rates are within required facility limits. Dose rate contour plots have been generated for the facility to visualize the effectiveness of the shield walls and entrance mazes and to illustrate the spatial profile of the radiation dose field above the facility and the effects of skyshine around the vaults.

First results of the search for neutrinoless double-beta decay with the NEMO 3 detector.

The NEMO 3 detector, which has been operating in the Fréjus underground laboratory since February 2003, is devoted to the search for neutrinoless double-beta decay (beta beta 0v). The half-lives of the two neutrino double-beta decay (beta beta 2v) have been measured for 100Mo and 82Se. After 389 effective days of data collection from February 2003 until September 2004 (phase I), no evidence for neutrinoless double-beta decay was found from approximately 7 kg of 100Mo and approximately 1 kg of 82Se. The corresponding limits are T1/2(beta beta0v) > 4.6 x 10(23) yr for 100Mo and T1/2(beta beta 0v) > 1.0 x 10(23) yr for 82Se (90% C.L.). Depending on the nuclear matrix element calculation, the limits for the effective Majorana neutrino mass are < 0.7-2.8 e/v for 100Mo and < 1.7-4.9 eV for 82Se.

The impact of anti HPV vaccination on cervical cancer incidence and HPV induced cervical lesions: consequences for clinical management.

Cervical cancer is the second most common cause of cancer-related deaths in women worldwide. Screening for cervical cancer is accomplished utilizing a Pap smear and pelvic exam. While this technology is widely available and has reduced cervical cancer incidence in industrialized nations, it is not readily available in third world countries in which cervical cancer incidence and mortality is high. Development of cervical cancer is associated with infection with high risk types of human papillomavirus (HPV) creating a unique opportunity to prevent or treat cervical cancer through anti-viral vaccination strategies. Several strategies have been examined in clinical trials for both the prevention of HPV infection and the treatment of pre-existing HPV-related disease. Clinical trials utilizing prophylactic vaccines containing virus-like particles (VLPs) indicate good vaccine efficacy and it is predicted that a prophylactic vaccine may be available within the next five years. But, preclinical research in this area continues in order to deal with issues such as cost of vaccination in underserved third world populations. A majority of clinical trials using therapeutic agents which aim to prevent the progression of pre-existing HPV associated lesions or cancers have shown limited efficacy in eradicating established tumors in humans possibly due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Future trends in clinical trials with therapeutic agents will examine patients with early stage cancers or pre-invasive lesions in order to prevent invasive cervical cancer. Meanwhile, preclinical studies in this field continue and include the further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. Given that cervical cancers are caused by the human papillomavirus, the prospect of therapeutic vaccination to treat existing lesions and prophylactic vaccination to prevent persistent infection with the virus are high and may be implemented in the near future. The consequences for clinical management may include a significant reduction in the frequency of Pap smear screening in the case of prophylactic vaccines, and the availability of less invasive and disfiguring treatment options for women with pre-existing HPV associated lesions in the case of therapeutic vaccines. Implementation of both prophylactic and therapeutic vaccine regimens could result in a significant reduction of health care costs and reduction of worldwide cervical cancer incidence.